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6
Methods
This chapter describes the methods by which the committee evaluated
the evidence regarding the efficacy and effectiveness of cognitive rehabilita-
tion therapy (CRT) for traumatic brain injury (TBI), including the means by
which the committee searched for and organized the literature. The chapter
also includes an assessment of the quality of study design and its related
impact on how the studies were evaluated. The committee searched for and
reviewed evidence of CRT interventions by either specific cognitive domain
(i.e., memory, attention, executive function, visuospatial perception, and
communication and language) or multi-modal/comprehensive CRT.
The committee iteratively developed a protocol to address the follow-
ing questions:
• o cognitive rehabilitation interventions improve function and re-
D
duce cognitive deficits in adults with mild or moderate-severe TBI?
• re any cognitive rehabilitation interventions associated with risk
A
for adverse events or harm?
• re cognitive rehabilitation interventions delivered through tele-
A
health technology safe and efficacious?
LITERATURE REVIEW
The committee reviewed published systematic reviews (Cicerone et al.
2000, 2005, 2011; ECRI 2009; Kennedy et al. 2008) and worked with a
research librarian to develop search strategies to identify pertinent evidence.
The strategy included searches in the following electronic bibliographic
115
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116 COGNITIVE REHABILITATION THERAPY FOR TBI
databases: Medline, EMBase, PsycInfo, Education Resources Information
Center (ERIC), and Cochrane (e.g., Cochrane DB of Systematic Reviews,
Database of Reviews of Effects [DARE] and Cochrane Central Register of
Controlled Trials). Key terms and Medical Subject Headings (keywords for
Medline) focused on subject areas related to brain injury and CRT. Strategy
parameters limited searches to human subjects, the English language, and
results published between January 1991 and April 2011. The time period
was chosen to include articles prior to Operation Desert Storm, which
began in 1991. Setting time parameters allowed for the evaluation of the
most recent research of relevance, acknowledging that more recent studies
build on the evidence base created by older literature. Furthermore, because
TBI has occurred more frequently among service members in recent con-
flicts, beginning with Operation Desert Storm, research in the field of TBI
and CRT has greatly expanded since that time. To ensure it captured all
relevant studies, the committee conducted a secondary search to identify
articles not found during the electronic search. This practice is common
when conducting a literature review. To complete the secondary search, the
committee extensively examined the bibliographies of previously published
systematic reviews on cognitive rehabilitation therapy for TBI, reading all
full-text articles contained in those reference lists that had not been iden-
tified in the primary search. The committee determined it would include
studies from these reference lists that met inclusion criteria (as described
in Box 6-1), regardless of publishing date. The committee reviewed many
excellent studies during this process; however, not all studies met inclusion
criteria. The secondary search identified 12 additional articles, 2 of which
were published prior to 1991. No other study published prior to 1991, that
the committee reviewed, met inclusion criteria.
The committee focused on studies that used one or several forms of
CRT to ameliorate the effects of traumatic brain injury. Per its charge, the
committee considered CRT for TBI across all severities of injury (mild and
moderate-severe) and across all stages of recovery (acute, subacute, and
chronic). For the purposes of this review, the committee defined the time
periods for acute, subacute, and chronic phases of recovery following TBI
(see Table 6-1). The searches limited the scope of terms to traumatic brain
injury, and did not consider other forms of acquired brain injury, such as
those due to stroke, ischemia, infection, or malignancy. Similarly, the com-
mittee did not review literature on the effects of CRT for non-TBI cognitive
conditions, such as schizophrenia, dementia, or learning disabilities.
The initial electronic search identified 856 studies. Upon review of
titles and abstracts, 121 studies were selected for more detailed review. At
least two committee members reviewed each full text article to determine
relevancy, based on the committee’s inclusion and exclusion criteria, shown
in Box 6-1. Upon full-text review, 43 studies were excluded. An additional
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117
METHODS
BOX 6-1
Inclusion and Exclusion Criteria
1.0 Participants
1.1 Sample is composed of individuals with TBI (open or closed, with or
without secondary hypoxic/ischemic injury), as evidenced by
a. Initial loss/alteration of consciousness on clinical assessment (ab-
normal GCS or posttraumatic amnesia); OR
b. Findings on neuro-imaging consistent with TBI; OR
c. Focal impairment on neurologic exam consistent with TBI; OR
d. Documentation of injury for patients with mild TBI (plausible history
is sufficient for patients with moderate-severe TBI);
OR
1.2 Sample is mixed between TBI and non-TBI but results are reported
separately for TBI subjects (who meet the above definition); OR
1.3 Sample is mixed but contains a majority of TBI participants; AND
1.4 Sample is composed of individuals age 18 or older.
2.0 Treatment
2.1 The intervention is sufficiently described for classification/categorization
as CRT; AND
2.2 Studies that primarily evaluated drug efficacy are excluded.
3.0 Outcome Measures
3.1 Outcome measure(s) could be either objective or subjective measures;
AND
3.2 Studies where the only outcome measures are performance of tasks
that were directly practiced in the treatment protocol are excluded.
4.0 Study Design
4.1 Uncontrolled case reports or case series are excluded.
4.2 Single subject experimental designs (i.e., designs focusing on outcome
within a subject, while incorporating experimental controls) are included.
4.3 or pre-post studies conducted during a postinjury period and over
F
a duration in which substantial change might be expected in the pri-
mary outcome(s), studies with no comparison group (since measured
improvement may be “spontaneous”) (e.g., if mild TBI occurred over 6
months or fewer, and moderate-severe TBI occurred over 12 months or
fewer) are excluded.
4.4 or studies conducted in a postacute period, pre-post studies with no
F
comparison group and only subjective self-report outcomes (which may
be strongly affected by expectation) are excluded.
5.0 Other
5.1 Only studies available in the English language are included.
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118 COGNITIVE REHABILITATION THERAPY FOR TBI
TABLE 6-1 Definitions of Acute, Subacute, and Chronic Phases of
Recovery Post-TBI
Mild TBI Moderate-Severe TBI
Acute < 3 months Acute hospital care
Subacute > 3 months < 6 months Inpatient rehabilitation
Chronic > 6 months < 12 months Outpatient rehabilitation
12 studies were added through the secondary search (i.e., culling refer-
ence lists), for a total of 90 studies upon which the committee based its
conclusions.
The committee designed forms for extracting and summarizing data
from each study, including information about study design and methods,
patient characteristics, treatment interventions and outcomes (i.e., World
Health Organization International Classification of Functioning, Disability
and Health [WHO-ICF] framework), and funding source. The Institute of
Medicine (IOM) contracted two individuals with knowledge and expertise
in CRT to extract data from selected studies; these individuals (i.e., coders)
were neither IOM staff nor members of the committee. At least two com-
mittee members read each of the original articles and compared information
from the studies to the evidence tables completed by the independent cod-
ers. The committee assessed methodologic limitations of studies, described
each study, and synthesized the evidence in a narrative form.
The committee conceptually categorized CRT interventions as either
(1) modular strategies aimed at attention, memory, executive function,
language or social communication, or visuospatial deficits or (2) multi-
modal, comprehensive strategies. The intent of the therapy was categorized
as restorative or compensatory and the goals and setting of therapy as
decontextualized or contextualized. Compensatory strategies for cognitive
impairment (e.g., memory aids) that involved changes to the environment
were categorized as external; strategies that did not involve environmental
changes were categorized as internal. The committee recognizes that con-
ceptual categorizations may not translate to real-world application; these
categories were useful for organizing and evaluating of the evidence. The
separation between modular and multi-modal/comprehensive strategies was
specific to the committee’s charge.
EVALUATION OF THE EVIDENCE
The committee found 90 studies that met selection criteria. Of these,
37 were randomized controlled trials (RCTs) (2 of the 37 addressed both
memory and attention deficits); 15 were nonrandomized, parallel group
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119
METHODS
controlled trials; 19 were pre-post single group studies; and 15 were reports
of one or more single subject, multiple baseline experiments. Of the stud-
ies, 21 addressed multi-modal or comprehensive cognitive rehabilitation,
including RCTs, crossover group, nonrandomized controlled parallel group,
and pre-post single group designs. Table 6-2 provides information about
the number of studies, by design, were identified in each cognitive domain
or multi-modal/comprehensive CRT.
The committee did not identify any CRT studies in the acute phase
of recovery following TBI. Several studies of multimodal/comprehensive
treatment programs were conducted in the subacute phase, but most of
the modular treatment studies were conducted in the chronic phase. Few
studies included in this review specifically enrolled individuals with mild
TBI, or reported results separately for those with mild injuries who were
enrolled in mixed studies. Where evidence exists with respect to treatment
of participants in the subacute phase, or those with mild injuries, the com-
mittee highlighted these studies and relevant findings.
As charged, the committee reviewed evidence across intervention types
to determine if there was evidence regarding efficacy or effectiveness in
individual cognitive domains and multi-modal/comprehensive CRT. Studies
were assessed for improvements in objective measures of benefit, or short-
and long-term treatment effects. Studies were also assessed for subjective
self-reports by patients or family members of treatment benefit, or patient-
centered outcomes. These distinctions are useful because achievements on
objective measures of benefit may not translate into improvement in real-
world functioning. It is important to note that standards for other aspects
of medical practice and research, such as pharmacologic agents, do not
require patient-centered outcomes, such as return to work or improved
quality of life, to show any treatment benefit or to receive regulatory ap-
TABLE 6-2 Study Design by Treatment Domain or Strategy
Study Design
by Treatment Language Multimodal/
Domain or Executive and Social Comprehensive
Strategy Attention Function Communication Memory CRT
RCTs 6 10 4 13 6
Nonrandomized,
0 4 1 2 8
Parallel Group
Pre-Post Single
2 4 0 6 7
Group
Single Subject
1 8 0 6 0
Multiple Baseline
TOTAL 9 26 5 27 21
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120 COGNITIVE REHABILITATION THERAPY FOR TBI
proval or coverage by insurers. Therefore, the absence of patient-centered
outcomes did not necessarily detract from a study’s evidence base. However,
the committee acknowledges that these are important outcomes to report,
especially in goal-oriented and interactive rehabilitation. The committee
also reviewed studies where use of telehealth technology was employed, to
determine the safety and efficacy of CRT applied through these technolo-
gies, compared to interventions applied in clinical settings. The potential
for adverse effects or harm was also evaluated among the included studies.
Also per its charge, the committee separately evaluated studies by the
type of comparator arm, including inert or no treatment, a non-CRT treat-
ment, or another form of CRT. Varying comparators were not considered
more or less useful, only that they answer different questions about the
value of CRT for TBI. To determine efficacy, the committee relied on stud-
ies that compared the primary CRT treatment to either no treatment or a
non-CRT treatment. To determine effectiveness, the committee evaluated
studies comparing CRT treatment to another form of CRT. Comparative
effectiveness studies may be premature without preceding efficacy trials of
the interventions applied in each arm. Furthermore, cognitive processes are
complex and intertwined. Likewise, treatment activities generally employ
multifaceted tasks. Therefore, attempts to predict a highly specific effect
of one CRT intervention (e.g., attention process training) on an isolated
cognitive process (e.g., attention) is difficult without considering the effect
another CRT treatment (e.g., notebook training for a memory deficit) may
have on the original cognitive function of interest (e.g., attention). For
these reasons, interventions comparing one form of CRT to another were
less helpful in determining the impact of a specific intervention to improve
a specific cognitive function.
The committee discussed at length the need to establish relevant crite-
ria for interpreting the studies under review to address the study questions
asked by the Department of Defense. The committee reached consensus on
the grading system shown in Box 6-2.
In an interactive and collaborative process, the committee graded the
overall body of evidence for each CRT category (by domain, TBI sever-
ity, and recovery phase [for example, CRT interventions for attention in
moderate-severe TBI patients in the chronic phase of recovery]). To draw
conclusions about treatment efficacy or effectiveness, the committee quali-
tatively assessed the strength of individual studies, as well as the consistency
of treatment effect among studies. The strength of each study was based on
an iterative quality assessment, considering study design, size of the sample,
reported characteristics of the sample (e.g., injury severity) and treatment
(e.g., dosage, frequency, and timing), control for potentially confounding
factors, magnitude of the treatment effect, statistical significance of the
findings, and the length of follow-up.
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METHODS
BOX 6-2
Evidence Grades
· one or Not informative (0): No evidence because the intervention has not
N
been studied or uninformative evidence because of null results from flawed or
otherwise limited studies
· Limited (+): Interpretable result from a single study or mixed results from two
or more studies
· odest (++): Two or more studies reporting interpretable, informative, and
M
largely similar results
· trong (+++): Reproducible, consistent, and decisive findings from two or
S
more independent studies characterized by the following: (1) replication, re-
flected by the number of studies (multiple, at least two) in the same direction
(2) statistical power and scope of studies (N size of the study and single or
multi-site); and (3) quality of the study design to measure appropriate end-
points (to evaluate efficacy and safety) and minimize bias and confounding
The committee gave more weight to controlled designs than uncon-
trolled (e.g., results of RCTs were given more weight than results from
pre-post single group designs). Conclusions were not based solely on find-
ings from uncontrolled studies; however, the committee included pre-post
single group designs and single subject, multiple baseline experiments in
the review because uncontrolled studies may include useful information
about nascent interventions or lend support to a controlled design with
similar results. Where evidence was informative, the committee specifically
identifies the treatment mode and cites the one or more studies that led to
its conclusion.
QUALITY OF STUDY DESIGNS
In making its conclusions, the committee found most informative
those studies that failed the fewest criteria. Evidence ruled “limited” does
not mean an intervention was inadequate; it may simply mean there were
methodological flaws in the study design. As is commonly seen among
studies evaluating rehabilitation strategies, the overall limitations of the
evidence were due to a number of identified issues in study designs. Some
of these issues involved the heterogeneity and lack of operational defini-
tions of different forms of CRT; small sample sizes; the variety of premor-
bid, comorbid, and environmental factors that may moderate the value of
a given form of CRT across patients; and the range of outcomes that may
be targeted.
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122 COGNITIVE REHABILITATION THERAPY FOR TBI
None of the included studies were absent of limitations in study design.
About one-third of the RCTs were small studies involving fewer than 20
participants, and about 20 percent were larger studies involving more than
50 participants. The severity of TBI was described as moderate or severe in
22 trials and as mild to moderate or mild to moderate-severe in 5 trials, and
was unclearly specified in 10 trials. Most trials included participants who
were many months postinjury (i.e., chronic TBI). Settings for 7 of the larger
trials included a suburban rehabilitation hospital in the northeastern United
States (Cicerone et al. 2008), a rehabilitation center in Colorado (Dahlberg
et al. 2007), three brain injury units in Sydney, Australia (McDonald et
al. 2008), a neuropsychological rehabilitation program at a metropolitan
medical center in New York (Rath et al. 2003), a U.S. military medical
referral center (Salazar et al. 2000),1 four U.S. Department of Veterans
Affairs’ acute inpatient rehabilitation programs (Vanderploeg et al. 2008),
and an academic neurosurgical unit in Hong Kong (Zhu et al. 2007). About
20 percent of the trials described adequate methods to generate random
allocation sequences and assure allocation concealment. A few trials used
quasi-experimental designs that matched patient characteristics such as age
and severity of injury before or after randomization. Few reports detailed a
priori sample size calculations. Some trial reports provided consort figures
or detailed descriptions of follow-up including number of participants ran-
domized to groups, completeness of follow-up, and amount of missing data
by group; most trials did not report all of this information. Few trial reports
detailed analytic methods that were used to handle missing data or specified
numbers of people included in analyses of each outcome measure that was
reported. Trials generally evaluated a heterogeneous group of interventions
including focused interventions targeted at specific and sometimes narrow
deficits and more complex interventions targeted toward multiple deficits.
Trials also had heterogeneous comparison groups. Whether participants
received co-interventions or ancillary treatments such as antidepressants or
pain medications that might augment or interfere with cognitive rehabilita-
tion effects was rarely described. In only a few trials were attempts made to
blind personnel administering objective outcome measures to group assign-
ments of trial participants. The limitations of the evidence do not rule out
meaningful benefit. The committee did not identify methodological issues
in this report to hold CRT research to a higher standard than rehabilitation
research at large; it serves merely as an overt discussion of the issues that
cloud determination of efficacy and effectiveness.
1 The committee reviewed Salazar et al. 2000, with Braverman et al. 1999, and Warden et
al. 2000.
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METHODS
ORGANIZATION OF THE EVIDENCE CHAPTERS
In the chapters that follow, the committee applies the methods and
background knowledge described in the present and previous chapters
to assess the available evidence on CRT treatments for TBI-related defi-
cits in attention, executive function, language and social communication,
memory, and multi-modal/comprehensive CRT (Chapters 7 through 11,
respectively). The committee did not identify any relevant literature for
treatment of visuospatial perception deficits, which are more common after
stroke than TBI. These five chapters include evidence tables with key infor-
mation about included studies. Chapter 12 summarizes studies that applied
telehealth technology, and Chapter 13 describes possible adverse events or
harm from CRT. Conclusions are made within each chapter. Conclusions
about the evidence were not compared to the findings of other systematic
reviews, which the committee deemed beyond its charge.
Each chapter begins with an overview describing the presentation of
studies. As various domains required differential distinctions for proper
analysis, the chapters do not follow a consistent format. The evidence is
organized by the conceptual categories that provided the most use in draw-
ing overall conclusions, dictated by the available body of evidence. The
committee did not interpret the evidence differently within these categories.
For example, memory strategies were divided by internal, external, or re-
storative within mild or moderate-severe TBI. Whereas attention strategies
were divided by those found in the subacute or chronic phase of recovery
in patients with moderate-severe TBI (as no studies were identified of pa-
tients with mild TBI with attentional deficits). When the committee found
evidence showing treatment benefit, the conclusions explicitly identify the
specific intervention and cite the study in which it was described.
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