PREDICTION of PATIENT OUTCOMES after TRAUMATIC SPINAL CORD INJURY … · 2015. 6. 10. · ii Prediction of Patient Outcomes after Traumatic Spinal Cord Injury using Acute Clinical

PREDICTION of PATIENT OUTCOMES after TRAUMATIC SPINAL CORD INJURY using ACUTE

CLINICAL and RADIOLOGICAL VARIABLES

by

Jefferson R. Wilson

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy

Institute of Medical Sciences University of Toronto

© Copyright by Jefferson R. Wilson (2013)

ii

Prediction of Patient Outcomes after Traumatic Spinal Cord Injury

using Acute Clinical and Radiological Variables

Jefferson R. Wilson

Doctor of Philosophy

Institute of Medical Sciences

University of Toronto

2013

Abstract

There is a pressing unmet need, in the acute setting after traumatic spinal cord injury (SCI), to

predict both short and long-term clinical outcomes for individuals affected. Possessing this

ability would not only facilitate improved communication and treatment planning in the clinical

realm, but also would allow for enhanced study of SCI patients in the research realm. Presently,

there is little available to scientifically guide clinicians and researchers alike with respect to this

topic. In this thesis, it is hypothesized that clinical outcomes can accurately be predicted after

SCI based on acute patient, injury and radiological features. In order to investigate this

hypothesis, a series of investigations have been undertaken, using a combination of two large

prospective SCI datasets, to explore the impact of acute clinical and radiological factors on long-

term functional outcome, long-term neurological outcome and in-hospital complication

occurrence. First, after performing a comprehensive systematic review of existing literature, a

clinico-radiographic model was created and internally validated using a combination of pre-

specified clinical and magnetic resonance imaging (MRI) variables obtained in the first 3 days

after injury, to predict functional outcome at 1 year. Second, the acute radiological finding of

facet dislocation (FD) was evaluated and found to predict reduced motor neurological recovery at

1 year, even after adjusting for individuals’ baseline degree of injury severity. Third, a

iii

combination of clinical variables predicting in-hospital complication development after cervical

SCI were identified and used to develop a model to predict the occurrence of these complication

events. Finally, the impact of age as an effect modifier governing the relationship between acute

neurologic status and long-term functional outcome was evaluated. This analysis demonstrated

older age to have the greatest negative impact on functional outcome in patients with lesions of

intermediate severity. Although future validation studies are required, the findings presented in

this thesis have provided new insights into relationships between acute predictor and outcome

variables in the context of traumatic SCI. Further, these analyses have demonstrated the

feasibility, and potential advantages, of using a combination of acute clinical and radiological

variables, to predict outcome after SCI.

iv

Acknowledgments

My sincerest gratitude goes to my supervisor Dr. Michael Fehlings. It was five years ago, while a

junior resident on your spine service at Toronto Western Hospital, that I was first inspired to

formally pursue spinal cord injury related research. Since then, you have been an unyielding

source of encouragement, advice and wisdom. Thank you for your continued mentorship.

I would also like to thank the members of my post-graduate advisory committee including Dr.

Aileen Davis, Dr. Abhaya Kulkarni and Dr. Alex Kiss; your contributions to, and careful critique

of this work have truly been invaluable.

This work would also not have been possible without the contributions of Dr. Robert Grossman

and Dr. Ralph Frankowski from the North American Clinical Trials Network for the Treatment

of Spinal Cord Injury, who were, and continue to be, outstanding collaborators.

I would also like to acknowledge and thank all of my friends and mentors from the Division of

Neurosurgery at the University of Toronto who have provided encouragement, reassurance and

camaraderie throughout my years away from clinical training. A special thanks to Dr. James

Rutka, Dr. Charles Tator, Dr. Andres Lozano, Dr. Abhaya Kulkarni, Dr. David Cadotte, Dr. Nir

Lipsman and Dr. Mike Ellis.

I am very grateful to the following organizations who contributed financially toward the

successful completion of this work: The Christopher and Dana Reeve Foundation, The Cervical

Spine Research Society, The United States Department of Defense and the University of Toronto

Surgeon Scientist Program.

Finally, I owe a great debt of gratitude to my family for their never ending love and support.

-JRW 2013

v

Table of Contents

Acknowledgments .......................................................................................................................... iv

Table of Contents ............................................................................................................................ v

List of Tables .................................................................................................................................. x

List of Figures ............................................................................................................................... xii

List of Appendices ....................................................................................................................... xiii

List of Abbreviations ................................................................................................................... xiv

Preamble ......................................................................................................................................... 1

Thesis Structure .............................................................................................................................. 2

1 Chapter 1: Overview of Current Epidemiology, Pathophysiology, Treatment and

Assessment Standards for Traumatic Spinal Cord Injury .......................................................... 3

1.1 Introduction ......................................................................................................................... 4

1.2 Epidemiology and Cost ....................................................................................................... 4

1.3 Pathophysiology of SCI ...................................................................................................... 6

1.4 Current Approach to Clinical and Radiological Assessment .............................................. 7

1.4.1 Neurological Assessment of SCI patients ............................................................... 7

1.4.2 Radiological Assessment ........................................................................................ 9

1.5 Time periods after SCI ...................................................................................................... 10

1.6 Outcome Assessment after SCI ........................................................................................ 10

1.7 Treatments Available ........................................................................................................ 13

1.7.1 Supportive/Critical Care Therapy for SCI ............................................................ 13

1.7.2 Pharmacologic Therapy for SCI ........................................................................... 14

1.7.3 Surgery for SCI ..................................................................................................... 16

1.7.4 Cellular based Therapy ......................................................................................... 17

2 Chapter 2: Clinical and Radiological Predictors of Neurological outcome, Functional

outcome and Complication development after Traumatic Spinal Cord Injury: A Systematic

Review ...................................................................................................................................... 18

vi

2.1 Abstract ............................................................................................................................. 19

2.2 Introduction ....................................................................................................................... 20

2.3 Common Systematic Review Methods ............................................................................. 20

2.4 Literature Review Section 1: The impact of clinical variables on outcome after SCI...... 23

2.4.1 Results ................................................................................................................... 23

2.4.2 Discussion ............................................................................................................. 40

2.4.3 Summary: The impact of clinical variables on outcome after SCI ....................... 47

2.5 Literature Review Section 2: The impact of radiological variables on outcome after

SCI .................................................................................................................................... 48

2.5.1 Results ................................................................................................................... 48

2.5.2 Discussion ............................................................................................................. 54

2.5.3 Summary: The impact of radiological variables on clinical outcomes after SCI . 59

2.6 Limitations of systematic review ...................................................................................... 60

2.7 Conclusion ........................................................................................................................ 61

2.8 Rationale, Overarching Hypothesis and Specific Aims .................................................... 62

2.8.1 Overarching Hypothesis ........................................................................................ 64

2.8.2 Specific Aims ........................................................................................................ 65

3 Chapter 3: Description of Datasets and Approach to Missing Data ........................................ 66

3.1 Introduction ....................................................................................................................... 67

3.2 Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) Database ..................... 67

3.3 North American Clinical Trials Network for SCI (NACTN) Database............................ 67

3.4 Combined/Harmonized Dataset ........................................................................................ 68

3.5 Approach to missing data within the combined dataset .................................................... 70

4 Chapter 4: A Clinical Prediction Model for Long-Term Functional Outcome after

Traumatic Spinal Cord Injury Based on Acute Clinical and Imaging Factors......................... 72

4.1 Abstract ............................................................................................................................. 73

4.2 Introduction ....................................................................................................................... 74

vii

4.3 Methods: ........................................................................................................................... 74

4.3.1 Data Source ........................................................................................................... 74

4.3.2 Predictor Variables ................................................................................................ 76

4.3.3 Outcome and Follow-up ....................................................................................... 77

4.3.4 Statistical methods ................................................................................................ 79

4.4 Results: .............................................................................................................................. 80

4.4.1 Study Population ................................................................................................... 80

4.4.2 Functional Outcomes ............................................................................................ 83

4.4.3 Model Development and Validation ..................................................................... 84

4.5 Discussion: ........................................................................................................................ 85

4.5.1 Study Limitations .................................................................................................. 89

4.6 Conclusion: ....................................................................................................................... 90

5 Chapter 5: The Impact of Facet Dislocation on Neurological Outcome after Cervical

Spinal Cord Injury .................................................................................................................... 91

5.1 Abstract ............................................................................................................................. 92

5.2 Introduction ....................................................................................................................... 93

5.3 Methods ............................................................................................................................. 94

5.3.1 Patient Population ................................................................................................. 94

5.3.2 Outcome Variables ................................................................................................ 95

5.3.3 Statistical Analysis ................................................................................................ 95

5.4 Results ............................................................................................................................... 97

5.4.1 Patient Population ................................................................................................. 97

5.4.2 Treatment .............................................................................................................. 98

5.4.3 Outcome ................................................................................................................ 99

5.5 Discussion ....................................................................................................................... 100

5.5.1 Study Strengths and Limitations ......................................................................... 102

viii

5.6 Conclusion ...................................................................................................................... 102

6 Chapter 6: Predicting Inpatient Complications after Traumatic Cervical Spinal Cord Injury

through the use of Acute Clinical Variables .......................................................................... 104

6.1 Abstract ........................................................................................................................... 105

6.2 Introduction: .................................................................................................................... 106

6.3 Methods: ......................................................................................................................... 107

6.3.1 Study Population: ................................................................................................ 107

6.3.2 Candidate Complication Predictor Variables: .................................................... 107

6.3.3 Complication Categorization and primary outcome: .......................................... 108

6.3.4 Statistical Analysis: ............................................................................................. 108

6.4 Results: ............................................................................................................................ 109

6.5 Discussion: ...................................................................................................................... 113

6.5.1 Study Limitations: ............................................................................................... 115

6.6 Conclusion: ..................................................................................................................... 115

7 Chapter 7: Defining Age Related Differences in Functional Outcome after Traumatic

Spinal Cord Injury .................................................................................................................. 117

7.1 Abstract ........................................................................................................................... 118

7.2 Introduction ..................................................................................................................... 119

7.3 Methods ........................................................................................................................... 120

7.3.1 Study Population ................................................................................................. 120

7.3.2 Age as a predictor variable.................................................................................. 121

7.3.3 Outcome and follow-up ...................................................................................... 121

7.3.4 Statistical Methods .............................................................................................. 122

7.4 Results ............................................................................................................................. 122

7.4.1 Patient Population ............................................................................................... 122

7.4.2 Univariable analysis ............................................................................................ 124

7.4.3 Multivariable analysis ......................................................................................... 125

ix

7.5 Discussion ....................................................................................................................... 129

7.5.1 Study Limitations ................................................................................................ 130

7.6 Conclusion ...................................................................................................................... 131

8 Chapter 8: Summary of Findings, General Discussion, Thesis Limitations and Future

Directions ............................................................................................................................... 132

8.1 Summary of Findings and Unifying Discussion ............................................................. 133

8.1.1 Clinical Variables ................................................................................................ 134

8.1.2 Demographic Variables....................................................................................... 136

8.1.3 Radiological Variables ........................................................................................ 137

8.1.4 Outcome variables............................................................................................... 139

8.2 Thesis Limitations ........................................................................................................... 140

8.3 Future Directions ............................................................................................................ 142

References ................................................................................................................................... 144

Appendices .................................................................................................................................. 166

x

List of Tables

Table 1-1: Epidemiology and Costs of Spinal Cord Injury ............................................................ 5

Table 1-2: The International Standards for Neurological Classification of Traumatic Spinal Cord

Injury. .............................................................................................................................................. 8

Table 1-3: Current Evidence for the Treatment of SCI. ............................................................... 16

Table 2-1: Inclusion and Exclusion Criteria for Systematic Review ............................................ 21

Table 2-2: Evidentiary Table Summarizing Clinical Predictors of Neurological Outcome ......... 25

Table 2-3: Evidentiary Table Summarizing Clinical Predictors of Functional Outcome ............. 32

Table 2-4: Evidentiary Table Summarizing Clinical Predictors of Complications ...................... 37

Table 2-5: Evidentiary table summarizing radiological predictors of outcome............................ 50

Table 3-1: Variables included in Combined/Harmonized Dataset.. ............................................. 69

Table 4-1: Pre-specified Predictor Variables utilized in the development of prediction models . 77

Table 4-2: Functional Independence Measure (FIM) motor score ............................................... 78

Table 4-3: Patient Characteristics at hospital admission .............................................................. 81

Table 4-4: Mean Follow-up FIM motor score by baseline characteristics ................................... 83

Table 4-5: Parameter Estimates for Models predicting a) FIM motor score and b) Functional

Independence, at 1 year follow-up from original sample and bootstrap replicates ...................... 84

Table 4-6: Predicted Estimates for Hypothetical Patients ............................................................ 87

Table 5-1: Baseline Patient Characteristics .................................................................................. 96

Table 5-2: Clinical Outcomes at 1 year Follow-up, FD vs. Non-FD Cohort ................................ 99

Table 5-3: Clinical Outcomes at Follow-up, Unilateral FD vs. Bilateral FD patients ................ 100

xi

Table 5-4: Results of Multivariable Analysis (Outcome variable: Change in ASIA motor score at

1-year follow-up) ........................................................................................................................ 100

Table 6-1: Results of univariable analysis comparing patients who experienced at least one

complication to those who experienced no complications ......................................................... 111

Table 6-2: Results from the multivariable logistic regression model predicting complication

development. ............................................................................................................................... 112

Table 6-3: Predicted Probability estimates for hypothetical SCI patients .................................. 113

Table 7-1: Patient characteristics at acute hospital admission .................................................... 123

Table 7-2: Functional and Neurological Outcomes at Follow-up............................................... 125

Table 7-3: Results of linear regression analysis relative to outcome variable FIM motor score 126

Table 7-4: Results of multivariable analysis adjusted for additional variables .......................... 127

xii

List of Figures

Figure 1-1: Pathophysiology of traumatic SCI. .............................................................................. 7

Figure 4-1: Flow chart of the study design ................................................................................... 82

Figure 4-2: Predictive Model Equations ....................................................................................... 86

Figure 5-1: Number of Facet Dislocations per disc space level ................................................... 97

Figure 5-2: Treatment Flow for patients with Facet Dislocation .................................................. 98

Figure 6-1: Number of Events per Complication Category ........................................................ 110

Figure 7-1: Diagram depicting study goal. ................................................................................. 120

Figure 7-2: Interaction plot demonstrating the modification effect of age on the relationship

between acute injury severity and functional outcome ............................................................... 128

Figure 8-1: Summary of Main Relationships between Acute Predictors and Outcomes Explored

in Multivariable Analyses throughout Thesis ............................................................................. 134

xiii

List of Appendices

Appendix 1: International Standards for the Neurological Classification of Spinal Cord.......... 166

Appendix 2: Emerging Therapies for Acute Traumatic Spinal Cord Injury............................... 168

Appendix 3: Determination of Level of Evidence for papers included in Systematic Review .. 181

Appendix 4: Summary of Data in Combined Dataset ................................................................ 187

xiv

List of Abbreviations

AD Autonomic Dysreflexia

AIS grade ASIA Impairment Scale grade

AMS ASIA Motor Score

AP Antero-posterior

ASIA American Spinal Injury Association

ASS ASIA Sensory Score

AUC Area under the Curve

CT Computerized Tomography

DU Decubitus Ulcer

DVT Deep Venous Thrombosis

FD Facet Dislocation

FIM Functional Independence Measure

HD Herniated Disc

ICU Intensive Care Unit

ISNCSCI International Standards for the Neurological Classification of SCI

ISS Injury Severity Score

LEMS Lower Extremity Motor Score

MAR Missing at Random

MCAR Missing Completely at Random

MCC Maximal Canal Compromise

mJOA modified Japanese Orthopedic Association

MNAR Missing Not at Random

MPSS Methylprednisolone Sodium Succinate

MRI Magnetic Resonance Imaging

MSCC Maximal Spinal Cord Compression

NACTN North American Clinical Trials Network

NASCIS National Acute Spinal Cord Injury Study

NLI Neurological Level of Injury

OPLL Ossification of Posterior Longitudinal Ligament

OR Odds Ratio

ROC Receiver Operator Curve

SCI Spinal Cord Injury

SCIM Spinal Cord Independence Measure

STASCIS Surgical Timing in Acute SCI Study

UEMS Upper Extremity Motor Score

ZPP Zone of Partial Preservation

1

Preamble

Clinicians’ ability to accurately predict future health outcomes for patients suffering from injury

or disease is of obvious importance. From the standpoint of the health care provider, all of the

important events that occur in the early stages after injury or diagnosis, such as therapeutic

decision making, discharge/disposition planning and patient/family counseling, are potentially

facilitated by attaining an adept understanding of the most likely clinical course for the patient in

question. From the standpoint of the patient or family affected, having access to such information

early in the disease process facilitates the management of expectations throughout the pathway

of care, allowing for mental preparedness and resource planning and allocation. From the

research perspective, achieving a sound understanding of the acute factors predicting future

health events and outcomes is also imperative for purposes of planning and completing clinical

trials, decision analysis projects and cost-effectiveness analyses.

As will be expounded upon in the following sections, traumatic spinal cord injury (SCI) remains

one of the most devastating conditions encountered in clinical medicine. That said, there is

substantial variability in reported outcomes with surviving patients populating a spectrum

between minimally impaired to severely affected. In the long-term, while some patients progress

to become functionally independent, others are relegated to a life of severe disability, dependent

on others for the majority of their daily care needs. It follows from this, that identifying, and

quantifying, the relative impact of factors that influence recovery across this spectrum, is of

immense interest from both the clinical and research perspective. Further, since a large

proportion of the decision making and counseling occurs in acute period after SCI, it is of

particular interest to investigate predictive factors which are of relevance during this acute

period. To date, the majority of the existing literature on this topic comes from outside the acute

realm. Consequently, there is a need to further characterize how acute variables can be used by

the clinician and researcher alike to develop accurate outcome predictions for patients with SCI.

Given this background, the preeminent goal of this thesis is to investigate the use of clinical,

demographic and radiological variables obtained during the acute period after SCI, for purposes

of predicting both short-term and long-term clinical outcomes. As described below, a multi-

faceted definition of outcome has been employed in order to attain a more comprehensive

understanding of how these acute variables affect patients’ future status.

2

Thesis Structure

This thesis is organized according to the “multiple paper format” using primarily unaltered peer

reviewed material. As opposed to the “single continuous paper format”, the chosen structure

allows for multiple self-contained research aims to be addressed under the overall umbrella of

the main thesis topic. Also, since different partitions of the same datasets were used depending

on the specific aim, this format allowed for a description of the data considered and the specific

methods used in each case. In certain instances, when constructing a particular chapter based on

a specific peer reviewed paper, the writing or the content of the chapter may have been altered

from the original paper, in order to ensure homogeneity within the document overall.

Chapter 1 primarily serves as an introduction to the topic of SCI, reviewing basic epidemiology,

standards for clinical and radiological assessment, outcome assessment and the current treatment

options and evidence. Chapter 2 is a modified version of a paper published in “Journal of

Neurosurgery: Spine” and consists of a systematic review of the acute clinical and radiological

variables predicting outcome after SCI. The final section of chapter 2 outlines the overall

hypothesis and the specific aims of this thesis. Chapter 3 is a brief section which provides a basic

summary of the datasets used in this thesis. Chapter 4 is a reformatted version of a paper

published in “Journal of Neurotrauma” describing the development and internal validation of a

clinico-radiographic model to predict functional outcome. Chapter 5 is a reformatted version of a

paper published in the journal "Spine” describing the impact of facet dislocations on neurological

outcomes after cervical SCI. Chapter 6 is a reformatted version of a paper published in “Journal

of Neurosurgery: Spine” which explores the combination of clinical variables predicting acute

inpatient complications. Chapter 7 is a reformatted version of a paper, currently under peer

review, which explores the impact of increasing age on long-term clinical outcomes. Finally,

chapter 8 is a general discussion which collates the results presented in each chapter and

summarizes the main conclusions of this thesis as well as opportunities for future investigation.

It should be noted that explicit permission from the publisher was obtained prior to use of all

previously published material contained in this thesis. Copyright acknowledgements can be

found at the conclusion of this document.

3

1 Chapter 1 Overview of Current Epidemiology, Pathophysiology, Treatment and Assessment Standards for Traumatic Spinal Cord Injury

Section 1.7 is modified from the following:

Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal

cord injury. CMAJ. Epub: Dec 10, 2012.1

4

1.1 Introduction

As defined by Chin and colleagues, spinal cord injury (SCI) is “an insult to the spinal cord

resulting in a change, either temporary or permanent, in its normal motor, sensory, or autonomic

function”2. Although SCI can result from traumatic and non-traumatic etiologies alike, this thesis

exclusively relates to traumatic SCI. The goal of this chapter is to provide a basic overview of

the epidemiology, standards for initial assessment and outcome measurement, as well as a brief

description of current treatment options for the management of traumatic SCI. This is included as

a general primer on the topic of SCI to provide context and serve as frame of reference for the

reader throughout the remainder of this thesis.

1.2 Epidemiology and Cost

In Canada, approximately 85,000 individuals live with a diagnosis of SCI, with an incidence rate

of approximately 40 cases per million per year3-7

. At present, SCI is diagnosed in approximately

5% of all major trauma patients presenting to hospital and in about 25% of patients with a

diagnosed injury to the vertebral column8. Internationally, the epidemiology of SCI has been

shown to vary between countries9-11

. Annual incidence rates as low as 14.5 per million per year

have been reported in Australia, while rates as high as 57.8 per million per year have been

reported in Portugal12,13

. While some of these differences may truly reflect differences in the

frequency and overall burden of SCI between regions, it is more likely that they reflect

differences in case reporting standards internationally.

Regardless of the region or country considered, studies report similar findings related to

characteristics of injured populations. From a mechanistic standpoint, the majority of injuries

arise from either motor vehicle accidents (accounting for 30-60% of injuries) or falls (accounting

for 20-60% injuries), with the remaining injuries secondary to violence, sports related/diving

accidents, or work related accidents14-18

. Regarding the level of injury, there is consistency in the

finding that most injuries (55-75%) occur at cervical levels, with the remaining roughly equally

distributed between thoracic and lumbosacral levels9,10,19

. In the majority of published

epidemiological studies, the age distribution of SCI appears bimodal with the first peak occurring

in adolescence/young adulthood between the ages of 15 and 30 (related to an increase in injuries

secondary to violence, sports accidents, and motor vehicle accidents) and the second peak

occurring in those greater than 70 years old (related to an increase in fall related SCI in the

5

elderly)6,7,20

. With the overall aging of the population and the demographic restructuring of

society, it is likely that the proportion of injuries seen amongst the elderly will continue to rise in

the coming years21,22

. Finally, a higher incidence of injuries amongst men as compared to

women has consistently been observed at a ratio of approximately 2.5 to 8:114,20,23-25

.

Table 1-1: Epidemiology and Costs of Spinal Cord Injury

Parameter Value

World Wide Incidence: Range 14- 57/million/year

Canadian Incidence: Range 22-52/million/year

World Wide Prevalence: 680-750/million

Age Distribution: Bimodal Distribution with early peak amongst young adults

and a late peak amongst the elderly

Gender: Male predominance with a male to female ratio of 2.5 to 8:1

Common Injury Etiology: Motor Vehicle Accidents most common amongst younger

patients, falls most common amongst elderly patients

Neurological Level of

Injury:

Cervical: 55-75%

Thoracic:15-30%

Lumbosacral:10-20%

Severity of Injury: AIS grade A (45%), AIS grade B (15%), AIS grade C (10%)

and AIS grade D (30%)

Case Fatality Rate During

Acute Hospitalization:

4.4-16.7%

Annual Mortality Rate

After Acute discharge:

First year: 3.8%

Second year: 1.6

Years thereafter: 1.2%

Annual Cost for:

Complete SCI

Incomplete SCI

121,600 CDN*

42,100 CDN *

*Cost in the first year after SCI (2002 costs).

AIS: ASIA Impairment Scale

While the case fatality rate associated with the initial traumatic event remains high (upwards of

15%), life expectancy post injury has improved dramatically over the past several decades,

primarily as a result of improved supportive management and improved medical treatment for

post-injury complications26

. That said, SCI patients continue to die at higher rates than their non-

injured counterparts27-29

. In a large longitudinal analysis, DeVivo et al showed that even at 3

years after injury, the annual mortality rate amongst SCI patients is about 2.5 times higher than

that expected amongst the general population30

. Those that do survive are often left with

significant disability requiring lifelong assistance with basic daily care needs and activities of

6

daily living. It has been estimated that SCI patients, on average, require 30 times the amount of

home care services as compared to individuals in the general population31

. Given the intensity

and duration of care required for these patients, it not surprising that SCI has been ranked among

the most expensive medical conditions to treat, second only to respiratory distress syndrome in

the pre-term infant32

. Quantifying this economic burden, a Canadian study estimated that the

average direct healthcare costs in the first year for a patient with a complete injury were

$121,600 (2002 CDN dollars), whereas the average costs for a patient with an incomplete injury

over the same period were $ 42,100 (2002 CDN dollars)33

. At the societal level, in Canada, it

has been estimated that the total direct and indirect costs attributable to SCI approach $4 billion

annually (2012 CDN dollars)34

.

1.3 Pathophysiology of SCI

Although a detailed description of the pathophysiology of SCI falls outside the purview of this

thesis, a brief overview is provided for contextualization purposes. It is now well recognized that

the initial compressive force applied to the spinal cord at the time of injury (known as the

primary injury) initiates a deleterious cascade of patho-biological processes collectively referred

to as secondary injury mechanisms35-37

. Initially, an increased region of spinal cord ischemia

develops as a consequence of micro-vessel thrombosis and vasospasm38-41

. This leads to

physiologic derangements at the neuronal level which include cell membrane peroxidation and

destruction, ionic imbalances, cellular swelling and the release of toxic levels of the excitatory

neurotransmitter glutamate42-45

. These events begin within seconds of the primary injury and

continue for up to several weeks, ultimately expanding the region of neural tissue damage and

worsening clinical outcomes46

. Many of the therapeutic strategies currently in use, or under

investigation for future use, aim to maximize individuals’ potential for neurologic recovery by

averting different elements of this secondary injury cascade46

.

7

Figure 1-1: Pathophysiology of traumatic SCI: Schematic illustrating the time related

progression of secondary injury related pathological mechanisms after the primary injury event.

These secondary events increase neural tissue damage and negatively impact long-term clinical

outcomes.

1.4 Current Approach to Clinical and Radiological Assessment

1.4.1 Neurological Assessment of SCI patients

In 1982, in order to introduce standardized methods which clinicians could use to precisely

evaluate and document the extent of neurological deficit in the post SCI setting, the American

Spinal Injury Association (ASIA) produced the first version of the International Standards for

Neurological Classification of Spinal Cord Injury (ISNCSCI)47

. Now in its 5th

iteration, the

international standards have been uniformly adopted by the SCI community for purposes of

evaluating the baseline neurological status and for documenting neurological recovery over

follow-up48,49

. Of note, there are three main components to the International Standards exam:

ASIA motor score (AMS), ASIA sensory score (ASS) and ASIA impairment scale (AIS) grade.

AMS records muscle power in 10 myotomes bilaterally (each with a maximum power of 5)

resulting in a cumulative score with a minimum value of 0 and a maximum value of 100 (25

points attributed to each extremity). For ASIA sensory score (ASS), pinprick and light touch

sensation are assessed in 28 dermatomes bilaterally(C2-S5), with each dermatome receiving a

score of 0, 1 or 2 depending on whether the sensation is absent, abnormal or normal respectively.

8

This results in cumulative scores for both pinprick and light touch with minimum values of 0 and

maximum values of 112. Finally, based on the complete motor and sensory assessment, which

includes a digital rectal examination, the AIS grade is determined according the criteria outlined

in Table 1-2. According to epidemiologic studies, AIS grade A injuries are generally the most

common injuries encountered, followed in sequential decreasing order by AIS D, AIS B and AIS

C injuries9.

Table 1-2: The International Standards for Neurological Classification of Traumatic Spinal

Cord Injury. Important terminology within this classification is described below. (Full details

can be found in Appendix #1)

Parameter Diagnostic Criteria/Explanation

ASIA Impairment Scale (AIS) grade A No sensory or motor function is preserved in

the sacral segments S4-5

ASIA Impairment Scale (AIS) grade B Sensory but not motor function is preserved

below the neurological level of injury and

includes the sacral segments S4-5. No motor

function is preserved more than three levels

below the neurological level of injury

ASIA Impairment Scale (AIS) grade C Motor function is preserved below the

neurological level and less than half of the key

muscle below the neurological level of injury

have a muscle grade less than 3

ASIA Impairment Scale (AIS) grade D Motor function is preserved below the

neurological level and at least half of the key

muscles below the neurological level of injury

have a muscle grade less than 3

ASIA Impairment Scale (AIS) grade E Normal sensory and motor function in a patient

who previously had deficits

ASIA Motor Score Ordinal Score between 0-100 reflecting the

power of 10 key muscle groups (each scored

out of 5) on each side of the body

ASIA Sensory Score Ordinal Score reflecting pain and light touch

sensation in 28 dermatomes on each side of the

body.

Neurological Level of Injury (NLI) The most caudal segment of the cord with

intact sensation and anti-gravity muscle

function on both sides of the body

Zone of Partial Preservation (ZPP) In AIS grade A patient only. The myotomes

and dermatomes caudal to the neurological

level of injury that remain partially innervated

Modified from Kirshblum et al, J Spinal Cord Med, 201149

9

In terms of defining relevant terminology, according to the neurological standards, a patient with

a complete injury has no sensory or motor function in the distal most sacral segment, whereas a

patient with an incomplete injury does have evidence of sensory or motor preservation within

this segment (“sacral sparing”). Also important to delineate is the neurological level of injury,

which is defined as the most caudal segment of the spinal cord with normal sensory and motor

function on both sides of the body. Finally, the zone of partial preservation, applies only to

complete or AIS grade A injuries, and refers to those myotomes and dermatomes caudal to the

neurological level of injury that remain partially innervated.

From a psychometric standpoint, the neurological standards have demonstrated high intra- and

inter-rater reliability, with intraclass correlation coefficients >0.90 consistently seen throughout

the literature50-53

. While it is difficult to evaluate concurrent validity in the absence of a

measurement gold standard, these measures have shown to be correlative with other clinical,

radiologic and electrophysiologic measures which approximate injury severity and hence have

shown substantial evidence of convergent construct validity54

.

1.4.2 Radiological Assessment

Traditionally, the standard radiological test to screen trauma patients suspected of harboring a

spinal injury was X-Ray55,56

. However recently, X-Ray has largely been supplanted by CT due to

findings that plain radiographs alone may miss a large proportion of spine fractures57,58

. In the

acute setting, while CT allows for accurate diagnosis of spinal fractures or dislocations, it is

poorly suited for visualizing soft tissues. As a result, MRI is the preferred modality for

diagnosing injuries to soft tissue structures, such as ligaments and intervertebral discs, and for

visualizing the spinal cord and nerve roots. Relating specifically to the evaluation of the spinal

cord, MRI may be used to identify the exact anatomic location of injury, to assess the degree and

nature of spinal compression, and to assess for the presence or absence of abnormal

intramedullary signal characteristics associated with specific pathological states (i.e. hemorrhage

or edema). These MRI findings are important not only for purposes of initial evaluation and

treatment planning, but also for long-term prognostication. The current state of evidence

surrounding the use of acute imaging variables for purposes of outcome prediction is reviewed in

depth in the subsequent chapter.

10

Overall, the current recommendation is that patients be assessed in the acute period following

injury with both CT, for evaluating the bony injury, and MRI for evaluating the soft tissues and

neural elements59,60

. Although interesting from a research standpoint, at present, other imaging

modalities, such diffusion tensor imaging (DTI)61-63

, magnetic resonance spectroscopy

(MRS)64,65

and functional magnetic resonance imaging (fMRI)66-68

, have no standard role in the

routine clinical assessment and management of SCI patients.

1.5 Time periods after SCI

In general, SCI is classified as acute, sub-acute or chronic depending on the time elapsed from

the injury event. For purposes of this thesis, the time windows used by the International

Campaign for Cures of spinal cord injury Paralysis were used to define these periods. The first 3

days after injury represent the acute period during which the patient arrives at the trauma center,

initial clinical and radiological assessments occur, acute medical and surgical therapy is initiated

and enrollment in trials investigating acute therapeutics takes place. The sub-acute stage

represents the period between 3 days and 1 year after injury, during which the majority of

neurological recovery occurs, as is explained below. The chronic stage is attained at 1 year after

injury, at which point the majority of patient recovery has taken place. Throughout this thesis,

discussions and analyses surrounding acute clinical and radiological predictors refer to those that

have been obtained within the first 3 days after injury. The one exception to this rule pertains to

Chapter 6 of this thesis on the topic of “acute complications”. In this one instance, acute refers to

complications events that occur during the period from acute hospital admission to acute care

discharge.

1.6 Outcome Assessment after SCI

There are many frameworks for discussing and reporting on health outcomes. Perhaps the most

widely accepted at present is the World Health Organization (WHO) International Classification

of Functioning, Disabilities and Health which encourages us to consider a bio-psycho-social

definition of health status that includes physical, psychological and social components69

.

However for purposes of this thesis, which explores the predictors of outcome after SCI,

neurologic outcome, functional outcome and complications will serve as the central focus for

investigation and discussion. These particular outcomes have been chosen as they are felt to be at

the very core of well-being for SCI patients70,71

. Moreover these represent outcomes of particular

11

relevance and interest to clinicians and researchers, having been the central outcomes considered

in most of the large SCI clinical studies performed to date. Other outcomes such as quality of

life, pain, disability and mental health are of immense importance however will not be explored

at significant length in this thesis.

Traditionally, neurological improvement at follow-up has been the main outcome of interest in

the majority of SCI clinical trials, as defined by change in AIS grade, AMS or ASS between

hospital admission and follow-up70

. Other neurological outcome measures such as Frankel scale,

NASCIS motor and sensory scores and modified Benzel scale have been considered in past

trials, however use of these has largely been abdicated in favor of the international standard

ASIA indices discussed above72,73

.

The timing of follow-up neurological exam has largely been dictated by the temporal profile for

neurological recovery after injury. While the majority of recovery is known to occur within the

first 4-6 months after injury, a small proportion of patients have been shown to experience

improvement up to 5 years out from injury74

. In an analysis of AIS grade conversion rates from

the multicenter Sygen study which followed patients for 1 year, investigators observed that 77%

of patients who improved at least 2 grades did so before 4 months post injury and 92% did so

before 6 months post injury24

. However, in a separate study, Kirshblum and colleagues

demonstrated that approximately 5% of patients who were AIS grade A at 1 year converted to

incomplete status by year 575

. Taking all these points together, for purposes of defining terms of

reference for this thesis, throughout the subsequent analyses, 1 year follow-up was considered to

be “long-term” outcome. This was felt to best balance the desire to capture the full extent of

individuals’ recovery with the practical challenges of following large groups of patients over

long periods of time.

Several measures of neurological outcome, including AIS grade conversion, have shown to be

poorly predictive of future functional capacity76

. In light of these findings, the International

Campaign for Cures of spinal cord injury Paralysis has prioritized the use of neurologic and

functional outcome assessment tools in current and future SCI clinical trials70

. When considering

functional outcome in the context of SCI, while a number of different indices have arisen over

the years, two main measures are generally considered central: the Functional Independence

Measure (FIM) and the Spinal Cord Independence Measure (SCIM). FIM is a generic

12

neurological functional outcome assessment tool that has been widely used in the clinical

neurosciences throughout the last 2 decades. It consists of 2 subscales: motor and socio-

cognitive, with the socio-cognitive subscale often considered less relevant in SCI outcome

assessment. The FIM motor subscale consists of 13 items which assess individuals’ level of

functional independence across four different domains which include self-care, sphincter control,

transfers and locomotion. The FIM socio-cognitive subscale consists of 5 items which assess

individuals’ communication and social cognition. The performance level for each item is strictly

defined and ranges in value from 1 to 7, where 1 indicates complete dependence in an activity

and 7 indicates complete independence. A score of 6 or greater for each item indicates that a

patient is capable of performing that activity independently, without supervision or help.

Patients’ total cumulative score ranges from 18 to 126 when considering both subscales, or from

13 to 91 when considering just the motor subscale, with a higher value reflecting superior

functional status in either case. The psychometric profile of FIM has been intensively studied in

the context of SCI, with findings of good inter and intra-rater reliability and an acceptable body

of evidence establishing its convergent construct validity in relation to other indices that reflect

severity of impairment post injury77-80

. While FIM is likely the best researched of any functional

outcome measure used in SCI, one frequently cited limitation is, that because it is a generic tool,

it is less responsive or sensitive to subtle changes in functional status within this population81

. In

addition, ceiling effects may also be an issue for patients with less severe injuries when using

FIM. These ceiling effects are especially evident for the socio-cognitive subscale and less so for

the motor subscale82

. While formally speaking, FIM is a measure of functional independence,

hereafter and throughout this thesis, it will be referred to as a measure of functional outcome.

Developed by Catz and colleagues, SCIM is an SCI specific functional outcome measure that has

gained acceptance in the field over the last 5-10 years83

. The most recent SCIM version (version

III) contains 19 items which assess function over domains of self-care, respiration and sphincter

management and mobility84

. The individual items are weighted according to clinical relevance

and when summated result in a total combined score out of 100, with a higher value reflecting

superior functional status. Like the FIM, SCIM has shown demonstrate good inter and intra-rater

reliability85

. From the standpoint of concurrent validity SCIM has shown to correlate highly with

the FIM and, because SCIM is specific for SCI, it has been shown to be more responsive to

subtle changes in function as compared to FIM81,85-87

. Overall both SCIM and FIM are well

13

studied and appropriate for functional outcome measurement in the context of traumatic SCI.

While SCIM overcomes some of the responsiveness issues identified with FIM, it is a relative

new comer to the field and hence databases or studies commenced before its introduction may

not have incorporated it as a standard follow-up measure. It should be noted that many additional

less frequently utilized measures of functional status have been studied in the context of SCI

with some assessing self-care capacities (i.e. Modified Barthel Index, Quadriplegia Index of

Function, Self-Care Assessment Tool) while others are focused on mobility and ambulation (i.e.

Walking Index for Spinal Cord Injury, 10 Meter Walking Test)88-91

.

Apart from neurologic and functional outcomes after SCI, it is also of interest to understand

deleterious patient outcomes such as complications. Complications occur with a high frequency

after SCI and are known not only to increase morbidity and mortality, but also to negatively

impact neurologic and functional recovery92

. While a standard method of complication reporting

has yet to be uniformly adopted by the clinical and research SCI communities, complication

events can be broadly defined as either acute complications (during acute hospital admission) or

sub-acute/chronic complications (sustained after acute discharge). This distinction is important

since the type and frequency of complications affecting patients differ between these time

periods as will be discussed further in the subsequent chapters.

1.7 Treatments Available

In general, the main acute therapies for SCI can be discussed across four broad categories:

supportive, pharmacologic, surgical and cellular based. While not discussed at significant length

here, the importance of neuro-rehabilitation in helping individuals achieve their maximum

potential for neurological and functional recovery cannot be overemphasized.

1.7.1 Supportive/Critical Care Therapy for SCI

Perhaps the most significant advances in the management of SCI have related to ensuring

adequate perfusion and oxygenation of the injured spinal cord as well to the prevention of

secondary complications during the acute setting. The deleterious effects of hypotension in the

setting of injury to the central nervous system are well established93,94

. As a result, avoiding

hypotension and maintaining adequate blood pressure targets are of paramount importance in

helping to optimize patients’ likelihood of recovery. According to the most recent American

14

Association of Neurological Surgeons guidelines for the management of acute SCI, it is

recommended that in addition to avoiding hypotension, mean arterial pressure should be

maintained between 85-90mmHg for the first 7-14 days after injury95

. In addition to

optimization of blood pressure parameters, it is also recommended that injured patients,

particularly those with severe cervical injuries, be admitted to an intensive care unit setting for 7-

14 days where continuous cardiac, hemodynamic and respiratory monitoring can be undertaken.

In this setting, the commonly encountered early medical complications that contribute substantial

morbidity to SCI patients can promptly be identified and averted96

. The standardized adoption of

such physiological targets as well as ICU admission has been associated with improved

neurological recovery and reduced mortality rates in several observational and quasi-

experimental studies97-101

.

Over the years, a variety of studies have also investigated the use of locally applied (during

surgery) or systemically administered hypothermia, in the acute stages post SCI102

. These studies

are based on promising laboratory data suggesting that cooling reduces tissue energy metabolism

and mitigates secondary injury mechanisms early after injury. To date there is no data to support

the efficacy of local or systemic hypothermia in the context of SCI102

. In the analogous condition

of traumatic brain injury, randomized controlled trials have failed to associate cooling with long-

term clinical benefit103

. Of note however, a recently completed phase I study showed systemic

moderate hypothermia delivered for the first 48 hours after injury to be safe104

. Larger efficacy

trials investigating this therapy are in the planning stages.

1.7.2 Pharmacologic Therapy for SCI

To date, a total of 5 drug therapies for acute SCI have been evaluated in the context of phase III

efficacy trials. Unfortunately, while controversy continues to loom over the use of

methylprednisolone, none of these medications have shown to reliably improve long-term

outcomes for affected individuals.

Of the drugs that have been evaluated, Methylprednisolone Sodium Succinate (MPSS) has been

the most intensively investigated, predominately in the context of the three National Acute

Spinal Cord Injury Studies (NASCIS). In the first NASCIS study (NASCIS I), comparison of a

10 day regimen of medium dose MPSS to low dose MPSS revealed no difference with respect to

neurological recovery at 6 months follow-up72

. In the subsequent NASCIS II, a 24 hour high

15

dose MPSS regimen was compared to placebo with respect to the primary outcome of NASCIS

motor score recovery at 6 months follow-up105

. While the primarily analysis failed to a find a

difference between treatment arms, a pre-specified secondary analysis demonstrated that when

treatment was commenced within 8 hours of injury, those treated with MPSS experienced

significantly greater motor recovery. However, in the MPSS treated group, there were also weak

trends towards increased rates of wound infections and gastrointestinal hemorrhage. In the

subsequent NASCIS III study, a 48 hour infusion of high dose MPSS was compared to the 24

hour infusion from NASCIS II106

. In the primarily analysis, the 48 hour regimen failed to

demonstrated evidence of efficacy and was associated with strong trends towards increased

infectious complications. Collating the results of these and other studies on the topic, consensus

guidelines from the relevant physician led organizations, including the American Association of

Neurological Surgeons as well as the Canadian Spine Society and the Canadian Association of

Emergency Physicians, have recommended that the 24 hour infusion of high dose MPSS is only

a treatment option that should only be administered with the knowledge of the potential for

increased infection related complications107-110

. Throughout the individual analyses that comprise

this thesis, administration of the NASCIS II 24hour regimen of MPSS was permitted to SCI

patients, at the discretion of involved clinicians.

Four other agents including the ganglioside compound GM-1 (Sygen), the opiate receptor

blocker naloxone, the L-type calcium channel blocker nimodipine and the putative

neuroprotective agent Tirilazad mesylate, have been evaluated in the context of phase III trials.

Unfortunately, none of these drugs have demonstrated clear evidence of efficacy105,106,111

.

However, in spite of these failures, there are a number of promising new neuroprotective and

neuroregenerative agents in various stages of clinical development, that appear poised to

overcome the limitations of the discussed drugs112-114

. At present, there is no accepted or

standard drug treatment for SCI.

16

Table 1-3: Current Evidence for the Treatment of SCI.

Therapy Current Status of Evidence

Critical-care setting/Hypothermia -Patients with severe cervical level SCI should

be managed in an Intensive Care Unit setting

with continuous hemodynamic, cardiac and

respiratory monitoring for the first 7-14 days

post injury.

-No established role for systemic or local

hypothermia

Hemodynamics Hypotension should be avoided with Mean

Arterial Pressure maintained between 85 and

90 mmHg for the first 7 days post injury

Pharmacologic Therapy -Administration of methylprednisolone for

either 24 or 48 hours is an option that should

only be undertaken with the knowledge of the

potential for an increased occurrence of

complications

Surgical Decompression -Decompressive surgery within 24 hours after

injury has been shown to be safe and feasible

-Prospective non-randomized studies have

associated early surgery with improved

neurological recovery

Cellular Transplantation -Purely an investigation therapy at present time

Modified from Hadley et al, Neurosurgery, 2002 and Wilson et al, CMAJ, 2012

1.7.3 Surgery for SCI

In the context of traumatic SCI, there are three interrelated goals of surgical care: 1) re-establish

the alignment of the spinal column; 2) re-establish the stability of the spinal column; and, 3)

decompress the injured spinal cord115

. Until recently however, spine surgeons were reticent to

proceed to surgery in the early phases post SCI due to concerns that peri-operative hemodynamic

changes could compromise perfusion of the spinal cord and exacerbate neural injury1. As well,

until the advent of instrumented fusion techniques, surgery meant further destabilization of an

already unstable spine. In recent years this perception has changed in light of several factors.

First, a compelling body of preclinical evidence has arisen to support the fact that ongoing

compression of the spinal cord is a potentially reversible form of secondary injury that can be

mitigated through early surgery115-117

. Second, a growing body of clinical literature has

17

confirmed the safety of early decompressive surgery as well as its potential for positive impact

on long-term clinical outcomes118-121

. The recently published Surgical Timing in Acute Spinal

Cord Injury Study (STASCIS), evaluated the safety and efficacy of early (before 24 hours post

SCI) vs. late (at or after 24 hours post SCI) surgical decompression119

. In the final analysis of

this prospective cohort study, early surgery was found to be safe and was associated with a

significantly higher rate of neurological recovery as defined by a 2 AIS grade improvement at 6

months follow-up. Recent survey studies, gauging international surgical opinion, have

determined that at present, the majority of the spine surgery community considers early

decompressive surgery in the setting of SCI a priority, based on the best available evidence122

.

1.7.4 Cellular based Therapy

Implantation of a variety of stem cells and autologous non-stem cells has been associated with

improved neurobehavioral recovery in animal SCI models123

. Theorized mechanisms of action

vary depending on the cellular subtype considered and include: 1) release of growth promoting

trophic factors; 2) environmental modification; and, 3) cellular replacement. While implantation

of several sub-types has shown to be safe in early phase clinical trials, none have demonstrated

evidence of clinical efficacy and as a result, this therapy is presently investigational.

18

2 Chapter 2: Clinical and Radiological Predictors of Neurological outcome, Functional outcome and Complication development after Traumatic Spinal Cord Injury: A Systematic Review

This chapter is modified from the following:

Wilson JR, Cadotte D and Fehlings MG. Clinical predictors of neurological outcome,

functional status, and survival after traumatic spinal cord injury: a systematic review.

Journal of Neurosurgery: Spine 2012 (1Sup); 17:11-26.124

19

2.1 Abstract

A comprehensive systematic review of the literature was performed to identify clinical and

radiological predictors of outcome in the context of traumatic SCI. The review was performed in

two sections. The first section included studies identifying clinical predictors of: 1) neurologic

outcome; 2) functional outcome; or, 3) complication occurrence. Clinical predictors related to

patient demographics, injury mechanism or neurological exam, were extracted from studies

included and the individual relationship to outcome was defined. The second section included

studies identifying acute imaging related variables predicting the same three outcomes. For this

section the relationship between specific quantitative and qualitative imaging variables and

outcome was defined. Selected articles, in both sections, were classified according to their level

of evidence. Overall, the severity of neurological injury (as measured by admission ASIA

Impairment Scale grade, Frankel grade or injury completeness), level of injury and the presence

of a zone of partial preservation were consistent predictors of neurological outcome. The severity

of neurological injury, level of injury, reflex pattern and age were consistent predictors of

functional outcome. As regards complications, severity of neurological injury, level of injury,

and age were the strongest predictors of both acute and chronic complication events. Finally,

regarding imaging predictors, signal pattern consistent with intramedullary hemorrhage was

consistently associated with poor outcome, whereas absence of any abnormal intramedullary

signal change was associated with excellent long-term outcome. There is also consistency that

signal patterns consistent with edema or contusion reflect injuries of intermediate severity in

which the potential for recovery is variable but generally better than patients with hemorrhage

and worse than those with normal cord appearance. Based on the review of literature, the last

section of this chapter frames the overarching hypothesis and central aims of this thesis.

20

2.2 Introduction

To identify acute variables known to be of predictive importance in determining outcome after

traumatic SCI, a systematic literature review was performed. This review was completed in two

parts, with the first section dedicated to identifying clinical variables of predictive significance

and the second component dedicated to identifying radiological variables of predictive

significance. The results of this literature review were used primarily to identify clinical and

radiological variables that could be incorporated as candidate predictor variables in the

construction of clinical prediction models. As well, this review served as the basis to identify

unanswered questions and opportunities for additional investigation, pertinent to the topic of

clinical prediction in the realm of traumatic SCI.

Throughout this chapter the significance of predictive variables were gauged relative to three

main outcomes: 1) neurological outcome, 2) functional outcome, and 3) complication

development. In the first component, the factors examined for their potential predictive value

included the basic clinical elements which physicians gather at patient presentation and which

often influence therapeutic decision-making. For purposes of standardization, these elements fall

into 3 main categories: 1) neurological exam characteristics 2) demographics, and 3) injury

mechanism/etiology. For the second component the factors examined for their potential

predictive value included the radiological (CT and MRI) variables that are used as diagnostic

adjuncts in the acute clinical setting. For purposes of standardization, these variables fall in 2

main categories: 1) qualitative radiological variables, and 2) quantitative radiological variables.

Contained in the last section of this chapter, and based on the findings of this systematic review,

is the overarching hypothesis and specific aims of this thesis that serve as the central framework

for all analyses presented in subsequent chapters.

2.3 Common Systematic Review Methods

We performed a comprehensive computerized literature review using MEDLINE, PubMed,

EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews. For the first

component focused on clinical variables, search items included the MeSH terms: “spinal cord

injury” “prediction” “prognosis” “neurologic outcome measure” “functional outcome measure”

“complications” “adverse event”. For the second component focused on radiological variables,

21

search items were change to include the MeSH terms: “spinal cord injury” “computerized

tomography scan” “magnetic resonance imaging” “neurologic outcome measure” “functional

outcome measure” “complications” “adverse event”.

The literature search was limited to human and English language studies published between 1975

and 2011 (Table 2-1). Case reports and case series with less than 15 patients were excluded.

Studies involving patients with both blunt and penetrating injury mechanisms were included. We

required included studies to correlate clinical and radiological features within 1 month of initial

injury to clinical outcome status at least 3 months after injury. The exception to this was for

studies examining complication outcomes, for which any duration of follow-up was acceptable.

Studies examining the predictive capacity of electrophysiologic investigations were excluded.

When several different studies used the same dataset at different time points, we utilized the

study which displayed the most complete version of the dataset. Information from textbooks or

expert opinion was not included in this analysis.

Table 2-1: Inclusion and Exclusion Criteria for Systematic Review

Study Component Inclusion Exclusion

Participants -Patients with traumatic SCI

-Injury severity ASIA A-D

-Any level of injury

-Age >18

-Non traumatic SCI

-Injury severity ASIA E

Outcomes - Studies containing:

1) clinical information available up to 1

month post injury

2)Functional and Neurologic outcome

data available at least 3 months post

injury or complication data at any time

point

-Studies evaluating predictive

capacity of electrophysiologic

features

Publication -Published in English peer reviewed

journals after January 1, 1975.

-Meeting abstracts, editorials,

letters and narrative or

systematic reviews

-Articles identified as

preliminary reports when

results are published in later

versions

Study Design -Case series or cohort studies of 15 or

more patients

-Case reports or case series

with < 15 patients

22

Each abstract was reviewed to identify relevance to our study question and to confirm

inclusion/exclusion criteria. Citations that appeared to be appropriate or those that could not be

excluded unequivocally from the title and abstract were identified, and the corresponding full

text reports were reviewed. Articles were then manually cross-referenced with their

corresponding reference lists to find a more complete data set. Articles selected for inclusion

were then classified by level of evidence. The method used for assessing the quality of evidence

of individual studies incorporates aspects of the rating scheme developed by the Oxford Centre

for Evidence-based Medicine125

and modified by Wright et al126

. Appendix 3 contains the

evidence appraisal for each of the studies included.

For both components of this review, articles were stratified into one of three domains depending

on whether the primary focus was clinical prediction of: 1) neurologic outcome: study’s main

outcome was a neurological exam feature (i.e. improvement in muscle power) or a neurological

outcome measure validated for use in SCI (i.e. ASIA Impairment Scale, ASIA motor score,

Frankel Grade); 2) functional outcome: study’s main outcome was a functional goal (i.e.

ambulation) or a functional outcome measure validated for use in SCI (i.e. Functional

Independence Measure); or, 3) complications: study’s outcome was the development of

complications post SCI. When a single study related to more than one of the above outcome

groups it was assigned to both or all three. Within each study we examined the relationship

between acute clinical and radiological variables and future outcome.

After compilation and classification of relevant studies, for the first component of this review

concentrated on clinical predictors, we attempted to answer the following three questions, in

order to provide a focused summary of findings:

1) How does neurological examination at admission relate to outcome after traumatic SCI?

2) How do patient demographics relate to outcome after traumatic SCI?

3) How does injury mechanism or etiology relate to outcome after traumatic SCI?

For the second component of the review, concentrated on radiological predictors, the following

two questions were posed:

1) How do quantitative radiological variables relate to outcome after traumatic SCI?

2) How do qualitative radiological variables relate to outcome after traumatic SCI?

Below, results and discussion are compiled in two separate sections, with the first dedicated to

review of clinical predictors and the second dedicated to review of radiological predictors.

23

2.4 Literature Review Section 1: The impact of clinical variables on outcome after SCI

2.4.1 Results

The initial search resulted in 385 citations. Application of the inclusion and exclusion

criteria reduced this to 85 citations including those obtained after a secondary review of

bibliographies. After review of these, 54 relevant articles that identified the clinical predictors of

neurologic, functional, or complication outcomes were identified and graded by the authors. Of

the relevant articles, 26 provided predictors for neurologic outcome, 23 for functional outcome

and 14 for complications, with several of the articles providing information on more than one

type of outcome. As regards level of evidence, all of the included studies were designated as

either level II, or III.

2.4.1.1 Neurological Outcome

The 26 articles identifying clinical predictors of neurological outcome are displayed in Table 2-2.

Specific outcome measures utilized in these studies included: ASIA impairment scale (AIS)

grade or ASIA Motor/Sensory score (AMS/ASS) in 14 studies16,76,127-139

, muscle power grade in

11 studies134-137,140-146

, Frankel grade in 3 studies16,147,148

, Modified Benzel scale in 1 study149

and National Acute Spinal Cord Injury Study motor/sensory scores in 1 study150

. Nine of the

studies were classified as level II evidence while the remaining 17 studies were classified as

level III.

The most frequent predictor of neurological outcome was baseline neurological exam.

Consistently, the presence of an incomplete injury as compared to a complete injury76,130,144,147-

149 and the presence of a Zone of Partial Preservation (ZPP) in those with a complete

injury133,135,140,142,145,146

, were associated with improved neurological recovery. In addition, three

studies reported a worse prognosis for neurologic recovery for complete SCI patients with a

Neurological Level of Injury (NLI) within in the thoracic region 16,134,149

.

Three studies addressed the impact of injury etiology on neurological prognosis16,127,138

. Marino

et al reported that complete injuries arising from violent injuries were more likely to remain

complete as compared to nonviolent injuries, with 95% of the violent injuries noted to be

penetrating in nature. In contrast, in 2 separate studies, Waters et al failed to find an effect of

24

etiology (penetrating vs. non-penetrating injuries and stab-wound related vs. non-stab wound

related injuries) on long-term neurologic recovery.

Age effects were addressed by 4 studies, with 2 of these suggesting a smaller amount of

neurologic recovery with increased age131,132

and a third finding diminished recovery only

amongst older patients with incomplete SCI147

. In contrast, the remaining study found motor

recovery to occur independently of patients’ age at time of injury and sensory recovery to be

superior amongst older patients (age >65 years)150

.

Only one study examined the influence of gender, with Sipski et al reporting superior AMS

recovery amongst women as compared to men on analysis of over 14,000 patients (11,762 males

and 2671 females) within the Model systems database129

.

25

Table 2-2: Evidentiary Table Summarizing Clinical Predictors of Neurological Outcome

Paper LoE Number of

Patients

Predictive factors

assessed

Primary

Outcome(s)

Follow-

up

Findings

Bravo et al,

Paraplegia,

1996

III 50 SCI with

vertebral

fracture

Age

Frankel score on

admission and discharge

Frankel

grade at

follow-up NR

Incomplete lesions and vertebral displacement <30% were

statistically associated with improved neurologic recovery; p

< .001 for both

Age was a factor only in patients with incomplete lesions:

those who were aged < 30 years did significantly better than

those > 30 years, p < .001

Brown et al,

AMPR, 1991

III 29 with C4-

7 motor

complete

injuries

<24-hour MMT

72-hour MMT

Success=

Grade ≥4/5

muscle

strength

(MMT)

3

months

Short-term functional muscle recovery better predicted by the

72-hour MMT than the <24 hour MMT

o At 24 hours, 12/17 (71%) subjects with grade 3 and 4/12

(33%) with grades 1 or 2 achieved success (p > .05)

o At 72-hours, 11/11 (100%) with grade 3 and 5/18 (28%)

with grades 1 or 2 achieved success (p < .001)

Browne et al,

AMPR, 1993

II 24 with

motor

complete

C4-5

injuries

C5 pin sensation

ECR strength

ECR

Power 1 year

Only 2/9 ( 22%) patients with absent C5 pin sensation

recovered ECR to ≥3/5, whereas 14/15 (93%) patients with ½

or 2/2 C5 pin sensation had ECR motor recovery to >3/5

The presence of 1/5 to 2/5 initial ECR strength or ½ or 2/2 C5

pin sensation were highly significant predictors of ECR motor

recovery to ≥3/5

Cifu et al,

APMR, 1999

III 375 cervical

injuries

Age AMS at

follow-up

4-10

months

The two younger groups of patients had a more significant

improvement than did older patients, as indicated by AMS

Coleman et al,

Spine J, 2004

III 760 with

injuries

rostral to

T10

Age

AIS

NLI

Marked

recovery

(MR)*

Modified

Benzel

scale

26

weeks

Injury severity was strongest predictor of MR with AIS

Groups C and D having more MR (84.0%) than Group B

(46.6%), which recovered more than Group A (12.8%); p <

.0001.

The cervical group showed more MR than the thoracic group,

37.2% vs. 15.9, p < .0001

Within AIS Group A the cervical subgroup had higher MR

than the thoracic one (15.5% vs. 7.0%, p < .02), but MR was

nearly equal between regions in the B and CD groups.

Ditunno et al, III 35 with C4-

Power in biceps and

ECR

Power

(strength)

tests at 8

Initial biceps strength is a reliable indicator of wrist extensor

recovery

Most, if not all, C5 neurologic patients will gain one full

26

AMPR, 1987 6 motor

complete

injuries

follow-up months motor level

Ditunno et al,

AMPR, 1992

III 150 with

C4-6 motor

complete

injuries

Power of key muscles in

U/E

Power of

key U/E

muscles at

follow-up

24

months

More subjects with some motor power initially improved to

grade 3/5 at all intervals earlier than those with no motor

power (p<.005)

For the 67 patients with 1-2.5 power in the ZPP, the

improvement to grade 3/5 in the key muscles was

significantly greater than for those with no initial motor power

(68% to 82% vs. 14% to 36%, p<.001)

Ditunno et al,

AMPR, 2000

II 167 with

cervical

injuries

MMT

Power in key muscles of

U/E

U/E motor

recovery

(≥grade

3/5)

Muscle

power at

follow-up

2 years Predicting U/E recovery at a specific motor level is possible

within the first week of injury

Recovery of the biceps (C4 group) showed 70% of complete

compared with 90% of incomplete injuries recovered (p <

.001)

Extensor carpi radialis (C5 group): 75% complete and 90%

incomplete recovered (p < .002)

Triceps (C6 group): 85% of complete and 90% of incomplete

injuries recovered (p < .16)

Fasset et al, J

Neurosurg

Spine, 2007

III 3481 from

SCI registry

Age

AIS

AMS

Level of injury

AIS at

follow-up

Mortality

1 year Patients age >70 years:

were less likely to have as severe neurologic deficits as

younger patients; AIS grade C and D 63% vs. 40%, p < .001

had higher mortality rates (both during hospitalization and 1-

year follow-up); 27.7% vs. 3.2%, p < .001

o Mortality rates in older population directly correlate with

the severity of neurological injury (1-year mortality rate:

AIS grade A 66% vs. grade D 23%, p < .001)

Furlan et al, J

Neurotrauma,

2009

II 499 injuries

Age

NASCIS scores

Pain

Motor

Sensory

NASCIS

scores at

follow-up

1 year

Age and motor recovery or pain scores were not significantly

correlated

Older age was associated with greater sensory recovery and

with greater disability, as assessed using the FIM

27

Katoh et al,

Paraplegia,

1995

III 21 with

Frankel B

injuries

Pattern of sensory

sparing

AMS

1 year

Patients with spinothalamic sensory preservation between the

NLI and the last sacral dermatomes had larger improvements

in AMS at 1 year as compared to those with dull or no

sensation in the sacral dermatomes; 40.3 ± 10.7 vs. 16.5 ±

16.0, p < .001

Similarly, a greater number of patients with sensory

preservation between the NLI and the last sacral dermatomes

were able to walk at 1 year compared with the other 2 groups

combined; 75% vs. 32.5% , p = .02.

Mange et al,

1992

III 39 with C4-

6 motor

complete

injuries

Frankel grade


U/E

Time to

recovery

(assessed by

muscle

power at

follow-up)

6

months

Initial muscle strength was a significant predictor for time to

recovery to specific motor grades

Subjects whose most rostral key muscle in the ZPP who had a

motor power grade of 1/5 had a median time to recovery to

grade 3/5 of 3 months compared to 0.5 months for subjects

with initial motor power grade of 2/5 (p<.001)

Marino et al,

AMPR, 1999

III 3585

injuries

Frankel grade

AIS

AMS

NLI

AMS at

follow-up

AIS at

follow-up

Frankel at

follow-up

1 year Neurologic recovery is influenced by etiology and severity of

injury, as predicted by AMS and AIS

Motor score improvements were related to severity of injury,

with greater increases for better AIS grades except Grade D,

because of ceiling effects

Motor score improvement also depended on the NLI for

complete patients, with paraplegic patients (thoracic and

lumbar injuries) experiencing reduced AMS recovery as

compared to quadriplegic patients (cervical injuries)

Maynard et

al, J

Neurosurg,

1979

III 123 with

cervical

injuries

Frankel grade at 72 hours

post-injury

Frankel

grade at

final follow-

up

1 year

81% (50/62) with Frankel grade A (complete injuries) were

unchanged at 1 year vs. 39% (7/18) with grade B and 30%

(7/23) with grade C.

Pollard et al,

Spine, 2003

III 412 with

incomplete

cervical

injuries

AMS

ASS

AIS

Neurologic

recovery

(determine

d by AMS

and ASS

recovery)

2 years

Most important prognositc variable is the completeness of the

lesion

Improved neurologic outcomes were noted in incomplete SCI,

and younger patients (P = 0.002), and those with either a

central cord or Brown-Sequard syndrome (P = 0.019)

Neurologic recovery was not related to gender, race, type of

fracture, mechanism of injury, high-dose methylprednisolone

28

administration, early definitive surgery, early anterior

decompression for burst fractures or disc herniations, or

decompression of stenotic canals without fracture

Sipski et al,

AMPR, 2004

III 14,433

injuries

AMS

AIS

Gender

AMS at

follow-up 1 year

When grouped by severity of injury, AMS improvements

were significantly greater for women than men with either

complete (P = .035) or incomplete (P = .031) injuries

Women may have more natural neurologic recovery than

men; however, for a given level and degree of neurological

injury, men tend to do better functionally than women at time

of discharge from rehabilitation

Steeves et al,

Spinal Cord,

2011

III 426 cervical

motor-

sensory

complete

AMS

AIS

ASS

AMS at

follow-up

AIS at

follow-up

UEMS at

follow-up

1 year

AIS grade conversion did not significantly influence motor

level changes

Average spontaneous improvement in AMS was 10 points

Moderate relationship between a change in UEMS and a

change in cervical motor level

Distribution of the UEMS change may be more important

functionally than the total UEMS recovered

van

Middendorp

et al, Spinal

Cord, 2009

III 273 injuries

AIS

TUG test

10MWT

AIS

follow-up

Ability to

walk

1 year AIS conversion outcome measure is poorly related to the ability

to walk

Ratio of patients with both recovery of ambulatory function

and AIS conversion (n=101) differed significantly (P < 0.001)

between the acute phase AIS grade scores

Waters et al,

AMPR, 1992

II 148 with

complete

thoracolumb

ar injuries

NLI

ASS

AMS

AIS

Power in key muscles

Motor

function

AMS at

follow-up

Muscle

power at

follow-up

1 year

No patients with a NLI above T9 regained any LE motor

function; 38% of those with a NLI at or below T9 had some

return of LE motor function

Motor function dependent on initial NLI; sensory independent

on initial NLI

Six (4%) of the 148 patients demonstrated “late” conversion

(more than 4 months after injury) from complete to

incomplete SCI status

Waters et al,

AMPR, 1993

II 61 with

complete

cervical

injuries

AIS

AMS

ASS


AMS at

follow-up

Muscle

power at

follow-up

3 years

55/61 (90%) remained complete; 6/51 cases underwent late

conversion to incomplete injury status

97% of muscles at 1/5 or 2/5 strength one month after injury

recovered to ≥ 3/5 strength

Muscles with 0/5 strength one month after injury and located

one level below the most caudal level having motor function

regained ≥ 3/5 strength in only 27% of cases and at two levels

in 1% of cases

29

Waters et al,

AMPR, 1994a

II 54 with

incomplete

paraplegia

NLI

AIS

AMS

Frankel grade


LEMS at

follow-up

AMS at

follow-up

Muscle

power at

follow-up

1-2

year

LEMS differed significantly (p < .03) between groups of

patients partitioned by category of initial NLI

Improvement in LEMS independent of NLI

o 74% showed no improvement in NLI

Absence of any motor function 1 month after injury is not an

absolute indicator of poor motor recovery

Waters et al,

AMPR, 1994b

II 50 with

incomplete

tetraplegia

AIS

AMS

ASS


AMS at

follow-up

LEMS

Communit

y

ambulation

Muscle

power at

follow-up

1 year

0/5 patients who were motor complete with the presence of

sacral sensation unilaterally recovered any L/E motor function

8 initially motor complete subjects retained presence of

bilateral sacral sharp/ dull sensation, mean LEMS increased to

12.1 7.8

87% (20/23) of patients having a LEMS ≥ 10 at 1 month were

community ambulators using crutches and orthoses at 1 year

follow-up

Waters et al,

AMPR, 1995

II 278 injuries

AMS

Injury etiology

(penetrating vs. non-

penetrating)

AMS at

follow-up 1 year

Although the etiology injury determined the severity of the

initial neurologic deficit, it did not provide additional

predictive power concerning the amount of motor recovery

Waters et al,

Paraplegia,

1995b

II 32 injuries

Injury etiology (stab

wound)

AMS

1 year

Average change in AMS from admission to follow-up was

16.9 overall, 6.0 in complete tetraplegics and 22.7 in

incomplete tetraplegics.

No difference in motor recovery noted between current series

of stab wound patients and those with injuries from other

etiologies.

Wu et al,

AMPR, 1992

III 34 with C4-

7 motor

complete

injuries


U/E

Frankel grade

Power in

U/E

muscles at

follow-up

1 year

Subjects with no initial motor power in the ZPP had a much

better chance of recovery to grade 3/5 strength by one year

post-injury if they developed grade 2/5 strength by 3 months

post-injury (p < .001)

Zariffa et al,

Spinal Cord,

2011

III 399 thoracic

motor-

sensory

complete

AIS grade

AMS

SCIM

Neurological level

Sensory level (ASS)

AIS at

follow-up

AMS at

follow-up

ASS at

follow-up

1 year

Any length of a sensory ZPP at baseline does not predict

either a change in sensory level or a change in LEMS

A baseline sensory ZPP of three or more segments correlated

with an increase in the proportion of subjects who converted

to a grade of AIS-B or greater by 48 weeks

Sensory levels and neurological levels exhibited minor

changes but most subjects remained within one segment of

their initial injury level

Motor recovery occurred predominately in subjects with low

30

AMS: ASIA Motor Score; ASS: ASIA Sensory Score; AIS: ASIA Impairment Severity grade; ECR: extensor carpi radialis; FIM:

Functional independence measure; LEMS: Lower extremity motor score; LoE: level of evidence; MMT: manual muscle test; MPSS:

methylprednisolone sodium succinate; MR: Marked Recovery; primary endpoint of study; NLI: Neurological Level of Injury; SCI: spinal

cord injury; SCIM: Spinal cord independence measure; TUG: timed up and go; UEMS: Upper extremity motor score; ZPP: zone of partial

preservation; 10MWT: 10-meter walk test. *Defined as improvement of at least 2 grades from AIS at baseline to Modified Benzel Scale at

week 26.

thoracic SCI

31

2.4.1.2 Functional Outcome

Twenty-three articles were identified addressing the clinical predictors of functional outcome

after SCI (Table 2-3). A diverse array of outcome measures were used across these studies

including: ambulatory status in 13 studies76,133,134,136,137,148,151-157

, Functional Independence

Measure (FIM) in 7 studies129,132,150,158-161

, Walking Index for Spinal Cord Injury II (WISCI II)

in 1 study162

, 10 Meter Walk Test (10MWT) in 1 study76

, Timed Up and Go test in 1 study76

,

Modified Barthel Index in 1 study163

and the 6 minute walk test in 1 study162

. Six of the studies

were classified as level II evidence while the remaining 17 studies were classified as level III.

As seen with neurological recovery, baseline neurological exam features were the predictors of

functional recovery most frequently observed. Overall, a less severe pattern of neurological

injury76,133,136,137,148,151,155,158,159,162-165

, absence of a delayed plantar response (DPR)154,157

,

presence of hyperactive deep tendon reflex responses152

and a more caudal location for the

NLI134,158,160

were associated with a superior degree of functional recovery after SCI.

One study found no impact of injury etiology (gunshot related vs non-gunshot related) on FIM

scores at rehabilitation discharge161

.

One study addressed the influence of gender, finding greater FIM improvements in males with

motor complete lesions129

, and 3 studies addressed the influence of age, with a consensus finding

that older age is associated with worse functional outcome at long term follow-up132,150,158

.

32

Table 2-3: Evidentiary Table Summarizing Clinical Predictors of Functional Outcome

Paper LoE Number of

Patients

Predictive factors

assessed

Primary

Outcome(s)

Follow-

up

Findings

Burns et al,

AMPR, 1997

III 105 ASIA

C/D cervical

injuries

AIS

Age

Ambulation

NR

91% of ASIA C patients younger than 50 years became

ambulatory by discharge, versus 42% of those older than 50

years

All ASIA D patients became ambulatory by discharge

Calancie et al,

Clinical

Neurophysiol

ogy, 2004

II 229 injuries

Tendon reflex responses Ambulation

1 year

Larger deep tendon response amplitudes and the presence of

the crossed adductor response to patellar taps at the acute

stage were highly predictive of functional motor recovery

following SCI (motor-complete accuracy: 100%; motor-

incomplete accuracy: 91%)

Cifu et al,

APMR, 1999

III 375 cervical

injuries

AMS

FIM

Age

FIM at

follow-up 4-10

months

Younger patients’ scores on the FIM motor subscale improved

significantly more than did the older groups

Crozier et al,

APMR, 1991

III 27 Frankel

B injuries

Muscle strength

(quadriceps)

Ambulation

1 year

Motor incomplete SCI patients who recovered to a >3/5

quadricep strength by 2 months post injury had an excellent

prognosis for subsequent ambulation by 6 months post injury

Furlan et al, J

Neurotrauma,

2009

II 499 injuries

Age

FIM

FIM at

follow-up 1 year

Patients >65 years experienced greater functional deficit

(based on FIM scores) than younger individuals despite

experiencing similar rates of sensorimotor recovery

Katoh et al,

Paraplegia,

1995

III 21 with

Frankel B

injuries

Sensory sparing Ambulation

1 year

Patients with spinothalamic sensory preservation between the

NLI and the last sacral dermatomes had higher rates of

ambulation as compared to those with dull sensation in the

sacral dermatomes

Kay et al,

APMR, 2007

III 343 injuries

AIS

Level of injury

Age

FIM walking

instrument 2

months

At discharge from in-patient rehab, 0.9% of ASIA A or B

patients, 28.3% of ASIA C patients, and 67.2% of ASIA D

patients were ambulatory

Subjects with AIS grades C and D injuries were equally likely

to walk at discharge regardless of injury level

Age 50 years or older had a significant negative effect on

ambulation in ASIA D patients

Ko et al, III 50 injuries

Reflexes (BC, DPR,

CRM, AJ, KJ, NPR)

Ambulation

6-8

14 patients who became functional ambulators on f/u either

had no DPR or a DPR of only one day’s duration

33

Spinal Cord,

1999

weeks 35 subjects had a DPR of 2 days or longer duration and these

subjects were not ambulatory

Lazar et al,

APMR, 1989

III 78 injuries

MIS MBI

NR (≥ 2

months)

For quadriplegics the initial MIS positively correlated strongly

with functional status (MBI) at admission (p = .001), at 60

days, and rehab discharge (p = .001)

For paraplegics, the MBI total score at admission, discharge,

and at 30-day intervals did not correlate with early motor

function

For paraplegics the initial MIS positively correlated

significantly with MBI self-care sub-score at 60 days and at

discharge

Marino et al,

APMR, 2004

III 4338

injuries

U/E and L/E AMS

Total AMS

FIM

1.5

months

Use of separate ASIA upper extremity and lower extremity

motor scores improved prediction of motor FIM scores more

so than that of the total ASIA motor score (R2= .71 vs .59,

respectively)

Maynard et

al, J

Neurosurg,

1979

III 123 with

cervical

injuries

Frankel classification Ambulation

1 year

Of patients with sensory incomplete injuries at 72 hours, 47%

were walking at 1 year

Of patients with motor incomplete injuries at 72 hours, 87%

were walking at 1 year

McKinley et

al, AJPMR,

1999

III 217 injuries

Injury etiology (gunshot

wound)

FIM

Rehab

discharg

e

No significant difference in FIM score at discharge between

gunshot wound (FIM=94.8) and non-gunshot wound groups

(FIM=86.4).

Oleson et al,

AMPR, 2005

III 131 ASIA B

injuries

L/E and sacral pin prick

preservation

Ambulation

1 year

Baseline lower-extremity pinprick preservation (>50% of L/E

L2-S1 dermatomes) and sacral pinprick preservation at 4

weeks post-injury are associated with an improved prognosis

for ambulation at 1 year

Ota et al,

Spinal Cord,

1996

III 100 with

motor

complete

injuries

AMS

FIM

NLI

FIM at

follow-up NR

Sequential increase in mean FIM scores at follow-up with a

more caudal initial level of injury

Sipski et al,

AMPR, 2004

III 14, 433

injuries

AMS

FIM instrument score

Gender

FIM at

follow-up 1 year

Men had higher FIM motor scores at rehab discharge as

compared to women among those with motor complete lesions

except for those with C1-4 and C6 neurologic level

van

Middendorp

III 273 injuries

AIS TUG

10MWT

Ambulation 6 month

The AIS conversion outcome measure is poorly related to the

ability to walk. The ratio of patients with both recovery of

ambulatory function and AIS conversion differed significantly

34

et al, Spinal

Cord, 2009

between the acute phase AIS grade scores

van

Middendorp

et al, Lancet,

2011

III 492 injuries

Age

Motor scores of the

quadriceps femoris (L3)

Motor scores of the

gastrocsoleus (S1)

muscles

Light touch sensation of

dermatomes L3 and S1

Ambulation

1 year

Lower age and higher motor scores of the quadriceps femoris,

gastrocsoleus, and light touch sensation of dermatomes L3 and

S1 were the best predictors of independent ambulation at 1

year

Vasquez et al,

J Forensic

and Legal

Medicine,

2008

III 173 injuries

AIS grade Rate of

reaching

“functional

levels”

5 years

Only 6% (4/68) of AIS A patients showed neurologic

improvement, with no patients reaching functional levels

33% (9/27) of AIS B patients showed neurologic

improvement of whom 33% were functional

74% (38/51) of AIS C patients showed neurologic

improvement all of whom were functional

All ASIA D patients were functional at discharge

Waters et al,

AMPR, 1992

II 148 with

complete

thoracolumb

ar injuries

NLI

Ambulation

1 year

Of the 142 (96%) patients who remained complete injuries at

f/u, none with an intial NLI above T9 regained any L/E motor

function

38% of patients with an initial NLI at or below T9 had some

return of L/E motor function

20% of those with a NLI below T12 were able to achieve

reciprocal ambulation

Waters et al,

AMPR, 1994a

II 54 with

incomplete

paraplegia

NLI

LEMS

Ambulation

1 year

The amount of motor recovery was independent of the initial

NLI

All patients with a 1 month LEMS >10 with hip flexion or

knee extension >2/5 were able to ambulate in the community

Waters et al,

AMPR, 1994b

II 50 with

incomplete

cervical

injuries

LEMS Ambulation

1 year

87% (20/23) of patients having a LEMS ≥ 10 at 1 month were

community ambulators using crutches and orthoses at 1 year

follow-up, compared to 11% (3/27) of patients with a LEMS <

10

Weinstein et

al, J of Spinal

Cord Med,

1997

III 36 SCI

subjects

DPR Ambulation

4

months

DPR associated with poor prognosis for recovery of

ambulation

High correlation of the DPR with motor complete injuries

35

Zorner et al, J

Neurotrauma,

2010

III 90 motor

incomplete

injuries

LEMS

AIS

WISC II

6 minute

walk test 6

months

Initial, higher LEMS was most predictive, alone or in

combination with a higher SSEP or with the AIS, for

ambulatory capacity

AJ: Ankle jerk; AMS: ASIA Motor Score; AIS: AIS grade Impairment Severity grade; BC: bulbo-cavernosis; CRM: cremasteric; DPR:

Delayed plantar response; FIM: Functional independence measure; KJ: Knee jerk; LEMS: Lower extremity motor score; LoE: level of

evidence; MBI: Modified Barthel index; MIS: Motor index score; MMT: manual muscle test; MPSS: methylprednisolone sodium

succinate; MR: Marked Recovery; primary endpoint of study; NLI: Neurological Level of Injury; NPR: Normal plantar response; SCI:

spinal cord injury; SSEP: somatosensory evoked potential; TUG: timed up and go; 10MWT: 10-meter walk test

36

2.4.1.3 Complications

Fourteen articles specifically examined clinical features predicting complication occurrence post

SCI (Table 3-4). Six of these studies were classified as providing level II evidence, and 8 studies

were considered level III. Ten studies examined complication development in the sub-acute or

chronic period while the remaining 4 considered complications during the acute hospital period.

Neurological exam features were consistently important in predicting complication occurrence

with more severe patterns of neurological injury31,166-173

and a more cephalad neurologic level of

injury166,167,169-173

associated with a higher incidence of complications.

One study identified violence related etiologies (either gunshot or stabbing related), with a higher

incidence of complications167

.

Increasing age appeared as a positive predictor of complications across 8 of the studies

examined21,166,167,169-172,174

. One study showed no effect of age on complications175

. As regards

gender, while no study demonstrated significant differences in the overall incidence of

complications between men and women, 2 studies demonstrated gender specific differences in

the profile of complications experienced170,176

. A single study demonstrated no influence of

racial background on complication development177

.

37

Table 2-4: Evidentiary Table Summarizing Clinical Predictors of Complications

Paper LoE Number of

Patients

Predictive factors

assessed

Primary

Outcome(s)

Complication

assessment

Findings

Haisma et al,

J Rehabil

Med, 2007

II 212 injuries

Age

Level of Injury

Severity of Injury

Cause of injury

Complication

occurrence Rehab up to 1

year post

admission

Urinary Tract Infection and Decubitus Ulcers were

most common complications encountered (47% and

36% respectively)

Increased age, traumatic lesions, cervical level of

injury and AIS A injuries were associated with greater

risk of secondary complications

Werhagen et

al, Spinal

Cord, 2004

III 402 injuries

Age

Gender

Level of Injury

Severity of Injury

Neuropathic

Pain

occurrence After Acute

discharge 2

months-

46years

Increased age associated with increased risk of

developing neuropathic pain post injury

McKinley et

al, APMR,

1999

III 6,776

injuries

Age

Gender

Level of Injury

Mechanism of

Injury

Severity of Injury

Complication

occurrence Chronic

period1-20

years post SCI

Decubitus ulcers, AD, pneumonia and atelectasis were

most common complications

Risk factors included AIS A injuries, tetraplegia, older

age, violent injury mechanism and concomitant illness.

Aito et al,

Spinal Cord,

1991

III 588 injuries

Lesion Severity Complication

occurrence Acute period

up to 60 days

AIS A patients had a greater risk of respiratory

complications, decubitus ulcers and heterotopic

ossification.

Injury severity had no impact on urinary complications

or thrombo-embolic complications.

Chen et al,

APMR, 1999

III 1649

injuries

Age

Gender

Injury Severity

Level of Injury

Complication

Occurrence During Acute

Rehab

Admission

Complete injuries associated with increased incidence

of decubitus ulcers

Complete cervical injuries associated with greatest risk

of AD.

Patients less than 20y.o. had reduced rate of DVT (5%)

as compared to those >20y.o.(9.8-15.3%)

Older age, cervical level of injury and complete lesions

associated with an increased risk of respiratory

complication development.

Greater incidence of GI hemorrhage in patients over

age 50.

38

DeVivo et al,

Arch Neurol,

1990

II 886 injuries

Age Complicati

on

occurrence Chronic period

up to 2 years

Patients ≥61 demonstrate 2.1x greater risk of

pneumonia, 2.7x greater risk of GI hemorrhage, 5.6x

greater risk of PE and 16.8x greater risk of

nephrolithiasis as compared to those between the ages

of 16 and 30.

Levi et al,

Paraplegia,

1995

III 353 injuries

Injury Severity

Level of injury

Age

Gender

Complication

occurrence 0-44 years post

injury

Multivariate analysis demonstrated: Lower age at

injury associated with increased risk of spinal

deformity, male sex increase sexual problems, female

sex and fractures/spinal deformity, complete injuries

decubitus ulcers as well as urinary tract infections,

cervical injuries spasticity

Dryden et al,

Spinal Cord,

2004

III 233 injuries

Injury Severity Complication

Occurrence Chronic period

up to 6 years

93.2% of complete patients were treated for

complications as compared to 47.1% of patients with

incomplete injuries.

Krassioukov

et al, J

Neurotrauma,

2003

III 58 injuries

Age Complication

Occurrence Within 2

months of

injury

Incidence of complication for patients ≥60 y.o. 14.3%

vs. 6.7% in patients <60 y.o. (p=0.42)

No difference in profile of complications between age

groups

Furlan et al, J

Neurotrauma,

2005

II 55 injuries

Gender Complication

Occurrence Within 2

months of

injury

Overall incidence of complications 44.7% amongst

males and 52.9% amongst females (p=0.77)

Trend towards higher incidence of DVT and

depression amongst women.

Meade et al,

APMR, 2004

II 628 injuries

Race (African

American and White

Caucasian)

Complication

Occurrence During acute

hospital and

rehab stay

No difference in the incidence and the profile of

complications between African American and White

Caucasian SCI patients.

Hitzig et al,

AJPMR, 2008

II 781 injuries

Age

Years post injury

Injury Severity

Level of Injury

Complication

Occurrence Chronic phase

1-60 years

Multivariate Analysis demonstrated:

Increased age assoc. with increased odds of

cardiorespiratory complications; Increased age

associated with decreased odds of AD, bladder

infections and heterotopic ossification.

Complete injuries assoc. with increased odds of

decubitus ulcers, AD and bladder infection.

Cervical injuries assoc. with increased odds of AD

Vidal et al, III 884 injuries

Age

Gender

Decubitus

Ulcer Chronic

Patients with DU more likely to be frankel A and older

than those without DU.

39

Paraplegia,

1991

Level of Injury

Injury Severity

Education

Psychiatric Co-

morbidity

occurrence unspecified Those with DU more likely to have psychiatric illness

and addiction problems as compared to those without

DU.

No association with gender, education.

Groah et al,

Spinal Cord,

2001

II 545

Injury Severity

Level of Injury

Incidence of

Cardiovascula

r disease Min 20 years

After Age Adjustment Rates of CV disease were 35.3,

29.9 and 21.2 per 1000 in Cervical Frankel A-C,

Thoracic/Lumbar Frankel A-C and all Frankel D

groups respectively.

DU: Decubitus Ulcer; AD: Autonomic Dysreflexia; CV: Cardiovascular; DVT: Deep Venous Thrombosis; AIS grade: ASIA Impairment

Scale Grade;

40

2.4.2 Discussion

For purposes of focusing the conclusions of this review, we have used the results of our analysis

to answer the 3 pre-formulated research questions described in the methods section.

How does neurological examination at admission relate to outcome after traumatic SCI?

2.4.2.1 AIS grade & neurological outcome

Injury severity is historically considered to be the most important predictor of future neurological

outcome after traumatic SCI. This is typically documented as the initial neurological exam in the

form of AIS grade or Frankel grade. In general, the extent of anticipated recovery diminishes as

the injury severity increases. Approximately 10-15% of individuals designated initially as having

complete lesions (AIS grade A) will convert to incomplete status, with only 2% converting from

complete (AIS A) to AIS D16,178

. AIS grade A tetraplegic patients will experience, on average, a

12 point improvement in AMS (of a total of 100 points) over the course of follow-up. For AIS

grade B patients, the mean AMS recovery at one year post injury is approximately 28 points for

tetraplegics, with one third generally remaining motor complete, one third converting to AIS

grade C and one third converting to AIS grade D or E16,178

. For AIS grade C patients, the mean

AMS recovery at one year post injury is approximately 43 points for tetraplegic patients with

approximately 70% converting to AIS grade D or E16,178

. The motor gains and conversion rates

are more limited with AIS grade D injuries. This is the result of a ceiling effect, an inherent

limitation with this grading scale, whereby only 4% of AIS grade D patients convert to AIS

grade E at one year16,178

.

2.4.2.2 Neurological Level of Injury & neurological outcome

In addition to injury severity, initial neurological level of injury is an important component of the

neurological exam that has been shown to be predictive of outcome. From a neurological

outcome perspective, the average improvement in AMS 1 year after AIS grade A SCI is 9.6

points (out of a maximum of 100) for cervical as compared to 2.6 points for thoracic/lumbar

complete lesions16

. This finding is supported by Coleman and Geisler’s analysis of the Sygen

trial data, which revealed that amongst AIS grade A patients, the cervical subgroup had a higher

frequency of marked neurologic recovery as compared to the thoracic one (15.5% vs. 7.0%)149

.

41

The explanation for this difference in recovery has been related to our inability to manually test

for motor recovery between T2 and T12 thus allowing structural repair to occur without clinical

motor change appreciated. As a result, patients with an AIS grade A injury, high thoracic SCI

(between T1 and T9) are unlikely to experience significant improvement in ASIA motor scores

at follow-up, since any small degree of motor recovery that does occur will not be captured by

this outcome measure134

. Similarly, these same patients are unlikely to experience conversion to

AIS grade C or D status at follow-up, since this would require some degree of motor recovery.

Another possible explanation for the reduced recovery is, in light of the mechanical

reinforcement provided by the rib cage in the thoracic spine, the biomechanical forces involved

in thoracic complete SCI are likely to be larger than in cervical SCI, potentially leading to a

greater degree of neurological tissue destruction. Overall, there seems to be consensus across the

literature that patients with complete thoracic injuries experience a reduced potential for

neurologic recovery at follow-up as compared to cervical complete patients. However, the same

cannot be said in comparing incomplete cervical to thoracic patients, who have demonstrated

similar degrees of neurological recovery across the literature. As an example, in the same

analysis of the Sygen data described above, there was no difference in marked neurologic

recovery between the cervical and thoracic groups for patients with incomplete injuries149

.

2.4.2.3 AIS grade & functional outcome

The severity of initial injury pattern impacts the extent of functional recovery in a similar

fashion. For patients with motor complete SCI, the likelihood of future ambulation is limited.

Waters et al reported that 5% of complete paraplegics were walking at 1 year, and that none of

61 complete tetraplegic patients were ambulatory in spite of 10% converting to motor incomplete

status134,135

. This is consistent with the work of Kay et al who found that zero out of 135

complete tetraplegic patients and 2 out of 84 complete paraplegic patients (2.4%) returned to

walking at discharge from rehabilitation158

. For motor incomplete SCI, the prognosis for

ambulation is more optimistic but remains varied throughout the literature. At discharge from

rehabilitation, Kay et al have reported ambulation rates for ASIA C tetraplegic and paraplegic

patients at 27.3% and 31.3% respectively, implicating that future ability to walk is not dependent

on neurological level of injury in the context of ASIA C injuries158

. These rates are less

optimistic than those published by others including Waters et al. who found that 67% of ASIA C

tetraplegics ambulated at discharge from rehabilitation137

. Disparities in rates between individual

42

studies can be explained based on differences in timing of initial assessment, definition of

“walking”, and duration and intensity of inpatient rehabilitation. In general, 1.5 to 6 times as

many ASIA D patients are ambulatory at discharge from rehab as compared to ASIA C

patients151

. Ambulatory rates for ASIA D patients at discharge from rehab range from 67-100%

and appear to be independent of the neurological level of injury158

.

2.4.2.4 Neurological level of injury & functional outcome

From the standpoint of functional outcome, although the level of injury has little impact on the

likelihood of walking for patients with complete injuries, it has shown to significantly relate to

the ability to function independently and to perform activities of daily living. In an attempt to

link motor level to function status, Ota et al found that for patients with complete injuries and an

initial level at C4, 5, 6, 7 or 8, there was a sequential increase in mean FIM scores at follow-up

with a more caudal initial level of injury160

. These incremental improvements in FIM score

translate into meaningful improvements in self-care, eating, dressing, toileting and transferring

to/from a wheelchair160

.

2.4.2.5 Neurological exam & complications

There is consistency in the finding that injury severity influences the overall incidence of

complication development during both the period of acute hospitalization and during the chronic

phases post SCI, with more severe injuries portending a higher likelihood of complication

development. In studies evaluating the impact of acute factors on individual complication

occurrence, complete injuries (AIS A or Frankel A injuries) have routinely been associated with

an increased risk of decubitus ulcer development, urinary tract infections, respiratory

complications, autonomic dysreflexia, venous thromboembolism and heterotopic

ossification31,166-172

. Haisma et al reported that as compared to patients with incomplete injuries,

those with complete injuries were associated with 1.73 and 1.81 times greater odds of decubitus

ulcer and urinary tract infection development respectively166

. Chen et al noted that the incidence

of autonomic dysreflexia decreases sequentially according to injury severity with the incidence

among complete patients 12.8%, sensory incomplete (AIS B) patients 8.7% and motor

incomplete (AIS C) patients 4.3%169

. Regarding respiratory complications, including pneumonia

or atelectasis, the same study reported a 16.3% incidence in complete patients and 7.2%

incidence in patients with incomplete injuries169

.

43

While injury completeness is of significant importance in predicting complication occurrence, in

many instances this relationship seems to be moderated by the neurological level of injury. More

specifically, complete injuries are associated with a greater incidence of complication

development when paired with a cervical neurological level of injury as compared to a thoracic

or lumbar neurological level. As an example, Chen et al demonstrated that 23.1% of patients

with complete paraplegia developed a decubitus ulcer during rehabilitation versus 39.5% of

patients with complete tetraplegia169

. Similarly, with respect to respiratory complications, the

incidence among complete paraplegics at 2 years follow-up was 2.0% versus 9.8% among

complete tetraplegics. The same phenomenon has been shown for cardiac complications

including autonomic dysreflexia171,173

. Overall this finding can be attributed to the progressive

increase in the burden of neurological and physiological impairment that occurs for complete

patients as the lesion level extends progressively cephalad. For patients with less severe,

incomplete injuries, the effect of neurological level on complication development is less

significant; this is likely a reflection of the fact that incomplete patients experience significant

neurological/functional recovery independent of initial injury level and are therefore less

susceptible to complications related to immobility and neurological dysfunction.

2.4.2.6 The special case of Zone of Partial Preservation

Another clinical entity that has been shown repeatedly to influence neurologic recovery in

complete injuries is the degree of motor/sensory preservation in the zone of partial preservation.

The term “zone of partial preservation” applies only to complete injuries and refers to those

myotomes and dermatomes caudal to the neurological level of injury that remain partially

innervated74

. From a motor perspective, for cervical complete lesions, 90% of muscles with

grade 1-2 /5 power in the zone of partial preservation one month post injury improved to 3/5 or

greater power by 1 year post injury135

. Conversely, muscles with 0/5 strength one month after

injury and located one neurologic level below the most caudal level having motor function

regained greater than 3/5 strength in only 27% of cases135

. Similarly, Wu et al, demonstrated that

100% of cervical complete patients by 1 year experienced recovery to at least grade 3/5 power in

the muscle innervated by the cord segment directly rostral to the NLI if power was at least 2/5 in

this muscle in the acute setting post injury142

. From a sensory perspective, in a study that

included C4-5 complete patients, extensor carpi radialis recovery was more likely to occur in

those patients with spared pin prick sensation in the C5 dermatome as compared to those with

44

absent sensation in this region141

. In general, sensory and motor preservation within the zone of

partial preservation positively influences neurological recovery after complete SCI.

2.4.2.7 The special case of Reflex pattern

In addition to loss of motor and sensory function caudal to the injury site, severe SCI also can

result in an immediate and prolonged depression of stretch reflex excitability in spinal segments

lying caudal to the injury152

. Hence the presence or absence of reflexes, as well as the evolution

of reflex recovery over time is important when attempting to predict recovery. Calancie et al

found that hyperactive deep tendon reflexes, which were confirmed by EMG, in addition to the

presence of a crossed-adductor response in the acute period post SCI, portended a favorable

prognosis for functional motor recovery in the long term152

. In contrast, the presence and

persistence of a pathological reflex, called the delayed plantar response, was associated with a

poor prognosis for recovery of ambulation in two studies154,157

. The delayed plantar response

requires an unusually strong stimulus applied by stroking with a blunt instrument upward from

the heel toward the toes along the lateral sole of the foot then continued medially across the

metatarsal heads157

. When the delayed plantar response is present, this stimulus is followed by

toe flexion and relaxation in a delayed sequence.

How do patient demographics relate to outcome after traumatic SCI?

2.4.2.8 Demographic variables & neurological outcome

The effect of age on neurologic recovery remains controversial. Cifu et al, found that patients

aged 18-64 had significantly larger gains in ASIA motor score improvement over time as

compared to injury matched patients older than 65132

. However, based on analysis of the

NASCIS III dataset, the Fehlings group found motor recovery to be independent of age, with

older age predicting superior sensory neurological recovery but worse functional recovery at

follow-up150

. The fact that older SCI patients may experience similar neurologic improvements

as compared to younger patients is mitigated by the common finding that this neurologic

improvement fails to be translated into an equivalent functional gain132,150,158

.

45

In analyzing the Model System data, Sipski et al demonstrated that improvement in ASIA motor

scores from admission to 1 year post injury were significantly greater for women than men,

implicating that women potentially possess a slightly greater natural potential for neurologic

recovery129

. However, in the absence of confirmatory evidence, and without a sound supporting

biological rationale, this finding must be interpreted with caution.

2.4.2.9 Demographic variables & functional outcome

As noted above, age has been found consistently to influence outcome across studies examining

long term functional status. Cifu et al and Furlan et al have shown that patients older than 65

experience smaller improvements in FIM scores over follow-up as compared to younger patients

matched for injury characteristics132,150

. In evaluating ambulation rates amongst AIS grade C

patients with tetraplegia, Burns et al reported that 91% of patients younger than 50 became

ambulatory whereas only 42% of those older than 50 achieved the same outcome. Although the

specific cutoff value varies, there is general agreement between studies that older age at the time

of SCI portends worse functional outcome.

In the same study that demonstrated superior neurological recovery for females, males with

motor complete lesions were found to have significantly greater FIM motor scores compared to

women at rehabilitation discharge129

. Given the paucity of evidence available, no specific

conclusions can be made regarding the effects of gender on outcome after SCI. Future

prospective studies, supported by biological rationale from the basic science realm, are necessary

to answer this question definitively.

2.4.2.10 Demographic variables & complications

Across the literature, older age is associated with an overall increased risk of complication

development21,166,167,169,171,172,174

. One study found that age, dichotomized at 60, was not a

significant factor predicting the overall occurrence of complications175

. However this study did

find a trend towards increased complications in the older group and was likely underpowered to

detect a statistically significant difference. When considering individual complications post SCI,

the impact of age is differential. The incidences of pulmonary infections and cardiovascular

disease have consistently been elevated in older as compared to younger patients. Chen et al

demonstrated the incidence of pneumonia over a five year post injury period to be 7.1% for those

46

older than 60, 4.1% for those between the ages of 40-59 and 2.2% for those younger than 40169

.

Considering age as a continuous variable, Haisma et al found that a per year increase in age at

time of injury was associated with 1.05 times greater odds of both pulmonary infection and

cardiovascular disease166

. The increased incidence of these complications amongst older patients

likely reflects the decreased physiological reserve seen within increasing age. Other

complications reported less frequently but noted to be increased in older age groups include

gastro-intestinal hemorrhage and nephrolithiasis21

. The development of decubitus ulcers was not

consistently related to age across the reviewed articles. In two studies, older age was negatively

associated with the development of autonomic dysreflexia, however the authors of these articles

were unable to provide a biological explanation for these findings166,167

.

No study has shown that the overall incidence of complications differs between men and women.

However, 2 studies have shown gender specific differences in the profile of complications

observed post SCI. Levi et al showed male sex to be associated with increased incidence of

subjective sexual problems and female sex to be associated with an increase in fractures and

spinal deformity at long-term follow-up170

. In addition, Furlan et al showed trends towards an

increased incidence of deep venous thrombosis and depression amongst women176

. However, in

both of these studies it may be that observed gender associations are non-specific to SCI patients

and are a reflection of the general population as a whole.

In a single study specifically examining the impact of race on clinical outcomes, no difference

was observed with respect to the incidence or profile of complications between African

American and Caucasian SCI patients177

.

How does injury mechanism or etiology relate to outcome after SCI?

Since the etiology/mechanism of SCI influences the degree of neural tissue destruction and

injury severity, one would expect this factor to have a significant impact on neurological and

functional recovery, in addition to complications after SCI. However, relatively few studies have

explored these clinical hypotheses in detail.

2.4.2.11 Injury Mechanism & Neurological/Functional Outcome

Using information from the Model Systems database, Marino et al found that individuals

with SCI that resulted from violent trauma were more likely to be complete than those with

47

nonviolent injuries and, if complete, were more likely to remain complete than those with

nonviolent injuries16

. In contrast however, Waters et al performed a similar analysis and

concluded that although injuries more severely disruptive of the spinal canal were more likely to

result in complete SCI, there was no significant difference in motor recovery based on type of

injury (penetrating vs. non-penetrating), type of spinal fracture, or bullet location138

. Exploring

violence related injuries in slightly greater detail Waters et al found that motor recovery after

injuries related to stab wounds was no different than for non-stab wound related injuries127

.

Similarly, McKinley et al showed that gunshot etiology was not a significant predictor of follow-

up functional status161

.

Overall, based on the available evidence, it remains unclear whether specific SCI etiologies (i.e

MVA vs. fall), differentially influence neurological or function recovery.

2.4.2.12 Injury Mechanism & Complications

One study associated violence related injuries with increased complications as compared to non-

violence related injuries167

. However, it is likely that the difference observed is secondary to the

confounding influence of the aforementioned finding that violent injuries were more likely to be

complete and, if complete, were more likely to remain complete than those with nonviolent

injuries.

2.4.3 Summary: The impact of clinical variables on outcome after SCI

Clearly the single most important clinical predictor of the three outcomes considered in this

section is the acute neurological examination, more specifically, the severity of neurological

injury as measured by the AIS or Frankel grade. Consistently patients with more severe injuries

at presentation experienced worse neurological and functional outcomes and a higher incidence

of complications. With respect to neurological level of injury, complete thoracic injuries are

associated with reduced motor recovery as compared to complete cervical injuries predominately

due to our inability to clinically test for motor recovery in the thoracic region. A progressively

more cephalad neurological level of injury is generally associated with reduced functional

outcome and increased complications. Increasing age has shown to be associated with reduced

functional outcome and increased complications but has no clear association with long-term

neurological outcome. Gender has had no demonstrable impact on neurologic or functional

48

outcome or on the overall incidence of complications post injury. However, individual studies

have shown that the profile of complications observed may be different between male and female

patients. There is currently no consistent evidence suggesting that specific injury mechanisms are

predictive of neurologic, functional or complication outcomes after SCI.

2.5 Literature Review Section 2: The impact of radiological variables on outcome after SCI

2.5.1 Results

The initial search resulted in 250 citations. Application of the inclusion and exclusion criteria

reduced this to 190 citations including those obtained after a secondary review of bibliographies.

After review of these, 18 relevant articles that identified radiological predictors of neurologic,

functional, or complication outcomes were identified and graded. Of the relevant articles, 15

provided predictors for neurologic outcome, 2 for functional outcome and 1 for complications.

As regards level of evidence, all of the included studies were designated as providing level I, II,

or III. While several MRI variables were found to be important, no significant CT related

predictors were discovered. The timing of acute radiological evaluation varied across studies,

with 7 reporting MRI completion prior to 72 hours and 11 studies reporting completion outside

of this window.

2.5.1.1 Neurological Outcome

The 15 articles identifying radiological predictors of neurological outcome are displayed in Table

2-5. Specific outcome measures utilized in these studies included Frankel classification in 6

studies179-185

, AIS grade in 2 studies186,187

, ASIA motor score or ASIA sensory score in 4

studies187-189

, “neurological deficit resolution” in 2 studies190,191

, motor index score in 1 study186

,

NASCIS motor and sensory scores in 1 study192

and trauma motor index in 1 study179

. Nine of

the studies were classified as level II evidence while the remaining 6 studies were classified as

level III.

MRI intramedullary signal characteristics were shown to be of importance in predicting

neurological outcome across all 15 of the studies examined. Most frequently these studies

evaluated qualitative evidence of intramedullary hemorrhage, edema or contusion.

Intramedullary hemorrhage was consistently the strongest negative predictor of neurological

49

recovery with the absence of abnormal signal consistently the strongest positive predictor of

neurological recovery. In 3 studies, the cranio-caudal length of intramedullary signal change was

found to significantly predict neurological recovery184,187,193

. Two studies associated focal spinal

cord swelling with reduced neurological recovery at follow-up181,188

Four out of the 5 studies that considered the impact of spinal cord compression on neurological

outcomes found increasing cord compression to be a negative predictor of

recovery180,181,184,186,188

. In only one of these studies was the degree of spinal cord compression

quantified using objective radiological measurement methods188

. Two studies evaluated the

impact of spinal canal size on neurological outcome; neither of these studies found a significant

association180,188

. The presence of a disc herniation or fracture/deformity was not associated with

neurological outcome in individual studies181,188

.

2.5.1.2 Functional Outcome

The 2 articles identifying radiological predictors of functional outcome are also displayed in

Table 2-5. In the respective studies, FIM motor score194

and the Japanese Orthopedic Association

Scale195

were the functional outcome measures assessed. Both studies were classified as

providing level III evidence.

The study by Fladers et al found the qualitative presence of intramedullary hemorrhage and

increased length of intramedullary edema along the longitudinal axis to be associated with worse

functional outcome194

. The second study by Yamazaki et al found the antero-posterior diameter

of the cervical spinal canal to be positively associated with functional outcome195

. In the same

study, the presence of T2 signal change, disc herniation and/or ossification of the posterior

longitudinal ligament had no significant impact of functional outcome.

2.5.1.3 Complications

One study identifying radiological predictors of pulmonary complications is displayed in Table

2-5196

. This study provided level 1 evidence associating increased MRI intramedullary lesion

length with an increased risk of pulmonary complications during the acute and chronic phases

post SCI.

50

Table 2-5: Evidentiary table summarizing radiological predictors of outcome

Paper LoE Number of

Patients

Predictive factors

assessed

Primary

Outcome(s)

F/U Findings

Aarabi et al,

J Neurosurg

Spine, 2012

I 109 -Length of IM Lesion,

MSCC, MCC

-Occurrence of

Respiratory

Complications

-Mean 9.5

months

post SCI

- In multivariate negative binomial model length of IM lesion

>40 mm associated with 2.04 RR of pulmonary complication

development

Bondurant et

al, Spine, 1990

II 37 - IM signal intensity

pattern

-1.5 Tesla MRI within 1

to 8 days of injury

-Frankel

classification

-TMI recovery

Mean 12.1

month

post SCI

-Four patterns of signal intensity were noted which correlated

to neurological outcome:

-Type 1(27% patients): decreased T2 signal consistent with

IM hemorrhage.

-Type 2 (43.2% patients): increased T2 signal consistent

with IM edema

-Type 3(8.1% of patients): Mixed T2 signal consistent with

contusion.

-No signal change (20%)

- Patients with Type 1 injuries showed no Frankel

improvement, whereas all Type 2&3 injuries showed at least

one grade improvement.

- Average TMI recovery: 10.3 for type 1, 21.1for type 2 and

38.4 for type 3.

Bouldin et al,

Spine, 2006

II 29 -Presence of IM

hemorrhage and length

of hematoma


to 12 days of injury

-Recovery rate

of AMS, ASS

and AIS grade

24-65

months

post SCI

-Presence of hemorrhage associated with decreased sensory

recovery, and trend towards decreased motor recovery.

-In patients with hemorrhage 5/17 improved at least 1 AIS

grade whereas 11/112 patients with no hemorrhage improved

at least 1 AIS grade.

-Length of hemorrhage <4mm positively associated with AIS

grade improvement.

Flanders et al,

AJNR, 1999

III 49 -Presence of IM

hemorrhage and length

of edema

-1.5 Tesla MRI within

72 hours of injury

-FIM Motor

score

Rehab

discharge

-Mean FIM motor score at rehab discharge was 39.8 amongst

patients w/o IM hemorrhage and 21.8 amongst those w/ IM

hemorrhage (p<0.01). Largest difference noted for self- care.

- Increased length of edema and more cephalad location

correlated with worse FIM motor.

Hayashi et al,

Paraplegia,

1995

III 31 cervical

SCI

-Severity of Spinal Cord

Compression, the canal

narrowing, IM signal

intensity changes.

-0.2-1.5 Tesla MRI: 17

patients before 2 weeks,

-Frankel

Classification

Mean

13months

post SCI

-Absence of IM signal intensity changes was associated with

improved outcome.

-Patients with severe spinal cord compression showed poor


51

14 patients after 2 weeks

post SCI

Mascalchi et

al, Clinical

Radiology,

1993

II 32 injuries -IM signal change, cord

swelling, cord

compression,

fracture/deformity


days of injury

- Frankel

Classification

(Dichotomize

d Frankel A-

C and D and

E)

Mean 13

months

post SCI

- T2 hypointensity (hemorrhage) seen more frequently in

patients with Frankel A-C at follow-up (10/15) and T2

hyperintensity or no signal seen more frequently in patients

with Frankel D-E (13/13).

- Cord swelling seen in 11/14 Frankel A-C patients at follow-

up and in 4/13 Frankel D-E patients.

-Fractures/deformity seen in 12/14 Frankel A-C patients at

follow-up and in 4/13 Frankel D-E patients.

Miyanji et al,

Radiology,

2007

II 100 cervical

injuries

- MSCC, MCC, IM

edema, IM hemorrhage,

STI, HD, Spinal Cord

Swelling

-1.5 Tesla MRI within 24-

48 hours of injury

-ASIA motor

score

Mean 7.3

months

post SCI

-In multi-variable linear model IM hemorrhage, spinal cord

swelling and MSCC were independent predictors of AMS at

follow-up

-After adjusting for baseline AMS only IM hemorrhage and

cord swelling were independent predictors of f/u AMS.

O’Beirne et

al, Injury,

1993

III 44 injuries -IM signal characteristics

-1.5 Tesla MRI conducted

predominately within first

week post injury

-Frankel

Scale

NR -12/20 patients without Frankel scale improvement had IM

signal change consistent with hemorrhage or transection.

-All 17 patients that improved at least one Frankel grade had

no IM signal change or IM edema.

Ramon et al,

Spinal Cord,

1997

III 55 injuries -IM signal characteristics,

spinal cord compression,

spinal cord transection

-1.5 Tesla MRI completed

on average at 8 days post

SCI.

-AIS grade

-MIS

Mean 17.4

moths post

SCI

- Type 1 patients (IM hemorrhage): 0/14 experienced at least a

1 AIS grade improvement at f/u. Mean MIS improvement 5

points

-Type 2 patients (IM edema):11/15 experienced at least a 1

AIS grade improvement at f/u. Mean MIS improvement 21

points

-Type 3 patients (IM contusion): 6/10 experienced at least a 1

AIS grade improvement at f/u. Mean MIS improvement 52

points.

-Type 4 patients (Spinal Cord Compression):2/8 experienced

at least a 1 AIS grade improvement at f/u. Mean MIS

improvement 8 points.

-Type 5 patients (Transection): 0/2 patients experienced at

least a 1 AIS grade improvement at f/u. No MIS improve.

Sato et al,

Paraplegia,

1994

III 18 cervical

injuries

-IM signal characteristics


within 3 to 48 hours post

injury

-Frankel

Scale

Mean 12

months

post SCI

-Patients with slightly low signal on T1 and low signal on T2

demonstrated the worst prognosis for neurological recovery

(0/6 patients experienced at least 1 Frankel grade

improvement).

Schaefer et al, III 57 cervical -IM signal characteristics -Motor Mean 7.8 -Group 1(IM signal consistent with hemorrhage): Median

52

J Neurosurg,

1992

injuries -1.5 Tesla MRI completed

within 2 weeks of injury

percent

recovery

months

post SCI

percent recovery was 9%

-Group 2(IM signal consistent with edema over ≥1 spinal

segment): Median percent recovery was 41%

-Group 3(IM signal consistent with edema over < 1 spinal

segment: Median percent recovery was 72%.

Selden et al,

Neurosurgery,

1999

II 55 cervical

injuries

-presence and length of

IM hematoma, length of

IM edema, CC and CC

from extra-axial

hematoma


within 22 hours of injury

- Frankel

Scale

Mean 18.5

months

post SCI

-Presence of IM hematoma, CC and CC from extra-axial

hematoma negatively associated with Frankel grade recovery

at F/U.

- All patients with Frankel A at admission and IM hematoma

failed to improve at F/U whereas 32% of patients with IM

hematomas and less severe injuries improved at F/U.

- In multivariate analysis presence of IM hematoma, length of

IM hematoma, length of IM edema, and presence of CC from

extra-axial hematoma were significant negative predictors of

recovery.

Shepard and

Bracken,

Spinal Cord,

1999

II 199 injuries -IM signal characteristics

consistent with

hemorrhage, edema or

contusion.

-MRI within 72 hours of

injury

-NASCIS

motor, light

touch and

pinprick score

6 weeks

post SCI

-With respect to the outcome of motor recovery multi-variable

linear regression revealed trends towards a negative

association with IM hemorrhage (p=0.29), IM contusion

(p=0.87), IM edema (0.06)

Shimada et al,

Spinal Cord,

1999

II 75 cervical

injuries


-1.5 Tesla MRI performed

within 48 hours of injury

-“Neurologic

deficit

resolution”

6months/1

year post

SCI

-Four patterns identified:

-Type 1 (no signal change): 10/10 patients demonstrated

neurologic recovery

-Type 2 (T2 hyperintensity): 24/25 demonstrated neurologic

recovery

-Type 3(T2 hyperintensity with delayed T1 hypointensity):

16/30 demonstrated neurologic recovery

-Type 4(T2 hypointensity/hyperintensity): 1/10 demonstrated


Shin, Yonsei

Medical

Journal, 2005

II 30 cervical

injuries



within 7 days of injury

- Neurological

Level

improvement

-Motor/Sensory

percent

recovery

-6 months

post SCI

- IM edema associated with at least a 1 segment neuro

recovery in 7/15 patients.

- mixed IM signal associated with at least a 1 segment neuro

recovery in 5/14 patients.

-Motor recovery ratio 35.10 in patients with IM edema and

6.35 in patients with mixed IM signal(p<0.05).

-Sensory recovery ratio 50.27 in patients with IM edema and

17.14 in patients with mixed IM signal(p<0.05).

53

Takahashi, J

Ortho Surg,

2002

II 43 cervical

injuries



within

“Neurological

Deficit

resolution”

1 year post

SCI

Three patterns noted

Type 1 (T2 hyperintensity): 10/10 demonstrated neurologic

recovery

-Type 2(T2 hyperintensity with delayed T1 hypointensity):

22/31 demonstrated neurologic recovery

-Type 3(T2 hypointensity with delayed T1 hypointensity): 0/2

demonstrated neurological recovery

Tewari et al,

Surg Neurol,

2005

III 40 injuries -IM signal changes

-MRI performed within

72 hours of injury

-Frankel Scale -Acute

hospital

discharge

- Patients with normal MRI or IM edema 6/6 recovered useful

neurological function (Frankel D/E)

-Patients with IM hematoma or contusion 13/13 failed to

recover useful neurological function (Frankel D/E)

Yamazaki et

al, Surg

Neurol, 2005

III 47 cervical

“central cord

sydrome”

injuries

-AP diameter of canal,

presence of canal stenosis,

spur formation, OPLL,

HD, Presence of IM

signal change.

- Timing of MRI NR

-Japanese

Orthopedic

Assoc. Scale

Mean 40.6

months

post SCI

-Divided into excellent recovery and poor recovery groups

-AP diameter 10.3mm in excellent recovery and 8.8mm in

poor recovery(p=0.04)

-No difference in outcome related to presence of canal

stenosis, spur formation, OPLL or HD.

MRI: Magnetic Resonance Imaging; IM: Intramedullary; MSCC: Maximum Spinal Cord Compression; MCC: Maximal Canal

Compromise; HD: Herniated Disc; OPLL: Ossification of Posterior Longitudinal Ligament; AP: Antero-posterior; CC: Cord

Compression; AIS: ASIA Impairment Scale; AMS: ASIA motor score;

54

2.5.2 Discussion

How do Qualitative Radiological Variables Relate to Outcome after SCI?

2.5.2.1 MRI Intramedullary Signal Characteristics

Intramedullary signal has been the most frequently studied MRI parameter for purposes of

predicting outcome post SCI. The initial qualitative classification system proposed by Bodurant

and colleagues outlined four major patterns of intramedullary signal change, each reflective of

specific pathological states179

. In this scheme, pattern number 1, defined as decreased signal

intensity on T2 weighted MRI sequences, represented spinal cord hemorrhage. All 10 patients

with this signal pattern were Frankel grade A at admission and failed to improve beyond this at

long-term follow-up. Pattern number 2, defined as increased signal intensity on T2 weighted

MRI, represented spinal cord edema and was associated with a substantially better prognosis; at

least a 1 Frankel grade improvement was seen in 10/11 patients that presented with neurological

deficit and this pattern of signal change. Pattern number 3 appeared as a mixed picture, with

regions of increased and decreased T2 signal change. This pattern was thought to reflect

petechial hemorrhage or spinal cord contusion surrounded by a region of edema. All three

patients with this imaging pattern recovered 2 Frankel grades at follow-up. Finally, 7 patients in

this study had no evidence of intramedullary signal change on the acute MRI. All of these

patients achieved perfect neurological status at follow-up. Overall, this study defined a severity

spectrum of imaging findings that correlates with the potential for neurological recovery post

injury. On one end of the spectrum, absence of intramedullary signal change predicts excellent

neurologic recovery. At the opposite extreme, intramedullary hemorrhage portends negative

neurological outcome. Signal change consistent with edema and/or contusion reflect lesions of

intermediate severity where the predicted potential for recovery falls between that predicted for

those with no signal change and those with intramedullary hemorrhage.

Follow-up studies have confirmed the predictive importance of the qualitative variables

originally studied by Bondurant and colleagues. Shimada et al demonstrated a similar sequential

stepwise reduction in neurological recovery in association with MRI findings of no

intramedullary signal change, signal change consistent with edema and signal change consistent

with hemorrhage190

. Bouldin et al demonstrated that 5/17 patients with MRI evidence of

55

intramedullary hemorrhage improved at least 1 AIS grade at a minimum follow-up of 2 years,

whereas 11/12 patients with no evidence of hemorrhage experienced this degree of recovery187

.

Even after adjusting for baseline neurological exam status, Miyanji and colleagues found that the

presence of intramedullary hemorrhage remained a significant predictor of motor neurological

recovery188

. In opposition to these findings, an analysis of imaging data collected in the NASCIS

III study revealed no significant association between MRI signals consistent with intramedullary

hemorrhage or edema and 6 week motor recovery192

. However, this study has been criticized for

using 6 week follow-up scores, a time point which is inadequate to fully observe individuals’

profile of motor recovery (plateaus at 4-6 months post injury).

Although the majority of studies evaluating the predictive significance of intramedullary signal

characteristics considered neurological outcomes, Flanders et al considered functional outcome

and showed that the mean Functional Independence Measure motor score at rehabilitation

discharge was significantly lower amongst patients with MRI evidence of hemorrhage (21.8) as

compared to those with no evidence of hemorrhage (39.8)194

. No studies that addressed the

impact of qualitative intramedullary signal change on complication outcomes were identified.

It is important to note that the patterns of MRI signal change which we associate with specific

pathological states, such as edema and hemorrhage, have been validated in both animal and

human studies. Preclinical experiments involving rats, cats and dogs have confirmed that during

the acute period following injury, increased signal intensity on T2 weighted images is associated

with the pathological presence of white and grey matter tissue edema/swelling as well as axonal

degeneration197-202

. In these same experiments the appearance of intramedullary blood has been

shown to appear hypo-intense on acute T2 weighted images. This hypo-intense appearance of

blood is thought to be secondary to the oxidative denaturation of deoxyhemoglobin which

commences shortly after hematoma formation. As the denaturation and decomposition of

hemoglobin continues, the appearance of the hemorrhagic lesion on MRI evolves. Several

clinical studies which have correlated acute MRI findings with post-mortem pathological

findings have by in large confirmed the findings of these animal studies203-205

. Although the

validity of these MRI signal patterns have been confirmed in numerous studies their reliability

remains substantially less studied. There is no existing study that has evaluated the intra-rater or

inter-rater reliability of detecting hemorrhage, contusion or edema on spinal MRI at any time

point after SCI. We can only extrapolate from studies evaluating the reliability of MRI in

56

detecting intra-cranial hemorrhage which have revealed high inter and intra-rater agreement206

.

The lack of a well-defined reliability profile for the discussed qualitative variables is one of the

largest limitations surrounding their use in clinical research.

2.5.2.2 Qualitative Spinal cord compression and swelling

From a qualitative standpoint the definition of spinal cord compression employed throughout the

literature is variable. Of four studies investigating this parameter on acute MRI, one study

reported severe and mild compression (severe defined by distortion of the cord diameter by

greater than approximately 2/3rds normal diameter), one study reported only severe compression

(no criteria defined) and 2 studies reported any degree of spinal cord compression. Given the

variability in its classification, it is unsurprising that the impact of spinal cord compression on

outcomes has found to be differential throughout the literature. Mascalchi et al found that the

proportion of patients with good neurological outcomes at follow-up that had spinal cord

compression on acute MRI was no different than the proportion of patients with poor

neurological outcomes who had this acute finding181

. In contrast, Hayashi et al found that as

compared to mild compression, severe compression was a negative predictor of Frankel grade

improvement at follow-up, however this effect was not quantified in the manuscript text180

.

Similarly, Ramon et al associated severe compression with diminished recovery, finding that of 9

patients with SCI and severe compression, 7 were motor sensory complete at final follow-up186

.

Given the heterogeneity in qualitative compression classification, as well as in its predictive

implications, it is apparent that compression is more suitably defined as a quantitative imaging

variable

A total of 2 studies evaluated the impact of the presence or absence of spinal cord swelling on

long-term neurological outcomes. Although methods for determining the presence of swelling

were not explicitly described in either paper, the authors make mention that this refers to the

presence of a focal widening of the cord at the site of injury. In the study by Miyanji et al,

swelling was found to be a statistically significant negative predictor of future motor

neurological outcome after adjusting for baseline motor neurological status and the presence of

intramedullary hemorrhage188

. The second study Mascalchi et al found that at a mean of 13

months post SCI, a higher proportion of patients experiencing unfavorable outcomes (Frankel

grade A-C) had swelling identified on the acute MRI as compared to those with a favorable

57

outcome (Frankel grade D and E) at follow-up181

. Overall swelling seems to be a negative

predictor of future neurological recovery, however relatively few studies have examined this

parameter in detail. Further, standardized methods for determining the presence of swelling do

not appear throughout the literature, a fact that diminishes its appeal for routine use in the

clinical or research settings.

2.5.2.3 Miscellaneous Qualitative Variables

Two studies demonstrated that the presence of a disc herniation on acute MRI had no impact on

neurological outcome, as measured by AMS recovery, or on functional outcome, as measured by

follow-up mJOA scores188,195

. Individual studies have also shown no association between

paravertebral soft tissue injury, qualitative presence of spinal canal stenosis, or the presence of

vertebral fractures/deformity on clinical outcomes post SCI181,188,195

.

How do Quantitative Radiological Variables Relate to Outcome after SCI?

2.5.2.4 Length of Intramedullary Lesion

Instead of commenting on the presence of hemorrhage or edema, several groups have quantified

the burden of this pathology by measuring the length of corresponding MRI signal change along

the longitudinal axis of the spinal cord. Selden et al found that increased length of intramedullary

signal compatible with either hemorrhage or edema was a significant predictor of a worse

Frankel grade at a mean of 18.5 months post injury184

. In attempting to define a potentially

clinically important threshold for length of intramedullary hemorrhage, Boldin et al reported that

lesion length less than 4 millimeters was uniformly associated with a less severe degree of initial

injury and improved AIS grade recovery at long term follow-up187

. However, in the same study,

a multivariate analysis controlling for the baseline neurological exam found that the length of

intramedullary edema was the only significant predictor of outcome with each millimeter

increase in length associated with a 1.15 times increased risk of retaining complete SCI. Schaefer

et al also explored the predictive significance associated with the length of intramedullary signal

consistent with edema193

. In this study the authors found that patients with edema spanning

greater than 1 vertebral body segment experienced a median percent motor recovery of 41% as

compared to 72% amongst patients with edema spanning less than a vertebral segment.

However, both of these groups experienced comparatively favorable outcomes as compared to

58

patients with MRI evidence of intramedullary hemorrhage who collectively experienced a 5%

median motor recovery.

From the perspective of functional outcome, Flanders et al demonstrated that increases in the

length of intramedullary edema signal negatively correlated with FIM motor score at

rehabilitation discharge (Pearson correlation coefficient -0.36, p<0.05)194

. In addition to

considering the raw length of edema related signal present, the investigators also evaluated the

predictive significance of the location of this signal change, finding that extension of edema to a

more cephalad location negatively correlated with functional outcome. Finally, as regards

complication development, Aarabi et al concluded that intramedullary lesion length greater than

40 millimeters was associated with a 2-fold increased risk of experiencing a pulmonary

complication as compared to lesion length less than 20 millimeters196

. However in this article,

the authors did not specify the MRI characteristics of the intramedullary lesion measured. As a

result it is unclear whether hemorrhage, edema or both were considered in these measurements.

This is significant given that the predictive importance of these measures would likely differ

depending on the nature of the underlying pathology.

Theoretically, numerically quantifying the length of intramedullary signal change present on

acute MRI should provide a more precise estimate of the burden of neural tissue damage and

allow for more accuracy in prediction of long-term outcome. However, several limitations must

be noted when discussing these measurements. First, different authors have employed different

methods and used different MRI sequences for performing these measurements. As a result it is

often difficult to draw direct comparisons between study findings. Second, although the number

of studies exploring the predictive significance of quantitative methods is much less than the

number evaluating qualitative methods, based on the available evidence there is no conclusive

evidence that quantitative methods are of greater value in predicting future outcome. As

standardized methods for measuring intramedullary signal length are validated and accepted

throughout the field, the predictive utility of these measures are likely to improve.

2.5.2.5 Quantitative Spinal Cord Compression

Of the studies included in this review, 2 employed quantitative methods to determine the extent

of spinal cord compression. Both of these studies utilized a valid and reliable measurement

strategy developed by Fehlings and colleagues207,208

. This measurement value, called the

59

maximal spinal cord compression (MSCC), compares the antero-posterior spinal cord diameter at

the level of maximal compression with the cord diameter at the nearest normal levels above and

below, using the mid-sagittal MRI. Using this technique, Miyanji et al found that in a

multivariate analysis, including only imaging related predictors, increased MSCC was a

significant negative predictor of motor neurological status at long-term follow-up188

. However,

when considered in a second multivariate model including baseline motor neurological status,

MSCC was no longer found to be a significant predictor of outcome. In the second study, Aarabi

and colleagues found that while there was a trend towards increased pulmonary complications

amongst patients with higher MSCC values this finding did not reach significance196

.

2.5.2.6 Quantitative Spinal Canal Narrowing

In conjunction with developing MSCC to quantify the degree of spinal cord compression,

Fehlings et al also defined and validated the maximum canal compromise (MCC) measure,

which is a standardized method to quantify the extent of spinal canal compromise on acute

MRI207,208

. This is calculated by comparing the AP canal diameter at the level of maximum

injury with the AP canal diameter at nearest normal levels above and below, using the mid-

sagittal MRI. MCC was not found to be of importance in predicting motor neurological status or

pulmonary complications in two of the studies included in this review. A third article which

examined the association between the raw spinal canal diameter an functional outcome in

patients with central cord syndrome found that the mean diameter was significantly higher in

patients with excellent functional recovery (10.3 mm) as compared to patients with poor

functional recovery (8.8mm)195

. However since the later method uses only a single measurement

in isolation it is unclear whether this finding reflects true focal stenosis or simply congenitally

smaller spinal canal amongst patients with worse functional outcomes.

2.5.3 Summary: The impact of radiological variables on clinical outcomes after SCI

Presently, there is no clear consensus surrounding which acute radiological variables are the best

suited to predict long-term outcome after SCI. A 2007 evidence based review on neuroimaging

for SCI performed through the United States National Institute on Disability and Rehabilitation

Research concluded that “MRI findings of parenchymal hemorrhage/contusion, edema and

spinal cord disruption in acute and subacute SCI may contribute to the understanding of severity

60

of injury and prognosis for neurological improvement”60

. While this statement is rather vague in

its direction, it is a reflection of the current state of the evidence on this topic. Overall, however,

it is clear that qualitative intramedullary signal characteristics are the best studied imaging

variables for purposes of outcome prediction. Further, there is consistency across the studies

considered that signal pattern consistent with intramedullary hemorrhage is associated with poor

outcome whereas absence of any abnormal intramedullary signal change is uniformly associated

with excellent long-term outcome. There is also consistency that signal patterns consistent with

edema or contusion reflect injuries of intermediate severity in which the potential for recovery is

variable but generally better than patients with hemorrhage and worse than those with normal

cord appearance.

Apart from intramedullary signal characteristics, the remaining qualitative variables considered

were found to have inconsistent effects or had an insufficient body of evidence available to

support their use as predictive variables.

As regards the quantitative variables considered, the major challenge arises with respect to

standardization of measurement techniques. Techniques for quantifying the extent of

intramedullary signal change to provide a numeric estimate of the spinal cord damage appear

promising. However, none of these measures have been standardized or validated. Further, to

date, none of these measures have demonstrated clear evidence of superior predictive capacity as

compared to the discussed qualitative intramedullary signal characteristics. Of studies that did

use standardized and validated measurement techniques (i.e MSCC and MSC) there is

insufficient evidence that these are of independent importance with respect to long-term outcome

prediction.

2.6 Limitations of systematic review

The quality of evidence on this topic is varied with the majority of studies found to be either

retrospective or prospective cohort studies (levels 1, 2, and 3), with only one case-control study

(level 3) (Appendix 3). However, the consistency of findings across these studies reinforces the

predictive importance of many of the clinical and radiological variables discussed. Another

potential challenge is the lack of uniformity in definitions of outcome across the literature.

Although the International Standard ASIA indices are now accepted as the standard method for

recording neurological outcome, such uniformity does not exist in the reporting of functional

61

outcome measures. While it is true that different functional outcome measurement tools assess

different aspects of functional recovery, the objective was to define the predictors of functional

outcome in general, not simply as measured by a single outcome measure. Similarly, with

respect to complications, there was considerable heterogeneity in the reporting and

categorization of these events across studies. This point underlies the need for the development

of a standardized SCI complications reporting system for implementation in future clinical

studies. As acknowledged above, with respect to the MRI variables considered, one major

limitation is the lack of psychometric information available for these indices. For the qualitative

MRI variables associating specific patterns of intramedullary signal intensity with specific

pathological states (spinal cord hemorrhage, contusion or edema), there is a significant body of

pre-clinical and clinical literature establishing their validity. However there are no studies

available exploring the reliability of these characteristics. With the exception of MCC and

MSCC, the psychometric properties associated with the remaining qualitative and quantitative

MRI variables remain largely unexplored.

2.7 Conclusion

Given the clinical and pathological heterogeneity of SCI, identification of a single predictor that

is capable of accounting for the full extent of the outcome spectrum, is a formidable challenge.

Based on a systematic review of the literature, this chapter summarizes the constellation of

clinical and radiological variables relating to neurological and functional outcome, as well as

complication development. As mentioned in the introduction, defining these relationships will

help with the selection of candidate predictor variables in the creation of clinical prediction

models and has allowed for the identification of variety of new research opportunities, pertinent

to the topic of clinical prediction in the realm of traumatic SCI.

62

2.8 Rationale, Overarching Hypothesis and Specific Aims

It is apparent that the first few days after SCI, from both a diagnostic and therapeutic perspective,

are critical. To standardize terminology within the field, the International Campaign for Cures of

Spinal Cord Injury Paralysis consensus guidelines defined the first 3 days after injury as the

“acute” injury period, as discussed in chapter 1. During this acute period, the initial neurological

exam, as well as diagnostic imaging tests are performed to determine the injury severity and to

characterize anatomical injury characteristics. Based on this information, practitioners make a

number of treatment decisions related to the acute medical stabilization of the injured patient and

formulate a definitive management strategy, which often includes surgical decompression of the

spinal cord. Not surprisingly, this same acute period coincides with the time of greatest anguish

for an injured patient and their family as they face significant prognostic uncertainty. In this

setting, it is the responsibility of the clinicians involved to use acute diagnostic information,

coupled with the available scientific literature, to provide a prognosis and manage expectations

for the future.

From a research perspective, many trials investigating the effectiveness of a particular

pharmaceutical or surgical intervention in patients with SCI are underway46

. However it is

difficult to meaningfully analyze for treatment effects in such a diverse patient population

without defining homogenous subgroups178

. Such subdivision would require a detailed

understanding about how acute injury variables relate to patient outcomes in the long-term, so

that individuals could be classified at the time of hospital admission depending on their expected

outcome.

To achieve these clinical and a research goals, a number of studies have shown several

individual clinical, radiological and demographic variables to be of importance in predicting

clinical outcome after traumatic SCI73,74,130,141,147,149,150,152,153,160,163

. A comprehensive review of

these variables is presented in the first part of this chapter. When considering the studies

presented in the above review, it is apparent that analyses assessing the significance of

combining individual parameters to improve outcome predictions, are sparse in the literature.

Further, the few existing studies that employ a combination of variables to predict long-term

outcome, use information collected outside the initial injury period (greater than 3 days post

SCI) and are therefore less useful as acute clinical prediction tools156,162

Zoerner et al produced a

63

clinical algorithm to predict ambulatory capacity 6 months post SCI, based on 90 patients with

incomplete SCI (79% traumatic, 21% non-traumatic)162

. A more recent study from the European

Multicenter SCI study group generated a clinical prediction rule for future ambulatory outcomes

using age, motor scores from the quadriceps and soleus muscles and light touch sensations in the

L3 and S1 dermatomes, as predictor variables156

. This analysis was based on traumatic SCI

patients with neurological examination variables obtained up to 15 days after injury, with the

vast majority of examinations taking place after 3 days post injury.

These studies provide evidence that the use of a combination of variables may enable a more

reliable prediction of long-term outcome after SCI as compared to the use of single predictors in

isolation. However, a number of key limitations in the existing literature must be recognized.

Previous studies have demonstrated that extraneous patient and injury related variables in the

acute setting can interfere with the accuracy of the initial neurological examination, yielding

results that are discordant with those obtained later post admission148,209

. Hence, previous

prediction rules formed using data outside the acute period are less suitable for use at the time of

patient admission to hospital, a fact which diminishes their clinical and research utility. In the

controlled setting of a hospital ward several weeks after injury, there are few distractions

impeding the accuracy of exam findings; in this setting the complete ISNCSCI neurological

exam is likely sufficient for purposes of outcome prediction. However in the first hours and days

post injury, time constraints as well as factors such as distracting injuries, sedation and patient

fatigue may impede clinicians’ ability to obtain the desired quality of neurological exam. This

fact addresses the need for prediction models that reflect the realities and the challenges of

patient assessment during the acute period. Ideally, such models would incorporate parameters

that can be easily collected during the acute injury setting. As an example, collecting

electrophysiological measurements or obtaining a very precise ASIA motor score value may not

always be realistic. Further, the variables incorporated should be familiar to acute care

physicians and should be part of the routine diagnostic work-up performed to investigate SCI

patients. As an example, radiologic investigations, both CT and MRI alike, are important

diagnostic adjuncts, used by modern day clinicians, to make management decisions and outcome

predictions. None of the existing SCI prediction models incorporate radiological variables as

predictors; these would be important for consideration in future acute models.

64

From an outcome assessment standpoint, the majority of previous studies exploring the

predictors of outcome after SCI, including the studies mentioned above, have utilized walking or

motor recovery as the primary measure of long-term outcome133,151,152,154,156,164

. While these

outcomes are certainly of interest, it is of paramount importance to consider other dimensions of

functional and neurological status at long-term follow-up. In a large survey assessing quality of

life in over 200,000 SCI patients, regaining arm and hand function was the highest priority for

quadriplegics, while regaining bowel/bladder and sexual function were the highest priorities for

paraplegics71

. These results underscore the importance of incorporating assessment tools that

include multi-dimensional assessments of outcome. On the topic of outcome it is also noteworthy

that our review of the literature identified a paucity of studies exploring predictors of

complications occurrence during the acute in-hospital period. Since these complication events

are known to affect both mortality rates and rates of neurological recovery, achieving an adept

understanding of the interplay of factors affecting their occurrence is important for purposes of

quality improvement and optimization of long-term outcomes.

There appears considerable opportunity to contribute to, and improve upon, the existing body of

knowledge pertaining to the acute prediction of outcome after traumatic SCI. To address this

void, this thesis relies on acute care data obtained exclusively within 3 days of injury for all

patients, which is used to generate predictive models that can be used at the time of admission by

acute care practitioners and SCI researchers to estimate short-term and long-term clinical

outcomes. In addition to a wide range of clinical factors, this thesis also explores and

incorporates relevant information obtained from acute diagnostic imaging to predict outcome.

Lastly, this thesis makes use of several outcome measures at follow-up that assess a spectrum of

outcomes important to clinicians, researchers and patients alike.

2.8.1 Overarching Hypothesis

Given the information presented above, it is hypothesized that clinical outcomes can accurately

be predicted after traumatic spinal cord injury based on acute patient, injury and radiological

features, leading to improved communication in the clinical realm and facilitating the

classification of patients within future clinical trials. To fully explore this hypothesis, outcome

has been defined in 3 ways: neurological outcome, functional outcome and complications.

65

2.8.2 Specific Aims

To investigate the overarching hypothesis and to expand upon the existing body of literature, 5

interrelated projects have been completed each with a specific aim related to outcome prediction

after SCI. Each of these projects represents a single chapter within this thesis, with several

supplemental chapters included for purposes of additional description and discussion, as outlined

below:

Specific Aim 1: To perform a comprehensive literature review identifying important clinical

predictors of neurological, functional and complication outcomes. (presented above as Chapter

2)

Specific Aim 2: To develop and internally validate a regression model to predict long-term

functional outcome after SCI based on acute clinical and radiological features (Chapter 4)

Specific Aim 3: To evaluate the radiologic finding of cervical facet dislocation as a predictor of

neurological outcome after SCI (Chapter 5)

Specific Aim 4: To identify the combination of clinical variables that predict acute in-hospital

complications and to develop a model to predict their occurrence (Chapter 6)

Specific Aim 5: To investigate age as a potential effect modifier influencing the relationship

between acute neurological status and long-term functional outcome after SCI. (Chapter 7)

A description of the data sources used (Chapter 3), in addition to a general combined discussion

section (Chapter 8), have been included as separate chapters.

66

3 Chapter 3: Description of Datasets and Approach to Missing Data

67

3.1 Introduction

The analyses included in the ensuing chapters incorporate 2 prospectively accrued multicenter

SCI datasets. Depending on the specific details of the individual analyses, one or a combination

of both these datasets, were utilized. Below is a description of each dataset as well as an outline

of steps taken to combine the data to produce a single harmonized dataset.

3.2 Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) Database

STASCIS was a prospective, multicenter, cohort study investigating the role of surgical timing in

cervical SCI119

. This study involved hospitals at seven institutions throughout North America

during a 7 year enrollment period between August 2002 and September 2009. All of the centers

included in this study were specialized and equipped to manage spinal trauma and acute SCI.

Since this study was primarily concerned with acute surgical intervention, patients arrived at the

study center and were enrolled within 24 hours of injury. At hospital arrival, acute neurological

examination was performed within 72 hours of injury according to the International Standards

for Neurological Classification of SCI (ISNCSCI)49

. The primary outcome point for this study

was 6 months, however data collection continued for up to 1 year for the majority of patients

enrolled. At both 6 month and 1 year follow-up points, ASIA neurological assessment and

functional outcome assessments were performed. In addition, data on acute in-patient

complications was available in this dataset.

3.3 North American Clinical Trials Network for SCI (NACTN) Database

NACTN is a clinical research consortium which consists of 8 North American university

affiliated departments of neurosurgery, each managing a high volume of SCI patients210

. Since

its creation in 2006, one of the principle mandates of NACTN has been to develop and maintain

a large prospective SCI registry to attain an improved understanding of the natural history of

recovery as well as to explore the factors predicting outcome. Similar to the STASCIS dataset,

the NACTN registry contains acute neurological examination data as well as acute imaging

related data. Follow-up neurological and functional outcome data are also available at 6 months

and 1 year after injury. Data on acute in-patient complications was not available in this dataset.

68

3.4 Combined/Harmonized Dataset

In order to maximize the sample size available for specific analyses the NACTN and STASCIS

datasets were combined. This was accomplished by identifying the common data elements

present in both datasets. The specific language used to define these common variables as well as

the coding schemes were modified wherever necessary to ensure harmony between the two

sources. Any data elements that were not common to the two datasets were excluded. With a

total of 426 patients contributed from the STASCIS database and 303 patients contributed by the

NACTN database, the combined harmonized dataset contained data on a total of 729 patients. A

complete list of acute and follow-up data elements included in the dataset can be found in Table

3-1.The combined dataset was used as the basis for analyses presented in Chapter 4 and 7. For

Chapters 5 and 6, only data from STASCIS was used in light of the absence of data fields in the

NACTN dataset pertinent to the study questions posed in those chapters.

69

Table 3-1: Variables included in Combined/Harmonized Dataset. Note, only variables found

in both the STASCIS and NACTN datasets were included in the final combined dataset. (Further information available in Appendix 4)

Panel A: Clinical and Radiological Variables Available from acute Admission

Dataset Gender Age Etiology Energy Admis. ASIA exam

Admis. GCS

MRI IM signal charac.

STASCIS X X X X X X X NACTN X X X X X X X Data present In C/H Dataset (/729)

729

100%

721

99%

714

98%

714

98%

729

100%

711

98%

312

43%

Admis: Admission; ASIA: American Spinal Injury Association; IM: Intramedullary; C/H:

Combined Harmonized; GCS: Glasgow Coma Scale;

Panel B: Treatment related variables

Dataset Steroid

Administration

Surgical

Decompression Surgical

Timing

Surgical

Details

STASCIS X X X X

NACTN X X X X

Data present

In C/H

Dataset (/729)

708

97%

674

92%

674

92%

674

92%

C/H: Combined Harmonized

Panel C: Outcome Variables

Dataset F/u

ASIA exam parameters

(6/12mos)

F/U

FIM

(6/12mos)

STASCIS X X

NACTN X X

Data present

In C/H

Dataset (/729)

458

63%

394

54%

C/H: Combined Harmonized; ASIA: American Spinal Injury Association; FIM: Function

Independence Measure;

70

3.5 Approach to missing data within the combined dataset

Once the combined dataset was created, the percentage of patient data missing for each variable

was quantified throughout. In general the pattern of missing data can be classified in one of three

ways as: missing not at random (MNAR), missing at random (MAR) and missing completely at

random (MCAR)211,212

. Missing not at random implies that the missingness of a given variable

X(1) is related to the specific value of variable X(1). For instance if the baseline neurological

status tends to be missing more frequently in patients with severe baseline injuries (AIS grade A)

this would represent a MNAR for the variable neurological status. Missing at random is the most

common pattern observed and implies that the missingness of a given variable X(1) is not related

to the value of X(1) but to the value of another patient variable X(2). For instance, if the baseline

neurological status tends to be missing more frequently in older patients and in men, this would

represent a MAR situation for the variable neurological status. Finally, in the case of missing

completely at random, missing values are a random sample from the complete population and are

not related to other known or unknown patient variables. Such missingness is rarely encountered

and when it does occur, is typically related to administrative errors where a random portion of a

dataset is deleted or misplaced.

Broadly speaking, there are 2 main approaches to dealing with missing data when considering

model development. The first is complete case analysis, which involves incorporating only

patients with data available for all of the variables of interest213,214

. From both a pragmatic and

methodological perspective, complete case analysis poses two main challenges. The first is that

since a large percentage of patients in most datasets will have at least one variable of interest

missing, this approach becomes very inefficient and often results in a dramatic reduction in the

sample size available for model generation. The second is that this approach may introduce bias

to the model. If the variables included in model have a significant proportion of values missing at

random this leads to biased estimates for model regression coefficients215

. Since MAR is the

most typical pattern of data missingness, and maximizing statistical power through sample size

preservation is a ubiquitous concern, complete case analysis is generally discouraged. The

alternative approach is implementing a statistical procedure to substitute the missing values with

plausible values to preserve sample size and avoid bias. While a variety of techniques have been

71

described for this purpose, each with their own set of strengths and limitations, the most accepted

and statistically robust technique presently available is multiple imputation216-218

.

Throughout a multiple imputations procedure, missing values are approximated estimating the

relationship between the missing and the available data through the generation of an imputation

model219

. This procedure continues in an iterative fashion until the imputation model converges,

generating a final dataset with missing values filled by final estimates. The process is repeated X

number of times generating X imputed versions of the datasets, each with slightly different final

estimates for the missing values. The variability in the estimates of the missing values between

the different imputed versions of the dataset provides an approximate measure of the uncertainty

of the accuracy of the estimated values. The individual imputed versions of the dataset or a

combination of these versions, are then used to generate the model.

In 2 of the ensuing chapters (Chapters 4 and 7) a multiple imputations procedure has been

utilized to estimate missing values amongst the utilized predictor variables to augment the

sample size and protect against bias. In the remaining chapters (5 and 6) a complete case analysis

was performed due to the fact that the proportion of missing data amongst predictor variables in

these analyses was small.

72

4 Chapter 4: A Clinical Prediction Model for Long-Term Functional Outcome after Traumatic Spinal Cord Injury Based on Acute Clinical and Imaging Factors


Wilson JR, Grossman RG, Frankowski RF, Kiss A, Davis AM, Kulkarni AV, Harrop JS,

Aarabi B, Vaccaro A, Tator CH, Dvorak M, Shaffrey CI, Harkema S, Guest JD and

Fehlings MG. A clinical prediction model for long-term functional outcome after

traumatic spinal cord injury based on acute clinical and imaging factors. J Neurotrauma

2012; 29:2263-2271.220

73

4.1 Abstract

To improve clinicians’ ability to predict outcome after spinal cord injury (SCI) and to help

stratify patients within clinical trials, a novel prediction model was created relating acute clinical

and imaging information to functional outcome at one year. Data were obtained from two large

prospective SCI datasets. Functional Independence Measure (FIM) motor score at one year

follow-up was the primary outcome. Functional independence (score ≥6 for each FIM-motor

item) was the secondary outcome. A linear regression model was created with the primary

outcome modeled relative to clinical and imaging predictors obtained within three days of injury.

A logistic model was then created using the dichotomized secondary outcome and the same

predictor variables. Model validation was performed using a bootstrap resampling procedure. Of

729 patients, 376 met the inclusion/exclusion criteria. The mean FIM-motor score at one year

was 62.9(±28.6). Better functional status was predicted by less severe initial ASIA Impairment

Scale grade and by an ASIA Motor Score >50 at admission. In contrast, older age and MRI

signal characteristics consistent with spinal cord edema or hemorrhage predicted worse

functional outcome. The linear model predicting FIM motor score accounted for 52% of variance

in the original dataset and 52%(95%CI:52-53%) across the 200 bootstraps. Functional

independence was achieved by 148 patients(39.4%). For the logistic model, the area under the

curve was 0.93 in the original dataset and 0.92(95%CI:0.92,0.93) across the bootstraps,

indicating excellent predictive discrimination. These models will have important clinical impact

to guide decision making and to help in the counseling of patients and families.

74

4.2 Introduction

Spinal cord injury (SCI) is a devastating and debilitating condition that affects all regions of the

world221

. The preponderance of those affected are young men, sustaining severe cervical injuries,

leading to devastating personal losses and imposing a significant economic burden on society as

a whole9,10,222

. In spite of the immense impact of SCI at a personal and societal level,

comprehensive treatment strategies, aimed at reducing the initial degree of neurologic injury and

improving patients’ functional capacity, are lacking112,223

.

There is a pressing unmet need to accurately predict, early after SCI, patients’ functional

outcome. During the first few days after SCI, definitive management strategies are formulated,

which often include aggressive surgical decompression of the spinal cord. This is also the time of

greatest anguish for an injured patient and their family as they face significant prognostic

uncertainty. From a research perspective, it is difficult to meaningfully analyze the efficacy of

novel interventions, without defining homogenous subgroups.

Unfortunately, physicians and researchers have little to scientifically guide their prediction of

outcome following SCI. The few existing studies often employ variables collected outside of the

initial injury period (greater than three days post SCI) and are therefore less useful as acute

clinical prediction tools156,162

. Further, the existing studies fail to incorporate imaging related

variables, which are known to be an important element of the diagnostic process in the modern

day.

To improve the ability of clinicians to predict long-term outcome in the acute clinical setting and

to aid in the stratification of patients within clinical trials, we aimed to create, and internally

validate, a clinical prediction model that relates clinical and imaging findings to functional

outcome at one year following SCI.

4.3 Methods

4.3.1 Data Source

These analyses are based on individual patient data from the combination of two prospective

datasets: the North American Clinical Trials Network for SCI (NACTN) database and the

75

Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) database. As described in the

previous chapter NACTN is a prospective registry enrolling patients with acute traumatic SCI

from eight North American Centers since 2006. STASCIS was a prospective, multicenter, cohort

study investigating the role of surgical timing in SCI119

. The NACTN and STASCIS datasets

contain similar acute data elements as well as long term functional and neurological outcome

data at 6 and 12 month follow-up points. Patients with severe head injury or poly-trauma,

defined by an inability to participate in a standardized ASIA neurological assessment during

acute admission, were not enrolled in either database. After research ethics board approval at

each participating site was obtained, the datasets were harmonized based on their common data

elements to produce a single database.

For all patients, neurologic examination was performed at patient presentation in concordance

with the recommendations of the International Standards for Neurological Classification of

Spinal Cord Injury by a trained physician, nurse or research assistant224

. Injury characteristics

were then classified according to neurologic level of injury (NLI), American Spinal Injury

Association motor score (AMS), American Spinal Injury Association sensory score (ASS) and

the overall American Spinal Injury Association Impairment Scale (AIS) grade. To identify

neuroanatomical injury characteristics, patients underwent magnetic resonance imaging (MRI) of

the spine shortly after hospital presentation. All patients received appropriate medical support

which included permissive or induced hypertensive therapy (mean BP > 85 mm Hg) in

accordance with the most recent consensus guidelines95

. Methylprednisolone was used at the

discretion of the treating team, according to the recommendations of the second National Acute

Spinal Cord Injury Study (NASCIS II) and based on established guidelines105,108

. Decisions

surrounding surgery, including the timing of decompression, were made by the attending spine

surgeon in each case. Whenever possible, patients with radiological evidence of spinal cord

compression underwent decompressive surgery within 24 hours post SCI. All patients underwent

an individualized rehabilitation protocol, tailored to specific needs and injury characteristics.

Using the combined dataset, the cohort of interest was defined to include patients 16 years of age

and older, presenting to an acute care facility with traumatic SCI and neurological deficit (AIS

grade A-D). Only patients with a documented ASIA neurological examination performed within

three days of injury were included. This criterion was included to ensure that only acute

variables were used as predictors in the development of the prediction model.

76

4.3.2 Predictor Variables

Clinical and radiological predictors were chosen based on three main criteria: 1) author

consensus of predictive importance of given variable; 2) literature support for the predictive

importance of given variable; and 3) the ease with which the given variable could be collected,

interpreted and recorded within the day to day acute injury setting. Based on these criteria, four

variables were selected to form the basis of model construction: 1) acute ASIA Impairment

Severity grade, 2) acute ASIA motor score (dichotomized at a score of 50), 3) patient age at

injury, and 4) intra-medullary signal characteristics on the spinal MRI(Table 4-1). All four of

these predictors have demonstrated predictive significance in relation to long-term functional

outcome after SCI132,150,151,158,159,164,185,190,194,225

. The two examination-related predictor variables,

AIS grade and AMS, were assessed and recorded within three days of injury for all patients. If an

individual patient underwent more than one neurological examination within the first three days,

we utilized the first examination that took place at acute hospital admission. Spinal MRI was also

performed within three days of injury and read by a site specific neuro-radiologist. With respect

to MR image acquisition, a two-dimensional spin echo sequence used for acquiring the T1

images and a two-dimensional fast-recovery fast spin-echo sequence used for acquiring the T2

images. Age was not categorized but rather its full variability was preserved in the form of a

continuous predictor as is the recommended practice211,212

.

77

Table 4-1: Pre-specified Predictor Variables utilized in the development of prediction

models

Predictor Coding

Initial ASIA Impairment

Scale (AIS) Grade

AIS grade A=1

no motor or sensory function is preserved in the

sacral segments

AIS grade B=2

sensory but no motor function is preserved below

the neurological level and includes the sacral

segments

AIS grade C=3

motor function is preserved below the neurological

level, and more than half of key muscles below this

level have a muscle grade less than 3

AIS grade D=4

motor function is preserved below the neurological

level, and more than half of key muscles below this

level have a muscle grade of 3 or more

Initial ASIA Motor Score

(AMS)

AMS ≤ 50 = 0

AMS > 50 = 1

Age Continuous predictor

Spinal MRI Intra-

medullary Signal

Characteristics

No Signal=0

Signal consistent with spinal cord edema=1

Signal consistent with spinal cord hemorrhage= 2

4.3.3 Outcome and Follow-up

The primary outcome variable was FIM motor score at one year post injury(Table 4-2). The FIM

motor score consists of 13 items which assess functioning across four different domains that

include self-care, sphincter control, transfers and locomotion. The performance level for each

item is strictly defined and ranges in value from one to seven, where one indicates complete

dependence in an activity and a score of six or greater indicates that a patient is capable of

performing that activity independently, without supervision or help. The result is an ordinal

outcome variable with a minimum value of 13 and a maximum value of 91, with a larger value

implying superior functional outcome. This outcome measure has been shown valid and reliable

for use in the setting of SCI78,226

. If outcome assessment was not available at one year, six month

FIM motor score was used. Given that the majority of functional recovery occurs in the first six

78

months after injury, this practice is considered valid and has been used in previous studies156,227

.

As a secondary outcome variable, the primary outcome was dichotomized and all of the patients

who achieved a score of at least six for all of the FIM motor score items were identified. These

patients were considered to have achieved functional independence across the 13 items assessed,

as has been the practice in previous stroke related research228

.

Table 4-2: Functional Independence Measure (FIM) motor score utilized as primary

outcome of interest. All patients who achieved a score of 6 or greater for each of these 13 items

were classified as having achieved “functional independence”.

Functional Domain Individual Items

1. Self-Care A. Eating /7

B. Grooming /7

C. Bathing /7

D. Dressing-Upper Body /7

E. Dressing-Lower Body /7

F. Toileting /7

2. Sphincter Control G. Bladder Management /7

H. Bowel Management /7

3. Transfers I. Bed, Chair, Wheelchair /7

J. Toilet /7

K. Tub, Shower /7

4. Locomotion L. Walk/Wheelchair /7

M. Stair /7

Total Score /91

79

4.3.4 Statistical methods

4.3.4.1 Model Creation

All analyses were performed using SAS version 9.3 (Cary, NC, USA) and R statistical software

version 2.14.1. Multi-collinearity was assessed through multivariate linear regression variable

tolerance testing, with a variable tolerance threshold set at 0.4. All missing data amongst the

predictors was assumed to be missing at random and a multiple imputations procedure with ten

imputation iterations was performed using Markov chain Monte Carlo methods to account for

this missing data. This resulted in an augmented dataset, containing ten-times the original sample

size, all with complete data. Such imputation is recommended as being less susceptible to bias

and more efficient than performing a complete case analysis by dropping cases with incomplete

variables211,217

. Of note, this is the preferred method, suggested by the Food and Drug

Administration, for handling missing data in therapeutic trials229

. Using the imputed dataset, with

follow-up FIM motor score as the dependent variable and initial AIS grade, dichotomized AMS,

age and intra-medullary MRI signal characteristics as the pre-specified four covariates, a linear

regression model was generated for each of the ten imputation iterations. A multiple imputation

analysis procedure was then employed, which combines the results of the analyses for each of

the imputation iterations to provide a single set of parameter estimates. R-squared values from

each of the imputation iterations were averaged to quantify the overall model performance.

A binary logistic regression model was created with the dependent variable of functional

independence modeled relative to the same four predictor variables. The model was tested

through the construction of receiver operator characteristic (ROC) curves, for each of the

imputation iterations. The area under the curve (AUC) is a summary measure of the

discriminative ability of the model, with values between 0.90 and 1.00 indicative of excellent

predictive discrimination. AUC values from each of the imputation iterations were averaged to

create a single value quantifying model discrimination.

Model Validation

Internal validation of the linear and logistic prediction models was performed using a bootstrap

re-sampling procedure of the imputed dataset using 200 individual bootstrap replicates (each

with n=376). A “bootstrap” is a group of subjects selected through random sampling with

80

replacement from the original dataset230

. The sampling is continued within each bootstrap

replicate until it contains a number of subjects equal to the total number of subjects in the

original dataset. Once the 200 bootstraps were generated, the pre-specified linear and logistic

models were fitted to each, and a 95% confidence interval was generated about the mean of the

200 replicate parameters estimate values for each covariate. The mean R-squared and AUC

values across the bootstrap replicates were also generated and were assumed to be an unbiased

estimate of the true values.

Finally, the regression coefficients obtained from the internally validated linear and logistic

models were used to estimate FIM motor score and the probability of achieving functional

independence at one year follow-up for hypothetical SCI patients based on their unique clinical

and radiological characteristics at hospital admission.

4.4 Results

4.4.1 Study Population

Prospective data from the NACTN and STASCIS protocols were combined to produce a single

harmonized dataset of 729 patients. From this original cohort, 33 patients did not have a

neurological assessment performed within the first three days after injury and were excluded.

Demographic, injury and imaging characteristics for the remaining 696 patients are listed in

Table 4-3.

81

Table 4-3: Patient Characteristics at hospital admission

Characteristic Patients meeting

Inclusion/Exclusion

criteria

N=696

Cohort

without

adequate

Follow-up

N=320

Cohort with

adequate

follow-up

used in final

analysis

N=376

p-value*

Mean age 44.5 (±17.3) 46·1(±17.5) 43·2 (±16.9) p=0.03

Male gender 531 (76.3%) 237(74.1%) 294(78.2%) p>0.05

Initial ASIA Impairment

Scale Grade:

AIS grade A

AIS grade B

AIS grade C

AIS grade D

258(37.1%)

115(16.5%)

119(17.1%)

204(29.3%)

122(38.1%)

52(16.3%)

61(19.1%)

85(26.6%)

136(36.2%)

63(16.8%)

58(15.4%)

119(31.7%)

p>0.05

Initial ASIA Motor Score

>50:

217(31.2%) 93(29.3%) 124(32.9%)

p>0.05

Neurological Level:

Cervical

Thoracic/Lumbar

633 (90.9)

63 (9.1%)

286(89.4%)

34(10.6%)

347(92.3%)

29(7.7%)

p>0.05

MRI Intra-medullary

signal characteristics:

No signal change

Consistent with edema

Consistent with hemor.

43(14.8%)

149(51.6%)

97(33.6%)

19(15.1%)

65(51·6%)

42(33·3%)

24(14.7%)

84(51·5%)

55(33·7%)

p>0.05

Etiology:

Motor Vehicle Accident

Fall

Sport or Diving Accident

Other

283(40.7%)

247(35.5%)

70(10.1%)

96(13.8%)

137(42.8%)

115(35.9%)

24(7.5%)

44(13.8%)

146(38.8%)

132(35.1%)

46(12.2%)

52(13.8%)

p>0.05

Received Steroids 410(60.7%) 183(59.0%) 227(62.1%) p>0.05

Mean time to

decompressive surgery post

injury (hours)

75.3 (±429.4) 74.5(±429.4) 76.1(±338.9) p>0.05

*Comparing difference between group with and without follow-up

82

Figure 4-1: Flow chart of the study design

.

83

4.4.2 Functional Outcomes

FIM motor score evaluations were available in 310 patients at one year and in 66 patients at six

months, leaving a total of 376 patients on which to base the analysis (Figure 4-1). There were no

significant differences in initial AIS grade, AMS or MRI intra-medullary signal characteristics

between patients included and those excluded due to inadequate follow-up (p>0.05) (Table 4-3).

Of the patients included in the analysis, 227(62.1%) received steroids and 358 (96.5%)

underwent decompressive surgery. There were no significant differences in the proportion of

steroid administration or in the mean time to surgery between patients included and those

excluded due to inadequate follow-up (p>0.05) (Table 4-3). The mean FIM motor score at

follow-up was 62.9(±28.6) with incrementally higher mean scores seen with a progressively less

severe acute admission AIS grade (Table 4-4). One-hundred and forty eight patients (39.4%)

achieved functional independence (a score of at least six on all of the FIM motor score items),

while 228 patients (60.6%) failed to achieve this milestone.

Table 4-4: Mean Follow-up FIM motor score by baseline characteristics

Characteristic Follow-up FIM motor

score

p-value*

Initial ASIA Impairment Scale

Grade:

AIS grade A

AIS grade B

AIS grade C

AIS grade D

41·5

55·7

71·6

87·2

P<0·01

Level:

AMS≤50

AMS>50

51·0

87·7

P<0·01

MRI Intra-medullary signal

characteristics:

No signal change

Consistent with edema

Consistent with hemorrhage

83·3

71·8

49·4

P<0·01

*p-value denotes significance level for the difference in FIM motor score between the different

levels of each predictor

84

4.4.3 Model Development and Validation

Predictor variable parameter estimates, significance values and bootstrapped estimates are found

in Table 4-5, Panel A for the linear model and Panel B for the logistic model. For both models,

the mean parameter estimate values for each covariate across the 200 bootstrap replicates closely

approximated the estimates from the original dataset. Furthermore the 95% confidence intervals

around these mean values are narrow and contain the parameter estimates generated from the

original dataset. For the linear model, performance, judged by the R-squared values averaged

across each of the ten imputation iterations, was 0.52 (min 0.51, max 0.54). The mean R-squared

value across the bootstrap replicates was 0.52 (95% CI: 0.52, 0.53), which is identical to the

model performance in the original dataset. For the logistic model based on the dichotomized

outcome variable, the AUC value averaged across the ten imputation iterations was 0.93 (min

0.91, max 0.93), indicating excellent model predictive discrimination. The mean AUC value

across the bootstrap replicates was 0.92 (95% CI: 0.92, 0.93). Figure 4-2 represents the

internally validated prediction model equations.

Table 4-5: Parameter Estimates for Models predicting a) FIM motor score and b)

Functional Independence, at 1 year follow-up from original sample and bootstrap

replicates

Panel A)

Prognostic

Variable

Parameter

Estimate

P-Value Bootstrap

Parameter Estimate

(95% CI)

Intercept 50.28 <0.01 49.73(49.0,50.5)

Age -0.33 <0.01 -0.33(-0.34,-0.32)

Admission AMS

>50

9.17 <0.01 9.11(8.61,9.61)

Admission AIS

grade

12.47 <0.01 12.54(12.34,12.76)

MRI signal -4.83 0.19 -4.65(-4.91,-4.40)

85

Panel B)

Prognostic

Variable

Parameter

Estimate

Odds Ratio P-Value Bootstrap

Parameter

Estimate (95% CI)

Intercept -2.93 - <0.01 -2.99(-3.11,-2.87)

Age -0.03 0.97 <0.01 -0.03(-0.03,-0.03)

Admission

AMS >50

1.35 3.86 <0.01 1.34(1.27,1.41)

Admission AIS

grade

1.36 3.90 <0.01 1.39(1.27,1.41)

MRI signal -0.29 0.75 0.54 -0.30(-0.34,-0.25)

Lastly, using the regression coefficients from the internally validated models, we estimated the

FIM motor score and the probability of achieving functional independence at one year follow-up

for a variety of hypothetical SCI patient scenarios (Table 4-6).

4.5 Discussion

The current analysis has led to the production of the first prediction models using acute clinical

and radiological data, obtained within the first three days after injury, to predict long term

functional outcome after traumatic spinal cord injury. Four pre-specified predictor variables,

ASIA impairment severity grade, dichotomized ASIA motor score, age and MRI intra-medullary

signal characteristics, were modeled relative to Functional Independence Measure motor score

for a large prospective cohort of SCI patients. The results of this modeling indicate that better

functional status is predicted by a sequentially less severe initial AIS grade and an AMS greater

than 50 at hospital admission. In contrast worse functional outcomes are predicted by older age

and by MRI intra-medullary signal characteristics consistent with spinal cord edema or

hemorrhage. The parameter estimates generated for these predictors were validated using a

bootstrap re-sampling procedure of observations from the original dataset. This research has

generated a simple equation that can be used to estimate long-term functional outcome by

substituting the applicable variables into the equation for each patient at acute hospital

admission. Next, by dichotomizing the primary outcome measure and generating a secondary

86

logistic model, the same four predictor variables demonstrated an excellent ability to

discriminate an individual who will achieve functional independence, from one who will not

achieve this threshold.

Figure 4-2: Predictive Model Equations

87

Table 4-6: Predicted Estimates for Hypothetical Patients

Characteristic Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6

Age 75 75 55 55 25 25

AIS A YES NO YES NO NO NO

AIS B NO NO NO NO NO YES

AIS C NO NO NO NO YES NO

AIS D NO YES NO YES NO NO

AMS >50 NO YES NO YES YES NO

MRI hemor. YES NO YES NO NO NO

MRI edema NO NO NO NO YES YES

Predicted

FIM-motor

28 85 44 91 84 62

Prob. of

Functional

Independence

0.01 0.83 0.08 0.90 0.72 0.22

As described in chapter 2, a number of studies have investigated the predictive significance of

individual clinical, radiological and demographic factors in relation to long-term functional

outcome after traumatic SCI74,130,141,149,150,152,153,163

. However, in the real world setting, clinicians

do not consider individual diagnostic elements in isolation, but rather synthesize treatment plans

and make outcome predictions by considering and weighing all pieces of information

simultaneously. Further, by employing statistical analyses which consider only one variable in

relation to outcome, it is impossible to discern, in quantitative terms, what the independent

effects of that variable are on outcome without adjusting for additional covariates known to be of

predictive importance. As a result, multivariable techniques are the preferred method for

investigating and modeling the impact of specific variables on long-term health-related

outcomes. To date, as described earlier in this thesis, a paucity of studies have assessed the

significance of combining individual parameters to improve functional outcome predictions after

SCI. Using clinical exam and electrophysiological parameters obtained from the subacute period

in 90 patients with incomplete SCI (79% traumatic, 21% non-traumatic), Zoerner et al produced

88

an algorithm to predict ambulatory capacity six months follow-up162

. In a more recent study from

Van Middendorp and colleagues, the European Multicenter SCI dataset was used to generate a

clinical prediction rule forecasting future ambulatory capacity using a combination of age, motor

scores from the quadriceps and soleus muscles and light touch sensations in the L3 and S1

dermatomes as predictor variables156

. However, it is noteworthy that the vast majority of

examinations used to construct this model took place after the acute 3 day time window, up to 15

days post SCI.

The studies described above have established the feasibility and potential benefits of using a

combination of variables to obtain more accurate estimates surrounding long-term functional

outcome after SCI. However, several factors limit the potential utility of existing models as

clinical prediction tools for use in the acute clinical setting. All of the existing studies employing

a combination of variables have relied largely on measurements obtained outside the critical first

three days after the injury: the period during which the majority of acute therapeutic decisions

are made and a time during which there is significant demand for the delivery of accurate

prognostic information. The existing literature suggests that during this acute injury window, a

variety of distracting patient and injury related factors, which are not germane during the sub-

acute period, can impede the process of obtaining an accurate neurologic exam148,209

. Previous

prediction rules were conceived without considering the presence of such distracting features and

as result they have incorporated predictors, such as electrophysiology and precise motor/sensory

examinations, which may be impractical or cumbersome for collection during the acute injury

window. Given our reliance on acute care data obtained exclusively within three days of injury

for all patients, the current predictive model can be used at the time of admission by acute care

practitioners to predict long-term functional status. The effects of inaccuracies surrounding the

acute neurological assessment of SCI patients were mitigated in the current prediction model in

two key ways. Firstly, we chose to use AIS grade and dichotomized AMS (above or below a

score of 50) as the main neurological exam predictor variables. Intuitively, these variables are

more easily obtained and categorized in the acute care period as compared to other neurological

parameters, such as specific AMS or ASS values. Secondly, as additional predictors, we included

age and MRI intramedullary signal characteristics which are objectively assessable regardless of

patients’ clinical status and are impervious to the same acute care biases that can affect

examination accuracy.

89

Previous prediction models and analyses exploring the predictors of future functional status have

predominately considered walking as the primary measure of long-term outcome151,152,156,164

.

While ambulatory capacity is of interest, in accordance with the findings of a large survey which

explored the main underpinnings of quality of life in SCI patients, it is also important to study

items such as arm and hand function as well as bowel/bladder and sexual function, in addition to

ambulation 71

. Moreover, only a small fraction of patients recover ambulatory capacity after SCI,

with a maximum of 5% of patients with complete SCI becoming ambulatory at one year,

irrespective of the initial neurological level of injury134,135

. This information reinforces the fact

that ambulation is an unrealistic endpoint for a large proportion of injured patients and

underscores the importance incorporating outcome tools that include multi-dimensional

assessments of functional outcome. In the current study we utilized the FIM motor score which,

in addition to mobility status, assesses items related to self-care, sphincter control and transfers,

areas of functioning that have great relevance to the majority of SCI patients on a daily basis.

One potential drawback of utilizing this outcome measure is its lack of interpretability. We know

that FIM motor values range from 13 (completely dependent) to 91(functionally independent)

and that lower values are associated with poorer functional status and higher values are

associated with better functional outcome. Previous studies have also demonstrated that higher

scores reflect fewer nursing care hours after patient discharge from rehabilitation231

. However,

for a given patient with a specific predicted value, it is difficult to precisely articulate exact

functional expectations within each of the four outcome domains based on the cumulative score.

We have attempted to mitigate this concern by producing a second model which predicts

functional independence: a more interpretable recovery threshold based on dichotomized FIM

motor score.

4.5.1 Study Limitations

While applying the pre-specified models to the bootstrap replicates confirms their validity within

our own dataset, establishing true external validity of this predictive model will require an

evaluation of its performance within a separate group of SCI patients. Before such an evaluation

takes place, the generalizablity of this model, as well as its suitability for use in the clinical

realm, remains unknown. Related to this, it is acknowledged that the majority of patients

included had a cervical neurological level, with a relatively low proportion of patients with

thoracic or lumbar SCI. As a result, these findings will need to be validated in datasets

90

containing a greater proportion of thoracic and lumbar SCI patients. We also recognize that a

large number of patients failed to be included in the analysis due to inadequate follow-up.

However, we have demonstrated that, with the exception of age, no significant differences

existed in the baseline characteristics between those included in the analysis and those excluded

due to inadequate follow-up. The difference in age (46.1 in patients with missing follow-up and

43.2 in patients with follow-up), although statistically significant, is not significant from a

clinical standpoint. We also recognize that treatment related factors not included in our model,

such as time to decompressive surgery or steroid administration, may have influenced patient

outcomes in this study. However this model was intended to incorporate only non-treatment

predictors related to the natural history of recovery for SCI patients. Lastly, while a standardized

MRI protocol was used for the acute evaluation of patients within this study, we acknowledge

the existence of other MR sequences, such as gradient echo, that may have provided a more

sensitive measure of intramedullary hemorrhage.

4.6 Conclusion

In this study, the first prediction models for functional outcome at one year, based on ASIA

Impairment Scale grade, dichotomized ASIA motor score, age and MRI intra-medullary signal

characteristics, with all predictor variables obtained within the first three days after injury for all

patients, have been created and internally validated. After establishing the performance of this

model within a separate cohort of patients, we look forward to its implementation as a predictive

tool in the realm of acute clinical care as well as a stratification tool in future clinical trials to

help produce balanced treatment groups. As additional future steps, we also look forward to

investigating the predictive capacity of different imaging modalities and MR imaging sequences,

as well as to producing models specifically focused on predicting outcome for important SCI

patient subgroups, such as those with incomplete injuries or central cord syndrome.

91

5 Chapter 5: The Impact of Facet Dislocation on Neurological Outcome after Cervical Spinal Cord Injury


Wilson JR, Vaccaro A, Harrop JS, Aarabi B, Shaffrey C, Dvorak M, Fisher C, Arnold P,

Massicotte EM, Lewis S, Rampersaud R, Okonkwo DO and Fehlings MG. The Impact of

Facet Dislocation on Clinical Outcomes after Cervical Spinal Cord Injury: Results of a

Multicenter North American Prospective Cohort Study. Spine (Phila Pa 1976)

2013;38:97-103 .232

92

5.1 Abstract

Reports of dramatic neurological improvement in patients with facet dislocation (FD) and

cervical spinal cord injury (SCI), treated with rapid reduction, have led to the hypothesis that this

represents a subgroup of SCI patients with significant potential for recovery. However, in the

absence of a large systematic analysis, evaluating outcomes in patients with FD and SCI as

compared to SCI patients without FD, this hypothesis remains untested. In the context of the

Surgical Timing in Acute Spinal Cord Injury Study (STASCIS), a multicenter prospective cohort

study, to define differences in baseline characteristics and neurological outcomes between

cervical spinal cord injury (SCI) patients with and without facet dislocation (FD), was

undertaken. Patients were classified into FD and non-FD groups depending on the results of

imaging investigations performed at admission and then followed prospectively over time. The

primary outcome measure was the change in ASIA motor score (AMS) at 1 year follow-up.

Secondary outcome measures included ASIA Impairment Scale (AIS) grade conversion as well

as length of acute hospital stay. Of 421 patients enrolled, 135(32.1%) had a FD and 286(67.9%)

had no FD. Patients in the FD group had significantly worse presenting AIS grade as compared

to those in the non-FD group (p<0.01). Forty of the 48 FD patients who were placed in traction,

successfully achieved closed reduction. There were no differences in baseline gender or age

between the 2 groups (P>0.05). Patients in the FD group more frequently experienced higher

energy injury mechanisms as compared to those in the non-FD group(p<0.01). The mean length

of acute hospital stay was 41.2 days amongst patients with FD and 30.0 amongst patients without

FD (p=0.04). At 1-year follow-up, FD patients experienced a mean AMS improvement of 18.0

points, whereas non-FD patients experienced a significantly larger improvement of 27.9

points(p<0.01). After adjusting for baseline neurological status using linear regression, patients

with FD continued to demonstrate a smaller degree of AMS recovery as compared to the non-FD

patients(p=0.04). Overall, as compared to those without FD, cervical SCI patients with FD

tended to present with a more severe degree of initial injury and displayed less potential for

motor recovery at one year follow-up.

93

5.2 Introduction

Cervical facet dislocation (FD) is an important and prevalent cause of cervical spinal cord injury

(SCI)233-236

. FD typically occurs as a result of a hyper-flexion injury to the neck, causing one, or

both, of the inferior facets of the upper dislocating vertebrae to slide over, and anteriorly to, the

superior facet(s) of the lower dislocating vertebrae237,238

. The final result is a narrowing of the

spinal canal that can lead to spinal cord compression and neurologic injury. While FD is

relatively rare amongst patients with cervical spine trauma in general, accounting for about 5-

10% of all cases seen, the consequences of these injuries are often devastating239

. Approximately

37% of unilateral FD patients, and upwards of 90% of patients with bilateral FD, are diagnosed

with SCI at presentation to hospital240,241

.

In spite of the high incidence of SCI seen with cervical FD, there are reports in the literature of

dramatic neurological recovery with rapid realignment of the spinal column and decompression

of the spinal cord242-247

. Contradicting these findings is the general clinical observation that FDs

are typically associated with high energy biomechanical forces causing significant tissue

disruption and a severe degree of primary neurologic injury248

. In the setting of such a severe

primary SCI, potential for significant neurologic recovery, even with rapid reduction, would

ostensibly be limited. However, in the absence of a large longitudinal analysis, the profile of

recovery for patients with FD and cervical SCI as compared to cervical SCI patients without FD,

remains largely unknown.

In the literature review presented in chapter 2 of this thesis, a paucity of CT or X-ray based

imaging findings were found to be predictive of long-term outcome. However FD, which is most

commonly diagnosed by these imaging modalities, has yet to be investigated for its potential

value in predicting outcome post cervical SCI.

To obtain an improved understanding of the natural history of patients with FD and SCI we have

completed a prospective cohort study comparing baseline characteristics and long-term

neurological outcomes between SCI patients with and without FD.

94

5.3 Methods

5.3.1 Patient Population

Within the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) a multicenter

prospective cohort study comparing baseline characteristics and long-term outcomes between

patients with and without FD was undertaken. During the 7 year study period between 2002 and

2009 patients were enrolled at 7 institutions throughout North America: 1) University of

Toronto, Toronto, Ontario, Canada; 2) Thomas Jefferson University, Philadelphia, PN, USA; 3)

University of Virginia, Charlottesville, VA, USA; 4) University of Maryland, Baltimore, MD,

USA; 5) University of British Columbia, Vancouver, British Columbia, Canada; 6) University of

Kansas, Kansas City, KS, USA; 7) University of Pittsburgh, Pittsburgh, PA, USA. During the

study period, any patient presenting to one of the participating centers, with traumatic cervical

SCI and radiologic evidence of spinal cord compression, was enrolled. Patients younger than 16

years of age and those with penetrating injuries were excluded. A standardized neurological

examination, performed in accordance with the International Standards for the Neurological

Classification of Spinal Cord Injury, was completed within 72 hours of injury224

. Also at

admission, demographic and injury related variables such as age, gender, mechanism of injury,

injury severity score (ISS) and Glasgow Coma Scale Score (GCS), were also collected. Motor

vehicle accidents were considered high energy injury etiologies, whereas falls from standing,

diving accidents or injuries resulting from blunt violence, were considered low energy etiologies.

At presentation, all patients underwent a cervical X-Ray and/or a CT scan. If unilateral or

bilateral FD was diagnosed, patients underwent either closed reduction, through application of

skeletal traction, or open reduction. If a trial of traction failed, with failure defined as a new or

worsening neurological deficit, medical instability, radiologic evidence of over distraction or

patient/equipment unable to tolerate additional weight, the treating team proceeded with open

reduction on an emergent basis. After a successful trial of closed reduction, a cervical magnetic

resonance imaging (MRI) study was obtained in the majority of cases, to document the degree of

decompression of the spinal cord achieved. If the post reduction MRI demonstrated incomplete

decompression of the spinal cord, then the patient underwent open reduction. Cervical SCI

patients without evidence of FD on initial X-Ray or CT underwent a cervical MRI, to document

the degree of spinal cord compression, followed by surgical decompression. Radiological

95

evidence of spinal cord compression was defined by the method previously described by the

Fehlings group208

. Decision of surgical timing was dependent on patients’ pre-hospital transport

time, the time to obtain diagnostic imaging, the time required for medical stabilization and the

discretion of the attending spinal surgeon.

All patients received standardized acute medical therapy which included permissive or induced

hypertensive therapy (mean BP > 85 mm Hg)95

. Acute administration of intravenous

methylprednisolone sodium succinate was permitted for use at the discretion of the treating team,

according to the recommendations of the second National Acute Spinal Cord Injury Study

(NASCIS-2) and based on established guidelines105,108

. All technical decisions surrounding

surgery were made by the attending spine surgeon in each case. Finally, all patients underwent a

customized course of inpatient spinal cord rehabilitation after acute care discharge.

5.3.2 Outcome Variables

Based on the presence or absence of FD on admission imaging, patients were divided into a FD

cohort and a non-FD cohort and followed prospectively over time. The primary outcome of

interest was the change in ASIA motor score (AMS) at 1 year follow-up, obtained by subtracting

the baseline AMS, obtained at acute hospital admission, from the AMS at 1 year follow-up, for

each patient. Change in ASIA Impairment Scale (AIS) grade was considered as a secondary

neurologic outcome measure. Finally, acute hospital length of stay was compared between the

FD and non-FD groups.

As a secondary analysis baseline characteristics, as well as clinical outcomes, were compared

between patients with bilateral FD and those with unilateral FD.

5.3.3 Statistical Analysis

All analyses were carried out using SAS version 9.2 (Cary, NC, USA). Descriptive statistics

were used to characterize patient demographics and injury characteristics at hospital admission.

Continuous outcome measures were compared between the cohorts using the Student’s t-test and

categorical outcomes were compared using the chi-squared or Fisher’s exact test. An adjusted

analysis was also completed, to account for the effects of confounding variables, using linear

regression. For this analysis the outcome variable was defined as the change in AMS from pre-op

to 1 year follow-up, while the predictor variable of interest was defined as the presence or

96

absence of a FD. Within this regression equation we also included admission AIS grade as a

predictor variable, thereby adjusting for the impact of initial injury severity, the variable known

to have the strongest impact on long-term motor recovery as discussed in Chapter 2.

Table 5-1: Baseline Patient Characteristics

Panel A: Facet Dislocation Cohort vs. Non Facet Dislocation Cohort

Characteristic Overall

(n=421)

FD (n=135) Non-FD

(n=286)

p-value

Presenting AIS

grade:

AIS grade A

AIS grade B

AIS grade C

AIS grade D

149(35.6%)

70(16.6%)

86(20.4%)

116(27.6)

69(51.1%)

18(13.3%)

18(13.3%)

30(22.2%)

80(28.0%)

52(18.2%)

68(23.8%)

86(30.1%)

P<0.01

Mean AMS 37.5(±31.2) 38.5(±34.8) 35.5(±31.3) P=0.37

Male gender 315(74.8%) 97(71.9%) 218(76.2%) p=0.53

Mean Age 48.2(±17.0) 46.4(±15.9) 49.0(±17.5) P=0.15

Mean Injury

Severity Score

12.4(±10.5) 12.8(±9.4) 12.2(±11.0) P=0.70

High energy 212(51.1%) 81(60.5%) 131(46.6%) P<0.01

Mean GCS 13.8(±3.4) 13.7(±3.5) 13.8(±3.3) P=0.70

Panel B: Unilateral Facet Dislocation patients vs. Bilateral Facet Dislocation patients

Characteristic Uni-FD=42 Bilat-FD=93 p-value

Presenting AIS

grade:

AIS grade A

AIS grade B

AIS grade C

AIS grade D

14(33.3%)

6(14.3%)

3(7.1%)

19(45.2%)

55(59.1%)

12(12.9%)

15(16.1%)

11(11.8%)

P<0.01

Mean AMS 51.6(±37.4) 28.1(±24.9) P<0.01

Mean age 45.7(±14.9) 46.8(±16.5) P=0.70

Male gender 28(66.7%) 69(74.2%) P=0.37

High Energy 24(58.5%) 57(61.3%) P=0.76

Mean Injury

Severity Score

11.7(±8.7%) 13.4(±9.8) P=0.51

Mean GCS 13.9(±3.0) 13.6(±3.6) P=0.64

97

5.4 Results


A total of 421 cervical SCI patients were enrolled during the study period, of which 135(32.1%)

had a FD and 286(67.9%) had no FD. Baseline characteristics of the FD and non-FD groups are

presented in Table 5-1, panel A. Patients in the FD group had a significantly worse presenting

AIS grade and higher energy injury mechanisms as compared to those in the non-FD

group(p<0.01). Of the 135 patients with FD, 42 patients (31.1%) had a unilateral FD and 93

patients (68.9%) had bilateral FD (Table 5-1, panel B). The neurological status on admission was

significantly different between the unilateral and bilateral FD groups, with AIS grade A injuries

most common amongst bilateral FD patients and AIS grade D injuries more common amongst

the unilateral FD patients. In addition, the mean AMS at admission was significantly higher

amongst patients with unilateral FD (50.4±37.1) as compared to patients with bilateral FD

(28.1±24.9). The vertebral level of injury for both unilateral and bilateral FD patients is

presented in Figure 5-1.

Figure 5-1: Number of Facet Dislocations per disc space level

98

5.4.2 Treatment

Of the 135 patients with FD, 48(35.6%) initially underwent skeletal traction and 87(64.4%)

initially underwent open reduction (Figure 5-2). Forty (83.3%) of the patients, who initially

received traction, were successfully reduced, while the remaining 8 patients (16.7%) failed, and

underwent surgical spinal cord decompression. There were no neurological complications during

the application of traction. The mean time to decompression in the FD group was 25.1(±34.8)

hours and 41.3(±44.6) hours in the non FD-group (p<0.01). Amongst FD patients, the mean time

to spinal cord decompression in the group initially treated with traction was 11.5(±10.0) hours

and 32.2(±40.7) hours amongst those who initially underwent open reduction (p<0.01). There

was no difference in the proportion of patients that received steroids between the FD and non-FD

groups (p=0.57).

Figure 5-2: Treatment Flow for patients with Facet Dislocation

99

5.4.3 Outcome

At 1 year post injury, follow-up neurological outcome data was available for 211 patients: 67 FD

patients (21 unilateral and 46 bilateral) and 144 non-FD patients. There were no differences in

the baseline characteristics of those with 1 year follow-up as compared to those without 1-year

follow-up (p>0.05 for all characteristics). Table 5-2 provides a comparison in outcomes between

the FD and non-FD group. Patients in the non-FD group had significantly larger improvement in

AMS at follow-up (p<0.01). There was a significant difference in the mean length of acute

hospital stay, with FD patients staying on average 41.2 days as compared to 30.0 days in the non-

FD group (p=0.04). Table 5-3 compares outcomes between unilateral and bilateral FD patients.

While there was a trend towards a shorter length of stay amongst unilateral FD patients, this

difference failed to achieve statistical significance.

Table 5-2: Clinical Outcomes at 1 year Follow-up, FD vs. Non-FD Cohort

Outcome Overall

(n=211)

FD

(n=67)

Non-FD

(n=144)

P-value

Change in AMS at 1

year F/U

24.6(±25.4) 18.0(±21.4) 27.9(±25.1) P<0.01

AIS grade

improvement

≥1grades

≥2grades

122(57.8%)

35(16.6%)

39(58.2%)

11(16.4%)

83(57.4)

24(16.7%)

P=0.93

P=0.96

Acute Length of Stay* 33.6(±53.4) 41.2(±75.2) 30.0(±38.5) P=0.04

*Based on the duration of stay of 421 patients during acute hospital admission

100

Table 5-3: Clinical Outcomes at Follow-up, Unilateral FD vs. Bilateral FD patients

Outcome FD-uni

(N=21)

FD-bi

(N=46)

p-value

Change in AMS at 1-

year F/U

18.8(±20.1) 19.2(±22.5) P=0.95

AIS grade

improvement

≥1grades

≥2grades

13(61.9%)

5(23.8%)

26(56.5%)

6(13.0%)

P=0.68

P=0.27

Acute Length of Stay* 23.9(±41.1) 49.7(±87.4) P=0.07

*Based on the duration of stay of 135 patients during acute hospital admission

For the multivariable analysis, with change in AMS at one year follow-up as the outcome

variable, FD (the predictor of interest) and admission AIS grade appeared as predictor variables

in the final regression equation. Parameter estimates and their corresponding p-values are found

in table 5-4. After adjusting for admission AIS grade, the presence of FD remained a significant

negative predictor of motor recovery at 1-year follow-up (p=0.04).

Table 5-4: Results of Multivariable Analysis (Outcome variable: Change in ASIA motor score

at 1-year follow-up)

Predictor Parameter Estimate p-value

FD vs. Non-FD -6.6 P=0.04

Admission AIS grade:

AIS grade A

AIS grade B

AIS grade C

AIS grade D (ref)

-0.5

23.3

30.2

-

P<0.01

5.5 Discussion

In summary, this represents the largest analysis evaluating the impact of facet dislocation on

outcomes after cervical SCI. In this patient population, we have shown that FD is more

frequently associated with severe neurological deficit at patient presentation and with high

energy injury mechanisms, as compared to non-FD related injuries. At follow-up, based on the

results of the unadjusted analyses, FD patients experienced a smaller amount of motor recovery,

101

as measured by the change in AMS from admission to 1 year, and had a significantly longer

length of acute hospital stay. In the adjusted analysis, after controlling for admission AIS grade,

the presence of FD was a significant predictor of inferior motor recovery 1 year after injury, with

a parameter estimate of -6.6. Stated plainly, after adjusting for admission neurological status,

patients with FD and SCI will experience approximately 7 fewer points in motor recovery at 1

year follow-up, as compared to those without FD and SCI.

In comparing patients with unilateral versus bilateral FD, patients with bilateral FD had a more

severe degree of neurological deficit at presentation. Although there were no statistically

significant differences in outcomes between these groups, the bilateral FD group had a longer

duration of acute hospital stay, with a difference that approached statistical significance.

In evaluating the available literature, there is a paucity of high quality studies which examine the

clinical outcomes of patients with cervical FD and SCI. Several studies have reported

considerable improvement in neurological status after rapid decompression of the spinal cord

through closed reduction243-247

. Although most of these studies are case reports or small case

series, this has led to the assertion that if treated promptly, patients with FD represent a subgroup

with considerable potential for recovery. However, the findings of the present study are contrary

to this observation. In spite of the fact that spinal cord decompression was achieved more rapidly

in the FD patients, whether through open or closed reduction, they exhibited a diminished

potential for motor recovery at long term follow-up as compared to non-FD patients. We

speculate that this finding is related to the observation that FD injuries are associated with higher

energy injury mechanisms causing a greater degree of primary neurologic injury, ultimately

resulting in a diminished potential for motor recovery at follow-up. Presently, it remains unclear

whether or not recovery for an individual patient with FD and SCI, may be optimized by prompt

reduction and decompression of the spinal cord. As a result, the findings of this study should not

deter clinicians from prioritizing the prompt decompression of patients with FD and SCI. We are

currently conducting a separate analysis to specifically determine how time to reduction in

patients with FD and SCI influences outcomes. Until the results of this study are available, we

continue to advocate for early intervention based on compelling biological rationale coupled with

the results of the recent STASCIS study119

.

102

Due to the increased use of sedation, intubation and ventilation in severely injured trauma

patients, a large percentage of those with SCI may not be examinable in the acute clinical setting.

In light of this observation, the identification of objective radiologic findings that help to classify

injury severity and prognosticate long-term outcome, is an important goal188

. Without any

knowledge of an individual trauma patient’s clinical history or physical exam, the current study

demonstrates that the presence of FD on admission X-ray or CT scan should inform the clinician

that the injury is likely to have resulted from a high energy injury mechanism and raise suspicion

of a potentially severe underlying neurological injury. This is significant in light of the pre-

existing absence of CT or X-ray based variables known to be predictive of long-term outcome, as

discussed in the literature review presented in Chapter 2. In terms of predicting long-term

outcome, understanding the negative impact of FD on motor recovery after SCI, will aid

clinicians in conveying accurate prognostic information to patients and their families. Moreover,

this prognostic information can be used to help stratify cervical SCI patients within clinical trials

evaluating the impact of novel therapeutic agents on neurological recovery.

5.5.1 Study Strengths and Limitations

As compared to a single center study, the multicenter nature of patient data accumulated in this

study increases the external validity of the results obtained. As with most observational

comparative studies, there are differences in patient characteristics between the cohorts that

could potentially impact observed outcomes. These imbalances were dealt with in the best way

possible, by performing a multivariate regression analysis, adjusting for relevant confounders. In

addition, a large number of patients were missing to follow-up at 1 year post injury. However the

challenges of obtaining long term follow-up in the trauma population, particularly among those

with severe mobility issues related to spinal cord injury, as compared to patients with electively

treated neurological diseases, are well recognized72,156

. In addition, we demonstrated that there

were no baseline differences in the characteristics of those with 1 year follow-up as compared to

those without available follow-up.

5.6 Conclusion

This analysis demonstrated that, in comparison to those without FD, patients with SCI in

association with cervical FD presented with a greater severity of neurological deficit and

experienced a smaller potential for motor recovery at long-term follow-up, even after adjusting

103

for baseline discrepancies in neurological status. From the standpoint of resource planning, this

analysis also demonstrated that patients with FD and SCI have longer periods of acute hospital

admission. These results have important implications for counseling patients and families

regarding prognosis and also for the stratification of patients within future SCI clinical trials. In

spite of the findings presented in this study, early spinal cord decompression for patients with FD

and SCI is recommended, based on the best available preclinical and clinical evidence115

.

104

6 Chapter 6 Predicting Inpatient Complications after Traumatic Cervical Spinal Cord Injury through the use of Acute Clinical Variables


Wilson JR, Arnold PM, Singh A, Kalsi-Ryan S and Fehlings MG. Clinical prediction

model for acute inpatient complications after traumatic cervical spinal cord injury: a sub-

analysis from the Surgical Timing in Acute Spinal Cord Injury Study. J Neurosurg Spine

2012; 17(Sup):46-51.249

105

6.1 Abstract

While the majority of existing reports focus on complications sustained during the sub-acute and

chronic stages after traumatic spinal cord injury (SCI), the objective of the current study was to

characterize and quantify acute in-patient complications as well as to identify the combination of

clinical variables predicting their occurrence. Based on these analyses, a prediction model using

clinical variables collected at hospital admission to predict complication development in cervical

SCI patients during the acute hospital stay was created. All analyses were based on data from the

Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) database. Complete complication

information was available for 411 patients at acute care discharge. One hundred and sixty

patients (38.9%) experienced 240 complications. The mean age amongst patients who

experienced at least one complication was 45.9 as compared to 43.5 in those who did not

experience a complication (p=0.18). In the univariable analysis, patients who experienced

complications were found to have a lower frequency of steroid administration at admission

(p=0.01), a greater severity of neurological injury as measured by ASIA impairment scale (AIS)

grade at presentation (p<0.01) and a higher frequency of significant comorbid illness (p=0.04).

In the creation of the multivariable logistic regression model, severe initial AIS grade (p<0.01),

high energy injury mechanisms (p=0.07), older age (p=0.047), absence of steroid administration

(p=0.02) and presence of comorbid illness (p=0.02) were associated with a higher odds of

complication development during the period of acute hospitalization. The AUC value for the full

model was 0.75, indicating acceptable predictive discrimination. These results will help

clinicians to identify those cervical SCI patients at greatest risk for complication development,

and based on this recognition, allow for the institution of aggressive complication preventive

measures.

106

6.2 Introduction

Although the incidence of traumatic spinal cord injury (SCI) is low (approximately 15-58 per

million per year in the general population), for the individual affected, this is a life changing

event which often results in significant disability, loss of independence and an increased risk of

mortality4,27,221,250

. In the absence of a proven regenerative or reparative therapy, the current

treatment approach is centered on optimizing long-term clinical outcomes by mitigating

secondary causes of injury and avoiding acute medical complications112,223

.

Given the extent of physiological disruption that can occur after SCI, patients are susceptible to a

myriad of secondary complications in the acute period following injury30,251

. Complications have

been reported to occur after SCI with incidence rates ranging from 20-77%

worldwide7,9,10,14,15,31,252,253

. However, comparisons of complication rates across the literature are

inherently challenging given the heterogeneity in complication categorization and specific time

period considered after injury. With the majority of existing reports having focused on sub-acute

and chronic complications sustained during the rehabilitation phase post SCI, a relative paucity

of studies have examined complications occurring during the period of acute hospitalization.

Regardless of the time point at which they occur, complications have been shown to lead to an

increased length of hospital stay, higher rates of mortality and diminished functional recovery at

long-term follow-up254,255

. As a result, a high degree of vigilance is required on the part of the

treating medical team to recognize their occurrence and promptly institute appropriate treatment.

However, such a process depends on medical practitioners having an understanding of the patient

and injury related factors that are the most predictive of complication development, with high

risk patients subsequently becoming the targets of aggressive complication prevention strategies.

As discussed in Chapter 2, while a variety of studies have identified individual clinical variables

of importance in predicting sub-acute/chronic complications post SCI, few studies have

evaluated the importance of such variables in predicting acute complications.

Given this background, our goal was to characterize and quantify complications occurring during

the acute hospital admission after cervical SCI, using a large prospective cervical SCI dataset.

Second, we planned to identify the combination of clinical variables that best predict acute

complication occurrence by developing a complication prediction model. Finally, based on this

107

analysis, we aimed to estimate the risk of acute complication development for a series of

hypothetical cervical SCI patients, based on their specific presenting characteristics.

6.3 Methods


A multi-center, North American prospective cohort study of early (<24hrs) versus late (≥24hrs)

spinal cord decompression following cervical SCI (STASCIS) was performed at 7 North

American centers256

. During the 7 year study period, between 2002 and 2009, any SCI patient

greater than 16 years old, presenting to one of these institutions with an ASIA Impairment Scale

(AIS) grade of A-D, a cervical neurological level of injury and radiological evidence of spinal

cord compression, was considered for enrolment. Spinal cord compression was determined

according to the radiologic methods previously described by the Fehlings group208,257

. For the

current analysis, only patients with a documented neurological examination performed within 72

hours of injury and follow-up information available at acute care discharge were included.

All patients included in this analysis received appropriate medical support according to the

recommendations of the 2002 American Association of Neurological Surgeons cervical SCI

guidelines95,96

. In each case, decisions surrounding surgery and methylprednisolone

administration were made at the discretion of the spinal surgeon and the treating team involved.

When methylprednisolone was given, the 24-hour NASCIS-II protocol was administered

invariably105

.

6.3.2 Candidate Complication Predictor Variables

At patient presentation, neurological examination was completed according to the International

Standards for the Neurological Classification of SCI, with ASIA impairment scale (AIS) grade

defined as the primary neurological predictor variable of interest for the purpose of this study224

.

In addition to neurological exam parameters, a variety of clinical variables were recorded at

admission including age, gender, energy injury mechanism, injury severity score (ISS) and

Charlson Co-morbidity index. For purposes of this analysis, all patients with an admission

Charlson Co-morbidity score ≥ 1 were considered to have co-morbid illness whereas those with a

score of 0 were considered to have no co-morbid illness. Motor vehicle accidents, including

motorcycle and all-terrain vehicle accidents, were considered to be high energy injury

108

mechanisms, whereas falls from standing, sporting related accidents and blunt violence were

considered low energy injury mechanisms.

6.3.3 Complication Categorization and primary outcome

During the period of acute hospitalization, complication information was collected prospectively

for each patient. For purposes of classification, complications were prospectively divided into 5

predefined categories: 1) cardio-pulmonary complications (e.g. pneumonia, acute respiratory

distress syndrome (ARDS), acute myocardial infarction, dysrhythmia); 2) surgical complications

(e.g. wound infection, dehiscence, construct failure, post-operative neurological deficit); 3)

thrombotic complications (e.g. deep venous thrombosis or pulmonary embolism); 4) infectious

complications (urosepsis, gastrointestinal infection, meningitis, other systemic infection); and 5)

decubitus ulcer development. We have not differentiated between major and minor

complications as all of the predefined categories were intended to capture only major

complication events with potential to impact clinical outcomes.

For this analysis, the primary complication outcome was binary, defined by the absence of a

complication event occurrence versus the occurrence of one or more complication events during

the acute inpatient hospital period.

6.3.4 Statistical Analysis

All analyses were completed using SAS version 9.2 (SAS Institute Inc. Cary, NC). An overall

complication incidence rate and category specific incidence rates were calculated. Univariable

statistical analyses were performed to investigate the relationship between complication

occurrence and individual demographic, injury and treatment predictor variables using the chi-

square test for categorical variables and the Student’s t-test for continuous variables.

Multivariable logistic regression was subsequently performed to identify the combination of

variables that predict the dichotomized primary complication outcome. Individual predictor

variables were considered for inclusion in the multivariate model if there was author consensus

about the predictive importance of the variable. Subsequently, these predictors were sequentially

eliminated in a backwards fashion if their corresponding p-value was greater than 0.10. The

predictive capacity of the final model in predicting complication occurrence was tested through

the construction of a receiver operator characteristic (ROC) curve. The area under the ROC

109

curve (AUC) is a summary measure of the discriminative ability of the model, with values

greater than 0.70 indicative of acceptable predictive discrimination.

Finally, the regression coefficients obtained from the full logistic model were used to estimate

the probability of acute complication development for hypothetical cervical SCI patients,

depending on the unique combination of clinical variables that are routinely recorded at hospital

admission.

6.4 Results

Four hundred and eleven patients had acute neurological exam data and prospective complication

information available from the period of acute hospitalization within the STASCIS dataset. The

mean time from admission to acute care discharge was 34.3(±54.6) days, with a significantly

longer mean length of stay noted for patients with a complication (51.5 days) as compared to

those who did not experience a complication (23.5 days) (p<0.01). One hundred and sixty

patients (38.9%) experienced 240 complications, with 59 of these patients experiencing at least 2

complications during the acute hospital admission. Of all 240 complications seen, 94 were

cardio-pulmonary (39.2%), 87 were infectious (36.3%), 28 were surgical (11.3%), 21 were

thrombotic (8.8%) and 11 involved decubitus ulcer development (4.6%) (Figure 6-1). There were

a total of 16 deaths within the study group, with 12 involving patients who experienced a

complication (7.5% mortality rate) and 4 involving patients who did not experience a

complication (1.6% mortality rate) (p<0.01). Within the infectious category, there were 14 post-

operative wound infections in total, 5 amongst patients receiving steroids (2.1%) and 9 amongst

those who did not receive steroids (5.6%) (p=0.07).

110

Figure 6-1: Number of Events per Complication Category

The mean age amongst patients who experienced at least one complication was 45.9 (±18.0) as

compared to 43.5(±16.4) amongst those who did not experience a complication (p=0.18). In the

univariable analysis (Table 6-1), patients who experienced at least 1 complication were found to

have a lower frequency of steroid administration at admission (p=0.02), and had a greater

severity of neurological injury as measured by AIS grade at presentation (p<0.01). In addition,

amongst those with a complication, 36 patients (22.5%) had a diagnosed comorbid illness at

hospital presentation as compared to 37 patients (14.7%) amongst those who did not experience

a complication (p=0.04).

111

Table 6-1: Results of univariable analysis comparing patients who experienced at least one

complication to those who experienced no complications

Predictor Variable Patients with

no

complications

N=251

Patients with at

least 1

complication

N=160

p-value

Mean Age 43.5(±16.4) 45.9(±18.0) p=0.18


AIS grade A

AIS grade B

AIS grade C

AIS grade D (ref)

57(22.7%)

38(15.1%)

59(23.5%)

97(38.7%)

87(54.4%)

28(17.5%)

27(16.9%)

18(11.3%)

p<0.01

Steroid

administration

155(63.8%) 78(52.0%) p=0.01

High energy injury

mechanism

119(47.6%) 90(57.0%) p=0.07

Male gender 186(74.1%) 122(76.3%) p=0.62

Mean Injury Severity

Score

12.1(±10.8) 13.2(±10.1) p=0.52

Co-Morbid Illness

No

Yes

214(85.3%)

37(14.7%)

124(77.5%)

36(22.5%)

p=0.04

Completion of the multivariable logistic regression analysis revealed 5 independent predictors of

complication development with a p-value<0.10: 1) Age (p=0.047); 2) admission AIS grade

(p<0.01); 3) energy level of injury mechanism (p=0.07); 4) steroid administration (p=0.02); and

5) presence of comorbid illness at presentation (p=0.02). Of note, ISS, felt to be a clinically

important predictor of complication development, was included in the model initially, but was

subsequently eliminated due to an adjusted p-value =0.60, greater than the 0.10 cutoff. Results

of the multivariable analysis with odds ratios and 95% confidence intervals are available in Table

6-2. The AUC value for the five predictor model was 0.75, indicating acceptable predictive

discrimination (Figure 6-2).

112

Table 6-2: Results from the multivariable logistic regression model predicting complication

development.

Predictor Variable Odds Ratio 95% Confidence

Interval

p-value

Age 1.02 1.00,1.03 p=0.047


AIS grade A

AIS grade B

AIS grade C

AIS grade D (ref)

9.44

4.76

2.00

1.00

4.90,18.16

2.22,10.18

0.95,4.19

-

p<0.01

Steroid administration 0.56 0.35,0.90 p=0.02

Co-morbid illness

No

Yes (ref)

0.46

1.00

0.24,0.91

-

p=0.02

High vs. Low energy

injury mechanism

1.57 0.96, 2.56 P=0.07

Finally, using the regression coefficients from the 5 predictor logistic model, we estimated the

probability of acute complication occurrence for a variety of cervical SCI patient scenarios, each

with different clinical characteristics at hospital admission (Table 6-3).

113

Table 6-3: Predicted Probability estimates for hypothetical SCI patients

Predictor Patient#1 Patient#2 Patient#3 Patient#4 Patient#5 Patient#6

Age 20 20 50 50 75 75

AIS A YES NO YES NO YES NO

AIS B NO NO NO YES NO NO

AIS C NO YES NO NO NO YES

High Energy YES NO YES NO YES NO

Steroid

Administration

YES NO YES YES NO NO

Co-morbid

illness

NO NO YES YES YES YES

Predicted

Probability of

Complication:

48% 17% 69% 47% 81% 42%

6.5 Discussion

In summary, this represents the largest analysis investigating acute in-hospital complications

after cervical SCI performed to date. In addition, this represents the first prediction model using

clinical data collected at hospital admission to predict complication development during the

acute in-hospital period. The results of this modeling indicated that a more severe initial AIS

grade, high energy injury mechanisms, older age, absence of steroid administration and presence

of comorbid illness to be associated with a greater odds of complication development during the

period of acute hospitalization. The combination of these 5 predictors demonstrated acceptable

predictive discrimination in predicting complication occurrence. Finally, we have demonstrated

that it is possible to practically apply the prediction model in the clinical realm, to estimate the

probability that an individual patient will experience an acute complication, based on their

presenting clinical characteristics.

114

Previous studies in the context of traumatic SCI have attempted to identify important patient risk

factors that are associated with the development of secondary complications23,253,254,258-261

. The

results of these studies indicate that increased age, increased body mass index, cervical lesions

and motor complete lesions are associated with an increased frequency of complications253,254,261

.

However, the vast majority of these studies have focused on data derived from the sub-acute or

chronic setting, with relatively few investigating acute in-patient complications. This is relevant

since the profile of complications post SCI is known to evolve as the time from injury

increases27,31

. As an example, clinical experience dictates that decubitus ulcer development and

psychiatric affective disorders are common in the chronic phases, but comparatively less

frequent during the acute phases post SCI262

. Hence, results from analyses based on data

obtained during the sub-acute and chronic stages are not necessarily valid in the acute stages.

Given that the acute hospital admission is the time during which patients are the most vulnerable

to medical instability and life threatening complications, recognizing and preventing

complication occurrence during this period is likely to have a substantial impact on improving

long-term clinical outcomes.

The associations found between the severity of neurological deficit, as well as injury energy

level, and complication development, are unsurprising given that these variables are surrogates

for the extent of neurological tissue destruction and hence the extent of motor weakness and

physiological derangement. Similarly, findings that increasing age was a positive predictor of

complication occurrence, and the absence of comorbid illness was a negative predictor of

complications, are expected in light of the decreased physiologic reserve seen amongst elderly

individuals and those with significant pre-existent disease.

The finding that steroid administration was associated with a reduced risk of complication

development is likely related to several observations. First, when administered, only the 24-hour

low dosage methylprednisolone regimen given in the NASCIS II study was utilized105

. This

dosing regimen has not been associated with a significantly greater incidence of complications at

any time point after injury. Second, this study considered only patients with cervical SCI, which

is in contrast to the NASCIS studies which considered patients with thoracic/lumbar injuries in

addition to cervical injuries. In NASCIS II the rate of wound infection in the steroid group was

7.1% in comparison to 3.6% in the placebo group, however the rate of wound infection in the

current study in the steroid group was 2.1%. This is explained by the fact that while surgery for

115

thoracic and lumbar SCI often involves relatively large posterior incisions, cervical injuries are

often treated with anterior approaches using small incisions and minimal soft tissue disruption.

As a result, cervical SCI patients would intuitively be at a lower risk for wound related infection

events irrespective of steroid use. Third, because we considered a broad range of complications,

and not just infection related events, it is possible that steroid administration mitigated

complication development in certain situations. For instance steroid administration has

previously shown beneficial, in select studies, in the setting of acute myocardial infarction, acute

respiratory distress syndrome (ARDS) and hypotensive shock, all of which were complications

tracked in this study263-265

. Finally, because this study was not intended as a primary efficacy

analysis to compare outcomes amongst steroid and non-steroid treated patients, it is possible that

the steroid effect reflects residual confounding unaccounted for by our modeling procedure.


Although the complication prediction model was constructed using a multicenter cervical SCI

database containing over 400 patients, the generalizability of this model, as well as its suitability

for use in the clinical realm, remain unproven. Hence, an independent evaluation of model

performance in a separate group of cervical SCI patients will be necessary to establish its

external validity. As well, we recognize that our method of complication categorization may not

capture all complication events that occurred during the acute hospital period. However, this

categorization scheme was developed to preferentially capture the major complication events

that would have the potential to impact long-term clinical outcomes. Finally, the current analysis

provides little granularity surrounding the predictors of specific complications such as

pneumonia. This analysis was primarily intended to look at relevant complications overall and

future analyses will focus on individual complications in the acute SCI period.

6.6 Conclusion

Complications occur with a high frequency after SCI with potentially significant long-term

sequelae. This analysis has identified a combination of factors that are predictive of complication

development in the acute setting post cervical injury. After external validation, these results will

likely help clinicians to identify those patients at greatest risk for complications, with these

116

patients becoming the targets for the administration of aggressive complication prevention

strategies.

117

7 Chapter 7: Defining Age Related Differences in Functional Outcome after Traumatic Spinal Cord Injury


Wilson JR, Davis AM, Kulkarni AV, Kiss A, Frankowski RF, Grossman RG, Fehlings

MG. Defining Age related Differences in Functional Outcome after Traumatic Spinal

Cord Injury. Currently under review at: The Spine Journal.

118

7.1 Abstract

The existing evidence suggests that while older spinal cord injury (SCI) patients experience a

similar degree of neurological recovery as younger patients, older patients experience diminished

functional outcomes at follow-up. However, all studies have assumed that the impact of age on

functional outcome is the same across the spectrum of injury severity. To test this assumption,

we evaluated age as a potential effect modifier governing the relationship between acute

neurological status and long-term functional outcome. Using a combination of the NACTN and

STASCIS datasets, age was primarily dichotomized at a threshold of 65 years. Multivariable

linear regression was used to investigate the modifying effects of age on the relationship between

acute ASIA Impairment Scale (AIS) grade and follow-up FIM motor score. An interaction plot

was generated to understand how the effect of age on long-term functional outcome changes

depending on the acute AIS grade. A second linear regression model investigating the modifying

effects of age was produced adjusting for additional relevant confounding variables. Of 729

patients in the combined dataset, 376 met the eligibility criteria. The mean age was 43.2 (±16.9),

with a total of 41 patients (10.9%) older than 65. In the univariable analysis there was no

significant age related difference in motor recovery at follow-up, however there was a

significantly lower mean FIM motor score observed amongst the older group at one year

(p<0.05). In the multivariable analysis, age was found to have a significant modifying effect on

the relationship between acute AIS grade and future functional outcome (p<0.05). The

interaction plot revealed that while older patients had decreased follow-up FIM motor scores

overall, this effect was largest for AIS B and C patients and smaller for AIS A and D patients.

Adjustment for additional covariates in the second linear model confirmed these results. These

findings will help to facilitate enhanced clinical communication as well as potentially aid in the

development of customized treatment and rehabilitation protocols.

119

7.2 Introduction

Increases in average life expectancy are leading to a shift in societal demographics, with the

proportion of the US population aged 65 and older expected to double over the next 40 years266

.

This demographic restructuring is likely to lead to changes in the epidemiology of traumatic

spinal cord injury (SCI) and result in a greater proportion of injuries amongst the elderly6,221

. As

a result, there is a need to achieve an enhanced understanding of how increasing age impacts

clinical outcomes after SCI. Such an understanding will facilitate the counseling of patients and

families within the acute clinical realm, as well as the design of patient-specific rehabilitation

programs within the sub-acute and chronic phases post SCI.

The existing evidence suggests that while older SCI patients experience a similar degree of

motor recovery as younger patients, older patients experience diminished functional outcomes at

long-term follow-up150,267-269

. However, all of these studies have assumed that the impact of age

on functional outcomes is the same across the spectrum of injury severity. For example, this

assumption implies that the effect of age on function is the same for an ASIA (American Spinal

Injury Association) impairment scale (AIS) grade A patient as it is for an AIS grade B, C or D

patient. In order to test this assumption it is necessary to evaluate age as a potential effect

modifier governing the relationship between acute neurological status and future functional

status (Figure 7-1). An effect modifier is a variable “M” whereby a given predictor variable and

outcome variable have a different relationship between each other at the various levels of “M”270

.

Given this background, we hypothesize that the impact of age on functional outcome is

differential depending on baseline injury severity. To explore this hypothesis, the primary

objective of the current study was to investigate the role of age as an effect modifier in the

relationship between acute neurological status after traumatic SCI and long-term functional

outcome. This was performed by applying well defined statistical procedures to a combined

prospective multicenter SCI dataset.

120

Figure 7-1: Diagram depicting study goal: To understand how the relationship between

baseline neurological severity and long-term functional status varies depending on age.

7.3 Methods


Two prospective SCI datasets were combined and used as the basis for all analyses. The North

American Clinical Trials Network for SCI (NACTN) database is a prospective registry that was

created in 2006 and enrolls patients from eight North American centers210

. The Surgical Timing

in Acute SCI Study (STASCIS) was a comparative effectiveness study of surgical timing that

enrolled patients from seven North American centers during a 7 year period beginning in

2002119

. These datasets contain common acute variables as well as outcome data at 6 and 12

month follow-up points. There was no overlap in patient enrollment between these datasets.

After research ethics board approval at each participating site was obtained, the databases were

harmonized and combined to produce a single dataset. Within this combined dataset, only adult

SCI patients (age>16) with an acute neurological exam performed within the first 3 days after

injury were considered in this analysis.

121

In all cases, neurologic assessment was completed at acute care admission according to the

International Standards for Neurological Classification of Spinal Cord Injury by a trained

physician, nurse or research assistant48

. Injury characteristics were classified according to

neurologic level of injury (NLI), ASIA motor score (AMS), ASIA sensory score (ASS) and the

overall ASIA Impairment Scale (AIS) grade. All patients received medical support according to

the recommendations of the 2002 American Association of Neurological Surgeons guidelines for

the treatment of SCI95,96

. When methylprednisolone was administered, a 24-hour high dose

infusion was given, according to the recommendations of the NASCIS-2 study105,108

. Whenever

possible, patients underwent surgical decompression of the spinal cord within 24 hours of injury.

Remaining surgical decisions were made on an individual basis by the attending spine surgeon

involved. After acute care discharge, patients underwent a customized course of rehabilitation

therapy.

7.3.2 Age as a predictor variable

To explore the impact of age as an effect modifier, it was transformed from a continuous variable

into a binary variable. Given that there is no standard definition of what constitutes an ‘old’ vs.

‘young’ SCI patient, age was dichotomized at a threshold of 65 years old, which is the cutoff

utilized by the United States Census Bureau to define the elderly population271

. For purposes of

performing a sensitivity analysis, evaluating a different threshold, all analyses were repeated

using age dichotomized at 60 years old.

7.3.3 Outcome and follow-up

The functional outcome of interest was Functional Independence Measure (FIM) motor score at

1 year follow-up. This functional outcome measure was created for generic use in the clinical

neurosciences and has been found valid and reliable for use in the setting of traumatic SCI78,226

.

Completion of the FIM motor score results in a discrete value between 13 and 91, with a higher

score indicating superior functional outcome. If 1 year follow-up data was not available for a

given patient, 6 month follow-up data was used instead, a practice which has been used and

shown appropriate in previous studies156

.

122

7.3.4 Statistical Methods

All analyses were performed using SAS version 9.3 (Cary, NC, USA). Descriptive analyses were

performed to characterize the demographics and injury characteristics of the patient population.

Missing data amongst predictor variables was assumed to be missing at random and was

accounted for using a multiple imputations procedure (Markov chain Monte Carlo methods) with

10 imputation samples. The first imputed sample was used as the basis for all subsequent

analyses. Such imputation is recommended as being more statistically robust, and less biased,

than removing cases with missing data points211,217

. The modifying effects of age on the

relationship between admission neurological status and follow-up functional outcome was

determined using regression procedures as described by Baron and Kenny272

. In the first linear

regression model we included age dichotomized at 65 and admission AIS grade, as well as their

interaction effect, as covariates modeled relative to the outcome variable of follow-up FIM motor

score. Effect modification exists if the interaction term explained a statistically significant

amount of the variance of the outcome variable, which equates to a p-value <0.05 for the

interaction term. This model was supplemented by graphing an interaction plot for dichotomized

age and admission AIS grade relative to follow-up FIM motor score. In the second linear

regression model, in addition to age, admission AIS grade and their interaction term, we also

included other covariates that could potentially influence long term functional status including

gender, admission Glasgow Coma Scale (GCS) score, neurological level of injury, admission

AMS and steroid administration, modeled relative to the outcome variable of follow-up FIM

motor score. As a sensitivity analysis, a second set of models was produced using age 60 as the

cut-off.

7.4 Results


Of the 729 patients within the combined dataset, 376 patients met eligibility criteria with a

baseline neurological exam available within the first three days after injury and with a FIM

motor score available at 6 months or 1 year follow-up. Amongst these patients, the overall mean

age was 43.2 (±16.9) years old, with a total of 70 patients (18.6%) older than 60 years old and a

total of 41 patients (10.9%) older than 65 years old. Table 7-1 compares baseline characteristics

between older and younger patients using both age cutoff points. There were no differences

123

between the young and old groups with respect to neurological status at admission as measured

by AIS grade, AMS or neurological level of injury (p>0.05). The older groups had a higher

proportion of female patients and a higher proportion of injuries secondary to falls, as compared

to the younger groups (p<0.05).

Table 7-1: Patient characteristics at acute hospital admission

Panel A: Age 65 used to distinguish Older vs. Younger

Characteristic Younger

n=335

Older

n=41

p-value

Age 39.7(±14.2) 72.5(±5.6) p<0.01

Male Gender 267(79.7%) 27(65.9%) p=0.04

Admission AIS

grade

AIS A

AIS B

AIS C

AIS D

126(37.6%)

53(15.8%)

49(14.6%)

107(31.9%)

10(24.4%)

10(24.4%)

9(22.0%)

12(29.3%)

P=0.19

Mean Admission

ASIA Motor Score

41.4(±31.7) 40.7(±30.2) P=0.91

Neurological Level

Cervical

Thoracic or

Lumbar

309(92.2%)

26(7.8%)

38(92.7%)

3(7.3%)

P=0.92

Mean Glasgow

Coma Scale Score

13.9(±3.0) 14.1(±2.6) P=0.77

Injury Etiology

MVA

Fall

Other

136(41.0%)

106(31.9%)

90(27.1%)

10(26.3%)

26(68.4%)

2(5.3%)

P<0.01

124

Panel B: Age 60 used to distinguish Older vs. Younger

Characteristic Younger

n=306

Older

n=70

p-value

Age 37.5(±12.9) 68.3(±6.7) P<0.01

Gender 248(81.1%) 46(65.7%) P<0.01

Admission AIS

grade

AIS A

AIS B

AIS C

AIS D

120(39.2%)

48(15.7%)

43(14.1%)

95(31.1%)

16(22.9%)

15(21.4%)

15(21.4%)

24(34.3%)

P=0.06

Mean Admission

ASIA Motor Score

40.7(±31.6) 44.0(±31.4) P=0.43

Neurological Level

Cervical

Thoracic or

Lumbar

280(91.5%)

26(8.5%)

67(95.7%)

3(4.3%)

P=0.23

Mean Glasgow

Coma Scale Score

14.0(±2.8) 13.7(±3.3) P=0.48

Injury Etiology

MVA

Fall

Other

132(43.6%)

87(28.7%)

84(27.7%)

14(20.9%)

45(67.1%)

8(11.9%)

P<0.01

7.4.2 Univariable analysis

Table 7-2 compares functional and neurological outcomes between the younger and older groups

using both age cutoff points. Using the age 65 cutoff there was a significantly lower mean FIM

motor score observed amongst the older group as compared to the younger group (p=0.03).

There was a similar trend observed using the age 60 cutoff, however this difference failed to

reach significance (p=0.08). There were no significant differences in motor neurological

recovery, as measured by AMS improvement, between the younger and older groups, regardless

of the cutoff considered (p>0.05).

125

Table 7-2: Functional and Neurological Outcomes at Follow-up


Outcome Younger

N=335

Older

N=41

p-value

FIM motor score 64.2(±28.0) 54.0(±31.7) P=0.03

Change in ASIA

motor score

24.1(±23.4) 20.7(±17.2) P=0.37


Outcome Younger

N=306

Older

N=70

p-value

FIM motor score 64.3(±28.1) 57.6(±30.2) P=0.08

Change in ASIA

motor score

23.9(±23.7) 23.1(±18.9) P=0.80

7.4.3 Multivariable analysis

Table 7-3 represents the results of the regression analyses investigating the modifying effect of

age on the relationship between admission neurological status and future functional status.

Overall, age was found to be a significant effect modifier, regardless of whether the age 65 or

age 60 cut-off was considered; older patients demonstrated decreased FIM motor scores at

follow-up however the relative impact of this age effect varied depending on the acute AIS

grade. As visualized in the interaction plot (Figure 7-2), this effect was particularly marked for

AIS B and AIS C patients and less prominent for AIS A and AIS D patients. In the multivariable

analysis adjusting for relevant confounding variables, the modifying effects of age on the

relationship between admission AIS grade and follow-up FIM motor score remained significant

(Table 7-4). Further, after covariate adjustment, the impact of the age effect continued to be

largest for AIS B and AIS C patients.

126

Table 7-3: Results of linear regression analysis relative to outcome variable FIM motor

score

Panel A: Age used to distinguish Older vs. Younger

Covariate Parameter estimate p-value

Admission AIS grade

AIS A

AIS B

AIS C

AIS D (ref)

-51.5

-56.0

-26.6

-

P<0.01 (overall)

P<0.01

P<0.01

P<0.01

Age

<65 years old

≥65 years old (ref)

1.8

-

P<0.01

Interaction (Age * AIS grade)

AIS A ≥65y.o. vs AIS A <65y.o.

AIS B ≥65y.o. vs AIS B <65y.o.

AIS C ≥65y.o. vs AIS C <65y.o.

AIS D ≥65y.o. vs AIS D <65y.o. (ref)

-5.7

-28.8

-12.7

-

P=0.02 (overall)

P=0.53

P=<0.01

P=0.18

-



Admission AIS grade

AIS A

AIS B

AIS C

AIS D (ref)

-53.6

-52.5

-23.4

-

P<0.01 (overall)

<0.01

<0.01

<0.01

-

Age

<60 years old


1.8

-

P<0.01






-8.3 -27.1

-10.2

-

P=0.01 (overall)

P=0.24 P<0.01

P=0.18

-

127

Table 7-4: Results of multivariable analysis adjusted for additional variables




Admission AIS grade

AIS A

AIS B

AIS C

AIS D (ref)

-25.2

-25.7

-11.5

-

P<0.01(overall)

P<0.01

P<0.01

P=0.16

-

Age

<65 years old


0.3

-

P<0.01

Male Gender -0.3 P=0.88

Steroid Administration 1.2 P=0.54

Acute Glasgow Coma Score 0.4 P=0.30

Neurological Level of Injury

Cervical (ref)

Thoracolumbar

-

8.6

P=0.03

Acute ASIA Motor Score 0.5 P<0.01






-8.4

-24.0

-19.5

-

P=0.02(overall)

P=0.31

P=0.01

P=0.02

-


Admission AIS grade

AIS A

AIS B

AIS C

AIS D (ref)

-25.4

-21.8

-5.1

-

P<0.01(overall)

P<0.01

P<0.01

P=0.42

-

Age

<60 years old


1.7

-

P<0.01

Male Gender -0.94 P=0.68

Steroid Administration 0.2 P=0.92

Acute Glasgow Coma Score 0.3 P=0.42

Neurological Level of Injury

Cervical (ref)

Thoracolumbar

-

8.0

P=0.04

Acute ASIA Motor Score 0.5 P<0.01






-8.8

-21.7

-13.6

-

P=0.01(overall)

P=0.17

P=0.01

P=0.04

-

128

Figure 7-2: Interaction plot demonstrating the modification effect of age on the relationship

between acute injury severity and functional outcome

129

7.5 Discussion

This is the first study to examine the modification effects of patient age on the relationship

between admission neurological status and long-term functional outcome after traumatic SCI.

The results of our analyses indicate that age is a significant effect modifier governing the

relationship between admission AIS grade and FIM motor score at follow-up. Stated plainly, it is

clear that while older patients will experience, on average, reduced future functional outcome as

compared to younger patients, this age related effect changes depending on patients’ AIS grade

at admission. The largest difference in functional outcome between the older and younger

groups was seen for those that were AIS grade B and C at admission. In comparison, the

magnitude of this difference was smaller for AIS A and AIS D patients, regardless of the age

cutoff considered.

To elaborate on the differential impact of age across the spectrum of injury severity, it is felt that

the reason for the diminished impact of age in the context of AIS A injuries is likely secondary to

the severe degree of primary neural tissue disruption that is often associated with these injuries.

As a result, functional outcomes are generally poor and additional variables, such as age, may

play less of a role in determining future functional status in this particular group. While AIS

grade B and C patients still harbor severe lesions, these individuals have been documented to

possess a greater potential for neurological recovery as compared to AIS A patients16

. In this

setting, other variables, such as older age, may prevent the translation of these neurological gains

into functionally meaningful recovery. On the opposite end of the severity spectrum, as regards

AIS D injuries, functional recovery at long term follow-up is usually excellent, as a result of a

comparatively reduced extent of spinal cord damage. In light of this favorable natural course of

recovery, the independent effects of additional variables, such as age, may be diminished. In

summary, it is felt that the increased age related effect seen within the AIS B and C groups

reflects the fact that these are lesions of intermediate severity where the potential for functional

recovery may be impacted by additional factors. This is in contrast to the very severe AIS A

injuries and the comparatively less serve AIS D injuries, where the potential for recovery is more

defined and less susceptible to the influence of outside factors.

Several studies have attempted to investigate the independent effects of age on clinical outcomes

after SCI. In a re-analysis of data from the NASCIS III study, Furlan et al demonstrated no

130

association between age and FIM scores at 6 months and 1 year follow-up in an unadjusted

analysis150

. However, after adjusting for relevant variables, such as severity of injury (complete

vs. incomplete), a linear increase in age was associated with decreased FIM scores at the same

follow-up points. In the same study, there was no association between age and motor recovery at

1 year follow-up. Cifu et al examined the impact of age on functional and neurological outcomes

in the rehabilitation setting post SCI267,268

. After accounting for the level and severity of injury,

increased age was found to be associated with reduced functional recovery as measured by FIM

change scores from rehabilitation admission to discharge for quadriplegics and paraplegics alike.

In the same studies, older tetraplegic patients were noted to experience reduced AMS

improvement from acute hospital admission to rehabilitation discharge, however there were no

age related differences in motor recovery observed for paraplegic patients. Overall, while there

continues to be controversy surrounding the effect of age on neurological recovery, the existing

evidence seems to suggest that older age is associated with worse functional status at long-term

follow-up124,177,273

. The current study has added to this body of evidence by demonstrating that

the effect of age on long-term functional status is differential, depending on patients’ admission

AIS grade.

From a clinical perspective, the results of the current study may allow for improved

communication and patient counseling within the acute clinical realm by permitting more

accurate outcome predictions based on acute clinical information. From the perspective of sub-

acute and chronic care, this research may allow for the development and institution of patient-

specific rehabilitation programs. For instance, since older AIS grade B patients have been shown

to experience significantly worse functional outcomes as compared to younger AIS B patients, in

spite of similar of similar neurological recovery, perhaps older AIS B patients should be targeted

with more intensive rehabilitation strategies to help optimize long-term functional status. From a

research perspective, the results of this study may be used to help stratify patients within the

context of future clinical trials and clinical therapeutic protocols.


It should be noted that in recent years, in addition to FIM, other functional outcome measures,

such as the Spinal Cord Independence Measure (SCIM), have been used to assess functional

outcome after SCI. However in the datasets used to complete this analysis, FIM was the primary

131

functional outcome assessment tool incorporated. It is speculated that since many of the items

contained in the SCIM questionnaire are similar to those in the FIM, that the results of this

analysis would not have differed substantially if SCIM had been used as the functional outcome

measure instead of FIM motor score. Finally, although we performed our analyses using a large

multicenter dataset, these findings must be validated using an external dataset before applied in

the clinical and research realms.

7.6 Conclusion

While increasing age has previously been associated with reduced functional outcome after SCI,

in the current study, we have attempted to provide further granularity on the topic by exploring

age as a potential effect modifier governing the relationship between acute neurological status

and functional outcome. This analysis has demonstrated that the negative impact of older age on

functional outcome varies across the spectrum of injury severity, with the largest effect noted for

AIS B and C patients and a comparatively smaller effect seen for AIS A and D patients. In the

future these findings will likely serve to assist in the counseling of SCI patients and their

families, and may help to direct the formation of customized treatment and rehabilitation

protocols, tailored to patient specific characteristics.

132

8 Chapter 8: Summary of Findings, General Discussion, Thesis Limitations and Future Directions

133

8.1 Summary of Findings and Unifying Discussion

As introduced at the outset of this thesis, there exists a strong imperative to provide clinicians

and researchers alike with an evidence based means of predicting future outcomes for patients

with traumatic SCI during the acute period after injury. Achieving progress on this topic serves

not only to aid communication in the clinical realm, but also permits enhanced study of this

patient population from the research perspective. The preceding analyses have each represented

separate aims engineered to probe different elements of the overall hypothesis that neurologic,

functional and complication related outcomes can be accurately predicted using acute patient,

injury and radiological features. Our use of a large combined prospective dataset permitted the

adequate sample size and the relevant data fields necessary to fully address each of these key

aims. Guided by the overarching hypothesis and specific aims, analysis of this dataset allowed

for: 1) the development and internal validation of a clinico-radiographic model predicting

functional outcome, 2) the exploration of facet dislocation (FD) as a radiological predictor of

neurological outcome, 3) the identification of the combination of variables predicting acute in-

hospital complication development after cervical SCI and the subsequent construction of a model

predicting complication occurrence, and 4) the exploration and clarification of the effect of age

on functional outcome. Figure 8-1 provides an overview of the main relationships explored

between acute predictor variables and outcome variables across the multivariable analyses

presented in each chapter of this thesis. In this section, these relationships, and the key findings

emanating from this body of work, are further contextualized and explained for each of the acute

predictor variables and outcomes that were considered.

134

Figure 8-1: Summary of Main Relationships between Acute Predictors and Outcomes

Explored in Multivariable Analyses throughout Thesis

AIS: ASIA Impairment Scale; AMS: ASIA motor score; IM: Intramedullary; FIM: Functional

Independence Measure;

Solid line: p<0.05 in multivariable analyses; Dotted line: p>0.05 in multivariable analyses

8.1.1 Clinical Variables

In each of the four analyses presented in chapters 4-7, while the predictive importance of many

different variables were assessed, neurological exam features were consistently important

predictors, regardless of the outcome considered. In particular, lesion severity, as measured by

the acute AIS grade, was a highly significant predictor of all three outcomes considered. As

discussed in chapter 2, previous studies have raised concern surrounding the accuracy of the

neurological exam when performed within 3 days of injury, thereby bringing into question the

utility of acute exam related variables for purposes of outcome prediction143

. In spite of these

concerns, the goal of the current body of work was to base predictions entirely on information

135

available to clinicians at the time of patients’ acute hospital admission. As a result, all exam

related data used to perform the preceding analyses were obtained within the first 3 days after

hospital admission for all patients. Although it was not possible to compare the predictive

capacity of these acute variables to those obtained from the sub-acute period, based on the

analyses presented above, this acute exam data proved to be a robust predictor of all outcomes

considered. Whenever possible, the effects of potential inaccuracies surrounding the acute

neurological assessment were mitigated in the current analyses through selection of neurological

exam predictors that were felt to be less susceptible to acute biases. As an example, in all four

analyses, AIS grade was chosen as one of the main neurologic exam related predictors of

interest. As opposed to AMS, which requires precise quantification of individual muscle strength

in 20 myotomes, AIS grade is more easily obtained in the acute care period, requiring

classification into only one of 5 broad categories. While acute care distractions such as patient

fatigue, pain or concomitant injuries are likely to impact on the accuracy of AMS values148,274

, it

was felt that the accuracy of AIS grade assessments were less susceptible to the influence of

these same factors. When AMS was used as a predictor of interest in the clinico-radiographic

model described in chapter 4, the dichotomized value (above or below a score of 50) was

considered. This approach was felt to be more tolerant to any inaccuracy present in the raw

ordinal scores, thereby limiting the impact of the aforementioned acute distractions on model

validity. ASS was not incorporated in any of the preceding analyses as the incremental predictive

value contributed by this parameter, over and above AIS grade, was felt to be minimal.

Apart from neurological exam parameters, the only other injury related variable considered in

this thesis was injury etiology. The literature review presented in chapter 2 did not provide

consistent support for the predictive importance of any injury mechanism in relationship to any

of the considered outcomes. However, the main challenge when examining this topic is the lack

of homogeneity between studies with respect to the classification of injury etiology. In analyzing

the combination of factors associated with acute complication development, high energy injury

mechanisms were associated with a trend towards an increased incidence of these events in both

the univariable and multivariable analyses. Overall, further future analyses employing a

standardized template for etiology categorization will be necessary to clarify the impact of this

variable on clinical outcomes post SCI.

136

8.1.2 Demographic Variables

A sizeable body of literature has accumulated over the years to support the conclusion that while

neurological recovery is unaffected by increasing age, long-term functional outcome is decreased

amongst elderly patients150,275

. However, the existing studies on this topic have suggested that

this detrimental impact of age is uniformly applicable to older SCI patients and do not consider

how additional patient and injury characteristics might contribute to this effect. The analysis

presented in chapter 7 has contributed new understanding to this topic by demonstrating that

while older patients do experience diminished functional outcomes in the long-term, the negative

effect of increased age is differential across the spectrum of injury severity. The most substantive

difference in functional outcome between older patients and younger patients was discovered for

those who presented acutely with AIS grade B or C injuries. In contrast, there was very little

difference in functional outcomes observed between the age groups for patients who presented at

the extremes of injury severity with either AIS grade A or AIS grade D. It is felt that these

findings reflect the fact that AIS B and C injuries are lesions of intermediate severity where the

potential for functional recovery may be impacted by additional variables such as age. In

contrast, for AIS A and D injuries, the profile for recovery is more defined and less susceptible

to the influence of extraneous variables. Overall, while this analysis has confirmed the negative

impact of increasing age on function, it has also served to refine and improve upon our

understanding of how this demographic variable affects outcome depending on additional injury

related characteristics.

In addition to considering the impact of age in relation to long-term functional outcome, the

effect of increasing age was also considered in relation to the occurrence of acute in-hospital

complications. While age has consistently shown to be of predictive importance with respect to

the development of such complication events, few studies have evaluated the independent effect

of age by adjusting for other relevant confounding variables, such as medical comorbidities. The

analysis presented in chapter 6 showed increasing age to significantly predict acute complication

occurrence, even after adjusting for covariates such as comorbid illness, acute AIS grade, injury

etiology and steroid administration.

While the predictive capacity of additional demographic features such as gender and race were

reviewed in Chapter 2, these were not explored in substantial detail in subsequent chapters. At

137

present time, there is lack of evidence supporting the predictive importance of these variables in

relation to both short-term and long-term outcomes post SCI.

8.1.3 Radiological Variables

When considering the current analyses in the setting of previous work evaluating the role of

radiological variables in predicting outcome after SCI, several points are pertinent. First, of the

quantitative and qualitative MRI variables that have been considered for their potential

importance in predicting outcome, qualitative intramedullary signal characteristics are the best

studied and have demonstrated value in this capacity, as discussed in Chapter 260,179,187

.

However, by in large, existing studies evaluated the importance of these MRI variables in

isolation, without considering them in the context of a broader array of diagnostic and clinical

variables that also have established value in predicting outcome. The goal of the current research

was not to develop or investigate the use of new MRI variables for purposes of outcome

prediction, but rather to use the existing variables known to be of importance in combination

with other non-radiological variables. Theoretically this approach optimizes the accuracy of

outcome predictions by permitting consideration of the holistic package of information that

clinicians use in the acute clinical realm to forecast predictions for the future. In chapter 4 we

showed that acute MRI intramedullary signal characteristics (no signal, signal consistent with

edema and signal consistent with hemorrhage) could be used in combination with demographic

and exam features to augment predictions of long-term functional outcome. More than anything

this analysis has demonstrated the feasibility, and potential value, in using radiological variables

as a supplement to provide an understanding of anatomic injury severity. Such an understanding

is especially of value in the acute injury setting when external influences can interfere with the

accuracy of neurological examination. In contrast to examination predictors, radiological

variables are immune to the described acute care biases and as a result, their accuracy and

predictive importance is unlikely to vary according to the time period. In the future, as the

accuracy of MRI in quantifying injury to neural tissue improves, the incremental predictive

utility contributed by these imaging variables is likely to increase in a commensurate fashion.

In the combined NACTN/STASCIS dataset, a large proportion of patients did not undergo MRI

within the first 3 days after injury, bringing into question the generalizability of a prediction

model which includes MRI variables. However the missing imaging data can be explained along

138

several lines. First, because the subjects contained in these datasets were enrolled up to 10 years

ago, several of the participating institutions, in the early years of enrolment, may not have

considered MRI as a standard part of the diagnostic work-up of an SCI patient. In the interim,

published guidelines have led many clinicians involved in the acute management of SCI to

prioritize early MRI as an essential element of the diagnostic work-up60

. Second, since STASCIS

focused on cervical injuries, a significant proportion of injured patients included in this dataset

had facet dislocations (FD). There is some remnant controversy about the role of acute MRI in

the setting of FD; while some clinicians forego MRI to expedite closed or open reduction of the

spinal column, others continue to rely on the anatomic information provided by MRI prior to

proceeding with reduction247

. As a result, a proportion of patients with cervical SCI secondary to

FD did not undergo MRI as a consequence of the preferences of the treating physician on this

subject. All perspectives considered, MRI has become the most useful imaging modality to direct

diagnosis, treatment and outcome predictions after SCI, justifying the use of MRI variables in the

clinico-radiographic model described in Chapter 460

.

In addition to compiling the existing data on MRI predictors of outcome, Chapter 2 also

underlined the absence of literature identifying CT or X-ray related variables of proven

predictive importance. Although CT and X-ray are poorly suited for visualizing the spinal cord

and neural structures, they are highly suited for diagnosing injury to the bony spinal column.

Further, at least one of either CT or X-ray is performed at admission in virtually every suspected

case of SCI. This is in contrast to MRI which, as acknowledged above, may not be performed in

certain patients with SCI for reasons including clinician preference, presence of implanted

metallic hardware or, in certain regions, inadequate patient access to the technology. In addition,

while MRI can often take several hours to organize and perform, X-ray and CT are typically

performed within minutes of hospital arrival55

. In chapter 5, the identification of FD as

significant predictor of motor recovery at 1 year follow-up, established the feasibility of using

patterns of bony injury, detected on acute X-ray or CT, to predict outcome. While these findings

will require confirmation in future studies, FD appears to be the first CT or X-ray based finding

to demonstrate predictive significance in the context of traumatic SCI.

139

8.1.4 Outcome variables

Long-term functional outcome, as measured by Functional Independence Measure (FIM) motor

score, was the outcome most often considered throughout this thesis. As opposed to neurological

outcome which refers to the direct assessment of the integrity and health of ones’ nervous

system, assessment of function allows us to understand how one interacts with their environment

and completes useful daily tasks. As a result, while neurological outcome is influenced

predominately by the severity of neurological injury, functional outcome is also influenced by

non-injury related factors, such as age, that affect the translation of neurologic function into

useful activity. The fact that a variety of different factors have the potential to underlie functional

outcome post SCI, explains our decision to often consider this outcome throughout the preceding

analyses. The work presented in this thesis has expanded our understanding of how such factors

can be used to improve functional outcome predictions after SCI. The analysis presented in

chapter 4 demonstrated, for the first time, the feasibility of using a combination of acute

variables, collected within the first 3 days after injury, to predict future functional status.

Furthermore, this work established that acute radiological, demographic and exam related

variables can be combined to accurately predict functional independence. Next, although

functional outcome has previously shown to be negatively affected by increasing age, the

analyses presented in chapter 7 brought further clarity to this topic by demonstrating this

negative age related effect to vary across the spectrum of injury severity, as explained above.

In chapter 5 neurological outcome, as defined by change in AMS from admission to 1 year

follow-up, was considered as the primary outcome of interest. Change in AMS, as reflected by

its selection as the primary outcome in previous SCI therapeutic trials, is considered by many

within the SCI research community to be the preferred measure of neurological recovery. As

identified in the preceding systematic review (Chapter 2), numerous patient, injury and MRI

related variables have been considered as potential predictors of this outcome, with injury

severity (AIS grade) generally having shown the greatest utility in this regard. However, little

investigation has probed the use of CT or X-ray related predictors of neurological recovery. The

analysis in chapter 5 showed that presence of FD on admission X-ray or CT was a significant

predictor of motor neurological recovery, even after adjusting for the baseline degree of

neurologic severity. Overall, these findings provide clinicians and researchers alike with a new

140

imaging predictor of future neurological status that can be obtained independent of a patients’

capacity to cooperate with neurological exam.

Acute complication development was the third outcome considered in relation to a variety of

clinical predictor variables within this thesis. Since the nature and severity of complication

events differ depending on the time elapsed since injury, it is essential to understand the specific

factors which portend a higher risk of complication development at each stage of patient care.

During the chronic stages after injury, the period considered in most of the topical studies,

complications are dominated by events related to prolonged immobilization and chronic

disability such as decubitus ulcer formation, urinary tract infections and the development of

psychiatric affective disorders. In contrast, during the initial in-hospital period, complications

events are more often severe and life-threatening in nature, reflecting the increased acuity of this

stage of patient care. In the literature review presented in chapter 2, of 14 articles identifying

clinical predictors of complication development, only 4 pertained to complications encountered

during the acute in-hospital period, with none of these employing multivariable techniques to

identify the combination of factors predicting this outcome. To overcome this void, in chapter 5,

a core set of five patient, injury and treatment related variables were identified that predicted,

with acceptable predictive discrimination, acute in-hospital complication occurrence after

cervical SCI. These variables form the basis of a new predictive model that can be used to

estimate individuals’ probability of acute complication at admission. Ideally this model will be

used to identify high risk patients that can subsequently be monitored in an intensive fashion to

prevent complication development and the attendant morbidity of such events.

8.2 Thesis Limitations

First, the presence of missing data within the combined dataset, both amongst acute predictor

variables and outcome variables, is a limitation that must be acknowledged for the analyses

presented in Chapters 4-7. This is particularly true in relation to some of the imaging related

data, for reasons enumerated in the discussion section above. For predictor variables, imputation

methods were used to minimize the introduction of bias and the negative impact of missingness

on sample size. For outcome variables, in each of the chapters, there did not appear to be

clinically significant differences in the characteristics of patients included and those excluded

due to inadequate follow-up. In spite of attempts to mitigate the effect of missing data, it is

141

acknowledged that complete datasets would have been preferable for completion of these

analyses. Second, with respect to the functional outcome measure used in these analyses, it

should be acknowledged that although FIM is among the best studied of any functional outcome

measure in the context of SCI, SCIM overcomes some of the responsiveness issues identified

with FIM. However, because SCIM is a relative newcomer, the databases employed in this study

did not routinely collect this information. It is speculated that since many of the items contained

in the SCIM questionnaire are similar to those in the FIM, that the results of this analysis would

not have differed substantially if SCIM had been used as the functional outcome measure instead

of FIM motor score. Third, the acute injury window was defined across these analyses as the first

3 days after injury, in accordance with the definitions put forward by the 2007 International

Campaign for Cures of spinal cord injury Paralysis70

. It is acknowledged however that this

definition is somewhat arbitrary and may need revisiting in the future, especially with emerging

evidence supporting early surgical intervention within the first 24 hours after injury119,120

. Fourth,

while one year was considered to represent long-term follow-up for both neurological and

function outcome in this thesis, it has been shown that patients can experience incremental

improvements beyond that time point75

. However, given that only a small proportion of patients

experience such recovery after one year, this was felt to be a reasonable assumption for the

purposes of this thesis. Finally, in chapters 4 and 7, analyses incorporated cervical, thoracic and

lumbar SCI patients. However, it is acknowledged that in both of these analyses, the majority of

patients studied had a cervical neurological level, with a relatively low proportion of patients

with thoracic or lumbar SCI. As a result, prior to clinical use, these findings will need to be

validated in external datasets, containing a greater proportion of thoracic and lumbar SCI

patients.

142

8.3 Future Directions

With the completion of this work, the next immediate step is to begin the process of establishing

external validity for the findings presented here within. As mentioned earlier, until such validity

is established, these results remain preliminary. Exploring the question of external validity will

require the use of new SCI datasets with data fields similar to the ones considered in the NACTN

and STASCIS datasets. In order to maximize generalizability, the new data should emanate from

centers that were not involved in enrolling subjects within NACTN or STASCIS, ideally from

outside North America. This would allow for confirmation of findings in a system or country

where assessment and treatment standards are subtly different from those observed in the North

American healthcare systems. Once such data is procured the next step would be to evaluate the

performance of the statistical models that were conceived in this thesis within the context of the

new datasets. As an example, for the clinico-radiographic prediction models described in chapter

4, the models themselves would be applied to the new data resulting in a new set of indices for

performance including R-squared and AUC values. These newly generated values would then be

compared to those obtained from the original data, to arrive at bias corrected indices. Assessment

of validity for such statistical models is an ongoing and iterative process that never leads to a

final conclusion of “valid” or “not valid”. Rather, through evaluation of model performance in

several different datasets, the generalizability of the model, and hence its appropriateness for use

in the clinical and research settings, becomes increasingly apparent. At present, efforts are

underway to obtain additional datasets for purposes of initiating such validity studies.

Once the generalizability of the preceding analyses are more completely understood, efforts will

be directed to translating these findings into more practical tools that can be used by clinicians

and researchers alike to help optimize clinical communication and facilitate improved

investigation. To this end, one potential strategy would be to simplify the predictive relationships

observed above into a straightforward predictive classification or score analogous to the Glasgow

Coma Score for traumatic brain injury. A simplified predictive classification system is more

facile for use is the often chaotic setting of acute clinical care as compared to the mathematical

equations presented above. Based on the analyses within this thesis, classifications predictive of

functional outcome and acute complications are currently under construction.

143

In chapter 7, age was found to significantly modify the relationship between acute injury severity

and long-term functional outcome. This raises the possibility of investigating the impact of

similar “third variable” effects on other predictor/outcome relationships in the context of SCI. In

addition to effect modification, it would also be of interest to investigate the mediating effects of

different variables on such relationships. To this end, future work will focus on developing a

theoretical framework for the relationship between predictor variables and outcomes,

incorporating such modification and mediation effects.

The current work has also highlighted the need for the development of improved imaging

variables that reflect injury severity and are predictive of outcome. Admittedly, the quantitative

presence of signal consistent with edema or hemorrhage within the spinal cord is a rather crude

method for this purpose as it does not consider the integrity of the individual anatomic tracts and

structures within the spinal cord itself. Fortunately imaging technology is evolving to a point

where high anatomic resolution will permit assessment of the structural integrity of individual

tracts. Further, the capacity of functional imaging modalities are progressing and may soon serve

to augment the structural information provided by traditional MRI by offering an imaging

representation of neurological function. When such technology becomes practical for use in the

acute clinical setting, assessing the added contributions of these imaging advances in predicting

outcome will be of definite interest.

Finally, outcomes considered in this thesis were limited to long-term functional outcome and

neurological recovery as well as acute in-hospital complications. However, the importance of

other outcomes not considered here, such as health related quality of life, pain and disability,

cannot be overemphasized. Future analyses investigating the underpinnings and predictors of

these and other outcomes are also planned with the overall goal of identifying specific factors

that can be targeted with intervention to improve the long-term health of SCI patients.

When considering these and other avenues of research stemming from the analyses presented

above, the opportunities for further work and investigation are truly unlimited.

144

References

1. Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord

injury. CMAJ. Dec 10 2012.

2. Chin L, Mesfin F, Dawodu S. Spinal Cord Injuries.

http://emedicine.medscape.com/article/793582-overview#a0101. Accessed December 12,

2012, 2012.

3. Couris C, Guilcher S, Munce S, et al. Characteristics of adults with incident traumatic

spinal cord injury in Ontario Canada. Spinal Cord. 2010;48:40-44.

4. Pickett G, Campos-Benitez M, Keller J, Duggal N. Epidemiology of Traumatic Spinal

Cord Injury in Canada. Spine. 2006;31:799-805.

5. Noonan V, Fingas M, Farry A, et al. The incidence and prevalence of spinal cord injury

in Canada: A National Perspective. Neuroepidemiology. 2011;38:219-226.

6. Farry A, Baxter D. The Incidence and Prevalence of Spinal Cord Injury in Canada

Overview and estimates based on current evidence. 2010;

http://www.urbanfutures.com/reports/Report%2080.pdf. Accessed June 15, 2011.

7. Dryden D, Saunders L, Rowe B, et al. The Epidemiology of Traumatic Spinal Cord

Injury in Alberta, Canada. Canadian Journal of Neurological Sciences. 2003;30:113-121.

8. Pirouzmand F. Epidemiological trends of spine and spinal cord injuries in the largest

Canadian adult trauma center from 1986 to 2006. Journal of Neurosurgery Spine.

2010;12:131-140.

9. Ackery A, Tator C, Krassioukov A. A global perspective on spinal cord injury

epidemiology. J Neurotrauma. 2004;21:1355-1370.

10. Sekhon L, Fehlings M. Epidemiology,demographics, and pathophysiology of acute spinal

cord injury. Spine. 2001;26:S1-12.

11. Kraus J, Franti C, Riggins R, Richards D, Borhani N. Incidence of traumatic spinal cord

lesions. J Chronic Dis. 1975;28:471-492.

12. Martins F, Freitas F, Martins L, Dartigues J, Barat M. Spinal cord injuries epidemiology

in Portugal's central region. Spinal Cord. 1998;36:574-578.

13. O'Connor P. Incidence and patterns of spinal cord injury in Australia. Accid Anal Prev.

2002;34:405-415.

14. Levy L, Makarowo S, Madzivire D, Bhebhe E, Verbeek N, Parry O. Problems, struggles

and some successes with spinal cord injury in Zimbabwe. Spinal Cord. 1998;36:213-218.

http://emedicine.medscape.com/article/793582-overview#a0101

http://www.urbanfutures.com/reports/Report%2080.pdf

145

15. Hart C, Williams E. Epidemiology of spinal cord injuries: a reflection of changes in

South African society. Paraplegia. 1994;32:709-714.

16. Marino R, Dittuno J, Donovan W, Maynard F. Neurologic Recovery after Traumatic

Spinal Cord Injury: Data from the Model Spinal Cord Injury Systems. Arch Phys Med

Rehab. 1999;80:1391-1396.

17. Catz A, Thaleisnik M, Fishel B, et al. Survival following spinal cord injury in Israel.

Spinal Cord. 2002;40:595-598.

18. Silberstein B, Rabinovich S. Epidemiology of spinal cord injuries in Novosibirsk, Russia.

Paraplegia. 1995;33:183-188.

19. Levi R, Hultling C, Nash MS, Seiger A. The Stockholm spinal cord injury study: 1.

Medical problems in a regional SCI population. Paraplegia. Jun 1995;33(6):308-315.

20. Nobunaga AI, Go BK, Karunas RB. Recent demographic and injury trends in people

served by the Model Spinal Cord Injury Care Systems. Arch Phys Med Rehabil. Nov

1999;80(11):1372-1382.

21. DeVivo MJ, Kartus PL, Rutt RD, Stover SL, Fine PR. The influence of age at time of

spinal cord injury on rehabilitation outcome. Arch Neurol. Jun 1990;47(6):687-691.

22. StatisticsCanada. Canada's Aging Population. 2004;

http://www.sustreport.org/signals/canpop_age.html. Accessed June 15, 2011.

23. Krassioukov A, Furlan J, Fehlings M. Medical Co-Morbidities, Secondary

Complications, and Mortality in Elderly with Acute Spinal Cord Injury. J Neurotrauma.

2003;20:391-399.

24. Geisler F, Coleman W, Grieco G, Poonian D. The Sygen multicenter acute spinal cord

injury study. Spine. 2001;26:87-98.

25. Hoque MF, Grangeon C, Reed K. Spinal cord lesions in Bangladesh: an epidemiological

study 1994 - 1995. Spinal Cord. Dec 1999;37(12):858-861.

26. Kraus J. Injury to the head and spinal cord: The epidemiological relevance of the medical

literature published from 1960 to 1978. J Neurosurgery. 1980:S3-10.

27. Krause J, Sternberb M, Lottes S, Maides J. Mortality after Spinal Cord Injury: An 11-

year prospective study. Arch Phys Med Rehab. 1997;78:815-821.

28. Krause J, Carter R, Pickelsimer E, Wilson D. A prospective study of health and risk of

mortality after spinal cord injury. Arch Phys Med Rehab. 2008;89:1482-1491.

29. O'Connor P. Survival after spinal cord injury in Australia. Arch Phys Med Rehab.

2005;86:37-47.

30. DeVivo M, Stover S. Long term survival and causes of death. Gaithersburg1995.

http://www.sustreport.org/signals/canpop_age.html

146

31. Dryden D, Saunders L, Rowe B, et al. Utilization of health services following spinal cord

injury: a 6-year follow-up study. Spinal Cord. 2004;42:513-525.

32. Winslow C, Bode R, Felton D, Chen D, Meyer R. Impact of respiratory complications on

length of stay and hospital costs in acute cervical spine injury. Chest. 2002;121:1548-

1554.

33. Dryden D, Saunders L, Jacobs P, et al. Direct health care costs after traumatic spinal cord

injury. J Trauma. 2005;59:443-449.

34. Rick-Hansen-Institute. High Cost of Healthcare. Information about SCI 2012;

http://www.rickhanseninstitute.org/en/information-about-sci/high-cost-of-healthcare.

Accessed December 12, 2012.

35. Amar A, Levy M. Pathogenesis and pharmacological strategies for mitigating secondary

damage in acute spinal cord injury. Neurosurgery. 1999;44:1027-1039.

36. Fehlings M, Sekhon L, eds. Cellular, ionic and biomolecular mechanisms of the injury

process. Chicago: American Association of Neurologic Surgeons; 2000. E B, CH T, eds.

Contemporary Management of Spinal Cord Injury: From Impact to Rehabilitation.

37. Tator C, Fehlings M. Review of the secondary injury theory of acute spinal cord trauma

with emphasis on vascular mechanisms. J Nerosurg. 1991;75:15-26.

38. Sandler A, Tator C. Review of the effect of spinal cord trauma on the vessels and blood

flow in the spinal cord. J Nerosurg. 1976;45:638-646.

39. Tator C, Koyanagi I. Secondary injury mechanisms of spinal cord trauma: a novel

therapeutic approach for the management of secondary pathophysiology with the sodium

channel blocker riluzole. J Neurosurg. 1997;86:483-492.

40. Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal

cord injury. J Neurosurg. Mar 1997;86(3):483-492.

41. Sandler A, Tator C. Effects of acute spinal cord compression injury on regional spinal

cord blood flow in primates. J Neurosurg. 1976;45:660-676.

42. Jorgensen M, Diemer N. Selective neuron loss after cerebral ischemia in the rat: possible

role of transmitter glutamate. Acta neurologica Scandinavica. 1982;66:536-546.

43. Braughler J, Duncan L, Chase R. Interaction of lipid peroxidation and calcium in the

pathogenesis of neuronal injury. Cent Nerv Syst Trauma. 1985;2:269-283.

44. Schwartz G, Fehlings M. Secondary injury mechanisms of spinal cord trauma: a novel

therapeutic approach for the management of secondary pathophysiology with the sodium

channel blocker riluzole. Prog Brain Res. 2002;137:177-190.

45. Rothman S, Olney J. Glutamate and the pathophysiology of hypoxic-ischemic brain

damage. Ann Neurology. 1986;19:105-111.

http://www.rickhanseninstitute.org/en/information-about-sci/high-cost-of-healthcare

147

46. Baptiste D, Fehlings M. Emerging drugs for Spinal Cord Injury. Expert Opin Emerg

Drugs. 2008;13:63-80.

47. ASIA, ed Standards for Neurological Classification of Spinal Injured Patients. Chicago:

American Spinal Injury Association; 1982.

48. Kirshblum SC, Waring W, Biering-Sorensen F, et al. Reference for the 2011 revision of

the International Standards for Neurological Classification of Spinal Cord Injury. J Spinal

Cord Med. Nov 2011;34(6):547-554.

49. Kirshblum SC, Burns SP, Biering-Sorensen F, et al. International standards for

neurological classification of spinal cord injury (revised 2011). J Spinal Cord Med. Nov

2011;34(6):535-546.

50. Marino RJ, Jones L, Kirshblum S, Tal J, Dasgupta A. Reliability and repeatability of the

motor and sensory examination of the international standards for neurological

classification of spinal cord injury. J Spinal Cord Med. 2008;31(2):166-170.

51. Mulcahey MJ, Gaughan J, Betz RR, Johansen KJ. The International Standards for

Neurological Classification of Spinal Cord Injury: reliability of data when applied to

children and youths. Spinal Cord. Jun 2007;45(6):452-459.

52. Marino R, Jones L, Kirshblum S, Tal J. Reliability of the ASIA motor and sensory

examination. J Spinal Cord Med. 2004;27:194.

53. Savic G, Bergstrom EM, Frankel HL, Jamous MA, Jones PW. Inter-rater reliability of

motor and sensory examinations performed according to American Spinal Injury

Association standards. Spinal Cord. Jun 2007;45(6):444-451.

54. Furlan JC, Fehlings MG, Tator CH, Davis AM. Motor and sensory assessment of patients

in clinical trials for pharmacological therapy of acute spinal cord injury: psychometric

properties of the ASIA Standards. J Neurotrauma. Nov 2008;25(11):1273-1301.

55. ACPS. Advanced trauma life support system program for physicians. Chicago: American

College of Physicians and Surgeons; 1993.

56. Mirvis S, Diaconis J, Chirico P. Protocol-driven radiologic evaluation of suspected

cervical spine injury: efficacy study. Radiology. 1989;170:831-834.

57. Acheson M, Livingston R, Richardson M, Stimac G. High-resolution CT scanning in the

evaluation of cervical spine fractures:Comparison with plain film examinations. AJR.

1987;148:1179-1185.

58. Woodring J, Lee C. Limitations of cervical radiography in the evaluation of acute

cervical trauma. J Trauma. 1993;34:32-39.

59. Vaccaro A, Hurlbert J, Patel A, et al. The Subaxial Cervical Spine Injury Classification

System. Spine. 2007;32:2365-2374.

148

60. Lammertse D, Dungan D, Dreisbach J, et al. Neuroimaging in traumatic spinal cord

injury: an evidence-based review for clinical practice and research. J Spinal Cord Med.

2007;30(3):205-214.

61. Krzyzak AT, Jasinski A, Weglarz WP, Adamek D, Sagnowskil P, Baj M. Visualisation of

the extent of damage in a rat spinal cord injury model using MR microsopy of the water

diffusion tensor. Acta Neurobiol Exp (Wars). 2005;65(3):255-264.

62. Schwartz ED, Yezierski RP, Pattany PM, Quencer RM, Weaver RG. Diffusion-weighted

MR imaging in a rat model of syringomyelia after excitotoxic spinal cord injury. AJNR

Am J Neuroradiol. Sep 1999;20(8):1422-1428.

63. Bammer R, Fazekas F. Diffusion imaging of the human spinal cord and the vertebral

column. Top Magn Reson Imaging. Dec 2003;14(6):461-476.

64. Pattany PM, Yezierski RP, Widerstrom-Noga EG, et al. Proton magnetic resonance

spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord

injury. AJNR Am J Neuroradiol. Jun-Jul 2002;23(6):901-905.

65. Winchester P, McColl R, Querry R, et al. Changes in supraspinal activation patterns

following robotic locomotor therapy in motor-incomplete spinal cord injury.

Neurorehabil Neural Repair. Dec 2005;19(4):313-324.

66. Cadotte DW, Stroman PW, Mikulis D, Fehlings MG. A systematic review of spinal fMRI

research: outlining the elements of experimental design. J Neurosurg Spine. Sep

2012;17(1 Suppl):102-118.

67. Cadotte DW, Bosma R, Mikulis D, et al. Plasticity of the injured human spinal cord:

insights revealed by spinal cord functional MRI. PLoS One. 2012;7(9):e45560.

68. Stroman PW, Kornelsen J, Bergman A, et al. Noninvasive assessment of the injured

human spinal cord by means of functional magnetic resonance imaging. Spinal Cord. Feb

2004;42(2):59-66.

69. World Health Organization International Classification of Functioning, Disabilities and

Health (ICF). 2001. http://www.who.int/classifications/icf/en/.

70. Steeves J, Lammertse D, Curt A, et al. Guidelines for conduct of clinical trials for spinal

cord injury as developed by the ICCP panel: clinical trial outcome measures. Spinal

Cord. 2007;45:206-221.

71. Anderson K. Targeting recovery: priorities of the spinal cord injured population. J

Neurotrauma. 2004;10:1371-1383.

72. Bracken M, Collins W, Freeman D, et al. Efficacy of methylprednisolone in acute spinal

cord injury. JAMA. 1984;251:45-52.

http://www.who.int/classifications/icf/en/

149

73. Frankel H, Hancock D, Hyslop G, et al. The value of postural reduction in initial

management of closed injuries of the spine with paraplegia and tetraplegia. Paraplegia.

1969;7:179-192.

74. Burns A, Ditunno J. Establishing Prognosis and Maximizing Functional Outcomes after

Spinal Cord Injury. Spine. 2001;26:S137-S145.

75. Kirshblum S, Millis S, McKinley W, Tulsky D. Late neurologic recovery after traumatic

spinal cord injury. Arch Phys Med Rehabil. Nov 2004;85(11):1811-1817.

76. Van Middendorp J, Hosman A, Pouw M. ASIA Impairment scale conversion in traumatic

SCI: is it related with the ability to walk? . Spinal Cord. 2009;47:555-560.

77. Hall KM, Cohen ME, Wright J, Call M, Werner P. Characteristics of the Functional

Independence Measure in traumatic spinal cord injury. Arch Phys Med Rehabil. Nov

1999;80(11):1471-1476.

78. Hamilton B, Laughlin J, Fiedler R, Granger C. Interrater reliability of the 7-level

functional independence measure (FIM). Scand J Rehab Med. 1994;26:115-119.

79. Ottenbacher KJ, Hsu Y, Granger CV, Fiedler RC. The reliability of the functional

independence measure: a quantitative review. Arch Phys Med Rehabil. Dec

1996;77(12):1226-1232.

80. Dodds TA, Martin DP, Stolov WC, Deyo RA. A validation of the functional

independence measurement and its performance among rehabilitation inpatients. Arch

Phys Med Rehabil. May 1993;74(5):531-536.

81. Anderson K, Aito S, Atkins M, et al. Functional recovery measures for spinal cord injury:

an evidence-based review for clinical practice and research. J Spinal Cord Med.

2008;31(2):133-144.

82. Davidoff GN, Roth EJ, Haughton JS, Ardner MS. Cognitive dysfunction in spinal cord

injury patients: sensitivity of the Functional Independence Measure subscales vs

neuropsychologic assessment. Arch Phys Med Rehabil. Apr 1990;71(5):326-329.

83. Catz A, Itzkovich M, Agranov E, Ring H, Tamir A. SCIM--spinal cord independence

measure: a new disability scale for patients with spinal cord lesions. Spinal Cord. Dec

1997;35(12):850-856.

84. Catz A, Itzkovich M, Tesio L, et al. A multicenter international study on the Spinal Cord

Independence Measure, version III: Rasch psychometric validation. Spinal Cord. Apr

2007;45(4):275-291.

85. Itzkovich M, Gelernter I, Biering-Sorensen F, et al. The Spinal Cord Independence

Measure (SCIM) version III: reliability and validity in a multi-center international study.

Disabil Rehabil. Dec 30 2007;29(24):1926-1933.

150

86. Catz A, Itzkovich M, Agranov E, Ring H, Tamir A. The spinal cord independence

measure (SCIM): sensitivity to functional changes in subgroups of spinal cord lesion

patients. Spinal Cord. Feb 2001;39(2):97-100.

87. Catz A, Itzkovich M, Steinberg F, et al. The Catz-Itzkovich SCIM: a revised version of

the Spinal Cord Independence Measure. Disabil Rehabil. Apr 15 2001;23(6):263-268.

88. Yavuz N, Tezyurek M, Akyuz M. A comparison of two functional tests in quadriplegia:

the quadriplegia index of function and the functional independence measure. Spinal

Cord. Dec 1998;36(12):832-837.

89. van Hedel HJ, Dietz V. Walking during daily life can be validly and responsively

assessed in subjects with a spinal cord injury. Neurorehabil Neural Repair. Feb

2009;23(2):117-124.

90. Dittuno PL, Ditunno JF, Jr. Walking index for spinal cord injury (WISCI II): scale

revision. Spinal Cord. Dec 2001;39(12):654-656.

91. Kucukdeveci AA, Yavuzer G, Tennant A, Suldur N, Sonel B, Arasil T. Adaptation of the

modified Barthel Index for use in physical medicine and rehabilitation in Turkey. Scand J

Rehabil Med. Jun 2000;32(2):87-92.

92. Failli V, Kopp MA, Gericke C, et al. Functional neurological recovery after spinal cord

injury is impaired in patients with infections. Brain. Nov 2012;135(Pt 11):3238-3250.

93. Chesnut R, Marshall L, Klauber M, et al. The role of secondary brain injury in

determining outcome from severe head injury. J Trauma. 1993;34:216-222.

94. Ploumis A, Yadlapalli N, Fehlings MG, Kwon BK, Vaccaro AR. A systematic review of

the evidence supporting a role for vasopressor support in acute SCI. Spinal Cord. May

2010;48(5):356-362.

95. Hadley M, Walters B, Grabb P, et al. Blood pressure management after acute spinal cord

injury. Neurosurgery. 2002;50:S58-62.

96. Hadley M, Walters B, Grabb P, et al. Management of Acute Spinal Cord Injuries in an

Intestive Care Unit or Other Monitored Setting. Neurosurgery. 2002;S51-57.

97. Vale F, Burns J, Jackson A, Hadley M. Combined medical and surgical treatment after

acute spinal cord injury: Results of a prospective pilot study to assess the merits of

aggressive medical resuscitation and blood pressure management. J Neurosurg.

1997;87:239-246.

98. Tator C, Duncan E, Edmonds V, Lapczak L, Andrews D. Changes in epidemiology of

acute spinal cord injury from 1947 to 1981. Surg Neurol. 1993;40:207-215.

99. Tator C, Rowed D, Schwartz M, et al. Management of acute spinal cord injuries.

Canadian journal of surgery. Journal canadien de chirurgie. 1984;27:289-294.

151

100. Levi L, Wolf A, Belzber H. Hemodynamic parameters in patients with acute cervical

cord trauma: Description, intervention, and prediction of outcome. Neurosurgery.

1993;33:1007-1017.

101. Gschaedler R, Dollfus P, Mole J, Mole L, Loeb J. Reflections on the intesive care of

acute cervical spinal cord injuries in a general traumatology centre. Paraplegia.

1979;17:58-61.

102. Kwon BK, Mann C, Sohn HM, et al. Hypothermia for spinal cord injury. Spine J. Nov-

Dec 2008;8(6):859-874.

103. Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane

Database Syst Rev. 2009(2):CD001048.

104. Levi AD, Casella G, Green BA, et al. Clinical outcomes using modest intravascular

hypothermia after acute cervical spinal cord injury. Neurosurgery. Apr 2010;66(4):670-

677.

105. Bracken M, Shepard M, Collins W, et al. A randomized, controlled trial of

methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of

the Second National Acute Spinal Cord Injury Study. New Engl J Med. 1990;17:1405-

1411.

106. Bracken M, Shepard M, Holford T, et al. Administration of methylprednisolone for 24 or

48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury.

Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial.

National Acute Spinal Cord Injury Study. JAMA. 1997;277:1597-1604.

107. Hugenholtz H, Cass D, Dvorak M. High dose methylprednisilone for acute closed spinal

cord injury—only a treatment option. Canadian Journal of Neurological Sciences.

2002(29):227-235.

108. Hadley M, Walters B, Grabb P, et al. Pharmacological Therapy after Acute Cervical

Spinal Cord Injury. Neurosurgery. 2002;50:563-572.

109. Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev.

2012;1:CD001046.

110. Hurlbert R. Methylprednisolone for acute spinal cord injury: an inappropriate standard of

care. J Nerosurg Spine. 2000;93:1-7.

111. Petijean M, Pointillart V, Dixmerias F, et al. Traitment medicamenteux de la lesion

medullaire traumatique au stade aigu. Annales fracaises d'anesthesie et de reanimation.

1998;17:115-122.

112. Rowland J, Hawryluk G, Kwon B, Fehlings M. Current status of acute spinal cord injury

pathophysiology and emerging therapies: promise on the horizon. Neurosurgical Focus.

2008;25(5):E2.

152

113. Fehlings MG, Wilson J, Frankowski R, et al. Riluzole for the Treatment of Acute

Traumatic Spinal Cord Injury: Rationale for and Design of the NACTN Phase I Clinical

Trial. J Neurosurgery: Spine. 2012;17:151-156.

114. Fehlings M, Theodore N, Harrop J, et al. A phase I/IIa clinical trial of a recombinant Rho

protein antagonist in acute spinal cord injury. J Neurotrauma. 2011;28:787-796.

115. Wilson J, Fehlings M. Emerging Approaches to the surgical management of acute

traumatic Spinal Cord Injury. Neurotherapeutics : the journal of the American Society for

Experimental NeuroTherapeutics. 2011;8:197-194.

116. Dolan E, Tator C, Endrenyi L. The value of decompression for acute experimental spinal

cord compression injury. J Neurosurgery. 1980;53:749-755.

117. Guha A, Tator C, Endrenyi L. Decompression of the spinal cord improves recovery after

acute experimental spinal cord compression injury. Paraplegia. 1987;25:324-339.

118. Furlan J, Noonan V, Cadotte D, Fehlings M. Timing of Decompressive Surgery of Spinal

Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-

Clinical and Clinical Studies. J Neurotrauma. 2009;27:1-29.

119. Fehlings MG, Vaccaro A, Wilson J, et al. Early versus Delayed Decompression for

Traumatic Cervical Spinal Cord Injury: Results of the Surgical Timing in Acute Spinal

Cord Injury Study (STASCIS). PLoS One. 2012;7(2):1-8.

120. Wilson JR, Singh A, Craven C, et al. Early versus late surgery for traumatic spinal cord

injury: the results of a prospective Canadian cohort study. Spinal Cord. May 8 2012.

121. Fehlings MG, Perrin RG. The timing of surgical intervention in the treatment of spinal

cord injury: a systematic review of recent clinical evidence. Spine (Phila Pa 1976). May

15 2006;31(11 Suppl):S28-35; discussion S36.

122. Fehlings M, Rabin D, Sears W, Cadotte D, Aarabi B. Current practice in the timing of

surgical intervention in spinal cord injury. Spine. 2010;35:166-173.

123. Tetzlaff W, Okon EB, Karimi-Abdolrezaee S, et al. A systematic review of cellular

transplantation therapies for spinal cord injury. J Neurotrauma. Aug 2011;28(8):1611-

1682.

124. Wilson JR, Cadotte D, Fehlings MG. Clinical predictors of neurological outcome,

functional status, and survival after traumatic spinal cord injury: a systematic review. J

Neurosurg Spine. 2012;17(1 Sup):11-26.

125. Phillips B, Ball C, Sackett D, et al. Oxford Center for Evidence-Based Medicine:Levels

of evidence 2003; http://www.cebm.net/index.aspx?o=1025. Accessed April 20, 2011,

2011.

126. Wright JG, Swiontkowski MF, Heckman JD. Introducing levels of evidence to the

journal. J Bone Joint Surg Am. Jan 2003;85-A(1):1-3.

http://www.cebm.net/index.aspx?o=1025

153

127. Waters RL, Sie I, Adkins RH, Yakura JS. Motor recovery following spinal cord injury

caused by stab wounds: a multicenter study. Paraplegia. Feb 1995;33(2):98-101.

128. Steeves J, Kramer J, Fawcett J, et al. Extent of spontaneous motor recovery after

traumatic cervical sensorimotor complete cord injury. Spinal Cord. 2011;49:257-265.

129. Sipski M, Jackson A, Gomez-Martin O, Estores I, Stein A. Effects of Gender on

Neurologic and Functional Recovery after Spinal Cord Injury. Arch Phys Med Rehab.

2004;85:1826-1836.

130. Pollard M, Apple D. Factors associated with improved neurologic outcomes in patients

with incomplete tetraplegia. Spine. 2003;28:33-39.

131. Fassett D, Harrop J, Maltenfort M, et al. Mortality rates in geriatric patients with spinal

cord injuries. J Neurosurgery Spine. 2007;7:277-281.

132. Cifu D, Seel R, Kreutzer J, McKinley W. A multicenter investigation of age-related

differences in lengths of stay, hospitalization charges, and outcomes for a matched

tetraplegic sample. Arch Phys Med Rehab. 1999;80:733-740.

133. Katoh S, Masry WE. Motor recovery of patients presenting with motor paralysis and

sensory sparing following cervical spinal cord injuries. Paraplegia. 1995;33:506-509.

134. Waters R, Yakura J, Adkins R, Sie I. Recovery Following Complete Paraplegia. Arch

Phys Med Rehab. 1992;73:784-789.

135. Waters R, Adkins R, Yakura J, Sie I. Motor and Sensory recovery following complete

tetraplegia. Arch Phys Med Rehab. 1993;74:242-247.

136. Waters R, Adkins R, Yakura J, Sie I. Motor and Sensory Recovery Following Incomplete

Paraplegia. Arch Phys Med Rehab. 1994;75:67-72.

137. Waters R, Adkins R, Yakura J, Sie I. Motor and sensory recovery following incomplete

tetraplegia. Arch Phys Med Rehab. 1994;80:733-740.

138. Waters R, Sie I, Adkins R, Yakura J. Injury pattern effect on motor recovery after

traumatic spinal cord injury. Arch Phys Med Rehab. 1995;76:440-443.

139. Zariffa J, Kramer J, Fawcett J, et al. Characterization of neurological recovery following

traumatic sensorimotor complete thoracic spinal cord injury. Spinal Cord. 2011;49:463-

471.

140. Dittuno J, Stover S, Freed M, Ahn J. Motor Recovery of the Upper Extremities in

Traumatic Quadriplegia: A Multicenter Study. Arch Phys Med Rehab. 1992;73:431-436.

141. Browne B, Jacobs S, Herbison G, Ditunno J. Pin Sensation as a Predictor of Extensor

Carpi Radialis Recovery in Spinal Cord Injury. Arch Phys Med Rehab. 1993;74:14-18.

154

142. Wu L, Marino R, Herbison G, Dittuno J. Recovery of zero-grade muscles in the zone of

partial preservation in motor complete quadriplegia. Arch Phys Med Rehab. 1992;73:40-

43.

143. Brown P, Marino R, Herbison G, Dittuno J. The 72-hour examination as a predictor of

recovery in motor complete quadriplegia. Arch Phys Med Rehab. 1991;72:546-548.

144. Ditunno J, Cohen M, Hauck W, Jackson A, Sipski M. Recovery of upper-extremity

strength in complete and incomplete tetraplegia: a multicenter study. Arch Phys Med

Rehab. 2000;81:389-393.

145. Mange K, Marino R, Gregory P, Herbison G, Dittuno J. Course of motor recovery in the

Zone of Partial Preservation in spinal cord injury. Arch Phys Med Rehab. 1992;73:437-

441.

146. Dittuno J, Sipski M, Posuniak E, Chen Y, Staas W, Herbison G. Wrist extensor recovery

in traumatic quadriplegia. Arch Phys Med Rehab. 1987;68:287-290.

147. Bravo P, Labarta C, Alcaraz M, Mendoza J, Verdu A. An assessment of factors affecting

neurologic recovery after spinal cord injury with vertebral fracture. Paraplegia.

1996;34:164-166.

148. Maynard F, Reynolds G, Fountain S, Wilmot C, Hamilton R. Neurologic prognosis after

traumatic quadriplegia. J Neurosurgery. 1979;50:611-616.

149. Coleman W, Geisler F. Injury severity as primary predictor of outcome in acute spinal

cord injury: retrospective results from a large multicenter clinical trial. Spine Journal.

2004;4:373-378.

150. Furlan J, Fehlings M. The impact of Age on Mortality, Impairment, and Disability among

Adults with Acute Traumatic Spinal Cord Injury. J Neurotrauma. 2009;26:1707-1717.

151. Burns S, Golding D, Rolle W, Graziani V, Dittuno J. Recovery of Ambulation in Motor-

Incomplete Tetraplegia. Arch Phys Med Rehab. 1997;78:1169-1172.

152. Calancie B, Molano M, Broton J. Tendon reflexes for prediction movement recovery

after acute spinal cord injury in humans. Clinical Neurophysiology. 2004;115:2350-2363.

153. Crozier K, Graziani V, Dittuno J, Herbison G. Spinal Cord Injury: Prognosis for

Ambulation Based on Sensory Examination in Patients Who are Initially Motor

Complete. Arch Phys Med Rehab. 1991;72:118-121S.

154. Ko H, Dittuno J, Graziani V, Little J. The pattern of reflex recovery during spinal shock.

Spinal Cord. 1999;37:402-409.

155. Oleson C, Burns A, Ditunno J, Geisler F, Coleman W. Prognostic Value of Pinprick

Preservation in Motor Complete, Sensory Incomplete Spinal Cord Injury. Arch Phys Med

Rehab. 2005;86:988-992.

155

156. Van Middendorp J, Hosman A, Donders A, et al. A clinical prediction rule for

ambulation outcomes after traumatic spinal cord injury: a longitudinal cohort study.

Lancet. 2011;377:1004-1010.

157. Weinstein D, Ko H, Graziani V, Dittuno J. Prognostic Significance of the Delayed

Plantar Reflex Following Spinal Cord Injury. J Spinal Cord Medicine. 1997;20:207-211.

158. Kay E, Deutsch A, Wuermser L. Predicting Walking at Discharge From Inpatient

Rehabilitation After a Traumatic Spinal Cord Injury. Arch Phys Med Rehab.

2007;88:745-750.

159. Marino R, Graves D. Metric Properties of the Asia Motor Score: Subscales Improve

Correlation with Functional Activities. Arch Phys Med Rehab. 2004;85:1804-1810.

160. Ota T, Akaboshi K, Nagata M, et al. Functional assessment of patients with spinal cord

injury:measured by the motor score and the Functional Indepedence Measure. Spinal

Cord. 1996;34:531-535.

161. McKinley WO, Johns JS, Musgrove JJ. Clinical presentations, medical complications,

and functional outcomes of individuals with gunshot wound-induced spinal cord injury.

Am J Phys Med Rehabil. Mar-Apr 1999;78(2):102-107.

162. Zorner B, Blanckenhom W, Dietz V, Group E-SS. Clinical Algorithm for Improved

Prediction of Ambulation and Patient Stratification after Incomplete Spinal Cord Injury. J

Neurotrauma. 2010;27:241-252.

163. Lazar R, Yarkony G, Ortolano D, et al. Prediction of Functional Outcome by Motor

Capacity after Spinal Cord Injury. Arch Phys Med Rehab. 1989;70:819-822.

164. Crozier K, Cheng L, Graziani V, Zorn G, Herbison G, Ditunno J. Spinal Cord Injury:

prognosis for ambulation based on quadriceps recovery. Paraplegia. 1992;30:762-767.

165. Vazquez X, Rodriguez M, Penaranda J, Concheiro L, Barus J. Determining prognosis

after spinal cord injury. Forensic and Legal Medicine. 2008;15:20-23.

166. Haisma JA, van der Woude LH, Stam HJ, et al. Complications following spinal cord

injury: occurrence and risk factors in a longitudinal study during and after inpatient

rehabilitation. J Rehabil Med. May 2007;39(5):393-398.

167. McKinley WO, Jackson AB, Cardenas DD, DeVivo MJ. Long-term medical

complications after traumatic spinal cord injury: a regional model systems analysis. Arch

Phys Med Rehabil. Nov 1999;80(11):1402-1410.

168. Aito S. Complications during the acute phase of traumatic spinal cord lesions. Spinal

Cord. Nov 2003;41(11):629-635.

169. Chen D, Apple DF, Jr., Hudson LM, Bode R. Medical complications during acute

rehabilitation following spinal cord injury--current experience of the Model Systems.

Arch Phys Med Rehabil. Nov 1999;80(11):1397-1401.

156

170. Levi R, Hultling C, Seiger A. The Stockholm Spinal Cord Injury Study: 2. Associations

between clinical patient characteristics and post-acute medical problems. Paraplegia. Oct

1995;33(10):585-594.

171. Hitzig SL, Tonack M, Campbell KA, et al. Secondary health complications in an aging

Canadian spinal cord injury sample. Am J Phys Med Rehabil. Jul 2008;87(7):545-555.

172. Vidal J, Sarrias M. An analysis of the diverse factors concerned with the development of

pressure sores in spinal cord injured patients. Paraplegia. May 1991;29(4):261-267.

173. Groah SL, Weitzenkamp D, Sett P, Soni B, Savic G. The relationship between

neurological level of injury and symptomatic cardiovascular disease risk in the aging

spinal injured. Spinal Cord. Jun 2001;39(6):310-317.

174. Werhagen L, Budh CN, Hultling C, Molander C. Neuropathic pain after traumatic spinal

cord injury--relations to gender, spinal level, completeness, and age at the time of injury.

Spinal Cord. Dec 2004;42(12):665-673.

175. Krassioukov AV, Furlan JC, Fehlings MG. Medical co-morbidities, secondary

complications, and mortality in elderly with acute spinal cord injury. J Neurotrauma. Apr

2003;20(4):391-399.

176. Furlan JC, Krassioukov AV, Fehlings MG. The effects of gender on clinical and

neurological outcomes after acute cervical spinal cord injury. J Neurotrauma. Mar

2005;22(3):368-381.

177. Meade MA, Cifu DX, Seel RT, McKinley WO, Kreutzer JS. Medical procedures,

complications, and outcomes for patients with spinal cord injury: A multicenter

investigation comparing African Americans and whites. Arch Phys Med Rehabil. Mar

2004;85(3):368-375.

178. Fawcett J, Curt A, Steeves J, et al. Guidelines for the conduct of clinical trials for spinal

cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord

injury and statistical power needed for therapeutic trials. Spinal Cord. 2007;45:190-205.

179. Bondurant FJ, Cotler HB, Kulkarni MV, McArdle CB, Harris JH, Jr. Acute spinal cord

injury. A study using physical examination and magnetic resonance imaging. Spine

(Phila Pa 1976). Mar 1990;15(3):161-168.

180. Hayashi K, Yone K, Ito H, Yanase M, Sakou T. MRI findings in patients with a cervical

spinal cord injury who do not show radiographic evidence of a fracture or dislocation.

Paraplegia. Apr 1995;33(4):212-215.

181. Mascalchi M, Dal Pozzo G, Dini C, et al. Acute spinal trauma: prognostic value of MRI

appearances at 0.5 T. Clin Radiol. Aug 1993;48(2):100-108.

182. O'Beirne J, Cassidy N, Raza K, Walsh M, Stack J, Murray P. Role of magnetic resonance

imaging in the assessment of spinal injuries. Injury. Mar 1993;24(3):149-154.

157

183. Sato T, Kokubun S, Rijal KP, et al. Prognosis of cervical spinal cord injury in correlation

with magnetic resonance imaging. Paraplegia. Feb 1994;32(2):81-85.

184. Selden NR, Quint DJ, Patel N, d'Arcy HS, Papadopoulos SM. Emergency magnetic

resonance imaging of cervical spinal cord injuries: clinical correlation and prognosis.

Neurosurgery. Apr 1999;44(4):785-792; discussion 792-783.

185. Tewari M, Gifti D, Singh P. Diagnosis and prognostication of adult spinal cord injury

without radiographic abnormality using magnetic resonance imaging: analysis of 40

patients. Surg Neurol. 2005;63:204-209.

186. Ramon S, Dominguez R, Ramirez L, et al. Clinical and magnetic resonance imaging

correlation in acute spinal cord injury. Spinal Cord. Oct 1997;35(10):664-673.

187. Boldin C, Raith J, Fankhauser F, Haunschmid C, Schwantzer G, Schweighofer F.

Predicting neurologic recovery in cervical spinal cord injury with postoperative MR

imaging. Spine (Phila Pa 1976). Mar 1 2006;31(5):554-559.

188. Miyanji F, Furlan J, Aarabi B, Arnold P, Fehlings M. Acute Cervical Traumatic Spinal

Cord Injury: MR Imaging Findings Correlated with Neurologic Outcome--Prospective

Study with 100 Consecutive Patients. Radiology. 2007;243:820-827.

189. Shin JC, Kim DY, Park CI, Kim YW, Ohn SH. Neurologic recovery according to early

magnetic resonance imaging findings in traumatic cervical spinal cord injuries. Yonsei

Med J. Jun 30 2005;46(3):379-387.

190. Shimada K, Tokioka T. Sequential MR studies of cervical cord injury: correlation with

neurological damage and clinical outcome. Spinal Cord. 1999;37:410-415.

191. Takahashi M, Harada Y, Inoue H, Shimada K. Traumatic cervical cord injury at C3-4

without radiographic abnormalities: correlation of magnetic resonance findings with

clinical features and outcome. J Orthop Surg (Hong Kong). Dec 2002;10(2):129-135.

192. Shepard MJ, Bracken MB. Magnetic resonance imaging and neurological recovery in

acute spinal cord injury: observations from the National Acute Spinal Cord Injury Study

3. Spinal Cord. Dec 1999;37(12):833-837.

193. Schaefer DM, Flanders AE, Osterholm JL, Northrup BE. Prognostic significance of

magnetic resonance imaging in the acute phase of cervical spine injury. J Neurosurg. Feb

1992;76(2):218-223.

194. Flanders AE, Spettell CM, Friedman DP, Marino RJ, Herbison GJ. The relationship

between the functional abilities of patients with cervical spinal cord injury and the

severity of damage revealed by MR imaging. AJNR Am J Neuroradiol. May

1999;20(5):926-934.

195. Yamazaki T, Yanaka K, Fujita K, Kamezaki T, Uemura K, Nose T. Traumatic central

cord syndrome: analysis of factors affecting the outcome. Surg Neurol. Feb

2005;63(2):95-99; discussion 99-100.

158

196. Aarabi B, Harrop JS, Tator CH, et al. Predictors of pulmonary complications in blunt

traumatic spinal cord injury. J Neurosurg Spine. Sep 2012;17(1):38-45.

197. Ohshio I, Hatayama A, Kaneda K, Takahara M, Nagashima K. Correlation between

histopathologic features and magnetic resonance images of spinal cord lesions. Spine

(Phila Pa 1976). Jul 1993;18(9):1140-1149.

198. Berens SA, Colvin DC, Yu CG, Yezierski RP, Mareci TH. Evaluation of the pathologic

characteristics of excitotoxic spinal cord injury with MR imaging. AJNR Am J

Neuroradiol. Aug 2005;26(7):1612-1622.

199. Fukuoka M, Matsui N, Otsuka T, Murakami M, Seo Y. Magnetic resonance imaging of

experimental subacute spinal cord compression. Spine (Phila Pa 1976). Jul 15

1998;23(14):1540-1549.

200. Hackney DB, Finkelstein SD, Hand CM, Markowitz RS, Black P. Postmortem magnetic

resonance imaging of experimental spinal cord injury: magnetic resonance findings

versus in vivo functional deficit. Neurosurgery. Dec 1994;35(6):1104-1111.

201. Ohta K, Fujimura Y, Nakamura M, Watanabe M, Yato Y. Experimental study on MRI

evaluation of the course of cervical spinal cord injury. Spinal Cord. Aug 1999;37(8):580-

584.

202. Takahashi T, Suto Y, Kato S, Ohama E. Experimental acute dorsal compression of cat

spinal cord: correlation of magnetic resonance signal intensity with spinal cord evoked

potentials and morphology. Spine (Phila Pa 1976). Jan 15 1996;21(2):166-173.

203. Becerra JL, Puckett WR, Hiester ED, et al. MR-pathologic comparisons of wallerian

degeneration in spinal cord injury. AJNR Am J Neuroradiol. Jan 1995;16(1):125-133.

204. Quencer RM, Bunge RP, Egnor M, et al. Acute traumatic central cord syndrome: MRI-

pathological correlations. Neuroradiology. 1992;34(2):85-94.

205. Quencer RM, Bunge RP. The injured spinal cord: imaging, histopathologic clinical

correlates, and basic science approaches to enhancing neural function after spinal cord

injury. Spine (Phila Pa 1976). Sep 15 1996;21(18):2064-2066.

206. Greenberg SM, O'Donnell HC, Schaefer PW, Kraft E. MRI detection of new

hemorrhages: potential marker of progression in cerebral amyloid angiopathy. Neurology.

Sep 22 1999;53(5):1135-1138.

207. Furlan J, Fehlings M, Massicotte E. A quantitative and reproducible method to assess

cord compression and canal stenosis after cervical spine trauma: a study of interrater and

intrarater reliability. Spine. 2007;32:2083-2091.

208. Fehlings M, Rao S, Tator C, et al. The Optimal Radiologic Method for Assessing Spinal

Canal Compromise and Cord Compression in Patients with Cervical Spinal Cord Injury

Part 2: Results of a multicenter study. Spine. 1999;24:605-613.

159

209. Cadotte D, Wilson J, Mikulis D, Stroman P, Brady S, Fehlings M. Conventional MRI as

a diagnostic and prognostic tool in spinal cord injury. Expert Opin Med Diang. 2011;5:1-

13.

210. Grossman RG, Toups EG, Frankowski RF, Burau KD, Howley S. North American

Clinical Trials Network for the Treatment of Spinal Cord Injury: goals and progress. J

Neurosurg Spine. Sep 2012;17(1):6-10.

211. Harrell F, ed Regression Modeling Strategies with Applications to Linear Models,

Logistic Regression and Survival Analysis. New York: Springer-Verlag; 2001.

212. Steyerberg E, ed Clinical Prediction Models: A Practical Approach to Development,

Validation, and Updating. New York: Springer; 2009.

213. Greenland S, Finkle WD. A critical look at methods for handling missing covariates in

epidemiologic regression analyses. Am J Epidemiol. Dec 15 1995;142(12):1255-1264.

214. Little R, ed Statistical analysis with missing data. 2nd ed. Hoboken, NJ: Wiley; 2002.

215. Vach W, Blettner M, eds. Missing data in epidemiologic studies. New York, NY: Wiley;

1998. Encyclopedia of Biostatistics.

216. Rubin DB. Inference and Missing Data. Biometrika. 1976;63:581-592.

217. Little R. Regression with missing X's: a review. J Am Stat Assoc. 1992;88:125-134.

218. van Buuren S, Boshuizen HC, Knook DL. Multiple imputation of missing blood pressure

covariates in survival analysis. Stat Med. Mar 30 1999;18(6):681-694.

219. Schaefer J, ed Analysis of incomplete multivariate data. London: Chapman & Hall; 1997.

220. Wilson JR, Grossman RG, Frankowski RF, et al. A clinical prediction model for long-

term functional outcome after traumatic spinal cord injury based on acute clinical and

imaging factors. J Neurotrauma. Sep 2012;29(13):2263-2271.

221. Wyndaele M, Wyndaele J. Incidence, prevalence, and epidemiology of spinal cord injury:

what learns a worldwide literature survey? Spinal Cord. 2006;44:523-529.

222. Burke D, Linden R, Zhang Y, Maiste A, Shields C. Incidence rates and populations at

risk for spinal cord injury: A regional study. Spinal Cord. 2001;39:274-278.

223. Hawryluk G, Roland J, Kwon B, Fehlings M. Protection and repair of the injured spinal

cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord

injury. Neurosurgical Focus. 2008;25:E14.

224. AmericanSpinalInjuryAssociation, ed International Standards for Neurological

Classification of Spinal Cord Injury. Chicago IL2000.

160

225. Liao C, Lui T, Chen L, Chuang C, Huang Y. Spinal cord injury without radiological

abnormality in preschool-aged children: correlation of magnetic resonance imaging

findings with neurological outcomes. J Neurosurgery. 2005;103:S17-23.

226. Dodds T, Martin D, Stolov W, Devo R. A validation of the functional independence

measurement and its performance among rehabilitation inpatients. Arch Phys Med Rehab.

1993;74:531-536.

227. van Middendorp J, Hosman A, Pouw M, Van de Meent H. Is determination between

complete and incomplete traumatic spinal cord injury clinically relevant? Validation of

the ASIA sacral sparing criteria in a prospective cohort of 432 patients. Spinal Cord.

2009;47:809-816.

228. Stineman M, Maislin G, Fiedler R, Granger C. A Prediction Model for Functional

Recovery in Stroke. Stroke. 1997;28:550-556.

229. Rubin DB. Expert Report on Multiple Imputation. 2006;

http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4269b1_05_sponsor.pdf.

Accessed December 2012.

230. Efron B, Tibshirani R. Bootstrap Methods for Standard Errors, Confidence Intervals, and

Other Measures of Statistical Accuracy. Statistical Science. 1986;1:54-75.

231. Heinemann A, Kirk P, Hastie B, et al. Relationships between disability measures and

nursing effort during medical rehabilitation for patients with traumatic brain and spinal

cord injury. Arch Phys Med Rehab. 1997;78:143-149.

232. Wilson JR, Vaccaro A, Harrop JS, et al. The Impact of Facet Dislocation on Clinical

Outcomes after Cervical Spinal Cord Injury: Results of a Multicenter North American

Prospective Cohort Study. Spine (Phila Pa 1976). Aug 14 2013;2:97-103.

233. Dvorak M, Fisher C, Aarabi B, et al. Clinical Outcomes of 90 Isolated Unilateral Facet

Fractures, Subluxations, and Dislocations Treated Surgically and Nonoperatively. Spine.

2007;32:3007-3013.

234. Scher A. Unilateral locked facet in cervical spine injuries. AJR. 1977;129:45-68.

235. Hadley M, Walters B, Grabb P, et al. Treatment of Subaxial Cervical Spinal Injuries.

Neurosurgery. 2002;50:S156-165.

236. Rogers W. Fractures and dislocations of the cervical spine: An end-result study. J Bone

Joint Surg 1957;39:341-376.

237. Durbin F. Fracture-dislocations of the cervical spine. J Bone Joint Surg Br. 1957;39:23-

38.

238. Sonntag V. Management of Bilateral Locked Facets of the Cervical Spine. Neurosurgery.

1981;8:150-152.

http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4269b1_05_sponsor.pdf

161

239. Maiman D, Barolat G, Larson S. Management of Bilateral Locked Facets of the Cervical

Spine. Neurosurgery. 1986;18:542-547.

240. Payer M, Schmidt M. Management of traumatic bilateral locked facets of the subaxial

cervical spine. Contemporary Neurosurgery. 2005;27:1-4.

241. Andreshak J, Dekutoski M. Management of unilateral facet dislocations: A review of the

literature. Orthopedics 1997;20:917-926.

242. Allen B, Ferguson R, Lehmann T. A mechanistic classification of closed, indirect

fractures and dislocations of the lower cervical spine. Spine. 1982;7:1-27.

243. Olerud C, Jonsson H. Compression of the cervical spinal cord after reduction of fracture

dislocations: Report of 2 cases. Acta Orthop Scand. 1991;62:599-601.

244. Lee A, MacLean C, Newton D. Rapid Traction for Reduction of Cervcial Spine

Dislocations. J Bone Joint Surg Br. 1994;76:352-356.

245. Evans D. Reduction of cervical dislocations. J Bone Joint Surg Br. 1961;43:552-555.

246. Brunette D, Rockswold G. Neurologic Recovery following Rapid Spinal Realignment for

Complete Cervical Spinal Cord Injury. Journal of Trauma. 1987;27:445-447.

247. Hadley M, Walters B, Grabb P, et al. Initial Closed Reduction of Cervical Spine Fracture-

Dislocation Injuries. Neurosurgery. 2002;50:S44-50.

248. Ivanic P, Pearson A, Tominaga Y, Simpson A, Yue J, Panjabi M. Mechanism of cervical

spinal cord injury during bilateral facet dislocation. Spine. 2007;15:2467-2473.

249. Wilson JR, Arnold PM, Singh A, Kalsi-Ryan S, Fehlings MG. Clinical prediction model

for acute inpatient complications after traumatic cervical spinal cord injury: a subanalysis

from the Surgical Timing in Acute Spinal Cord Injury Study. J Neurosurg Spine. Sep

2012;17(1 Suppl):46-51.

250. McDonald J, Sadowsky C. Spinal-cord injury. Lancet. 2002;359:417-425.

251. Wilson J, Fehlings M. Adrenal Insufficiency as a Cause of Refractory Hypotension in

Acure Period after Spinal Cord Injury: A Perspective Statement. World Neurosurgery.

2011.

252. Da Paz A, Beraldo P, Almeida M, Neves E, Alves C, Khan P. Traumatic injury to the

spinal cord. Prevalence in Brazilian Hospitals. Paraplegia. 1993;30:636-640.

253. Janneke H, van der Woude L, Stam H. Complications following spinal cord injury:

occurence and risk factors in a lognitudinal study during and after inpatient rehabilitation.

Journal of Rehabilitaion Medicine. 2007;39:393-398.

254. Noreau L, Proulx P, Gagnon L, Drolet M. Secondary impairments after spinal cord

injury: a population-based study. Am J Phys Med Rehab. 2000;79:526-535.

162

255. Valtonen N, Karlson A, Alaranta H. Work participation among persons with traumatic

spinal cord injury and meningomyelocele. J Rehabil Med. 1998;38:192-200.

256. Fehlings M, Wilson J. Timing of surgical intervention in spinal trauma: what does the

evidence indicate? Spine. 2010;35:S159-S160.

257. Furlan J, Kailaya-Vasan A, Aarabi B, Fehlings M. A Novel Approach to Quantitatively

Assess Posttraumatic Cervical Spinal Canal Compromise and Spinal Cord Compression:

A Multicenter Responsiveness Study. Spine. 2011;784-793.

258. Reines H, Harris R. Pulmonary complications of acute spinal cord injuries.

Neurosurgery. 1987;21:193-196.

259. Westgren N, Levi R. Quality of life and traumatic spinal cord injury. Arch Phys Med

Rehab. 1998;79:1433-1439.

260. Meyers A, Andersen E, Hagglund K. A model of outcomes research: spinal cord injury.

Arch Phys Med Rehab. 2000;81:S81-S90.

261. Winslow C, Rozovsky J. Effect of spinal cord injury on the respiratory system. Arch Phys

Med Rehab. 2003;82(803-814).

262. Grossman RG, Frankowski RF, Burau KD, et al. Incidence and severity of acute

complications after spinal cord injury. J Neurosurg Spine. Sep 2012;17(1):119-128.

263. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone

therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial.

JAMA. Jul 8 1998;280(2):159-165.

264. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for

treating severe sepsis and septic shock. Cochrane Database Syst Rev.

2004(1):CD002243.

265. Giugliano GR, Giugliano RP, Gibson CM, Kuntz RE. Meta-analysis of corticosteroid

treatment in acute myocardial infarction. Am J Cardiol. May 1 2003;91(9):1055-1059.

266. AdministrationOnAge. Profile of Older Americas. 2012;

http://www.aoa.gov/aoaroot/aging_statistics/Profile/index.aspx. Accessed April 20, 2012.

267. Cifu D, Seel R, Kreutzer J, McKinley W. Age, outcome, and rehabilitation costs after

paraplegia cause by traumatic injury of the thoracic spinal cord, conus medularis, and

cauda equina. J Neurotrauma. 1999;16:805-815.

268. Cifu DX, Seel RT, Kreutzer JS, McKinley WO. A multicenter investigation of age-

related differences in lengths of stay, hospitalization charges, and outcomes for a matched

tetraplegia sample. Arch Phys Med Rehabil. Jul 1999;80(7):733-740.

http://www.aoa.gov/aoaroot/aging_statistics/Profile/index.aspx

163

269. Seel RT, Huang ME, Cifu DX, Kolakowsky-Hayner SA, McKinley WO. Age-related

differences in length of stays, hospitalization costs, and outcomes for an injury-matched

sample of adults with paraplegia. J Spinal Cord Med. Winter 2001;24(4):241-250.

270. James L, Brett J. Mediators, moderators, and tests for mediation. Journal of Applied

Psychology. 1984;69:307-321.

271. U.S.-Census-Bureau. Sixty-Five Plus in the United States. Statistical Brief 2011;

http://www.census.gov/population/socdemo/statbriefs/agebrief.html. Accessed March 12,

2013.

272. Baron R, Kenny D. The Moderator-Mediator Variable Distinction in Social

Psychological Research: Conceptual, Strategic and Statistical Considerations. Journal of

Personality and Social Psychology. 1986;51:1173-1182.

273. Cifu D, Seel R, Kreutzer J, Martwitz J, McKinley W, Wisory D. Age, outcome and

rehabilitation costs after tetraplegic spinal cord injury. NeuroRehabilitation.

1999;12:177-185.

274. Herbison GJ, Zerby SA, Cohen ME, Marino RJ, Ditunno JF, Jr. Motor power differences

within the first two weeks post-SCI in cervical spinal cord-injured quadriplegic subjects.

J Neurotrauma. Winter 1992;9(4):373-380.

275. McKinley W, Cifu D, Seel R, et al. Age-related outcomes in persons with spinal cord

injury: a summary paper. NeuroRehabilitation. 2003;18(1):83-90.

276. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular

matrices and regeneration failure. Exp Neurol. Feb 2008;209(2):294-301.

277. Fehlings MG, Theodore N, Harrop J, et al. A phase I/IIa clinical trial of a recombinant

Rho protein antagonist in acute spinal cord injury. J Neurotrauma. May 2011;28(5):787-

796.

278. Bedbrook G, Sakae T. The managemet of spinal injuries-past and present. Int Rehabil

Med. 1982;2:45-61.

279. Lo TP, Jr., Cho KS, Garg MS, et al. Systemic hypothermia improves histological and

functional outcome after cervical spinal cord contusion in rats. J Comp Neurol. Jun 10

2009;514(5):433-448.

280. Braughler J, Hall E. Effects of multi-dose methylprednisolone sodium succinate

administration on injured cat spinal cord neurofilament degradation and energy

metabolism. J Neurosurg. 1984;61:290-295.

281. Baskin DS, Simpson RK, Jr., Browning JL, Dudley AW, Rothenberg F, Bogue L. The

effect of long-term high-dose naloxone infusion in experimental blunt spinal cord injury.

J Spinal Disord. Feb 1993;6(1):38-43.

http://www.census.gov/population/socdemo/statbriefs/agebrief.html

164

282. Fehlings MG, Tator CH, Linden RD. The effect of nimodipine and dextran on axonal

function and blood flow following experimental spinal cord injury. J Neurosurg. Sep

1989;71(3):403-416.

283. Bose B, Osterholm J, Kalia M. Ganglioside-induced regeneration and reestablishment of

axonal continuity in spinal cord-transected rats. Neuroscience Letters. 1986;63:165-169.

284. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). 2009.

285. Grossman RG, Fehlings MG, Frankowski RF, et al. A phase I multicenter trial to

investigate the safety and pharmacokinetics profile of riluzole in the treatment of

traumatic spinal cord injury. Session Number 123. Paper presented at: Society for

Neuroscience 2012; New Orleans, LA, USA.

286. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA.

Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease

expression early after spinal cord injury. J Neurochem. Jun 2006;97(5):1314-1326.

287. Teng YD, Mocchetti I, Taveira-DaSilva AM, Gillis RA, Wrathall JR. Basic fibroblast

growth factor increases long-term survival of spinal motor neurons and improves

respiratory function after experimental spinal cord injury. J Neurosci. Aug 15

1999;19(16):7037-7047.

288. Spillmann AA, Bandtlow CE, Lottspeich F, Keller F, Schwab ME. Identification and

characterization of a bovine neurite growth inhibitor (bNI-220). J Biol Chem. Jul 24

1998;273(30):19283-19293.

289. Freund P, Wannier T, Schmidlin E, et al. Anti-Nogo-A antibody treatment enhances

sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult

macaque monkey. J Comp Neurol. Jun 1 2007;502(4):644-659.

290. Sahni V, Kessler JA. Stem cell therapies for spinal cord injury. Nat Rev Neurol. Jul

2010;6(7):363-372.

291. Bradbury EJ, Carter LM. Manipulating the glial scar: chondroitinase ABC as a therapy

for spinal cord injury. Brain Res Bull. Mar 10 2011;84(4-5):306-316.

292. Luo J, Borgens R, Shi R. Polyethylene glycol immediately repairs neuronal membranes

and inhibits free radical production after acute spinal cord injury. J Neurochem. Oct

2002;83(2):471-480.

293. Das M, Patil S, Bhargava N, et al. Auto-catalytic ceria nanoparticles offer

neuroprotection to adult rat spinal cord neurons. Biomaterials. Apr 2007;28(10):1918-

1925.

294. Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the

lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after

motor complete paraplegia: a case study. Lancet. Jun 4 2011;377(9781):1938-1947.

165

295. Otani K, Abe H, Kadoya S. Beneficial effects of methylprednisolone sodium succinate in

the treatment of acute spinal cord injury. Sekitsy Sekizui 1994;7:633-647.

296. Geffner LF, Santacruz P, Izurieta M, et al. Administration of autologous bone marrow

stem cells into spinal cord injury patients via multiple routes is safe and improves their

quality of life: comprehensive case studies. Cell Transplant. 2008;17(12):1277-1293.

297. Yoon SH, Shim YS, Park YH, et al. Complete spinal cord injury treatment using

autologous bone marrow cell transplantation and bone marrow stimulation with

granulocyte macrophage-colony stimulating factor: Phase I/II clinical trial. Stem Cells.

Aug 2007;25(8):2066-2073.

298. Sykova E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in

patients with subacute and chronic spinal cord injury. Cell Transplant. 2006;15(8-9):675-

687.

299. Deda H, Inci MC, Kurekci AE, et al. Treatment of chronic spinal cord injured patients

with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year

follow-up. Cytotherapy. 2008;10(6):565-574.

300. Mackay-Sim A, Feron F, Cochrane J, et al. Autologous olfactory ensheathing cell

transplantation in human paraplegia: a 3-year clinical trial. Brain. Sep 2008;131(Pt

9):2376-2386.

301. Lima C, Escada P, Pratas-Vital J, et al. Olfactory mucosal autografts and rehabilitation

for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. Jan 2010;24(1):10-

22.

302. Saberi H, Moshayedi P, Aghayan HR, et al. Treatment of chronic thoracic spinal cord

injury patients with autologous Schwann cell transplantation: an interim report on safety

considerations and possible outcomes. Neurosci Lett. Sep 26 2008;443(1):46-50.

303. Knoller N, Auerbach G, Fulga V, et al. Clinical experience using incubated autologous

macrophages as a treatment for complete spinal cord injury: phase I study results. J

Neurosurg Spine. Sep 2005;3(3):173-181.

304. Lammertse DP, Jones LA, Charlifue SB, et al. Autologous incubated macrophage therapy

in acute, complete spinal cord injury: results of the phase 2 randomized controlled

multicenter trial. Spinal Cord. Sep 2012;50(9):661-671.

166

Appendices

Appendix 1: International Standards for the Neurological Classification of Spinal Cord

Injury (American Spinal Injury Association: International Standards for Neurological

Classification of Spinal Cord Injury, revised 2011; Atlanta, GA. Reprinted 2011)

167

168

Appendix 2: Emerging Therapies for Acute Traumatic Spinal Cord Injury

Modified from:

Wilson JR, Forgione N, Fehlings MG. Emerging Therapies for Acute Traumatic Spinal Cord

Injury. CMAJ, Epub Dec 10, 2012.

Abstract

At the patient level, traumatic spinal cord injury remains one of the most devastating conditions

encountered in clinical medicine. When considering losses in productivity and the costs of life

long care for affected individuals, the socioeconomic footprint of spinal cord injury is also

significant. Although a therapeutic breakthrough has yet to emerge, a recent surge in preclinical

spinal cord injury related research has led to the identification of several promising

neuroprotective and neuroregenerative therapies, which are currently in various stages of clinical

development. The current review provides general, as well as specialty physicians, with an

update on the current treatment evidence relating to the medical, surgical and cellular based

treatment of acute traumatic spinal cord injury.

Key Points:

1) Hemodynamic support (mean arterial pressure 85-90mmHg) and monitoring in an

intensive care unit setting for the first week after injury are recommended.

2) Decompressive surgery performed before 24 hours after injury has been shown safe,

feasible and, in prospective non-randomized trials, to be associated with improved rates of

neurological recovery.

3) Acute administration of intravenous methylprednisolone is not a standard of care but

rather a neuroprotective option that may be associated with an increased risk of

complications.

4) The safety of cellular transplantation in human spinal cord injury is under study in early

phase clinical trials and, at present, is purely an investigational therapy.

5) An improved understanding of pathophysiology has facilitated early phase clinical trials

with potential regenerative approaches involving Rho and Nogo inhibitors and

investigational neuroprotective therapies including riluzole, minocycline and hypothermia.

169

Keywords: Spinal Cord Injury; Neurotrauma; Drug Therapy; Spine Surgery; Cellular

Transplantation;

Introduction

At present, approximately 85,000 Canadians live with a diagnosis of spinal cord injury

and of these, more than half are secondary to trauma5. It is anticipated that as the population

continues to age, the annual incidence, and overall prevalence, of traumatic spinal cord injury

will continue to rise primarily as a result of increased fall related injuries amongst the elderly6.

Given this information, it is clear that the treatment of these injuries is relevant not only to spine

surgeons and physiatrists, but also to primary care physicians who may treat and counsel spinal

cord injury patients in the emergency department or family practice setting on a day to day basis.

In the current review, we present relevant pathophysiology and recent evidence pertaining to the

medical, surgical and cellular-based treatment of acute traumatic spinal cord injury. Most of the

identified pharmacologic studies were randomized trials or early phase non-randomized

prospective studies. Studies relating to the remaining topics were predominately observational in

design(Box1).

What are the key mechanisms that underlie neural injury and neural repair after spinal

cord injury?

The initial spinal cord trauma, or primary injury, initiates a sequence of pathological

events, collectively referred to as secondary injury. These secondary mechanisms begin within

seconds of the primary injury and continue for several weeks thereafter, leading to an expanded

region of tissue destruction. Initial disruption of the spinal cord vasculature leads to the

development of grey and white matter micro-hemorrhages, interstitial edema and release of

coagulation factors as well as vaso-active amines37

. These events promote thrombosis and

vasospasm of the cord microvasculature causing tissue hypoxia and impaired neuronal

homeostasis. At the cellular level, impairments include neuronal ionic imbalance, membrane

lipid peroxidation, free radical formation and release of toxic levels of the excitatory

neurotransmitter glutamate44

. Neuroprotective agents discussed below act to mitigate secondary

injury elements to reduce the extent of neural injury.

170

The regenerative capacity of Central Nervous System (CNS) neurons is severely limited

compared to neurons in the Peripheral Nervous System due largely to the production of

inhibitory molecules that thwart axonal growth, preventing regeneration of injured nerve tracts.

Nogo is a family of inhibitory proteins that bind to the Nogo receptor found on regenerating

axons276

. This binding leads to the activation of the Rho pathway, causing inhibition of axonal

growth and neuronal cytoskeletal development277

. As opposed to neuroprotective therapies that

limit the extent of acute neural injury, neuroregenerative therapies facilitate neuronal regrowth

by several mechanisms, including the blockade of these inhibitory pathways.

What supportive and surgical management is effective in spinal cord injury?

Historically, it was commonplace for injured patients to be placed in unmonitored

hospital ward beds for prolonged periods while elements of the bony injury healed. However this

approach has been supplanted by aggressive medical and surgical methods focused on

maintaining cord perfusion, avoiding complications, decompressing the spinal cord and

restoring spinal stability115

.

Medical Support

The negative consequences of hypotension on the injured CNS are well established93

.

There is consistent evidence that avoiding hypotension and maintaining aggressive blood

pressure targets during the acute phases post injury improves neurological recovery and reduces

mortality100

. Based on the existing, largely retrospective data, the American Association of

Neurological Surgeons recommends that patients’ mean arterial pressure be maintained at 85-

90mmHg for the first 7 days after injury95

. When volume replacement is inadequate to achieve

this goal, intravenous vasopressor medications may be introduced. In addition to blood pressure

maintenance, it is also recommend that patients, particularly those with severe cervical injuries,

be treated in an intensive care unit(ICU) setting with continuous cardiac, hemodynamic and

respiratory monitoring for the first 7-14 days post injury. The standardized admission of injured

patients to an ICU , has been associated in observational studies with reduced mortality and

morbidity, as well as improved neurological recovery96

.

Surgical Decompression

171

The preclinical literature provides a strong biological imperative to decompress the spinal

cord early after injury118

. In spite of compelling laboratory findings, for many years, surgeons

were reluctant to operate acutely, due to concerns that perioperative hemodynamic changes

would compromise cord perfusion 278

. Also, until the proliferation of instrumented spinal fixation

techniques in the 1990’s, decompression meant further destabilizing an already unstable spine.

In 2002, the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS), was

initiated to investigate the efficacy and safety of performing acute decompressive surgery 119

. In

this prospective, multi-center non-randomized cohort study, 313 patients were enrolled and

underwent either early (<24 hours after injury) or late (≥24 hours after injury) surgical

decompression. Early surgery was found to be safe with a trend towards reduced incidence of in-

hospital complications in the early (24.2%) versus the late (30.5%) surgical group (p=0.21). At

6-months follow-up, early surgery was associated with higher odds of neurological recovery as

defined by a 2 American Spinal Injury Association Impairment Scale grade improvement

(OR=2.57,95%CI:1.11,5.97). Although previous retrospective studies provide conflicting results

surrounding the impact of early surgery on neurological recovery, all studies on the topic have

shown early decompression to be safe121

. Moreover, these results validate the findings of recent

consensus surveys indicating surgeon preference towards early decompression122

.

In the specific case of cervical spine dislocation associated with spinal cord injury, rapid

closed reduction of the spine, using skeletal traction, remains a valid treatment option to achieve

spinal cord decompression. In this case, surgery is performed after closed reduction to re-

establish spinal stability.

Therapeutic Hypothermia

The rationale for therapeutic hypothermia after spinal cord injury emanates from

preclinical studies suggesting that cooling mitigates secondary injury mechanisms279

. Initial

clinical studies involving direct cooling of the cord during surgery failed to demonstratebenefit.

However, in a recent phase I trial, researchers at the University of Miami investigated the acute

use of modest (33ºC) systemic intravascular hypothermia 104

. In this study, there was no

difference in the complication profile observed in the cooled 14 patients and the 14 matched

control patients. As regards neurological recovery, 6 out 14 patients (42.9%) converted from

complete (no motor or sensory function below the level of the injury) to incomplete (motor or

172

sensory function present below the level of injury) status at 1-year follow-up which compares

favorably with the historical literature reported rate of 20%. While at present there is insufficient

evidence to support the use of systemic hypothermia, a multicenter efficacy trial exploring this

therapy is currently being planned

What Pharmacological Therapies have been evaluated for the treatment of spinal cord

injury?

To date, a total of five drug therapies have undergone evaluation in the context of phase

III trials (Table1). While controversy continues to loom over the use of methylprednisolone,

none of these agents have become standard of care.

Neuroprotective Agents

Methylprednisolone Sodium Succinate

Methylprednisolone, which attenuates membrane lipid peroxidation and post-traumatic

inflammation, has consistently been associated with improved neurobehavioral outcomes in

preclinical studies280

. However, the use of methylprednisolone in the clinical setting remains

controversial. In the most recent Cochrane review, the results of 3 studies were combined in

meta-analysis format109

. In the overall analysis, no treatment effect was observed for

methylprednisolone (24-hour regimen) with respect to motor recovery at 6-months follow-up

(Weighted Mean Difference=0.85, 95%CI:-1.79,3.49). However, when commenced within 8-

hours of injury, methylprednisolone administration was associated with an additional 4 points in

motor recovery (Weighted Mean Difference=4.06,95%CI:0.58,7.55). Trends were found

towards increased rates of GI hemorrhage (RR=2.18,95%CI:0.80,5.93) and wound infections

(RR=2.11,95%CI: 0.81,5.49) in methylprednisolone treated patients. Critics of

methylprednisolone cite these complication trends, as well as the use of subgroup analyses to

prove effect, as arguments against its use110

. Balancing the available evidence, consensus

guidelines recommend that 24-hour infusion of methylprednisolone, started within 8-hours of

injury, is a treatment option, that should only be undertaken with knowledge of potential for

treatment related complications107

.

173

Naloxone

The opioid antagonist naloxone demonstrated efficacy as a neuroprotectant in animal

studies by blocking the neurotoxic effects of the endogenous opioid Dynorphin A281

. In the

second National Acute Spinal Cord Injury Study, although overall group values were not

quantified, no difference in motor recovery was observed between the naloxone andplacebo

treated groups at 6-months follow-up105

.

Tirilazad-Mesylate

In the third National Acute Spinal Cord Injury Study, the efficacy of another putative

neuroprotective agent Tirilazad, a non-glucocorticoid 21-aminosteroid, developed to inhibit

neuronal membrane peroxidation, was evaluated in comparison to 24-hour methylprednisolone

infusion106

. At 6-months follow-up, there was no difference between groups with respect to

motor recovery (overall value for Tirilazad group not reported). There has been no large

systematic comparison of Tirilazad to placebo performed to date.

Nimodipine

Nimodipine, a calcium channel blocker, demonstrated efficacy in animal studies by

blocking the calcium-dependent activation of destructive cellular enzymes, and by blocking pre-

synaptic glutamate release282

. However, in a phase III trial evaluating this drug, there was no

difference in motor recovery between patients receiving placebo and those receiving Nimodipine

at 1-year follow-up.

Neuroregenerative Agents

GM-1(Sygen)

Gangliosides are complex glycolipid molecules that comprise an important structural

component of neuronal membranes. Laboratory studies have demonstrated that the

administration of gangliosides can enhance axonal regeneration after injury283

. In addition, a

variety of neuroprotective effects have been attributed to these compounds. In a randomized trial

involving 760 patients, ganglioside compound GM-1(Sygen) was compared to placebo 24

. At 6-

174

months follow-up, there was no difference between these groups in the proportion of patients

achieving marked neurologic recovery (overall quantitative group comparison not reported).

What Pharmacologic Therapies are in development for the treatment of spinal cord

injury?

Several neuroprotective and neuroregenerative agents, targeting specific pathological

mechanisms are now in the midst of clinical translation. While promising, these agents have yet

to demonstrate efficacy in phase III trials.

Neuroprotective Agents

Riluzole

Riluzole is a sodium channel blocker approved by the FDA and Health Canada for the

treatment of Amyotrophic Lateral Sclerosis (ALS). When started at diagnosis, riluzole reduces

motor neuron degeneration and prolongs survival for ALS patients 284

. In preclinical spinal cord

injury models, riluzole has shown to mitigate secondary injury by blocking pathological sodium

channel activation and reducing neuronal glutamate release44

. A phase I/II trial evaluating the

safety and pharmacokinetics of riluzole in human injury was initiated in 2010 and completed in

January 2012, with a preliminary analysis of results recently presented 113,285

.

Minocycline

Minocycline, a chemically modified form of tetracycline, also holds promise as a

neuroprotectant, although the exact mechanisms underlying its efficacy in animal injury models

remain incompletely understood 286

. In light of its preclinical efficacy, and favorable human

safety profile gleaned from its use in other clinical conditions such as acne, minocycline was

brought to trial by investigators at the University of Calgary. In this randomized placebo-

controlled phase II trial, minocycline administration was associated with a trend towards

improved motor recovery, with treated patients experiencing 6 additional points of American

Spinal Injury Association motor score recovery at 1-year follow-up(p=0.20 95% CI:-3,14).

Minocycline administration was also found to be safe, with a single case of transiently elevated

serum transaminases as the only drug related complication.

175

Basic Fibroblast Growth Factor

Injection of this factor has been shown to improve functional and respiratory parameters

in animal injury models, through a presumed mechanism of reducing glutamate mediated

excitotoxicity287

. A recombinant version of this molecule is the subject of a phase I/II trial

currently recruiting patients.

Neuroregenerative Agents

Cethrin

BA-210 is a bacterial derived toxin that inhibits the Rho pathway of inhibitory proteins

and has shown to promote axonal growth in-vitro. When combined with a biohemostatic

adhesive, BA-210 forms a permeable paste called Cethrin that is applied to the spinal cord dura

post injury. Based on documentation of preclinical efficacy, a phase I/IIa trial was undertaken

during which one of two Cethrin dosages was applied to the dura at surgery in 48 patients with

complete injuries114

. At 1-year no serious complications were attributed to Cethrin. Further, in

the 1mg and 3mg dosage groups, cervical injured patients experienced mean American Spinal

Injury Association motor score improvements of 27 and 21 points respectively, which compares

favorably to 10 points of motor recovery observed for similar patients in historical series.

Anti-Nogo

Nogo-A is a protein that has been shown to block axonal growth in the human CNS288

.

Anti-Nogo is a monoclonal antibody engineered to target Nogo-A and promote neural

regeneration 289

. This drug is currently in the midst of early stage clinical investigation.

What is the current status of Cellular Transplantation as a treatment for spinal cord

injury?

The transplantation of stem cells and autologous non-stem cells has been intensively

studied in preclinical injury models. A variety of cellular subtypes have been utilized for this

purpose with each theorized to act through one, or several, of three key mechanisms: 1) release

of growth promoting trophic factors, 2) environmental modification (i.e. reduction of scar or

inflammation) and 3) cellular replacement. The exploration of numerous cellular subtypes is a

176

reflection of the desire to implant the cell with the optimal balance of these functions. In

preclinical studies, cellular transplantation, either alone or in combination with other therapies,

has been associated with enhanced neurobehavioural recovery, with no one cellular subtype

demonstrating superiority290

. In the clinical realm, although prematurely used to treat injured

patients at institutions in several countries throughout the world, no study has established

efficacy for the transplantation of any cellular line. However, in the existing early phase trials,

major adverse events related to transplantation have been rare. Table 2 describes previous and

existing clinical studies involving transplantation of the relevant cellular subtypes. When

interpreting the results of these studies it is important to consider that independent of treatment,

most patients will experience some natural neurologic recovery which plateaus at 4-6 month

after injury. This is relevant since non-controlled studies in which patients are transplanted

before this plateau may report improvement in neurological function after treatment. In this

setting it is impossible to discern whether improvements are related to treatment or simply to

individuals’ natural recovery potential and hence results must be interpreted with caution.

Overall, cellular transplantation is purely an investigation therapy, which at present, should only

be undertaken in the context of clinical trials.

Future Directions

A substantial volume of recent laboratory work has identified a variety of promising

therapies, yet to appear on the clinical landscape. Chondroitinase ABC is a bacterial derived

enzyme which has shown beneficial effects in rodent injury models by degrading elements of the

glial scar that prevents post-traumatic axonal growth291

. Another compound, Polyethylene

glycol, a hydrophilic polymer, when combined with magnesium, has demonstrated

neuroprotective properties in animal models, by preserving neuronal membrane integrity292

. Both

of these treatments appear poised for eventual translation to the clinic. More recently, several

groups have begun to investigate the role of nanomedicine in promoting neuroprotection and

neuroregenerative after injury293

. Cerum-oxide and gold nano-particles have demonstrated

positive results in both in-vitro and in-vivo laboratory studies. Lastly, apart from pharmacologic

therapies, researchers are in the early phases of investigating neuromodulatory approaches, such

as epidural spinal cord stimulation, to aid rehabilitation efforts during the chronic phases after

injury294

. Although only described in case report form, such approaches appear promising, and in

177

the future may augment benefits contributed by acute therapeutics to maximize patients’ long-

term potential for recovery.

Box 1. Evidence used in this review:

We performed a comprehensive computerized literature search using MEDLINE with the key

word “spinal cord injury” and the subheading “treatment”. The literature search was limited to

clinical articles in English language journals, published between 1980 and 2012. Animal studies,

review articles and case reports were excluded. The search strategy was supplemented by

searching the Cochrane Database of Systematic Reviews with the search term “spinal cord

injury”. Through this process a total of 401 abstract were obtained and reviewed by the first

author for relevance to this topic. Of these abstracts, 45 full text articles were obtained and used

as the basis for this review. In addition, we also reviewed the 2002 American Association of

Neurological Surgeons/Congress of Neurological Surgeons cervical spinal cord injury consensus

guidelines as well as the Consortium for Spinal Cord Medicine 2008 spinal cord injury early

acute management clinical practice guidelines.

Box 2. How to use the results of this review in practice:

A 25 year old unrestrained male driver presents to the emergency department 30 minutes after a

high speed motor vehicle accident. His mean arterial pressure is 65mmHg. Neurological

examination reveals lack of motor or sensory function below the 5th

cervical neurologic level.

Subsequent CT scan and MRI reveal a fracture/dislocation of the cervical spine causing

compression of the spinal cord. No other major injuries are identified.

Immediate attention should be placed on optimizing oxygenation and hemodynamic status as

well as on ensuring immobilization of the craniospinal axis. A mean arterial pressure of 85-90

mmHg should be achieved and maintained for the first week following injury using volume

resuscitation augmented with vasopressors as needed. Consultation with the spine surgery

service should be obtained as early as possible to evaluate for suitably of immediate

decompressive/stabilization surgery. Although the patient presents within 8 hours of injury,

administration of methylprednisolone is not standard therapy, but rather is a treatment option that

may lead to increased complications. This patient should be admitted to an intensive care unit

with continuous cardiac, hemodynamic and respiratory monitoring for the first 1-2 weeks after

injury. Although a variety of additional treatments including pharmacologic agents, systemic

hypothermia and cellular transplantation appear promising in early phase trials, none are

recommended for routine clinical use at present.

178

Table 1: Acute pharmacologic agents previously studied in phase III efficacy trials for the

treatment of traumatic spinal cord injury Drug Purported Drug Mechanism Number of RCTs

evaluating drug

Evidence for use

Methylpredni-

solone Sodium

Succinate

(MPSS)

Neuroprotective Agent:

-Attenuates neuronal membrane

peroxidation

-reduced TNF-a release

-improved spinal cord perfusion

-reduced neuronal calcium

influx

-3 (evaluating high

dose 24hour MPSS

vs. placebo)105,111,295

-1 (evaluating high

dose 48hour MPSS

vs high dose 24hour

MPSS)106

- High dose 24hour MPSS infusion:*

- No difference in NASCIS motor

score recovery in overall analysis as

compared to placebo (WMD =0.85[-

1.79,3.49])

- Improved NASCIS motor score

recovery in subgroup receiving

treatment within 8 hours of injury as

compared to placebo (WMD

=4.06[0.58,7.55])

-Trend towards increased wound

infection rates (RR:2.11[0.81,5.49])

and GI bleeding (RR:2.18[0.80,5.93])

in steroid group

- High dose 48hour MPSS infusion:

-No difference in NASCIS motor

score recovery in overall analysis as

compared to 24 hour MPSS

(MD=3.37[-0.54,7.28])

- Trends towards increased rates of

severe sepsis (RR:4.0[0.45,35.38]) and

pneumonia (RR:2.25[0.71,7.15]) as

compared to 24hour MPSS

Naloxone Neuroprotective Agent:

-Blocks the neurotoxic effects

of the endogenous opioid

Dynorphin A

-1 (Naloxone vs.

placebo)105


score recovery between treatment and

placebo group

Nimodipine Neuroprotective Agent:

- L-type calcium channel

blocker

-Prevents activation of calcium

dependent apoptotic enzymes

and blocks presynaptic

glutamate release

-1 (Nimodipine vs.

placebo)111

- No difference in motor neurologic

status between treatment and placebo

groups with ASIA Motor Scores of

67[50-95] and 72[50-94] at 1-year

respectively.

Tirilazad

Mesylate (TM)

Neuroprotective Agent:

-Attenuates neuronal membrane

peroxidation

-1 (TM vs. 24hour

MPSS)106


score recovery between TM and

24hour MPSS group

-no placebo controlled evaluation

available

GM-1

Ganglioside

(Sygen)

Neuroregenerative Agent:

- Important component of CNS

neuronal membranes

-Facilitates axonal regrowth and

regeneration

-Several neuroprotective

properties also attributed to this

compound

-1 (GM-1 vs.

placebo)24

- No difference in marked neurological

recovery between treatment and

placebo groups as defined by at least a

2 grade improvement in modified

Benzel scale grade

WMD: Weighted Mean Difference MD: Mean Difference

NASCIS: National Acute Spinal Cord Injury Study

ASIA: American Spinal Injury Association

Modified Benzel Sale: Ordinal Scale between 1 and 7 with higher number reflecting superior neurologic status

*Reflects the results of meta-analysis combining results of three studies

179

Table 2: Summary of Cellular Sub-Types and Published or Ongoing Clinical Research Studies

Cell Type Clinical studies published or

underway

Patient Population and

time of Cell

Administration

Study Findings

Bone marrow

derived stem

cells (BMC)

1)Geffner 2008296

(Autologous BMC given via

intra-SC injection, IV or

topically)

2)Yoon 2007297

(Autologous BMC with

GM-CSF injected in SC at

lesion site)

3)Sykova 2006298

(Autologous BMCs given IA

or IV)

4) Deda 2008299

(Autologous BMCs intra-

SC)

1) 8 SCI patients: 4 acute

(5days-6months and 4

chronic (5-21yrs).

2) 35 SCI patients: 17

acute(<2weeks), 6

subacute (2-8weeks) and

12 chronic(>8weeks).

3) 20 SCI patients: 7

acute(10-30days) and 13

chronic(2-17mos)

4) 9 complete SCI

patients with chronic SCI

1) No major adverse events.

Improvements in QoL and

bladder function reported as

measured by Barthel Scale and

study specific bladder function

index respectively.

2) No major adverse events in

patients implanted. At least 1 AIS

grade improvement in 30.4% of

patients as compared to 0% in

historical cohort.

3)No major adverse events. 5/7

acute patients and 1/13 chronic

patients experienced neurological

improvement

4) All patients improved at least 1

AIS grade. No complications

reported.

Olfactory

Ensheathing

cells (OEC)

1)Mackay-Sim 2008300

(Autologous OEC injected

intra-SC)

2) Lima 2010301

(Olfactory mucosa

containing OECs injected

intra-SC)

1)6 complete thoracic

chronic (>6mos) SCI

patients

2) 20 complete chronic

(18-89mos) SCI patients

1) No adverse events. No

functional improvement. Sensory

improvement in 1 patient.

2) One case of aseptic meningitis.

At least 1 AIS grade improvement

in 55% of patients.

Schwann Cells

(ShC)

1)Saberi 2008302

(Autologous ShCs obtained

from sural nerve injected

intra-SC)

1)Interim safety report of

4/33 with chronic (28-

80mos) thoracic SCI

1) No major adverse events.

Transient paresthesia and muscle

spasms noted in all 4 patients.

Activated

Autologous

Macrophages

(AAM)

1)Knoller 2005303

(AAM injected intra-SC

immediately caudal to

lesion)

2)Lammertse 2012304

(AAM injected intra-SC

immediately caudal to

lesion)

1)8 complete acute

(<14days) SCI patients

2)43 patients (26

treatment, 17 control)

complete acute

(<14days) SCI patients

1) No major adverse events

related to implantation. At least 2

AIS grade improvement in 3

patients (38%)

2) At least 1 AIS grade

improvement in 7 active treatment

patients (27%) and 10 control

patients (59%). One case of post-

op spinal instability and one case

of post-op atelectasis attributed to

treatment.

Human

Embryonic

stem-cells

(hESC)

1)Geron Corp, Menlo Park,

CA

(hESC OPCs injected intra-

SC)

1)Target enrollment of 8

complete acute (7-

14days) thoracic SCI

patients

1)Trial halted prior to completion

after implantation of 4 patients.

Tissue derived

adult neural

stem cells

1)Curt (ongoing)

(allogeneic HuCNS-SC ®

injected intra-SC)

1)Target enrollment of

12 thoracic chronic

(>6weeks) SCI patients

1) Currently enrolling, no data

reported.

Intra-SC: Intra-Spinal Cord

GM-CSF: Granulocyte Macrophage Colony Stimulating Factor

IA: Intra-arterial IV: Intravenous

OPC: Oligodendroglial Precursor Cell

180

HuCNS-SC: Human CNS Stem Cells (Type of Adult neural stem cell registered to Stem Cell Inc.)

QoL: Quality of Life

AIS: ASIA (American Spinal Injury Association) Injury Scale: An ordinal scale with 5 levels ranging between grade

‘A’ (the most severe) and ‘E’ (perfect neurological status).

181

Appendix 3: Determination of Level of Evidence for papers included in Systematic Review

Author

year

Study Design Patients at similar

point in course of

disease or treatment

Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

Aarabi 2012 + + + + + I

Aito 2003 + + + + - III

Boldin 2006 + _ + + - II

Bondurant 1990 + _ + + _ II

Bravo 1996 + + - + + III

Brown 1991 + + - III

Browne 1993 + + + + - II

Burns 1997 + + - - - III

Calancie 2004 + + + - + II

Chen 1999 + + + + - III

Cifu 1999 + + - - + III

182

Author

year


point in course of


Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

Coleman 2004 + + - - III

Crozier 1992 + + + - III

DeVivo 1990 + + + + + II

Ditunno 1987 + + - - III

Ditunno 1992 + + + - III

Ditunno 2000 + + + - II

Dryden 2004 + - + + - III

Fasset 2007 + + + - III

Falnders 1999 + + + + _ III

Furlan 2005 + + + + + II

Furlan 2009 + + + - II

Groah 2001 + + + + + II

Haisma 2007 + + + - + II

183

Author

year


point in course of


Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

Hayashi 1995 + - + + - III

Hitzig 2008 + + + + + II

Katoh 1995 + + + + III

Kay 2007 + + - - III

Ko 1999 + + - + III

Krassioukov 2003 + + + + - III

Lazar 1989 + + - - III

Levi 1995 + _ + + + III

Mange 1992 + + - - III

Marino 1999 + + + - III

Marino 2004 + + - - III

Mascalchi 1993 + + + + - II

Maynard 1979 + + + + III

184

Author

year


point in course of


Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

McKinley 1999 + + + + III

Meade 2004 + + + + + II

Miyanji 2007 + - _ + + II

O’Beirne 1993 + _ + + _ III

Oleson 2005 + + + - III

Ota 1996 + + - - III

Pollard 2003 + + + - III

Ramon 1997 + - - + - III

Sato 1994 + + + + - III

Seldin 1999 + + + + + II

Shaefer 1992 + + + + - III

Shepard 1999 + + _ + + II

Shimada 1999 + + + + - II

185

Author

year


point in course of


Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

Shin 2005 + + + + - II

Sipski 2004 + + + - III

Steeves 2011 + + + - III

Takahashi 2002 + + + + + II

Tewari 2005 + + + + _ III

van

Middendorp

2009 + + + -

III

van

Middendorp

2011 + + + -

III

Vazquez 2008 + + + + III

Vidal 1995 + - + + + III

Waters 1992 + + + + II

Waters 1993 + + + + II

Waters 1994a + + + + II

186

Author

year


point in course of


Patients followed

long enough for

outcomes to occur

Complete

follow-up

of > 85%

Controlling for

prognostic

factors

Evidence

class

Prospective

cohort

Retrospective

cohort

Case-

control

Case-

series

Waters 1994b + + + + II

Waters 1995 + + + + II

Waters 1995b + + + + II

Weinstein 1997 + + - + III

Werhagen + - + + + III

Wu 1992 + + + - III

Yamazaki 2005 + + + + - III

Zariffa 2011 + + - - III

Zorner 2010 + + - + III

Level 1: Prospective Cohort Study; Level 2: Retrospective study; Level 3: Case Control; Level 4: Case Series; Level 5: Expert

Opinion; (Evidence maybe downgraded depending on patient follow-up, differences in disease time-course and adjustment for

confounders).

187

Appendix 4: Summary of Data in Combined Dataset

Dataset Gender Age Etiology Energy Admis. ASIA exam

Admis GCS

MRI IM signal charac.

F/U ASIA (6or12 mos)

F/u FIM (6or12 mos)

Ster. Adm.

Surg. Time

Surg. Details

STASCIS X X X X X X X X X X X X Data present /426

426 418 423 423 426 415 58 303 238 423 426 426

NACTN X X X X X X X X X X X X Data present /303

303 303 291 291 303 296 254 155 158 285 248 248

Data present In C/H Dataset /729

729 100%

721 99%

714 98%

714 98%

729 100%

711 98%

312 43%

458 63%

394 54%

708 97%

674 92%

674 92%

Admis: Admission; ASIA: American Spinal Injury Association; IM: Intramedullary; C/H: Combined Harmonized; FIM: Function Independence Measure;

Ster.:Steroids;Surg.:Surgery;

Documents

PREDICTION of PATIENT OUTCOMES after TRAUMATIC SPINAL CORD INJURY … · 2015. 6. 10. · ii Prediction of Patient Outcomes after Traumatic Spinal Cord Injury using Acute Clinical