- Email: [email protected]
Safety of Active Rehabilitation for Persistent Symptoms After Pediatric Sport-Related Concussion: A Randomized Controlled Trial
Accepted Manuscript Safety of active rehabilitation for persistent symptoms after pediatric sport-related concussion: A randomized controlled trial Catherine Chan, MPT, Grant L. Iverson, PhD, Jacqueline Purtzki, MD, Kathy Wong, BSR, Vivian Kwan, BSc, Isabelle Gagnon, PhD, Noah D. Silverberg, PhD PII:
S0003-9993(17)31251-0
DOI:
10.1016/j.apmr.2017.09.108
Reference:
YAPMR 57038
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 22 May 2017 Revised Date:
14 August 2017
Accepted Date: 6 September 2017
Please cite this article as: Chan C, Iverson GL, Purtzki J, Wong K, Kwan V, Gagnon I, Silverberg ND, Safety of active rehabilitation for persistent symptoms after pediatric sport-related concussion: A randomized controlled trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/j.apmr.2017.09.108. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Running head: Safety of active rehabilitation for concussion
RI PT
Safety of active rehabilitation for persistent symptoms after pediatric sport-related concussion: A randomized controlled trial
Catherine Chan, MPT GF Strong Rehab Centre; Department of Physical Therapy, University of British Columbia
SC
Grant L. Iverson, PhD Department of Physical Medicine and Rehabilitation, Harvard Medical School; Spaulding Rehabilitation Hospital; Home Base, A Red Sox Foundation and Massachusetts General Hospital Program; MassGeneral Hospital for Children™ Sport Concussion Program
M AN U
Jacqueline Purtzki, MD GF Strong Rehab Centre; Division of Physical Medicine & Rehabilitation, University of British Columbia Kathy Wong, BSR GF Strong Rehab Centre; Department of Physical Therapy and Department of Occupational Science and Occupational Therapy, University of British Columbia
TE D
Vivian Kwan, BSc University of Calgary
Isabelle Gagnon, PhD McGill University; Montreal Children’s Hospital
EP
Noah D. Silverberg, PhD* Division of Physical Medicine & Rehabilitation, University of British Columbia; Vancouver Coastal Health Research Institute Rehabilitation Research Program; Department of Physical Medicine and Rehabilitation, Harvard Medical School
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
*Corresponding author: Dr. Noah Silverberg, Rehabilitation Research Program, 4255 Laurel St., Vancouver, BC, Canada, V5Z 2G9. Phone: 604-734-1313. Email: [email protected] Acknowledgment of financial support: This study was funded by a Team Grant Award from the Vancouver Coastal Health Research Institute. Clinical trial registration number: NCT02031068
ACCEPTED MANUSCRIPT 1 Abstract
2
Objective: To examine the safety and tolerability of an active rehabilitation program for
3
adolescents who are slow to recover from a sport-related concussion. A secondary objective was
4
to estimate the treatment effect for this intervention.
5
Design: Single-site parallel open-label randomized controlled trial (RCT) comparing treatment
6
as usual (TAU) to TAU plus active rehabilitation.
7
Setting: Outpatient concussion clinic.
8
Participants: Adolescents aged 12-18 with postconcussion symptoms lasting >1 month after a
9
sports-related concussion.
M AN U
SC
RI PT
1
Interventions: TAU consisted of symptom management and return to play advice, return to
11
school facilitation, and physiatry consultation. The active rehabilitation program involved in-
12
clinic sub-symptom threshold aerobic training, coordination exercises, and visualization and
13
imagery techniques with a physiotherapist (M=3.4 sessions) as well as a home exercise program,
14
over six weeks.
15
Main outcome measures: A blinded assessor systematically monitored for predetermined
16
adverse events in weekly telephone calls over the six-week intervention period. The treating
17
physiotherapist also recorded in-clinic symptom exacerbations during aerobic training. The Post-
18
Concussion Symptom Scale was the primary efficacy outcome.
19
Results: Nineteen participants were randomized and none dropped out of the study. Of the 12
20
adverse events detected (6 in each group), 10 were symptom exacerbations from one weekly
21
telephone assessment to the next and 2 were Emergency Department visits. Four adverse events
22
were referred to an external safety committee and deemed unrelated to the study procedures. In-
23
clinic symptom exacerbations occurred in 30% (9 of 30) of aerobic training sessions, but
AC C
EP
TE D
10
ACCEPTED MANUSCRIPT 2 resolved within 24 hours in all instances. In linear mixed modeling, active rehabilitation was
25
associated with a greater reduction on the Post-Concussion Symptom Scale than TAU only.
26
Conclusions: The results support the safety, tolerability, and potential efficacy of active
27
rehabilitation for adolescents with persistent postconcussion symptoms.
RI PT
24
28
Key Words: Craniocerebral Trauma, Athletic Injuries, Post-Concussion Syndrome, Adolescent
30
Health, Physical Therapy Modalities
31
Trial Registration: NCT[De-identified]
32
Funding Source: Vancouver Coastal Health Research Institute (Team Grant)
AC C
EP
TE D
M AN U
SC
29
ACCEPTED MANUSCRIPT 3 Clinical management of athletes with persistent symptoms following sport-related
34
concussion is not well-defined1. Prolonged rest appears to not be an effective treatment option2,3.
35
Gagnon and colleagues4 introduced an alternative treatment approach for adolescents who are
36
slow to recover from concussion. Their active rehabilitation program included graduated aerobic
37
exercise, sport specific drills, and positive visualization techniques. All participants in Gagnon et
38
al’s case series4 experienced symptom improvement and returned to normal activities. A second
39
case series replicated these results5. Positive uncontrolled trials of graduated aerobic exercise in
40
adults have also been reported6,7.
SC
More methodologically rigorous designs are needed to verify the efficacy of aerobic
M AN U
41
RI PT
33
exercise-based interventions. However, safety could be considered a foremost concern given the
43
potential risks of early physical exertion after concussion. Although mixed8, some rodent studies
44
found that vigorous exercise too soon after fluid percussion brain injury could worsen behavioral
45
outcome9,10. Of note, 13 out of 16 participants in the original Gagnon et al4 study (M=7.0 weeks
46
post-injury) had their initial aerobic exertion session terminated because of an increase in
47
symptoms. The resolution of these symptom exacerbations were not systematically recorded.
48
Clinical guidelines for sport-related concussion caution against early physical activity that
49
provokes symptoms, while also acknowledging a potentially therapeutic role for exercise11. It is
50
therefore prudent to better establish the safety of active rehabilitation.
EP
AC C
51
TE D
42
The present study reports on a Phase I-II randomized controlled trial with two aims. The
52
primary aim was to evaluate the safety of active rehabilitation with graded aerobic exertion with
53
systematic surveillance for acute and subacute adverse effects. The secondary aim was to
54
estimate the treatment effect size to inform a Phase III clinical trial. We hypothesized that rates
55
of dropout and adverse events would be comparable between active rehabilitation and control
ACCEPTED MANUSCRIPT 4 groups, and that any symptom exacerbations following exercise would be transient. We further
57
hypothesized that active rehabilitation would be associated with greater improvement in
58
postconcussion symptoms (primary efficacy outcome), though any statistical tests of group
59
differences would likely be underpowered.
60
Methods
61
RI PT
56
The present study describes a parallel group randomized controlled trial with blinded assessors, conducted in a tertiary outpatient concussion clinic. The study protocol was approved
63
by the University of British Columbia Clinical Research Ethics Board and prospectively
64
registered with clinicaltrials.gov (NCT[De-identified]). Consecutive referrals to the clinic
65
between January 2015 and August 2016 were screened for eligibility. Participants were eligible
66
if they were 12-18 years old, sustained a sport-related concussion12, were >4 weeks post-injury,
67
and reported >2 persistent postconcussion symptoms. Exclusion criteria were history of
68
developmental disorder, previous moderate-to-severe traumatic brain injury, in active mental
69
health treatment, previous concussion within six months of the index injury. Note that we did not
70
require that patients self-report exertion tolerance or demonstrate exertion intolerance with
71
graded treadmill testing, unlike some prior trials6,13.
M AN U
TE D
EP
72
SC
62
Referred patients were contacted within one week for an eligibility screen. Potentially eligible participants were invited for an in-person meeting to obtain consent, assent from parental
74
guardian, complete baseline assessment measures, and undergo a medical evaluation with the
75
study physician to confirm their concussion diagnosis and rule out contraindications to exercise.
76
Confirmed eligible participants were randomized (1:1) according to predetermined simple
77
randomization sequence, concealed from the research team, to either treatment as usual (TAU) or
78
TAU plus an active rehabilitation program. Figure 1 depicts participants’ flow through the study.
AC C
73
ACCEPTED MANUSCRIPT 5 79 80
Treatment as Usual Both groups received TAU from an interdisciplinary team, which consisted of: (1) an education session by an occupational therapist about symptom management and return to play12;
82
(2) a school consultation with a hospital-affiliated teacher, who facilitated return to school; and
83
(3) a physiatrist consultation, which included medications prescriptions and referrals to
84
community therapists, as appropriate. These TAU interventions were provided prior to
85
randomization. However, several participants received medication follow-up from the physiatrist
86
after randomization and one participant (assigned to the TAU only group) received follow-up
87
support from the occupational therapist for mental health concerns after randomization.
88
Active Rehabilitation
SC
M AN U
89
RI PT
81
Participants randomized to the experimental arm engaged in active rehabilitation led by a physiotherapist. The active rehabilitation program is described by Gagnon et al.4,5. In brief, it
91
consists of four components: (1) sub-maximal aerobic training, (2) light coordination and sport-
92
specific exercises, (3) visualization and imagery techniques, and (4) a home exercise program.
93
To ensure fidelity, the program was administered according to a written manual. The
94
physiotherapist initially met with each participant to carry out components 1-3 and devise a
95
home exercise program. Follow-up clinic visits were scheduled on a weekly basis until
96
participants could independently carry out their home program.
97
Outcome measures
EP
AC C
98
TE D
90
The primary efficacy outcome was self-reported postconcussion symptoms, assessed with
99
the Post-Concussion Symptom Scale (PCSS)14. The PCSS consists of 22 symptoms rated on a 0-
100
6 scale. It has strong internal consistency (Cronbach’s alpha=.88-.94), sensitivity to concussion,
101
and responsiveness to change associated with natural recovery or treatment15–20. The PCSS was
ACCEPTED MANUSCRIPT 6 102
administered in the intake and follow-up assessments, as well as in each of the six intervening
103
weeks (by telephone), yielding a total of 8 repeated measures. Assessors were blinded to
104
participants’ group assignments. Secondary outcomes administered before and after intervention included measures of
106
health-related quality of life (Patient Reported Outcomes Measurement Information Systems,
107
pediatric short forms21–23), as well as measures of mood (Beck Depression Inventory for Youth-
108
Second Edition24), fatigue (Pediatric Quality of Life Multidimensional Fatigue Scale, Teen
109
Report Standard Version25,26), balance (Balance Error Scoring System27), and cognitive
110
performance (Immediate Post-Concussion Assessment and Cognitive Test28). All of these
111
measures have favorable psychometric properties but only the latter two have been extensively
112
validated in concussion27,28.
113
Safety and Adverse Events
SC
M AN U
A blinded research assistant telephoned participants weekly to administer the PCSS and
TE D
114
RI PT
105
systematically monitor for adverse events using a structured interview for predetermined events.
116
An adverse event was defined as any of the following: (1) significantly worsened symptoms
117
from one week to the next (reliable change on PCSS > 1020), (2) decrease in school attendance
118
and/or extracurricular activity due to symptoms, (3) Emergency Department visit related to
119
postconcussion symptoms, and (4) new injuries. For participants in the active rehabilitation
120
group, the treating therapist also monitored for in-session physical exertion-related symptom
121
exacerbation that did not resolve within 24 hours. Prior to initiating exercise in a given session,
122
the therapist asked the participant to rate all symptoms they were currently experiencing on a 0-
123
10 intensity scale. The therapist recorded participants’ heart rate, perceived exertion, and asked
124
about any new or worsening of symptoms at each minute of the aerobic exercise component,
AC C
EP
115
ACCEPTED MANUSCRIPT 7 using the same 0-10 scale. The protocol was for participants who reported any new symptom
126
(not present at the beginning of the exercise session) or symptom exacerbation (increase of 2 or
127
more points on the 0-10 scale) to discontinue exercise and be monitored for symptom resolution
128
for at least 15 minutes in-session, and if necessary, by telephone after the participant left clinic.
129
RI PT
125
In-session adverse events observed by the treating physiotherapist were reported directly to the Data and Safety Monitoring Committee. Potential adverse events reported to the research
131
assistant in weekly monitoring phone calls were reported to the study physician to determine
132
whether urgent medical attention was required and whether review from an independent Data
133
and Safety Monitoring Committee was warranted. The Committee consisted of a physical
134
therapist and physiatrist not otherwise associated with the study. Their mandate was to evaluate
135
whether the event was attributable to the experimental intervention or participation in the study
136
and if protocol changes were necessary to ensure participant safety.
137
Analyses
M AN U
TE D
138
SC
130
Safety data are reported descriptively. Linear mixed modeling was used to evaluate the effect of treatment on postconcussion symptoms. This statistical approach incorporates all
140
repeated measures (weekly PCSS scores throughout the observation period), allows individual
141
participants to differ at baseline (by including a random intercept), and incorporates all available
142
data (including data from participants with missing values at one or more time points). Because
143
baseline non-equivalency despite random assignment is common with small sample sizes, we
144
planned to statistically control for baseline group differences, if present. Missing data (N=0 from
145
baseline, N=1 for week 2, N=2 for week 3, N=1 from week 4, N=4 from week 5, N=3 from week
146
3, and N=0 from follow-up) was not imputed. Hypothesis testing was not conducted with
147
secondary outcomes due to the small sample size.
AC C
EP
139
ACCEPTED MANUSCRIPT 8 148
Results
149
Patient Characteristics As shown in Figure 1, 19 participants were enrolled. In the absence of prior controlled
150
trials to inform a power analysis, we initially planned to recruit 15 participants per group because
152
there are diminishing returns in precision of the estimated treatment effects with larger
153
samples29,30. However, we terminated recruitment due to slower than expected enrollment and a
154
change in TAU. No participants dropped out. Baseline sample characteristics are reported in
155
Table 1. The most commonly played sports at the time of injury were soccer (n=5), basketball
156
(n=4), and hockey (n=3). At study entry, most participants were attending school full-time (n=5)
157
or part-time (n=13).
M AN U
SC
RI PT
151
Insert Figure 1 and Table 1 about here
158 159
Implementation
As per Gagnon et al.4,5, the active rehabilitation program allowed for some individual
TE D
160
tailoring. The number of in-clinic sessions was determined by the treating physiotherapist based
162
on how quickly participants engaged with the home exercise program and whether they required
163
other physiotherapy modalities. Four participants had positive cervical findings and two patients
164
had positive vestibular findings on initial physical examination. These patients were treated with
165
manual therapy and vestibular rehabilitation, respectively. Note that manual therapy and
166
vestibular rehabilitation are not components of the Gagnon et al.4,5 protocol, but are consistent
167
with new evidence on physiotherapy for concussion31. Participants in the active rehabilitation
168
group received M=3.4 visits with the physiotherapist (range=2-5).
169
Safety
170 171
AC C
EP
161
There were six adverse events in each group. The most common was a reliable PCSS change (>10 points) from one week to the next. Of the 12 adverse events, 4 (3 in TAU only
ACCEPTED MANUSCRIPT 9 group and 1 in the active rehabilitation group) were reported to the external Data and Safety
173
Monitoring Board. One participant (in the TAU only group) had an exacerbation in symptoms
174
from one week to the next on the PCSS, and acknowledged feeling “overwhelmed” and recently
175
seeing a psychiatrist. Another participant (TAU only group) presented to the Emergency
176
Department with neck and headache pain. A third participant (TAU only group) had a significant
177
increase on the PCSS, and had developed focal scalp (injection site) pain after a lidocaine
178
injection. Lastly, the Committee considered an adverse event in the active rehabilitation group
179
secondary to a suspected medication interaction with the participant’s diabetes medication. All
180
four of the adverse events reviewed by the Committee were determined to be unrelated to the
181
intervention and participation in the study.
SC
M AN U
182
RI PT
172
For participants in the active rehabilitation group, there was an onset or worsening of symptoms (>1 on a 0-10 scale) in 37% (n=11 of 30) of clinic sessions involving aerobic exertion,
184
usually involving headache, dizziness, or “pressure in the head.” Most symptom exacerbations
185
occurred in the first (n=6) or second (n=4) aerobic exercise sessions. All symptom exacerbations
186
resolved within 24 hours, most (10 of 11 instances) within 15 minutes discontinuing exercise. All
187
participants were able to tolerate 15 minutes of aerobic exertion without symptom exacerbation
188
by their last clinic session.
189
Efficacy outcomes
EP
AC C
190
TE D
183
Plots of PCSS scores over time, stratified by group (Figure 2), showed subtle baseline
191
differences (higher PCSS score in the control) and a reasonably linear trajectory of symptoms,
192
with no obvious group by time interaction. We therefore controlled for baseline group
193
differences and analyzed time as a continuous variable. We initially fit a linear mixed model with
194
a random intercept and fixed effects for group (experimental vs. control), time, and baseline
ACCEPTED MANUSCRIPT 10 PCSS score. The effect for group was significant (Wald’s t=2.15, p=0.047). Adding a group by
196
time interaction term to the model did not achieve improved model fit [χ2(1)=0.45, p=0.50].
197
Separately adding sex to the model also did not improve model fit [χ2(1)=1.17, p=0.28].
198
Removing group from the original model resulted in a significant degradation of model fit
199
(χ2(1)=4.83, p=0.028), confirming a treatment effect. Re-analyzing these data with time as a
200
categorical variable produced very similar results. The mean change on PCSS from baseline to
201
follow-up was -24.7 (SD=19.1) in the active rehabilitation group and -15.8 (SD=12.5) in the
202
TAU only group, which is associated with a Cohen’s d treatment effect size of 0.55 (i.e., group
203
mean difference for pre-post change).
M AN U
SC
RI PT
195
Insert Figure 2 about here
204
Quality of life, mood, fatigue, balance, and cognition measures obtained prior to and
206
immediately following intervention are reported in Table 1. As mentioned above, these were
207
collected for exploratory and descriptive purposes. No inferential statistical testing was planned
208
or performed.
209
Discussion
TE D
205
Safe and effective interventions are needed for young athletes who do not swiftly recover
211
from sport-related concussion32, but rather have persistent symptoms that limit their participation
212
in school, sport, and other activities. Following up on an encouraging case series of an active
213
rehabilitation program involving aerobic exercise training4, we aimed to more rigorously
214
evaluate the safety and potential efficacy of this intervention in a randomized controlled trial in
215
which we systematically monitored for predetermined adverse events. Our main finding was that
216
adverse events were no more common in participants receiving active rehabilitation in addition
217
to TAU compared to those receiving TAU only, and no adverse events requiring review by an
AC C
EP
210
ACCEPTED MANUSCRIPT 11 218
independent Data and Safety Monitoring Committee were judged to be causally related to the
219
experimental intervention. We also report a statistically significant treatment effect on
220
postconcussion symptoms (primary efficacy outcome), despite a small sample size (N=19). Since launching the present study, several clinical trials involving a similar intervention
RI PT
221
and patient population were published. In an uncontrolled trial, Imhoff et al.33 reported
223
improvement in adolescents who were slow to recover from sport-related concussion with a
224
home exercise program. In a retrospective chart review of adolescents with persistent symptoms
225
who were treated with aerobic exercise training, Chrisman et al.34 found general symptom
226
improvement and noted that “no individual exhibited worsening of symptoms” after starting the
227
intervention (pg. 4). Two randomized controlled trials have also been recently published.
228
Kurowski et al.13 enrolled adolescents who met International Classification of Diseases-10
229
criteria for postconcussional syndrome and self-reported that their symptoms worsened with
230
physical exertion. Participants (N=30) were randomized to receive a home sub-symptom
231
threshold aerobic training program with a stationary bicycle or full-body stretching program (a
232
contact-matched control group). Both groups experienced improved postconcussion symptoms
233
over the six-week intervention period and there was evidence of benefit associated with aerobic
234
training (Cohen’s d=0.5-0.8), similar in magnitude to that found in the present study. No
235
intervention-related adverse events were observed, though it is unclear how Kurowski et al.13
236
monitored safety. In another study by Maerlender et al.35, “recently” concussed college athletes
237
(N=33) were randomly assigned to daily exercise on a stationary bike at mild to moderate
238
perceived exertion or usual care. The two groups did not differ in recovery time or pre/post
239
changes in cognitive performance. The authors noted that participants generally experienced less
240
symptom exacerbation with each consecutive ride.
AC C
EP
TE D
M AN U
SC
222
ACCEPTED MANUSCRIPT 12 241
The “active ingredients” and biopsychosocial mechanisms underlying improvements from this multifaceted active rehabilitation are uncertain. Restored cerebrovascular
243
autoregulation has been proposed to explain the therapeutic benefits of aerobic training after
244
concussion39,40, but this mechanism has yet to be empirically validated. Placebo effects and/or
245
natural recovery could be contributory. In our study and in another randomized trial13,
246
participants in the control group significantly improved. It is also possible that giving adolescents
247
“permission” to become more active helps to counter maladaptive illness beliefs (e.g.,
248
kinesophobia) and encourages them to reintegrate into their social and recreational activities,
249
which likely confers a number of mental and physical health benefits separate from the benefits
250
of aerobic exercise41. Patients in the active rehabilitation arm of our study with positive cervical
251
or vestibular exam findings were provided with targeted treatment for these conditions. Future
252
research will be required to learn whether these treatment components contribute to positive
253
outcomes above and beyond aerobic exercise training. It will also be helpful to identify patient
254
characteristics associated with treatment response.
255
Study Limitations
SC
M AN U
TE D
The present study has several limitations. First, the modest sample size (n=19) may have
EP
256
RI PT
242
prevented us from identifying rare adverse events and having sufficient power to detect small
258
group differences in observed adverse events. It likely also accounted for the failure of
259
randomization to achieve group balance on important baseline characteristics. We adjusted for
260
these baseline differences in mixed modeling analyses. Second, we did not restrict participants
261
from receiving concussion treatment outside of the study. With a large sample, randomization
262
should eliminate this potential confound of external treatment, but there could have been group
263
imbalance in our study. Of participants in the active rehabilitation group, only one acknowledged
AC C
257
ACCEPTED MANUSCRIPT 13 to the treating physiotherapist they were receiving treatment outside of the study protocol
265
(acupuncture). Third, the treatment we evaluated includes a home exercise program, but we did
266
not systematically monitor adherence levels to this component. Fourth, we assessed participants’
267
symptoms throughout the study period, including immediately post-treatment, but not beyond.
268
We do not know the long-term effects of the intervention or whether symptom improvements
269
translate into improvements in functional outcomes (e.g., sport and academic performance).
270
Fifth, the fact that we recruited from a specialty clinic and were only able to enroll ~13% of
271
screened patients points to a strong selection bias. The present findings may not generalize to
272
adolescents with relatively mild symptoms, seen more acutely or in different settings (e.g.,
273
primary care).
274
Conclusions
SC
M AN U
275
RI PT
264
The most important and unique contribution of the present study is prospective monitoring for predetermined adverse effects to more compellingly demonstrate safety of active
277
rehabilitation that incorporates aerobic exercise training in highly symptomatic patients who are
278
seen in a specialty clinic. This finding is in line with observational studies that found no
279
significant relationship between physical activity, symptom exacerbations, and clinical
280
outcomes36,37 or an inverse relationship (i.e., positive effects of physical activity)38. It should
281
help to quell concerns about prescribing increased physical activity for youth with ongoing
282
postconcussion symptoms. Our findings are also consistent with the conclusion of a very recently
283
published systematic review, that “closely monitored active rehabilitation programmes involving
284
controlled subsymptom threshold, submaximal exercise for adults and adolescents with
285
persistent symptoms after concussion may be of benefit” (pg. 4)3.
286
AC C
EP
TE D
276
ACCEPTED MANUSCRIPT 14 287
AC C
EP
TE D
M AN U
SC
RI PT
288
ACCEPTED MANUSCRIPT 15 References
290 291 292 293
1.
Makdissi M, Cantu RC, Johnston KM, McCrory P, Meeuwisse WH. The difficult concussion patient: what is the best approach to investigation and management of persistent (>10 days) postconcussive symptoms? Br J Sports Med. 2013;47(5):308313. doi:10.1136/bjsports-2013-092255.
294 295 296
2.
Thomas DG, Apps JN, Hoffmann RG, McCrea M, Hammeke T. Benefits of Strict Rest After Acute Concussion: A Randomized Controlled Trial. Pediatrics. 2015;135(2). doi:10.1542/peds.2014-0966.
297 298 299
3.
Schneider KJ, Leddy JJ, Guskiewicz KM, et al. Rest and treatment/rehabilitation following sport-related concussion: a systematic review. Br J Sports Med. 2017:bjsports2016-097475. doi:10.1136/bjsports-2016-097475.
300 301 302
4.
Gagnon I, Galli C, Friedman D, Grilli L, Iverson GL. Active rehabilitation for children who are slow to recover following sport-related concussion. 2009;23(November):956-964. doi:10.3109/02699050903373477.
303 304 305
5.
Gagnon I, Grilli L, Friedman D, Iverson GL. A pilot study of active rehabilitation for adolescents who are slow to recover from sport-related concussion. Scand J Med Sci Sport. 2016;26(3):299-306. doi:10.1111/sms.12441.
306 307 308
6.
Leddy JJ, Kozlowski K, Donnelly JP, Pendergast DR, Epstein LH, Willer B. A Preliminary Study of Subsymptom Threshold Exercise Training for Refractory PostConcussion Syndrome. Clin J Sport Med. 2010;20:21-27.
309 310 311
7.
Cordingley D, Girardin R, Reimer K, et al. Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes. J Neurosurg Pediatr. 2016:1-10. doi:10.3171/2016.5.PEDS16139.
312 313 314 315
8.
Mychasiuk R, Hehar H, Ma I, Candy S, Esser MJ. Reducing the time interval between concussion and voluntary exercise restores motor impairment, short-term memory, and alterations to gene expression. Eur J Neurosci. 2016;44(7):2407-2417. doi:10.1111/ejn.13360.
316 317 318 319
9.
Griesbach GS, Hovda D a, Molteni R, Wu a, Gomez-Pinilla F. Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience. 2004;125(1):129-139. doi:10.1016/j.neuroscience.2004.01.030.
320 321 322
10.
323 324 325
11.
McCrory P, Meeuwisse W, Dvorak J, et al. Consensus statement on concussion in sport— the 5 th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med. 2017:bjsports-2017-097699. doi:10.1136/bjsports-2017-097699.
326 327
12.
McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012.
AC C
EP
TE D
M AN U
SC
RI PT
289
Wells EM, Goodkin HP, Griesbach GS. Challenges in Determining the Role of Rest and Exercise in the Management of Mild Traumatic Brain Injury. J Child Neurol. 2016;31(1):86. doi:10.1177/0883073815570152.
ACCEPTED MANUSCRIPT 16 Br J Sports Med. 2013;47(5):250-258. doi:10.1136/bjsports-2013-092313.
328
13.
Kurowski BG, Hugentobler J, Quatman-Yates C, et al. Aerobic Exercise for Adolescents With Prolonged Symptoms After Mild Traumatic Brain Injury. J Head Trauma Rehabil. 2016;32(2):1. doi:10.1097/HTR.0000000000000238.
332 333 334 335
14.
Lovell MR, Iverson GL, Collins MW, et al. Measurement of Symptoms Following SportsRelated Concussion : Reliability and Normative Data for the Post-Concussion Scale Measurement of Symptoms Following Sports-Related Concussion : Reliability and Normative Data for the Post-Concussion Scale. 2010;(August 2011):37-41.
336 337 338 339
15.
McLeod TCV, Leach C. Psychometric properties of self-report concussion scales and checklists. J Athl Train. 2012;47(2):221-223. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3418135&tool=pmcentrez&re ndertype=abstract.
340 341 342
16.
Sullivan K, Garden N. A comparison of the psychometric properties of 4 postconcussion syndrome measures in a nonclinical sample. J Head Trauma Rehabil. 2011;26(2):170176. doi:10.1097/HTR.0b013e3181e47f95.
343 344 345
17.
Iverson GL, Brooks BL, Collins MW, Lovell MR. Tracking neuropsychological recovery following concussion in sport. Brain Inj. 2006;20(3):245-252. doi:10.1080/02699050500487910.
346 347
18.
Lovell MR, Collins MW, Iverson GL, et al. Recovery From Mild Concussion in High School Athletes. J Neurosurg. 2003;98:98295-301295. doi:10.3171/jns.2003.98.2.0296.
348 349 350
19.
Moser RS, Glatts C, Schatz P. Efficacy of immediate and delayed cognitive and physical rest for treatment of sports-related concussion. J Pediatr. 2012;161(5):922-926. doi:10.1016/j.jpeds.2012.04.012.
351 352
20.
Iverson GL, Lovell MR, Collins MW. Interpreting change on ImPACT following sport concussion. Clin Neuropsychol. 2003;17(4):460-467. doi:10.1076/clin.17.4.460.27934.
353 354 355
21.
Irwin DE, Stucky B, Langer MM, et al. An item response analysis of the pediatric PROMIS anxiety and depressive symptoms scales. Qual Life Res. 2010;19(4):595-607. doi:10.1007/s11136-010-9619-3.
356 357 358
22.
Varni JW, Stucky BD, Thissen D, et al. PROMIS Pediatric Pain Interference Scale: An Item Response Theory Analysis of the Pediatric Pain Item Bank. J Pain. 2010;11(11):1109-1119. doi:10.1016/j.jpain.2010.02.005.
359 360 361
23.
362 363
24.
Beck JS, Beck AT, Jolly JB, Steer RA. Beck Youth Inventories, Second Edition for Children and Adolescents (BYI-II). San Antonio: Harcourt Assessment; 2005.
364 365 366
25.
Varni JW, Limbers CA. The PedsQL??? Multidimensional Fatigue Scale in young adults: Feasibility, reliability and validity in a University student population. Qual Life Res. 2008;17(1):105-114. doi:10.1007/s11136-007-9282-5.
AC C
EP
TE D
M AN U
SC
RI PT
329 330 331
Varni JW, Magnus B, Stucky BD, et al. Psychometric properties of the PROMIS pediatric scales: Precision, stability, and comparison of different scoring and administration options. Qual Life Res. 2014;23(4):1233-1243. doi:10.1007/s11136-013-0544-0.
ACCEPTED MANUSCRIPT 17 26.
Varni JW, Limbers CA. The Pediatric Quality of Life Inventory: Measuring Pediatric Health-Related Quality of Life from the Perspective of Children and Their Parents. Pediatr Clin North Am. 2009;56(4):843-863. doi:10.1016/j.pcl.2009.05.016.
370 371
27.
Bell DR, Guskiewicz KM, Clark M a, Padua D a. Systematic review of the balance error scoring system. Sports Health. 2011;3(3):287-295. doi:10.1177/1941738111403122.
372 373 374
28.
Alsalaheen B, Stockdale K, Pechumer D, Broglio SP. Validity of the Immediate Post Concussion Assessment and Cognitive Testing (ImPACT). Sport Med. 2016;46(10):14871501. doi:10.1007/s40279-016-0532-y.
375 376
29.
Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharm Stat. 2005;4(4):287-291. doi:10.1002/pst.185.
377 378
30.
Stallard N. Optimal sample sizes for phase II clinical trials and pilot studies. Stat Med. 2012;31(11-12):1031-1042. doi:10.1002/sim.4357.
379 380 381
31.
Schneider KJ, Meeuwisse WH, Nettel-Aguirre A, et al. Cervicovestibular rehabilitation in sport-related concussion: a randomised controlled trial. Br J Sport Med. 2014;48:12941298. doi:10.1136/bjsports-2013-093267.
382 383 384 385
32.
Cancelliere C, Hincapié C a, Keightley M, et al. Systematic Review of Prognosis and Return to Play After Sport Concussion: Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3S):S210--S229. doi:10.1016/j.apmr.2013.06.035.
386 387 388
33.
Imhoff S, Fait P, Carrier-toutant F, Boulard G. Efficiency of an Active Rehabilitation Intervention in a Slow-to-Recover Paediatric Population following Mild Traumatic Brain Injury : A Pilot Study. 2016;2016. doi:10.1155/2016/5127374.
389 390 391
34.
Chrisman SPD, Whitlocka KB, Somers E, et al. Pilot study of the Sub-Symptom Threshold Exercise Program (SSTEP) for persistent concussion symptoms in youth. NeuroRehabilitation. 2017;Epub ahead.
392 393 394
35.
Maerlender A, Rieman W, Lichtenstein J, et al. Programmed Physical Exertion in Recovery From Sports-Related Concussion: A Randomized Pilot Study. Dev Neuropsychol. 2015;40(5):273-278. doi:10.1080/87565641.2015.1067706.
395 396 397 398
36.
Wiebe D, Nance M, Houseknecht E, et al. Ecologic Momentary Assessment to Accomplish Real-Time Capture of Symptom Progression and the Physical and Cognitive Activities of Patients Daily Following Concussion. JAMA Pediatr. 2016;170(11):11081110.
399 400 401
37.
402 403 404
38.
Grool AM, Aglipay M, Momoli F, et al. Association Between Early Participation in Physical Activity Following Acute Concussion and Persistent Postconcussive Symptoms in Children and Adolescents. Jama. 2016;316(23):2504. doi:10.1001/jama.2016.17396.
405
39.
Leddy JJ, Kozlowski K, Fung M, Pendergast DR, Willer B. Regulatory and autoregulatory
AC C
EP
TE D
M AN U
SC
RI PT
367 368 369
Silverberg ND, Iverson GL, McCrea M, Apps JN, Hammeke TA, Thomas DG. ActivityRelated Symptom Exacerbations After Pediatric Concussion. JAMA Pediatr. 2016;170(10):946-953. doi:10.1001/jamapediatrics.2016.1187.
ACCEPTED MANUSCRIPT 18 physiological dysfunction as a primary characteristic of post concussion syndrome : Implications for treatment. 2007;22:199-205.
406 407
40.
Leddy JJ, Sandhu H, Sodhi V, Baker JG, Willer B. Rehabilitation of Concussion and Postconcussion Syndrome. Sports Health. 2012;4(2):147-154. doi:10.1177/1941738111433673.
411 412 413
41.
DiFazio M, Silverberg ND, Kirkwood MW, Bernier R, Iverson GL. Prolonged Activity Restriction After Concussion: Are We Worsening Outcomes? Clin Pediatr (Phila). 2015. doi:10.1177/0009922815589914.
RI PT
408 409 410
414
AC C
EP
TE D
M AN U
SC
415
ACCEPTED MANUSCRIPT 19 416
Figure legends
417 418
Figure 1. CONSORT Flow Diagram.
RI PT
419
Figure 2. Plots of Post-Concussion Symptom Scale (PCSS) total score over time in weeks, stratified by group (active rehabilitation vs. treatment as usual).
422
(a) Raw data
423
(b) Baseline referenced, by subtracting each participant’s score from their own baseline.
SC
420 421
424
AC C
EP
TE D
M AN U
425
ACCEPTED MANUSCRIPT
Table 1. Participant characteristics and outcome data by group.
M=132; SD=52.0
M=123; SD=48.50
M=1.8; SD=1.17 12 Pre Post M SD M SD
M=1.7; SD=1.15 6 Pre Post M SD M SD
M=1.9; SD=1.20 6 Pre Post M SD M SD
28.6
32.3
25.1
56.9
31.0
40.3
29.4
51.5
27.8
25.0
19.4
16.9
19.7
24.2
15.7
36.3
18.5
32.2
16.5
40.8
14.6
17.0
11.5
12.7 12.7 13.3
5.9 5.3 6.6
11.0 9.6 10.9
5.9 4.6 5.8
12.4 10.6 13.3
7.2 5.7 6.7
11.3 8.6 12.3
7.1 5.0 5.1
13.0 14.6 13.2
4.8 4.3 6.9
10.7 10.6 9.6
5.1 4.3 6.3
58.7 53.4 61.8
9.3 9.1 12.8
54.9 48.6 56.8
17.6 9.5 14.1
59.2 54.0 60.7
10.1 10.7 61.8
54.3 49.0 57.0
22.8 10.5 17.7
58.2 52.8 62.8
9.0 8.0 12.0
55.4 48.3 56.6
12.6 9.1 11.1
54.2
13.1
49.7
10.2
55.2
13.9
50.8
11.2
53.2
13.1
48.8
10.7
48.2 13.7 16.2
10.9 11.0 11.9
51.8 11.3 10.8
8.0 8.6 5.5
48.6 14.7 16.3
13.1 13.4 15.7
50.4 10.2 11.4
8.9 9.3 7.4
47.9 12.7 16.0
8.9 8.8 8.1
53.0 12.2 10.3
7.4 8.3 3.2
77.1 65.7 31.2 0.7
12.3 14.0 6.8 0.1
82.2 73.5 37.1 0.6
11.0 14.1 7.0 0.1
78.3 69.0 30.9 0.69
12.2 11.3 5.4 0.1
77.6 75.8 37.9 0.57
11.1 16.2 3.1 0.0
75.9 62.7 32.6 0.7
12.9 16.0 8.0 0.1
86.3 71.5 36.3 0.6
9.6 12.4 9.4 0.1
SC
54.1
M AN U
Post-Concussion Symptom Scale Pediatric Quality of Life Multidimensional Fatigue Scale General Fatigue Sleep Cognitive Fatigue PROMIS Scales Pediatric Pain Impact Pediatric Anxiety Pediatric Fatigue Pediatric Depressive Symptoms Pediatric Peer Relationships Beck Depression Inventory Balance Error Scoring System ImPACT Cognitive Composites Verbal Memory Visual Memory Visual Motor Speed Reaction Time
TE D
Age Gender (n female) Time between injury and initial assessment (days) Number of prior concussions Adverse events (n)
Active Rehabilitation (N=10) M=15.9; SD=1.66 6 M=139; SD=56.30
RI PT
M=15.5; SD=1.47 14
Treatment As Usual (N=9) M=15.1; SD=1.42 8
Full Sample (N=19)
AC C
EP
Abbreviations: PROMIS = Patient Reported Outcomes Measurement Information Systems; ImPACT = Immediate Post-Concussion Assessment and Cognitive Test
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0003-9993(17)31251-0
DOI:
10.1016/j.apmr.2017.09.108
Reference:
YAPMR 57038
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 22 May 2017 Revised Date:
14 August 2017
Accepted Date: 6 September 2017
Please cite this article as: Chan C, Iverson GL, Purtzki J, Wong K, Kwan V, Gagnon I, Silverberg ND, Safety of active rehabilitation for persistent symptoms after pediatric sport-related concussion: A randomized controlled trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2017), doi: 10.1016/j.apmr.2017.09.108. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Running head: Safety of active rehabilitation for concussion
RI PT
Safety of active rehabilitation for persistent symptoms after pediatric sport-related concussion: A randomized controlled trial
Catherine Chan, MPT GF Strong Rehab Centre; Department of Physical Therapy, University of British Columbia
SC
Grant L. Iverson, PhD Department of Physical Medicine and Rehabilitation, Harvard Medical School; Spaulding Rehabilitation Hospital; Home Base, A Red Sox Foundation and Massachusetts General Hospital Program; MassGeneral Hospital for Children™ Sport Concussion Program
M AN U
Jacqueline Purtzki, MD GF Strong Rehab Centre; Division of Physical Medicine & Rehabilitation, University of British Columbia Kathy Wong, BSR GF Strong Rehab Centre; Department of Physical Therapy and Department of Occupational Science and Occupational Therapy, University of British Columbia
TE D
Vivian Kwan, BSc University of Calgary
Isabelle Gagnon, PhD McGill University; Montreal Children’s Hospital
EP
Noah D. Silverberg, PhD* Division of Physical Medicine & Rehabilitation, University of British Columbia; Vancouver Coastal Health Research Institute Rehabilitation Research Program; Department of Physical Medicine and Rehabilitation, Harvard Medical School
AC C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
*Corresponding author: Dr. Noah Silverberg, Rehabilitation Research Program, 4255 Laurel St., Vancouver, BC, Canada, V5Z 2G9. Phone: 604-734-1313. Email: [email protected] Acknowledgment of financial support: This study was funded by a Team Grant Award from the Vancouver Coastal Health Research Institute. Clinical trial registration number: NCT02031068
ACCEPTED MANUSCRIPT 1 Abstract
2
Objective: To examine the safety and tolerability of an active rehabilitation program for
3
adolescents who are slow to recover from a sport-related concussion. A secondary objective was
4
to estimate the treatment effect for this intervention.
5
Design: Single-site parallel open-label randomized controlled trial (RCT) comparing treatment
6
as usual (TAU) to TAU plus active rehabilitation.
7
Setting: Outpatient concussion clinic.
8
Participants: Adolescents aged 12-18 with postconcussion symptoms lasting >1 month after a
9
sports-related concussion.
M AN U
SC
RI PT
1
Interventions: TAU consisted of symptom management and return to play advice, return to
11
school facilitation, and physiatry consultation. The active rehabilitation program involved in-
12
clinic sub-symptom threshold aerobic training, coordination exercises, and visualization and
13
imagery techniques with a physiotherapist (M=3.4 sessions) as well as a home exercise program,
14
over six weeks.
15
Main outcome measures: A blinded assessor systematically monitored for predetermined
16
adverse events in weekly telephone calls over the six-week intervention period. The treating
17
physiotherapist also recorded in-clinic symptom exacerbations during aerobic training. The Post-
18
Concussion Symptom Scale was the primary efficacy outcome.
19
Results: Nineteen participants were randomized and none dropped out of the study. Of the 12
20
adverse events detected (6 in each group), 10 were symptom exacerbations from one weekly
21
telephone assessment to the next and 2 were Emergency Department visits. Four adverse events
22
were referred to an external safety committee and deemed unrelated to the study procedures. In-
23
clinic symptom exacerbations occurred in 30% (9 of 30) of aerobic training sessions, but
AC C
EP
TE D
10
ACCEPTED MANUSCRIPT 2 resolved within 24 hours in all instances. In linear mixed modeling, active rehabilitation was
25
associated with a greater reduction on the Post-Concussion Symptom Scale than TAU only.
26
Conclusions: The results support the safety, tolerability, and potential efficacy of active
27
rehabilitation for adolescents with persistent postconcussion symptoms.
RI PT
24
28
Key Words: Craniocerebral Trauma, Athletic Injuries, Post-Concussion Syndrome, Adolescent
30
Health, Physical Therapy Modalities
31
Trial Registration: NCT[De-identified]
32
Funding Source: Vancouver Coastal Health Research Institute (Team Grant)
AC C
EP
TE D
M AN U
SC
29
ACCEPTED MANUSCRIPT 3 Clinical management of athletes with persistent symptoms following sport-related
34
concussion is not well-defined1. Prolonged rest appears to not be an effective treatment option2,3.
35
Gagnon and colleagues4 introduced an alternative treatment approach for adolescents who are
36
slow to recover from concussion. Their active rehabilitation program included graduated aerobic
37
exercise, sport specific drills, and positive visualization techniques. All participants in Gagnon et
38
al’s case series4 experienced symptom improvement and returned to normal activities. A second
39
case series replicated these results5. Positive uncontrolled trials of graduated aerobic exercise in
40
adults have also been reported6,7.
SC
More methodologically rigorous designs are needed to verify the efficacy of aerobic
M AN U
41
RI PT
33
exercise-based interventions. However, safety could be considered a foremost concern given the
43
potential risks of early physical exertion after concussion. Although mixed8, some rodent studies
44
found that vigorous exercise too soon after fluid percussion brain injury could worsen behavioral
45
outcome9,10. Of note, 13 out of 16 participants in the original Gagnon et al4 study (M=7.0 weeks
46
post-injury) had their initial aerobic exertion session terminated because of an increase in
47
symptoms. The resolution of these symptom exacerbations were not systematically recorded.
48
Clinical guidelines for sport-related concussion caution against early physical activity that
49
provokes symptoms, while also acknowledging a potentially therapeutic role for exercise11. It is
50
therefore prudent to better establish the safety of active rehabilitation.
EP
AC C
51
TE D
42
The present study reports on a Phase I-II randomized controlled trial with two aims. The
52
primary aim was to evaluate the safety of active rehabilitation with graded aerobic exertion with
53
systematic surveillance for acute and subacute adverse effects. The secondary aim was to
54
estimate the treatment effect size to inform a Phase III clinical trial. We hypothesized that rates
55
of dropout and adverse events would be comparable between active rehabilitation and control
ACCEPTED MANUSCRIPT 4 groups, and that any symptom exacerbations following exercise would be transient. We further
57
hypothesized that active rehabilitation would be associated with greater improvement in
58
postconcussion symptoms (primary efficacy outcome), though any statistical tests of group
59
differences would likely be underpowered.
60
Methods
61
RI PT
56
The present study describes a parallel group randomized controlled trial with blinded assessors, conducted in a tertiary outpatient concussion clinic. The study protocol was approved
63
by the University of British Columbia Clinical Research Ethics Board and prospectively
64
registered with clinicaltrials.gov (NCT[De-identified]). Consecutive referrals to the clinic
65
between January 2015 and August 2016 were screened for eligibility. Participants were eligible
66
if they were 12-18 years old, sustained a sport-related concussion12, were >4 weeks post-injury,
67
and reported >2 persistent postconcussion symptoms. Exclusion criteria were history of
68
developmental disorder, previous moderate-to-severe traumatic brain injury, in active mental
69
health treatment, previous concussion within six months of the index injury. Note that we did not
70
require that patients self-report exertion tolerance or demonstrate exertion intolerance with
71
graded treadmill testing, unlike some prior trials6,13.
M AN U
TE D
EP
72
SC
62
Referred patients were contacted within one week for an eligibility screen. Potentially eligible participants were invited for an in-person meeting to obtain consent, assent from parental
74
guardian, complete baseline assessment measures, and undergo a medical evaluation with the
75
study physician to confirm their concussion diagnosis and rule out contraindications to exercise.
76
Confirmed eligible participants were randomized (1:1) according to predetermined simple
77
randomization sequence, concealed from the research team, to either treatment as usual (TAU) or
78
TAU plus an active rehabilitation program. Figure 1 depicts participants’ flow through the study.
AC C
73
ACCEPTED MANUSCRIPT 5 79 80
Treatment as Usual Both groups received TAU from an interdisciplinary team, which consisted of: (1) an education session by an occupational therapist about symptom management and return to play12;
82
(2) a school consultation with a hospital-affiliated teacher, who facilitated return to school; and
83
(3) a physiatrist consultation, which included medications prescriptions and referrals to
84
community therapists, as appropriate. These TAU interventions were provided prior to
85
randomization. However, several participants received medication follow-up from the physiatrist
86
after randomization and one participant (assigned to the TAU only group) received follow-up
87
support from the occupational therapist for mental health concerns after randomization.
88
Active Rehabilitation
SC
M AN U
89
RI PT
81
Participants randomized to the experimental arm engaged in active rehabilitation led by a physiotherapist. The active rehabilitation program is described by Gagnon et al.4,5. In brief, it
91
consists of four components: (1) sub-maximal aerobic training, (2) light coordination and sport-
92
specific exercises, (3) visualization and imagery techniques, and (4) a home exercise program.
93
To ensure fidelity, the program was administered according to a written manual. The
94
physiotherapist initially met with each participant to carry out components 1-3 and devise a
95
home exercise program. Follow-up clinic visits were scheduled on a weekly basis until
96
participants could independently carry out their home program.
97
Outcome measures
EP
AC C
98
TE D
90
The primary efficacy outcome was self-reported postconcussion symptoms, assessed with
99
the Post-Concussion Symptom Scale (PCSS)14. The PCSS consists of 22 symptoms rated on a 0-
100
6 scale. It has strong internal consistency (Cronbach’s alpha=.88-.94), sensitivity to concussion,
101
and responsiveness to change associated with natural recovery or treatment15–20. The PCSS was
ACCEPTED MANUSCRIPT 6 102
administered in the intake and follow-up assessments, as well as in each of the six intervening
103
weeks (by telephone), yielding a total of 8 repeated measures. Assessors were blinded to
104
participants’ group assignments. Secondary outcomes administered before and after intervention included measures of
106
health-related quality of life (Patient Reported Outcomes Measurement Information Systems,
107
pediatric short forms21–23), as well as measures of mood (Beck Depression Inventory for Youth-
108
Second Edition24), fatigue (Pediatric Quality of Life Multidimensional Fatigue Scale, Teen
109
Report Standard Version25,26), balance (Balance Error Scoring System27), and cognitive
110
performance (Immediate Post-Concussion Assessment and Cognitive Test28). All of these
111
measures have favorable psychometric properties but only the latter two have been extensively
112
validated in concussion27,28.
113
Safety and Adverse Events
SC
M AN U
A blinded research assistant telephoned participants weekly to administer the PCSS and
TE D
114
RI PT
105
systematically monitor for adverse events using a structured interview for predetermined events.
116
An adverse event was defined as any of the following: (1) significantly worsened symptoms
117
from one week to the next (reliable change on PCSS > 1020), (2) decrease in school attendance
118
and/or extracurricular activity due to symptoms, (3) Emergency Department visit related to
119
postconcussion symptoms, and (4) new injuries. For participants in the active rehabilitation
120
group, the treating therapist also monitored for in-session physical exertion-related symptom
121
exacerbation that did not resolve within 24 hours. Prior to initiating exercise in a given session,
122
the therapist asked the participant to rate all symptoms they were currently experiencing on a 0-
123
10 intensity scale. The therapist recorded participants’ heart rate, perceived exertion, and asked
124
about any new or worsening of symptoms at each minute of the aerobic exercise component,
AC C
EP
115
ACCEPTED MANUSCRIPT 7 using the same 0-10 scale. The protocol was for participants who reported any new symptom
126
(not present at the beginning of the exercise session) or symptom exacerbation (increase of 2 or
127
more points on the 0-10 scale) to discontinue exercise and be monitored for symptom resolution
128
for at least 15 minutes in-session, and if necessary, by telephone after the participant left clinic.
129
RI PT
125
In-session adverse events observed by the treating physiotherapist were reported directly to the Data and Safety Monitoring Committee. Potential adverse events reported to the research
131
assistant in weekly monitoring phone calls were reported to the study physician to determine
132
whether urgent medical attention was required and whether review from an independent Data
133
and Safety Monitoring Committee was warranted. The Committee consisted of a physical
134
therapist and physiatrist not otherwise associated with the study. Their mandate was to evaluate
135
whether the event was attributable to the experimental intervention or participation in the study
136
and if protocol changes were necessary to ensure participant safety.
137
Analyses
M AN U
TE D
138
SC
130
Safety data are reported descriptively. Linear mixed modeling was used to evaluate the effect of treatment on postconcussion symptoms. This statistical approach incorporates all
140
repeated measures (weekly PCSS scores throughout the observation period), allows individual
141
participants to differ at baseline (by including a random intercept), and incorporates all available
142
data (including data from participants with missing values at one or more time points). Because
143
baseline non-equivalency despite random assignment is common with small sample sizes, we
144
planned to statistically control for baseline group differences, if present. Missing data (N=0 from
145
baseline, N=1 for week 2, N=2 for week 3, N=1 from week 4, N=4 from week 5, N=3 from week
146
3, and N=0 from follow-up) was not imputed. Hypothesis testing was not conducted with
147
secondary outcomes due to the small sample size.
AC C
EP
139
ACCEPTED MANUSCRIPT 8 148
Results
149
Patient Characteristics As shown in Figure 1, 19 participants were enrolled. In the absence of prior controlled
150
trials to inform a power analysis, we initially planned to recruit 15 participants per group because
152
there are diminishing returns in precision of the estimated treatment effects with larger
153
samples29,30. However, we terminated recruitment due to slower than expected enrollment and a
154
change in TAU. No participants dropped out. Baseline sample characteristics are reported in
155
Table 1. The most commonly played sports at the time of injury were soccer (n=5), basketball
156
(n=4), and hockey (n=3). At study entry, most participants were attending school full-time (n=5)
157
or part-time (n=13).
M AN U
SC
RI PT
151
Insert Figure 1 and Table 1 about here
158 159
Implementation
As per Gagnon et al.4,5, the active rehabilitation program allowed for some individual
TE D
160
tailoring. The number of in-clinic sessions was determined by the treating physiotherapist based
162
on how quickly participants engaged with the home exercise program and whether they required
163
other physiotherapy modalities. Four participants had positive cervical findings and two patients
164
had positive vestibular findings on initial physical examination. These patients were treated with
165
manual therapy and vestibular rehabilitation, respectively. Note that manual therapy and
166
vestibular rehabilitation are not components of the Gagnon et al.4,5 protocol, but are consistent
167
with new evidence on physiotherapy for concussion31. Participants in the active rehabilitation
168
group received M=3.4 visits with the physiotherapist (range=2-5).
169
Safety
170 171
AC C
EP
161
There were six adverse events in each group. The most common was a reliable PCSS change (>10 points) from one week to the next. Of the 12 adverse events, 4 (3 in TAU only
ACCEPTED MANUSCRIPT 9 group and 1 in the active rehabilitation group) were reported to the external Data and Safety
173
Monitoring Board. One participant (in the TAU only group) had an exacerbation in symptoms
174
from one week to the next on the PCSS, and acknowledged feeling “overwhelmed” and recently
175
seeing a psychiatrist. Another participant (TAU only group) presented to the Emergency
176
Department with neck and headache pain. A third participant (TAU only group) had a significant
177
increase on the PCSS, and had developed focal scalp (injection site) pain after a lidocaine
178
injection. Lastly, the Committee considered an adverse event in the active rehabilitation group
179
secondary to a suspected medication interaction with the participant’s diabetes medication. All
180
four of the adverse events reviewed by the Committee were determined to be unrelated to the
181
intervention and participation in the study.
SC
M AN U
182
RI PT
172
For participants in the active rehabilitation group, there was an onset or worsening of symptoms (>1 on a 0-10 scale) in 37% (n=11 of 30) of clinic sessions involving aerobic exertion,
184
usually involving headache, dizziness, or “pressure in the head.” Most symptom exacerbations
185
occurred in the first (n=6) or second (n=4) aerobic exercise sessions. All symptom exacerbations
186
resolved within 24 hours, most (10 of 11 instances) within 15 minutes discontinuing exercise. All
187
participants were able to tolerate 15 minutes of aerobic exertion without symptom exacerbation
188
by their last clinic session.
189
Efficacy outcomes
EP
AC C
190
TE D
183
Plots of PCSS scores over time, stratified by group (Figure 2), showed subtle baseline
191
differences (higher PCSS score in the control) and a reasonably linear trajectory of symptoms,
192
with no obvious group by time interaction. We therefore controlled for baseline group
193
differences and analyzed time as a continuous variable. We initially fit a linear mixed model with
194
a random intercept and fixed effects for group (experimental vs. control), time, and baseline
ACCEPTED MANUSCRIPT 10 PCSS score. The effect for group was significant (Wald’s t=2.15, p=0.047). Adding a group by
196
time interaction term to the model did not achieve improved model fit [χ2(1)=0.45, p=0.50].
197
Separately adding sex to the model also did not improve model fit [χ2(1)=1.17, p=0.28].
198
Removing group from the original model resulted in a significant degradation of model fit
199
(χ2(1)=4.83, p=0.028), confirming a treatment effect. Re-analyzing these data with time as a
200
categorical variable produced very similar results. The mean change on PCSS from baseline to
201
follow-up was -24.7 (SD=19.1) in the active rehabilitation group and -15.8 (SD=12.5) in the
202
TAU only group, which is associated with a Cohen’s d treatment effect size of 0.55 (i.e., group
203
mean difference for pre-post change).
M AN U
SC
RI PT
195
Insert Figure 2 about here
204
Quality of life, mood, fatigue, balance, and cognition measures obtained prior to and
206
immediately following intervention are reported in Table 1. As mentioned above, these were
207
collected for exploratory and descriptive purposes. No inferential statistical testing was planned
208
or performed.
209
Discussion
TE D
205
Safe and effective interventions are needed for young athletes who do not swiftly recover
211
from sport-related concussion32, but rather have persistent symptoms that limit their participation
212
in school, sport, and other activities. Following up on an encouraging case series of an active
213
rehabilitation program involving aerobic exercise training4, we aimed to more rigorously
214
evaluate the safety and potential efficacy of this intervention in a randomized controlled trial in
215
which we systematically monitored for predetermined adverse events. Our main finding was that
216
adverse events were no more common in participants receiving active rehabilitation in addition
217
to TAU compared to those receiving TAU only, and no adverse events requiring review by an
AC C
EP
210
ACCEPTED MANUSCRIPT 11 218
independent Data and Safety Monitoring Committee were judged to be causally related to the
219
experimental intervention. We also report a statistically significant treatment effect on
220
postconcussion symptoms (primary efficacy outcome), despite a small sample size (N=19). Since launching the present study, several clinical trials involving a similar intervention
RI PT
221
and patient population were published. In an uncontrolled trial, Imhoff et al.33 reported
223
improvement in adolescents who were slow to recover from sport-related concussion with a
224
home exercise program. In a retrospective chart review of adolescents with persistent symptoms
225
who were treated with aerobic exercise training, Chrisman et al.34 found general symptom
226
improvement and noted that “no individual exhibited worsening of symptoms” after starting the
227
intervention (pg. 4). Two randomized controlled trials have also been recently published.
228
Kurowski et al.13 enrolled adolescents who met International Classification of Diseases-10
229
criteria for postconcussional syndrome and self-reported that their symptoms worsened with
230
physical exertion. Participants (N=30) were randomized to receive a home sub-symptom
231
threshold aerobic training program with a stationary bicycle or full-body stretching program (a
232
contact-matched control group). Both groups experienced improved postconcussion symptoms
233
over the six-week intervention period and there was evidence of benefit associated with aerobic
234
training (Cohen’s d=0.5-0.8), similar in magnitude to that found in the present study. No
235
intervention-related adverse events were observed, though it is unclear how Kurowski et al.13
236
monitored safety. In another study by Maerlender et al.35, “recently” concussed college athletes
237
(N=33) were randomly assigned to daily exercise on a stationary bike at mild to moderate
238
perceived exertion or usual care. The two groups did not differ in recovery time or pre/post
239
changes in cognitive performance. The authors noted that participants generally experienced less
240
symptom exacerbation with each consecutive ride.
AC C
EP
TE D
M AN U
SC
222
ACCEPTED MANUSCRIPT 12 241
The “active ingredients” and biopsychosocial mechanisms underlying improvements from this multifaceted active rehabilitation are uncertain. Restored cerebrovascular
243
autoregulation has been proposed to explain the therapeutic benefits of aerobic training after
244
concussion39,40, but this mechanism has yet to be empirically validated. Placebo effects and/or
245
natural recovery could be contributory. In our study and in another randomized trial13,
246
participants in the control group significantly improved. It is also possible that giving adolescents
247
“permission” to become more active helps to counter maladaptive illness beliefs (e.g.,
248
kinesophobia) and encourages them to reintegrate into their social and recreational activities,
249
which likely confers a number of mental and physical health benefits separate from the benefits
250
of aerobic exercise41. Patients in the active rehabilitation arm of our study with positive cervical
251
or vestibular exam findings were provided with targeted treatment for these conditions. Future
252
research will be required to learn whether these treatment components contribute to positive
253
outcomes above and beyond aerobic exercise training. It will also be helpful to identify patient
254
characteristics associated with treatment response.
255
Study Limitations
SC
M AN U
TE D
The present study has several limitations. First, the modest sample size (n=19) may have
EP
256
RI PT
242
prevented us from identifying rare adverse events and having sufficient power to detect small
258
group differences in observed adverse events. It likely also accounted for the failure of
259
randomization to achieve group balance on important baseline characteristics. We adjusted for
260
these baseline differences in mixed modeling analyses. Second, we did not restrict participants
261
from receiving concussion treatment outside of the study. With a large sample, randomization
262
should eliminate this potential confound of external treatment, but there could have been group
263
imbalance in our study. Of participants in the active rehabilitation group, only one acknowledged
AC C
257
ACCEPTED MANUSCRIPT 13 to the treating physiotherapist they were receiving treatment outside of the study protocol
265
(acupuncture). Third, the treatment we evaluated includes a home exercise program, but we did
266
not systematically monitor adherence levels to this component. Fourth, we assessed participants’
267
symptoms throughout the study period, including immediately post-treatment, but not beyond.
268
We do not know the long-term effects of the intervention or whether symptom improvements
269
translate into improvements in functional outcomes (e.g., sport and academic performance).
270
Fifth, the fact that we recruited from a specialty clinic and were only able to enroll ~13% of
271
screened patients points to a strong selection bias. The present findings may not generalize to
272
adolescents with relatively mild symptoms, seen more acutely or in different settings (e.g.,
273
primary care).
274
Conclusions
SC
M AN U
275
RI PT
264
The most important and unique contribution of the present study is prospective monitoring for predetermined adverse effects to more compellingly demonstrate safety of active
277
rehabilitation that incorporates aerobic exercise training in highly symptomatic patients who are
278
seen in a specialty clinic. This finding is in line with observational studies that found no
279
significant relationship between physical activity, symptom exacerbations, and clinical
280
outcomes36,37 or an inverse relationship (i.e., positive effects of physical activity)38. It should
281
help to quell concerns about prescribing increased physical activity for youth with ongoing
282
postconcussion symptoms. Our findings are also consistent with the conclusion of a very recently
283
published systematic review, that “closely monitored active rehabilitation programmes involving
284
controlled subsymptom threshold, submaximal exercise for adults and adolescents with
285
persistent symptoms after concussion may be of benefit” (pg. 4)3.
286
AC C
EP
TE D
276
ACCEPTED MANUSCRIPT 14 287
AC C
EP
TE D
M AN U
SC
RI PT
288
ACCEPTED MANUSCRIPT 15 References
290 291 292 293
1.
Makdissi M, Cantu RC, Johnston KM, McCrory P, Meeuwisse WH. The difficult concussion patient: what is the best approach to investigation and management of persistent (>10 days) postconcussive symptoms? Br J Sports Med. 2013;47(5):308313. doi:10.1136/bjsports-2013-092255.
294 295 296
2.
Thomas DG, Apps JN, Hoffmann RG, McCrea M, Hammeke T. Benefits of Strict Rest After Acute Concussion: A Randomized Controlled Trial. Pediatrics. 2015;135(2). doi:10.1542/peds.2014-0966.
297 298 299
3.
Schneider KJ, Leddy JJ, Guskiewicz KM, et al. Rest and treatment/rehabilitation following sport-related concussion: a systematic review. Br J Sports Med. 2017:bjsports2016-097475. doi:10.1136/bjsports-2016-097475.
300 301 302
4.
Gagnon I, Galli C, Friedman D, Grilli L, Iverson GL. Active rehabilitation for children who are slow to recover following sport-related concussion. 2009;23(November):956-964. doi:10.3109/02699050903373477.
303 304 305
5.
Gagnon I, Grilli L, Friedman D, Iverson GL. A pilot study of active rehabilitation for adolescents who are slow to recover from sport-related concussion. Scand J Med Sci Sport. 2016;26(3):299-306. doi:10.1111/sms.12441.
306 307 308
6.
Leddy JJ, Kozlowski K, Donnelly JP, Pendergast DR, Epstein LH, Willer B. A Preliminary Study of Subsymptom Threshold Exercise Training for Refractory PostConcussion Syndrome. Clin J Sport Med. 2010;20:21-27.
309 310 311
7.
Cordingley D, Girardin R, Reimer K, et al. Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes. J Neurosurg Pediatr. 2016:1-10. doi:10.3171/2016.5.PEDS16139.
312 313 314 315
8.
Mychasiuk R, Hehar H, Ma I, Candy S, Esser MJ. Reducing the time interval between concussion and voluntary exercise restores motor impairment, short-term memory, and alterations to gene expression. Eur J Neurosci. 2016;44(7):2407-2417. doi:10.1111/ejn.13360.
316 317 318 319
9.
Griesbach GS, Hovda D a, Molteni R, Wu a, Gomez-Pinilla F. Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience. 2004;125(1):129-139. doi:10.1016/j.neuroscience.2004.01.030.
320 321 322
10.
323 324 325
11.
McCrory P, Meeuwisse W, Dvorak J, et al. Consensus statement on concussion in sport— the 5 th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med. 2017:bjsports-2017-097699. doi:10.1136/bjsports-2017-097699.
326 327
12.
McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012.
AC C
EP
TE D
M AN U
SC
RI PT
289
Wells EM, Goodkin HP, Griesbach GS. Challenges in Determining the Role of Rest and Exercise in the Management of Mild Traumatic Brain Injury. J Child Neurol. 2016;31(1):86. doi:10.1177/0883073815570152.
ACCEPTED MANUSCRIPT 16 Br J Sports Med. 2013;47(5):250-258. doi:10.1136/bjsports-2013-092313.
328
13.
Kurowski BG, Hugentobler J, Quatman-Yates C, et al. Aerobic Exercise for Adolescents With Prolonged Symptoms After Mild Traumatic Brain Injury. J Head Trauma Rehabil. 2016;32(2):1. doi:10.1097/HTR.0000000000000238.
332 333 334 335
14.
Lovell MR, Iverson GL, Collins MW, et al. Measurement of Symptoms Following SportsRelated Concussion : Reliability and Normative Data for the Post-Concussion Scale Measurement of Symptoms Following Sports-Related Concussion : Reliability and Normative Data for the Post-Concussion Scale. 2010;(August 2011):37-41.
336 337 338 339
15.
McLeod TCV, Leach C. Psychometric properties of self-report concussion scales and checklists. J Athl Train. 2012;47(2):221-223. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3418135&tool=pmcentrez&re ndertype=abstract.
340 341 342
16.
Sullivan K, Garden N. A comparison of the psychometric properties of 4 postconcussion syndrome measures in a nonclinical sample. J Head Trauma Rehabil. 2011;26(2):170176. doi:10.1097/HTR.0b013e3181e47f95.
343 344 345
17.
Iverson GL, Brooks BL, Collins MW, Lovell MR. Tracking neuropsychological recovery following concussion in sport. Brain Inj. 2006;20(3):245-252. doi:10.1080/02699050500487910.
346 347
18.
Lovell MR, Collins MW, Iverson GL, et al. Recovery From Mild Concussion in High School Athletes. J Neurosurg. 2003;98:98295-301295. doi:10.3171/jns.2003.98.2.0296.
348 349 350
19.
Moser RS, Glatts C, Schatz P. Efficacy of immediate and delayed cognitive and physical rest for treatment of sports-related concussion. J Pediatr. 2012;161(5):922-926. doi:10.1016/j.jpeds.2012.04.012.
351 352
20.
Iverson GL, Lovell MR, Collins MW. Interpreting change on ImPACT following sport concussion. Clin Neuropsychol. 2003;17(4):460-467. doi:10.1076/clin.17.4.460.27934.
353 354 355
21.
Irwin DE, Stucky B, Langer MM, et al. An item response analysis of the pediatric PROMIS anxiety and depressive symptoms scales. Qual Life Res. 2010;19(4):595-607. doi:10.1007/s11136-010-9619-3.
356 357 358
22.
Varni JW, Stucky BD, Thissen D, et al. PROMIS Pediatric Pain Interference Scale: An Item Response Theory Analysis of the Pediatric Pain Item Bank. J Pain. 2010;11(11):1109-1119. doi:10.1016/j.jpain.2010.02.005.
359 360 361
23.
362 363
24.
Beck JS, Beck AT, Jolly JB, Steer RA. Beck Youth Inventories, Second Edition for Children and Adolescents (BYI-II). San Antonio: Harcourt Assessment; 2005.
364 365 366
25.
Varni JW, Limbers CA. The PedsQL??? Multidimensional Fatigue Scale in young adults: Feasibility, reliability and validity in a University student population. Qual Life Res. 2008;17(1):105-114. doi:10.1007/s11136-007-9282-5.
AC C
EP
TE D
M AN U
SC
RI PT
329 330 331
Varni JW, Magnus B, Stucky BD, et al. Psychometric properties of the PROMIS pediatric scales: Precision, stability, and comparison of different scoring and administration options. Qual Life Res. 2014;23(4):1233-1243. doi:10.1007/s11136-013-0544-0.
ACCEPTED MANUSCRIPT 17 26.
Varni JW, Limbers CA. The Pediatric Quality of Life Inventory: Measuring Pediatric Health-Related Quality of Life from the Perspective of Children and Their Parents. Pediatr Clin North Am. 2009;56(4):843-863. doi:10.1016/j.pcl.2009.05.016.
370 371
27.
Bell DR, Guskiewicz KM, Clark M a, Padua D a. Systematic review of the balance error scoring system. Sports Health. 2011;3(3):287-295. doi:10.1177/1941738111403122.
372 373 374
28.
Alsalaheen B, Stockdale K, Pechumer D, Broglio SP. Validity of the Immediate Post Concussion Assessment and Cognitive Testing (ImPACT). Sport Med. 2016;46(10):14871501. doi:10.1007/s40279-016-0532-y.
375 376
29.
Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharm Stat. 2005;4(4):287-291. doi:10.1002/pst.185.
377 378
30.
Stallard N. Optimal sample sizes for phase II clinical trials and pilot studies. Stat Med. 2012;31(11-12):1031-1042. doi:10.1002/sim.4357.
379 380 381
31.
Schneider KJ, Meeuwisse WH, Nettel-Aguirre A, et al. Cervicovestibular rehabilitation in sport-related concussion: a randomised controlled trial. Br J Sport Med. 2014;48:12941298. doi:10.1136/bjsports-2013-093267.
382 383 384 385
32.
Cancelliere C, Hincapié C a, Keightley M, et al. Systematic Review of Prognosis and Return to Play After Sport Concussion: Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil. 2014;95(3S):S210--S229. doi:10.1016/j.apmr.2013.06.035.
386 387 388
33.
Imhoff S, Fait P, Carrier-toutant F, Boulard G. Efficiency of an Active Rehabilitation Intervention in a Slow-to-Recover Paediatric Population following Mild Traumatic Brain Injury : A Pilot Study. 2016;2016. doi:10.1155/2016/5127374.
389 390 391
34.
Chrisman SPD, Whitlocka KB, Somers E, et al. Pilot study of the Sub-Symptom Threshold Exercise Program (SSTEP) for persistent concussion symptoms in youth. NeuroRehabilitation. 2017;Epub ahead.
392 393 394
35.
Maerlender A, Rieman W, Lichtenstein J, et al. Programmed Physical Exertion in Recovery From Sports-Related Concussion: A Randomized Pilot Study. Dev Neuropsychol. 2015;40(5):273-278. doi:10.1080/87565641.2015.1067706.
395 396 397 398
36.
Wiebe D, Nance M, Houseknecht E, et al. Ecologic Momentary Assessment to Accomplish Real-Time Capture of Symptom Progression and the Physical and Cognitive Activities of Patients Daily Following Concussion. JAMA Pediatr. 2016;170(11):11081110.
399 400 401
37.
402 403 404
38.
Grool AM, Aglipay M, Momoli F, et al. Association Between Early Participation in Physical Activity Following Acute Concussion and Persistent Postconcussive Symptoms in Children and Adolescents. Jama. 2016;316(23):2504. doi:10.1001/jama.2016.17396.
405
39.
Leddy JJ, Kozlowski K, Fung M, Pendergast DR, Willer B. Regulatory and autoregulatory
AC C
EP
TE D
M AN U
SC
RI PT
367 368 369
Silverberg ND, Iverson GL, McCrea M, Apps JN, Hammeke TA, Thomas DG. ActivityRelated Symptom Exacerbations After Pediatric Concussion. JAMA Pediatr. 2016;170(10):946-953. doi:10.1001/jamapediatrics.2016.1187.
ACCEPTED MANUSCRIPT 18 physiological dysfunction as a primary characteristic of post concussion syndrome : Implications for treatment. 2007;22:199-205.
406 407
40.
Leddy JJ, Sandhu H, Sodhi V, Baker JG, Willer B. Rehabilitation of Concussion and Postconcussion Syndrome. Sports Health. 2012;4(2):147-154. doi:10.1177/1941738111433673.
411 412 413
41.
DiFazio M, Silverberg ND, Kirkwood MW, Bernier R, Iverson GL. Prolonged Activity Restriction After Concussion: Are We Worsening Outcomes? Clin Pediatr (Phila). 2015. doi:10.1177/0009922815589914.
RI PT
408 409 410
414
AC C
EP
TE D
M AN U
SC
415
ACCEPTED MANUSCRIPT 19 416
Figure legends
417 418
Figure 1. CONSORT Flow Diagram.
RI PT
419
Figure 2. Plots of Post-Concussion Symptom Scale (PCSS) total score over time in weeks, stratified by group (active rehabilitation vs. treatment as usual).
422
(a) Raw data
423
(b) Baseline referenced, by subtracting each participant’s score from their own baseline.
SC
420 421
424
AC C
EP
TE D
M AN U
425
ACCEPTED MANUSCRIPT
Table 1. Participant characteristics and outcome data by group.
M=132; SD=52.0
M=123; SD=48.50
M=1.8; SD=1.17 12 Pre Post M SD M SD
M=1.7; SD=1.15 6 Pre Post M SD M SD
M=1.9; SD=1.20 6 Pre Post M SD M SD
28.6
32.3
25.1
56.9
31.0
40.3
29.4
51.5
27.8
25.0
19.4
16.9
19.7
24.2
15.7
36.3
18.5
32.2
16.5
40.8
14.6
17.0
11.5
12.7 12.7 13.3
5.9 5.3 6.6
11.0 9.6 10.9
5.9 4.6 5.8
12.4 10.6 13.3
7.2 5.7 6.7
11.3 8.6 12.3
7.1 5.0 5.1
13.0 14.6 13.2
4.8 4.3 6.9
10.7 10.6 9.6
5.1 4.3 6.3
58.7 53.4 61.8
9.3 9.1 12.8
54.9 48.6 56.8
17.6 9.5 14.1
59.2 54.0 60.7
10.1 10.7 61.8
54.3 49.0 57.0
22.8 10.5 17.7
58.2 52.8 62.8
9.0 8.0 12.0
55.4 48.3 56.6
12.6 9.1 11.1
54.2
13.1
49.7
10.2
55.2
13.9
50.8
11.2
53.2
13.1
48.8
10.7
48.2 13.7 16.2
10.9 11.0 11.9
51.8 11.3 10.8
8.0 8.6 5.5
48.6 14.7 16.3
13.1 13.4 15.7
50.4 10.2 11.4
8.9 9.3 7.4
47.9 12.7 16.0
8.9 8.8 8.1
53.0 12.2 10.3
7.4 8.3 3.2
77.1 65.7 31.2 0.7
12.3 14.0 6.8 0.1
82.2 73.5 37.1 0.6
11.0 14.1 7.0 0.1
78.3 69.0 30.9 0.69
12.2 11.3 5.4 0.1
77.6 75.8 37.9 0.57
11.1 16.2 3.1 0.0
75.9 62.7 32.6 0.7
12.9 16.0 8.0 0.1
86.3 71.5 36.3 0.6
9.6 12.4 9.4 0.1
SC
54.1
M AN U
Post-Concussion Symptom Scale Pediatric Quality of Life Multidimensional Fatigue Scale General Fatigue Sleep Cognitive Fatigue PROMIS Scales Pediatric Pain Impact Pediatric Anxiety Pediatric Fatigue Pediatric Depressive Symptoms Pediatric Peer Relationships Beck Depression Inventory Balance Error Scoring System ImPACT Cognitive Composites Verbal Memory Visual Memory Visual Motor Speed Reaction Time
TE D
Age Gender (n female) Time between injury and initial assessment (days) Number of prior concussions Adverse events (n)
Active Rehabilitation (N=10) M=15.9; SD=1.66 6 M=139; SD=56.30
RI PT
M=15.5; SD=1.47 14
Treatment As Usual (N=9) M=15.1; SD=1.42 8
Full Sample (N=19)
AC C
EP
Abbreviations: PROMIS = Patient Reported Outcomes Measurement Information Systems; ImPACT = Immediate Post-Concussion Assessment and Cognitive Test
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT