Association of Attention-Deficit/Hyperactivity Disorder Diagnoses With Pediatric Traumatic Brain Injury: A Meta-analysis

Robert F Asarnow; Nina Newman; Robert E Weiss; Erica Su

doi:10.1001/jamapediatrics.2021.2033

. 2021 Jul 12;175(10):1–9. doi: 10.1001/jamapediatrics.2021.2033

Association of Attention-Deficit/Hyperactivity Disorder Diagnoses With Pediatric Traumatic Brain Injury

A Meta-analysis

Robert F Asarnow ^1,^2,^3,^✉, Nina Newman ⁴, Robert E Weiss ⁵, Erica Su ⁵

¹Department of Psychiatry, University of California, Los Angeles

²Department of Psychology, University of California, Los Angeles

³Brain Research Institute, University of California, Los Angeles

⁴School of Psychology, Fielding Graduate University, Playa Vista, California

⁵Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, California

Accepted for Publication: April 8, 2021.

Published Online: July 12, 2021. doi:10.1001/jamapediatrics.2021.2033

^✉

Corresponding Author: Robert F. Asarnow, PhD, Department of Psychiatry, University of California, Los Angeles, 48-240 Semel Institute, 760 Westwood Plaza, Los Angeles, CA 90024 (rasarnow@mednet.ucla.edu).

Author Contributions: Drs Asarnow and Weiss had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Asarnow, Newman, Weiss.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Weiss, Su.

Obtained funding: Asarnow.

Supervision: Asarnow, Newman, Weiss.

Conflict of Interest Disclosures: Dr Su reported receiving grants from Della Martin Foundation during the conduct of the study. No other disclosures were reported.

Funding/Support: This research was supported by a gift from the Della Martin Foundation to Dr Asarnow. The gift provided a fellowship to Dr Su..

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Assistance with study selection was provided by librarian Bethany A. Myers, MS (University of California, Los Angeles). There was no compensation outside of university salary.

^✉

Corresponding author.

PMCID: PMC8276124 PMID: 34251435

Key Points

Question

Are traumatic brain injuries associated with increased risk for attention-deficit/hyperactivity disorder?

Findings

This meta-analysis of 24 studies including 12 374 children with traumatic brain injuries found that severe traumatic brain injuries appear to be associated with an increased risk for attention-deficit/hyperactivity disorder compared with noninjured and other injured controls; no association between attention-deficit/hyperactivity disorder and concussions and mild or moderate traumatic brain injury was identified. The rate of pretraumatic brain injury attention-deficit/hyperactivity disorder diagnoses was significantly greater than the incidence of attention-deficit/hyperactivity disorder in the general pediatric population.

Meaning

These findings show that clinicians should carefully review psychosocial and medical issues that antedate a traumatic brain injury that may need to be addressed to adequately treat attention-deficit/hyperactivity disorder symptoms in children with traumatic brain injuries.

Abstract

Importance

There are conflicting accounts about the risk for attention-deficit/hyperactivity disorder (ADHD) following traumatic brain injury (TBI), possibly owing to variations between studies in acute TBI severity or when ADHD was assessed postinjury. Analysis of these variations may aid in identifying the risk.

Objective

To conduct a meta-analysis of studies assessing ADHD diagnoses in children between ages 4 and 18 years following concussions and mild, moderate, or severe TBI.

Data Sources

PubMed, PsycInfo, and Cochrane Central Register of Controlled Trials (1981-December 19, 2019) were searched including the terms traumatic brain injury, brain injuries, closed head injury, blunt head trauma, concussion, attention deficit disorders, ADHD, and ADD in combination with childhood, adolescence, pediatric, infant, child, young adult, or teen.

Study Selection

Limited to English-language publications in peer-reviewed journals and patient age (4-18 years). Differences about inclusion were resolved through consensus of 3 authors.

Data Extraction and Synthesis

MOOSE guidelines for abstracting and assessing data quality and validity were used. Odds ratios with 95% credible intervals (CrIs) are reported.

Main Outcomes and Measures

The planned study outcome was rate of ADHD diagnoses.

Results

A total of 12 374 unique patients with TBI of all severity levels and 43 491 unique controls were included in the 24 studies in this review (predominantly male: TBI, 61.8%; noninjury control, 60.9%; other injury control, 66.1%). The rate of pre-TBI ADHD diagnoses was 16.0% (95% CrI, 11.3%-21.7%), which was significantly greater than the 10.8% (95% CrI, 10.2%-11.4%) incidence of ADHD in the general pediatric population. Compared with children without injuries, the odds for ADHD were not significantly increased following concussion (≤1 year: OR, 0.32; 95% CrI, 0.05-1.13), mild TBI (≤1 year: OR, 0.56; 0.16-1.43; >1 year: OR, 1.07; 95% CrI, 0.35-2.48), and moderate TBI (≤1 year: OR, 1.28; 95% CrI, 0.35-3.34; >1 year: OR, 3.67; 95% CrI, 0.83-10.56). The odds for ADHD also were not significantly increased compared with children with other injuries following mild TBI (≤1 year: OR, 1.07; 95% CrI, 0.33-2.47; >1 year: OR, 1.18; 95% CrI, 0.32-3.12) and moderate TBI (≤1 year: OR, 2.34; 95% CrI, 0.78-5.47; >1 year: OR, 3.78; 95% CrI, 0.93-10.33). In contrast, the odds for ADHD following severe TBI were increased at both time points following TBI compared with children with other injuries (≤1 year: OR, 4.81; 95% CrI, 1.66-11.03; >1 year: OR, 6.70; 95% CrI, 2.02-16.82) and noninjured controls (≤1 year: OR, 2.62; 95% CrI, 0.76-6.64; >1 year: OR, 6.25; 95% CrI, 2.06-15.06), as well as those with mild TBI (≤1 year OR, 5.69; 1.46-15.67: >1 year OR, 6.65; 2.14-16.44). Of 5920 children with severe TBI, 35.5% (95% CrI, 20.6%-53.2%) had ADHD more than 1 year postinjury.

Conclusions and Relevance

This study noted a significant association between TBI severity and ADHD diagnosis. In children with severe but not mild and moderate TBI, there was an association with an increase in risk for ADHD. The high rate of preinjury ADHD in children with TBI suggests that clinicians should carefully review functioning before a TBI before initiating treatment.

This meta-analysis examines the rates of attention-deficit/hyperactivity disorder reported in studies of children who have experienced traumatic brain injury.

Introduction

Traumatic brain injury (TBI) is the most common cause of death and acquired neurologic disability in children and youths in the industrialized world.^1,2 More than 600 000 children visit US emergency departments yearly for TBIs.³ Survivors of pediatric TBI often develop impaired cognitive, academic, and behavioral functioning.^4,5,6 Pediatric TBI can also result in serious psychiatric problems that adversely affect psychosocial development, family and peer relationships, and academic achievement.^7,8

Many clinicians believe and some studies⁹ report that attention-deficit/hyperactivity disorder (ADHD) occurs frequently following pediatric TBI. However, other studies did not report increased rates of ADHD following TBI. The conflicting results may be due to variations between studies in 2 key moderator variables: TBI injury severity and the timing of assessment relative to the injury. In this meta-analysis, we assessed the association of severity and assessment timing with ADHD diagnoses after TBI. Because ADHD occurs frequently in the general pediatric population, a key issue is the extent to which the risk for ADHD increases after TBI.

One meta-analysis of ADHD diagnoses in children and adults with mild TBI included 5 studies,¹⁰ with the most recent study published in 2009; the authors noted an association between mild TBI and ADHD. The meta-analysis reported herein included 24 studies, the most recent published in 2020, of children with concussions and mild, moderate, and severe TBI that provide quantitative estimates of the association of acute brain injury severity with the risk for ADHD following TBI. Given the clinical significance of ADHD in pediatric practices and parental concerns about the serious effects of mild TBI/concussion stimulated by media reports, information about the risk for ADHD following TBI may be useful in managing children with TBI and counseling their parents.

To our knowledge, this is the first meta-analytic review that integrates findings across study designs (eg, cross-sectional and longitudinal) to examine the association of injury severity and time since injury with the development of ADHD diagnoses following pediatric TBI. We estimate the magnitude of the association of injury severity at 2 time intervals following TBI.

Methods

Search Methods/Selection of Studies

This search was developed with the Health Sciences librarian at the University of California, Los Angeles. We searched PubMed, PsycInfo, and Cochrane Central Register of Controlled Trials (1981-December 19, 2020). Key terms were traumatic brain injury, concussion, brain injuries, closed head injury, blunt head trauma, attention deficit disorders, ADHD, or ADD and were searched in combination with the key words childhood, adolescence, pediatric, infant, child, young adult, or teen. We reviewed reference lists, articles that cited included studies, and review articles to identify studies that may have been missed in database searches. The search was limited to English-language publications in peer-reviewed journals and patient age between 4 and 18 years. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Titles and abstracts of all identified articles were independently reviewed by ³ of us (R.F.A., N.N., and E.S.). We eliminated studies that included duplicate data sets, review articles, book chapters, studies not involving TBI and/or concussions, and studies that included children younger than 2 years who experienced a TBI or inflicted injuries. At least 2 of the 3 authors who performed the initial screening reviewed all the remaining articles; differences about inclusion were resolved through consensus of all 3 authors. The same 3 authors rated the methodologic quality of each study using the Newcastle-Ottawa scale,¹¹ a rating scale of methodologic rigor for observational studies. Again, differences were resolved through consensus of these 3 authors. The Newcastle-Ottawa scale quality ratings for each study are included in Table 1, which also includes details on the methods (eg, clinician interview, medical records, or parent response on questionnaires) used in each study to diagnose ADHD.^{8,9,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33}

Table 1. Characteristics of Studies.

Source	Source of patients	Age at injury, y	Time at study	Control for preinjury ADHD	Source of data	Outcome measure	Injury severity	Control	Sample size, No. per group	Male sex, %	NO Scale score^a
Biederman et al,¹² 2015	Hospital admission	2-25	Preinjury	NA	Childhood	ADHD module of K-SADS-E; BRIEF	Mild	NIC	TBI, 29; NIC, 58	TBI, 52; NIC, 52	5
Bloom et al,¹³ 2001	Hospital admission	6-15	≥1 y	Yes	Child, parents	DICA-R	Mild, moderate, severe	None	TBI, 46	TBI, 63	7
Brown et al,¹⁴ 1981	Hospital admission	5-14	Preinjury	NA	Parents	Conners parental scale; Rutter scale	Severe	OIC	TBI, 28; OIC, 28	NA	9
Chasle et al,¹⁵ 2016	Hospital admission	6-16	Preinjury	NA	Parents	Conners Global Index	Mild	OIC	TBI, 34; OIC, 64	TBI, 74; OIC, 75	7
Ellis et al,¹⁶ 2015	Hospital admission	Mean (SD), 14.2 (2.3)	Preinjury, 0-12 mo	Yes	Child	Clinical interview, PCSS	Concussion	None	Concussion, 174	Concussion, 61	6
Gerring et al,¹⁷ 1998	Rehabilitation unit	4-19	Preinjury, 0-12 mo	Yes	Child	DICA-C/A/P	Moderate, severe	None	TBI, 99	TBI, 60	7
Königs et al,¹⁸ 2015	Hospital admission	6-13	Preinjury	NA	Parents, teachers	CBCL parent form and teacher form	Mild, moderate, severe	None	TBI, 137	TBI, 56	8
Konrad et al,¹⁹ 2003	Outpatient	4-11	Preinjury, ≥1 y	Yes	Parents	K-DIPS	Moderate, severe	None	TBI, 32	TBI, 70	5
Levin et al,⁸ 2007	Hospital admission	5-15	Preinjury, 0-12 mo, ≥1 y	Yes	Child, parents	K-SADS-PL	Mild, moderate, severe	None	TBI, 148	TBI, 71	8
Massagli et al,²⁰ 2004	Hospital admission; outpatient	0-14	Preinjury, 0-12 mo, ≥1 y	Yes in TBI but not in controls	Record review	ICD psychiatric: No. of disorders,hyperactivity	Mild	NIC	Mild, 421; NIC, 1470	Mild, 62; NIC, 62	8
Max and Koele, et al,²¹ 1998	Hospital admission	5-14	Preinjury, ≥1 y	Yes	Child, parents, record review	K-SADS diagnosis of novel ADHD/ADD	Mild; severe	OIC	TBI, 48; OIC, 24	TBI, 75; OIC, 75	9
Max et al²² 2004	Hospital admission	5-14	Preinjury, ≥1 y	Yes	Child, parents	K-SADS diagnosis of novel ADHD	Mild, moderate, severe	None	TBI, 50	TBI, 62	7
Max et al,²³ 1997	Hospital admission	Mean (SD), 6.14 (4.91)	Preinjury	NA	Child, parents	K-SADS-E, NPRS	Mild, moderate, severe	None	TBI, 50	TBI, 74	7
Max et al,²⁴ 2013	Hospital admission	5-14	Preinjury, 0-12 mo	NA	Child, parents, teachers	K-SADS-PL, SDI	Mild	None	TBI, 79	TBI, 68	7
Max et al,²⁵ 2013	Hospital admission	5-14	Preinjury, 0-12 mo	NA	Child, parents	K-SADS-PL	Mild	None	TBI, 87	TBI, 67	6
Max et al,²⁶ 2005	Hospital admission	5-14	Preinjury, 0-12 mo	Yes	Child, parents	K-SADS-PL; SDI	Moderate	None	TBI, 177	TBI, 65	7
Max et al,²⁷ 2012	Hospital admission	7-17	Preinjury, 0-12 mo	Yes	Child, parents	K-SADS-PL	Moderate, severe	OIC	TBI, 75; OIC, 66	TBI, 67; OIC, 71	9
Miller et al,²⁸ 2016	Hospital admission	4-18	Preinjury	NA	NA	Diagnosis in medical history	Concussion	None	Concussion: 294	Concussion: 74	5
Narad et al,²⁹ 2018	Hospital admission	3-7	Preinjury, 0-12 mo, ≥1 y	Yes	Parents	CBCL	Mild only for preinjury; moderate, severe for the other categories	OIC	TBI, 101; OIC, 117	TBI, 61; OIC, 57	7
Ornstein et al,³⁰ 2014	Hospital admission	6-16	Preinjury, 0-12 mo	Yes	Child, parents	K-SADS-PL; SDI	Mild, moderate, severe	None	TBI, 141	TBI, 69	7
Sinopoli et al,³¹ 2011	Hospital admission	7-17	Preinjury		Parents	Connors–3	Mild, moderate, severe	None	TBI, 63	NA	4
Slomine et al,³² 2005	Rehabilitation unit	7-18	Preinjury, ≥1 y	Yes	Child, parents	DICA psychiatric interview	Severe	None	TBI, 82	TBI, 55	7
Wade et al,³³ 2020	Hospital admission	3-18	Preinjury, 0-12 mo	Yes	Parents	CBCL	Moderate, severe	None	TBI, 587	TBI, 64	6
Yang et al,⁹ 2016	Hospital admission; outpatient	0-12	Preinjury, ≥1 y	Yes	Record review	Psychiatrist novel diagnosis	Mild, severe	NIC	Mild, 3605;severe, 5811; NIC, 41 664	TBI, 60.9; NIC, 60.9	9

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Abbreviations: ADD, attention-deficit disorder; ADHD, attention-deficit/hyperactivity disorder; BRIEF, Behavior Rating Inventory of Executive Function; CBCL, Child Behavior Checklist; DICA-C/A/P, Diagnostic Interview for Child and Adolescents-Child/Adolescent/Parent; DICA-R, Diagnostic Interview for Child and Adolescents-Revised; ICD, International Classification of Disease; K-DIPS, Diagnostisches Interview fur psychische Storungen im Kindesalter; K-SADS-E, Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiological; K-SADS-PL, Schedule for Affective Disorders and Schizophrenia-Present and Lifetime; NA, not applicable; NO, Newcastle-Ottawa; NIC, noninjured control; NPRS, Neuropsychiatric Rating Schedule; OIC, other injuries cohort; PCSS, Post-Concussion Symptom Scale; TBI, traumatic brain injury.

^{^a}

Maximum score, 9.

Only studies reporting descriptive group statistics about ADHD diagnoses before or following TBI were included. We excluded articles reporting on identical participant pools to avoid duplicate data.

Data Extraction

We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline for abstracting and assessing data quality and validity. Data from the selected studies were extracted and categorized based on 2 key moderator variables: injury severity and time since injury. One preinjury and 2 postinjury intervals were defined: (1) before injury, (2) 1 year or less postinjury (T1), and (3) more than 1 year postinjury (T2). We used the average time postinjury reported in the study when assigning the time to 1 of these categories; some studies reported results in both time intervals and we included both sets of results. Studies included in this review used either Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, or Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Revised criteria to diagnose ADHD. Classification of injury severity was typically based on Glasgow Coma Scale³⁴ (GCS) scores that were frequently confirmed by other clinical findings (eg, positive neuroimaging findings) along with concussion as a separate category. Although concussion is usually regarded as a form of mild TBI, we distinguished between mild TBI and concussion because differences in injury mechanism and patient ascertainment between these 2 conditions might result in subtle differences in injury severity. In the 2 studies of concussion, patients were ascertained from pediatric sports concussion clinics where they were first seen days to weeks after the injury. In studies of mild TBI, the patients had a variety of injury mechanisms and were diagnosed in emergency departments shortly after the injury. Consistent with convention, most studies reviewed used the following GCS score ranges to group samples on injury severity: mild (GCS, 13-15), moderate (GCS, 9-12), and severe (GCS, 3-8). Groups at baseline were noninjured controls (NICs), other injured controls (OICs), TBI groups of any severity, and concussion. In preliminary analyses, we found that preinjury rates of ADHD were not statistically significantly different between mild, moderate, and severe TBI, so we combined preinjury rates of ADHD across TBI severity. At follow-up, groups included OIC, concussion, mild TBI, moderate TBI, and severe TBI—all excluding groups of children with baseline ADHD or mild TBI including baseline ADHD. At T2 follow-up, we did not have data on concussion including baseline ADHD and mild TBI. The eMethods in the Supplement gives details of data extraction. For each group and interval reported in each study, we extracted (1) total number of participants in the group at each point; (2) number of ADHD diagnoses in each group; (3) breakdown of TBI severity if the group consisted of mixed severity; (4) whether the study controlled for preinjury ADHD; (5) GCS scores for TBI groups; (6) demographic data, such as age, sex, and race/ethnicity; and (7) diagnostic criteria used for ADHD.

Most studies reported the number of preinjury and novel (occurring only post TBI) ADHD diagnoses and total number of participants for each TBI severity level by time since injury group. In 7 studies,^{8,13,17,19,27,30,33} the number of diagnoses was reported for mixed severity levels. The eMethods in the Supplement details how we accommodated the data from the 7 studies.

A key methodologic issue in interpreting the results of individual studies was whether participants with preinjury ADHD were removed from the study sample before determining ADHD rates following TBI because, if studies did not exclude this cohort, interpretation of the results may overestimate the association between TBI and ADHD. Patients with preinjury ADHD were not included in analyses at T1 or T2, with the exception of 2 studies that included patients with preinjury ADHD at T1.^24,25 In those 2 studies, we subtracted the preinjury rate of ADHD pooled across TBI severity from the ADHD rate of ADHD at T1 in children with ADHD before mild TBI. For studies that excluded patients with preinjury ADHD, we did not need to subtract the pooled TBI preinjury ADHD rate because the reported rates were already of novel ADHD at T1 or T2.

Statistical Analysis

We used a bayesian random-effects meta-analysis model fit using Markov chain Monte Carlo³⁵ with JAGS³⁶ in R, version 3.6.3³⁷ to analyze the resulting data. The model included indicators for preinjury, T1, T2, TBI severity level, control groups (injured or noninjured), whether the study controlled for preinjury ADHD, TBI severity level by follow-up interactions, and random effects for study and group within the study. The eMethods in the Supplement gives a complete presentation of our statistical model, including the model and prior distribution. We estimated odds ratios (ORs) and 95% credible intervals (CrIs) comparing each group at each measurement point with the NIC at baseline and OIC at the same point. We calculated the estimated rates with 95% CrI of ADHD for each group at each point. All reported P values are 2 sided, with P < .05 considered statistically significant.

We conducted 3 sets of sensitivity analyses. First, we omitted data from groups in which we estimated TBI proportions in studies that reported ADHD diagnoses in pooled severity groups. Second, we considered an alternative prior distribution for the fixed effects with variances 9 times larger than those used in our primary model. Third, we refit our model 23 times, omitting data from exactly one study at each refit plus 1 refit omitting 2 studies.

Results

We included 24 studies in this review from the 378 studies screened (Figure 1) with 12 374 unique patients with TBI of all severity levels and 43 491 unique controls (NIC, 43 192; and OIC, 299). Males were the largest sex cohort (TBI, 61.8%; NIC, 60.9%; and OIC, 66.1%). Table 1 summarizes age, sex, NOS scale scores, and other characteristics of included studies.

Meta-analysis

Table 2 reports the numbers of studies and participants for each group at each measurement point and ORs for being diagnosed with ADHD compared with baseline NIC and OIC levels at the same point. eTable 4 in the Supplement reports raw data input into the meta-analysis models, eTable 1 in the Supplement reports ORs comparing TBI groups with the NIC or OIC groups, and eTable 3 in the Supplement reports pairwise OR values at each time. eTable 2 and eFigure 1 in the Supplement present results omitting studies in which the breakdown of TBI severity was not directly reported. Figure 2 illustrates the estimated rates of ADHD with 95% CrIs at preinjury, T1, and T2 for each group and the prevalence of ADHD in the pediatric population. eFigure 2 in the Supplement presents the same data using results from a less informative prior distribution. Estimated rates of ADHD at T2 are given in eFigure 3 in the Supplement for mild TBI and eFigure 4 in the Supplement for severe TBI after single-study deletion. eFigures 5-7 in the Supplement are forest plots of individual study and meta-analysis results.

Table 2. Odds Ratios Comparing Groups With NIC or OIC Groups.

TBI group	Studies/participants, No./total No.	Compared with baseline NICs		Compared with OICs at same time point
TBI group	Studies/participants, No./total No.	OR (95% CrI)	P value	OR (95% CrI)	P value
Preinjury point
NIC	3/43192	NA	NA	0.76 (0.27-1.69)	.41
OIC	5/299	1.64 (0.59-3.68)	.41
TBI	19/2023	2.10 (0.82-4.46)	.13	1.38 (0.67-2.52)	.43
Concussion	2/468	1.23 (0.26-3.65)	.97	0.80 (0.19-2.27)	.50
T1 point
OIC	2/126	0.61 (0.18-1.55)	.24
Concussion	1/160	0.32 (0.05-1.13)	.07	0.56 (0.12-1.64)	.23
Mild including preinjury ADHD	2/130	1.14 (0.27-3.22)	.91
Mild	3/476	0.56 (0.16-1.43)	.18	1.07 (0.33-2.47)	.85
Moderate	7/573	1.28 (0.35-3.34)	.88	2.34 (0.78-5.47)	.14
Severe	7/439	2.62 (0.76-6.64)	.14	4.81 (1.66-11.03)	.004
T2 point
OIC	2/114	1.14 (0.29-3.10)	.93
Mild	6/4098	1.03 (0.35-2.48)	.92	1.18 (0.32-3.12)	>.99
Moderate	5/117	3.67 (0.83-10.56)	.09	3.78 (0.93-10.33)	.07
Severe	7/5920	6.25 (2.06-15.06)	.001	6.70 (2.02-16.82)	.001

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Abbreviations: NA, not applicable; NIC, noninjured control; OIC, other injured control; OR, odds ratio; T1, time 1 year or less postinjury; T2, time more than 1 year postinjury; TBI, traumatic brain injury.

Figure 2. — Estimated rates are presented with 95% credible intervals (CrIs). Mild included indicates mild TBI with preexisting ADHD.

^aStatistically significant difference in ADHD rates between TBI groups and the general pediatric population at preinjury evaluation. Squares indicate studies that included preinjury ADHD diagnoses; diamonds indicate studies that excluded preinjury ADHD diagnoses.

Odds for a preinjury ADHD diagnosis were not significantly greater in concussion and TBI cohorts than in the NIC or OIC cohorts. However, the rates of ADHD were significantly greater in the TBI but not the concussion, NIC, or OIC groups compared with the pediatric population base rate. The rate of preinjury ADHD diagnoses was 16.0% (95% CrI, 11.3%-21.7%) across TBI injury severity. This rate was significantly greater than the general pediatric population base rate of 10.8% (95% CrI,10.2%-11.4%).

Compared with children without injuries, the odds for ADHD were not significantly increased following concussion (<1 year: OR, 0.32; 95% CrI, 0.05-1.13), mild TBI (≤1 year: OR, 0.56; 95% CrI, 0.16-1.43; >1 year: OR, 1.07; 95% CrI, 0.35-2.48), and moderate TBI (≤1 year: OR, 1.28; 95% CrI, 0.35-3.34; >1 year: OR, 3.67; 95% CrI, 0.83-10.56). Compared with children with other injuries, the odds for ADHD were not significantly increased following mild TBI (≤1 year: OR, 1.07; 95% CrI, 0.33-2.47; >1 year: OR, 1.18; 95% CrI, 0.32-3.12), and moderate TBI (≤1 year: OR, 2.34; 95% CrI, 0.78-5.47; >1 year: OR, 3.78; 95% CrI, 0.93-10.33). In contrast, the odds for ADHD following severe TBI were increased at both time points following TBI compared with children with other injuries (≤1 year: OR, 4.81; 95% CrI, 1.66-11.03; >1 year: OR, 6.70; 95% CrI, 2.02-16.82) and noninjured controls (≤1 year: OR, 2.62; 95% CrI, 0.76-6.64; >1 year: OR, 6.25; 95% CrI, 2.06-15.06). Of 5920 children with severe TBI, 35.5% (95% CrI, 20.6%-53.2%) were diagnosed with ADHD more than 1 year after TBI.

The odds for ADHD following severe TBI were significantly increased compared with concussion (≤1 year: OR, 12.89; 95% CrI, 2.13-43.09), mild TBI (≤1 year: OR, 5.69; 95% CrI, 1.46-15.67; >1 year: OR, 6.65; 95% CrI, 2.14-16.44). At both time points, the odds of ADHD did not differ between concussion, mild TBI, and moderate TBI.

Sensitivity Analysis

Sensitivity analyses are reported in the eMethods in the Supplement. The sensitivity analyses resulted in minor changes except when the studies by Narad et al²⁹ or Yang et al⁹ were omitted. Excluding these studies resulted in opposite changes in the rate of ADHD at T2 in patients with severe TBI. Omitting the Yang et al study increased the rate of ADHD from 35.9% to 51.6% (95% CrI, 32.3%-70.6%); omitting the Narad et al study decreased the rate of ADHD from 36.0% to 26.2% (95% CrI, 13.4%-43.4%). Omitting both studies left the rate estimate and interval slightly higher than retaining both studies (42.0%; 95% CrI, 21.8%-64.4%).

Discussion

Across TBI injury severity, the rate of preinjury ADHD diagnoses was 16.0%, which is significantly greater than the general pediatric population base rate of 10.8% in the most recent Centers for Disease Control and Prevention survey.³⁸ This result underscores the importance of controlling for preinjury ADHD in studies attempting to determine the association between TBI and ADHD. To the extent that patients with ADHD diagnoses before TBI are not removed from analysis, the association with TBI may be overestimated. Although the odds of preinjury diagnosis of ADHD in patients with TBI is almost double the odds in the NIC cohort, this difference was not statistically significant with the wide 95% CrIs. The odds of preinjury ADHD in patients with TBI do not significantly differ from the odds in the OIC cohort. These results suggest that comparisons between OIC and TBI may be one way to control for preinjury ADHD, but comparison with a noninjured sample does not adequately control for preinjury ADHD. Given the higher-than-expected rate of preinjury ADHD in patients with TBI, studies that remove preinjury cases from analysis have the most probative value in estimating the effect of TBI on ADHD diagnoses. The increase in rate of preinjury ADHD compared with the population base rate is consistent with studies that reported an increase in risk for TBI in children with ADHD.^39,40,41 Thus, ADHD appears to be a risk factor for TBI.

Figure 2 depicts an association between injury severity and odds for diagnosis of ADHD at T2 following a TBI. At T1 and T2, the odds for ADHD after concussion, mild TBI, and moderate TBI were not significantly increased compared with the odds in the NIC and OIC cohorts. In contrast, at T1, the odds for ADHD were significantly greater in patients with severe TBI than in the OICs. At T2, the odds for ADHD were significantly greater for patients with severe TBI than for the NIC and OIC cohorts: 35.5% (95% CrI, 20.6%-53.2%) of 5920 children with severe TBI had ADHD at T2. Although the association of severe TBI with an increase in risk for ADHD appeared to be relatively robust, there was a wide CrI for of moderate TBI, particularly at T2.

There may be less of an association of severe TBI at T1 than T2. There are a limited number of longitudinal studies in our analysis. The lack of association might reflect differences between the sample characteristics and diagnostic methods in the studies at T1 and T2 rather than true changes over time. Longitudinal studies with large representative samples are needed to evaluate the development of ADHD following TBI.

Sensitivity analyses generally resulted in minor changes in the estimates with slightly widened 95% CrIs (eMethods in the Supplement). Important exceptions were deletion of studies of Narad et al²⁹ and Yang et al⁹ on the estimated rate of ADHD after severe TBI at T2. Yang et al used different diagnostic criteria and ascertainment methods that resulted in a much lower rate of ADHD diagnoses (6% after 9 years) than other studies. Narad et al had a much higher rate of ADHD diagnoses (75%) than other studies, possibly as a result of broader diagnostic criteria.

The sensitivity to less informative prior distributions resulted in some changes in the estimates with wider 95% CrIs overall (eMethods in the Supplement). The odds of ADHD after concussion excluding baseline ADHD were lower than in the NIC cohort at T1 (OR, 0.17; 95% CrI, 0.01-0.83).

The results of this meta-analysis contradict the conclusion in the earlier meta-analysis that mild TBI was associated with an increase in risk for ADHD.¹⁰ Since that review, additional studies with more participants have been published. The meta-analysis in the earlier review included 5 studies. Only 2 of those studies reported the rates of ADHD after mild TBI; the other 3 studies did not specify whether ADHD occurred before or after TBI.

The risk for ADHD following TBI parallels earlier analyses on the association between TBI and cognitive and academic skills. Immediately after mild TBI, there was an acute, mild reduction in cognitive⁴ and academic⁵ function, but those functions recovered by T2. In contrast, severe TBI resulted in persistent impairments in cognitive function and academic skills. The persistence of functional impairments in children with severe TBI may be associated with the loss of white matter volume and organization^42,43 that worsens over the first 2 years post TBI. Similarly, in patients with ADHD following TBI, decreased white matter organization appears to be a central feature⁴⁴ of the pathophysiologic changes.

Despite the differences in the cause, children with moderate and severe TBI have similarities to children with primary ADHD in reduced white matter integrity⁴⁴ and appear to show enhanced cognitive function in response to methylphenidate, as in children with primary ADHD.⁴⁵

Limitations

A limitation of this meta-analysis was the small number of studies and patients in the OIC and concussion groups. When using the estimated rates of ADHD contained in Figure 2, the 95% CrIs need to be considered. In addition, the soundness of the conclusions of this meta-analysis are limited by the methodologic quality of the studies included in our analysis.

Conclusions

There are individual exceptions to the aggregate association with injury severity in meta-analyses. This is particularly relevant to clinical practice. There may be some patients with mild TBI who present with severe ADHD symptoms and diagnoses, and some patients with severe TBI may not have ADHD symptoms and diagnoses. By uncovering generalizable information from multiple studies, meta-analytic reviews focus additional scrutiny on exceptions to those generalizations. When confronted with claims that a mild TBI causes persistent, severe ADHD symptoms, clinicians should carefully review how the child was functioning before the TBI before concluding that the child developed ADHD as a result of a TBI. For example, parental educational level (eg, high school or college) and school performance before injury estimated which children with mild TBI had elevated rates of behavior problems⁴⁶ and poor performance on neuropsychological tests of attention.⁴⁷ There may be psychosocial and medical issues that antedated the TBI that need to be addressed to adequately treat a child’s ADHD symptoms.

Supplement.

eMethods. Detailed Description of Study Covariates and Data Extraction and Statistical Methods

eFigure 1. Sensitivity Analysis on Estimated Rates of ADHD Using Only Groups With Known TBI Severity Breakdown

eFigure 2. Sensitivity Analysis on Estimated Rates of ADHD Using Less Informative Priors

eFigure 3. Sensitivity analyses omitting one study at a time (and last line, omitting two studies) on Estimated Rates of ADHD for Mild TBI After Excluding for Pre-Injury ADHD at T2

eFigure 4. Sensitivity Analyses Omitting One Study at A Time (and Last Line, Omitting Two Studies) on Estimated Rates of ADHD for Severe TBI After Excluding for Pre-Injury ADHD at T2

eFigure 5. Forest Plot of ADHD Rates From Individual Papers by Severity Level at the Baseline Preinjury Time Point With 95% Confidence Intervals

eFigure 6. Forest Plot of ADHD Rates From Individual Papers by Severity Level at the T1 Time Point With 95% Confidence Intervals

eFigure 7. Forest Plot of ADHD Rates From Individual Papers by Severity Level at the T2 Time Point With 95% Confidence Intervals

eTable 1. Odds Ratios Comparing Groups To Non-Injured Or Other-Injured Control Groups Using Only Groups With Breakdown of TBI Severity

eTable 2. Odds Ratios Comparing Groups To Non-Injured Or Other-Injured Control Groups With Less Informative Priors

eTable 3. Pairwise Odds Ratios With 95% Credible Intervals and P Values Within Each Time Point

eTable 4. Raw Data Input Into the Meta-Analysis Models, Organized by Groups and Time Points

Click here for additional data file.^{(1.1MB, pdf)}

References

1.Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21(5):375-378. pii. doi: 10.1097/00001199-200609000-00001 [DOI] [PubMed] [Google Scholar]
2.Nguyen R, Fiest KM, McChesney J, et al. The international incidence of traumatic brain injury: a systematic review and meta-analysis. Can J Neurol Sci. 2016;43(6):774-785. doi: 10.1017/cjn.2016.290 [DOI] [PubMed] [Google Scholar]
3.Barlow KM. Traumatic brain injury. Handb Clin Neurol. 2013;112:891-904. doi: 10.1016/B978-0-444-52910-7.00011-8 [DOI] [PubMed] [Google Scholar]
4.Babikian T, Asarnow R. Neurocognitive outcomes and recovery after pediatric TBI: meta-analytic review of the literature. Neuropsychology. 2009;23(3):283-296. doi: 10.1037/a0015268 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Vu JA, Babikian T, Asarnow R. Academic and language outcomes in children after traumatic brain injury: a meta-analysis. Counc Except Child. 2011;77(3):263-281. doi: 10.1177/001440291107700301 [DOI] [Google Scholar]
6.Yeates K, Taylor H, Barry C, Drotar D, Wade S, Stancin T. Neurobehavioral symptoms in childhood closed-head injuries: changes in prevalence and correlates during the first year postinjury. J Pediatr Psychol. 2001;26(2):79-91. doi: 10.1093/jpepsy/26.2.79 [DOI] [PubMed] [Google Scholar]
7.Grados MA, Vasa RA, Riddle MA, et al. New onset obsessive-compulsive symptoms in children and adolescents with severe traumatic brain injury. Depress Anxiety. 2008;25(5):398-407. doi: 10.1002/da.20398 [DOI] [PubMed] [Google Scholar]
8.Levin H, Hanten G, Max J, et al. Symptoms of attention-deficit/hyperactivity disorder following traumatic brain injury in children. J Dev Behav Pediatr. 2007;28(2):108-118. doi: 10.1097/01.DBP.0000267559.26576.cd [DOI] [PubMed] [Google Scholar]
9.Yang L-Y, Huang C-C, Chiu W-T, Huang L-T, Lo W-C, Wang J-Y. Association of traumatic brain injury in childhood and attention-deficit/hyperactivity disorder: a population-based study. Pediatr Res. 2016;80(3):356-362. doi: 10.1038/pr.2016.85 [DOI] [PubMed] [Google Scholar]
10.Adeyemo BO, Biederman J, Zafonte R, et al. Mild traumatic brain injury and ADHD: a systematic review of the literature and meta-analysis. J Atten Disord. 2014;18(7):576-584. doi: 10.1177/1087054714543371 [DOI] [PubMed] [Google Scholar]
11.Wells G, Shea B, O’Connell D, Peterson J. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute; 2000. [Google Scholar]
12.Biederman J, Feinberg L, Chan J, et al. Mild traumatic brain injury and attention-deficit hyperactivity disorder in young student athletes. J Nerv Ment Dis. 2015;203(11):813-819. doi: 10.1097/NMD.0000000000000375 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Bloom DR, Levin HS, Ewing-Cobbs L, et al. Lifetime and novel psychiatric disorders after pediatric traumatic brain injury. J Am Acad Child Adolesc Psychiatry. 2001;40(5):572-579. doi: 10.1097/00004583-200105000-00017 [DOI] [PubMed] [Google Scholar]
14.Brown G, Chadwick O, Shaffer D, Rutter M, Traub M. A prospective study of children with head injuries: III; psychiatric sequelae. Psychol Med. 1981;11(1):63-78. doi: 10.1017/S0033291700053289 [DOI] [PubMed] [Google Scholar]
15.Chasle V, Riffaud L, Longuet R, et al. Mild head injury and attention deficit hyperactivity disorder in children. Childs Nerv Syst. 2016;32(12):2357-2361. doi: 10.1007/s00381-016-3230-z [DOI] [PubMed] [Google Scholar]
16.Ellis MJ, Ritchie LJ, Koltek M, et al. Psychiatric outcomes after pediatric sports-related concussion. J Neurosurg Pediatr. 2015;16(6):709-718. doi: 10.3171/2015.5.PEDS15220 [DOI] [PubMed] [Google Scholar]
17.Gerring JP, Brady KD, Chen A, et al. Premorbid prevalence of ADHD and development of secondary ADHD after closed head injury. J Am Acad Child Adolesc Psychiatry. 1998;37(6):647-654. doi: 10.1097/00004583-199806000-00015 [DOI] [PubMed] [Google Scholar]
18.Königs M, Heij HA, van der Sluijs JA, et al. Pediatric traumatic brain injury and attention deficit. Pediatrics. 2015;136(3):534-541. doi: 10.1542/peds.2015-0437 [DOI] [PubMed] [Google Scholar]
19.Konrad K, Gauggel S, Schurek J. Catecholamine functioning in children with traumatic brain injuries and children with attention-deficit/hyperactivity disorder. Brain Res Cogn Brain Res. 2003;16(3):425-433. doi: 10.1016/S0926-6410(03)00057-0 [DOI] [PubMed] [Google Scholar]
20.Massagli TL, Fann JR, Burington BE, Jaffe KM, Katon WJ, Thompson RS. Psychiatric illness after mild traumatic brain injury in children. Arch Phys Med Rehabil. 2004;85(9):1428-1434. Accessed May 6, 2015 https://www.ncbi.nlm.nih.gov/pubmed/15375812. doi: 10.1016/j.apmr.2003.12.036 [DOI] [PubMed] [Google Scholar]
21.Max JE, Koele SL, Smith WL Jr, et al. Psychiatric disorders in children and adolescents after severe traumatic brain injury: a controlled study. J Am Acad Child Adolesc Psychiatry. 1998;37(8):832-840. doi: 10.1097/00004583-199808000-00013 [DOI] [PubMed] [Google Scholar]
22.Max JE, Lansing AE, Koele SL, et al. Attention deficit hyperactivity disorder in children and adolescents following traumatic brain injury. Dev Neuropsychol. 2004;25(1-2):159-177. doi: 10.1080/87565641.2004.9651926 [DOI] [PubMed] [Google Scholar]
23.Max JE, Lindgren SD, Knutson C, Pearson CS, Ihrig D, Welborn A. Child and adolescent traumatic brain injury: psychiatric findings from a paediatric outpatient specialty clinic. Brain Inj. 1997;11(10):699-711. doi: 10.1080/026990597123070 [DOI] [PubMed] [Google Scholar]
24.Max JE, Pardo D, Hanten G, et al. Psychiatric disorders in children and adolescents six-to-twelve months after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2013;25(4):272-282. doi: 10.1176/appi.neuropsych.12040078 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Max JE, Schachar RJ, Landis J, et al. Psychiatric disorders in children and adolescents in the first six months after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2013;25(3):187-197. doi: 10.1176/appi.neuropsych.12010011 [DOI] [PubMed] [Google Scholar]
26.Max JE, Schachar RJ, Levin HS, et al. Predictors of attention-deficit/hyperactivity disorder within 6 months after pediatric traumatic brain injury. J Am Acad Child Adolesc Psychiatry. 2005;44(10):1032-1040. doi: 10.1097/01.chi.0000173293.05817.b1 [DOI] [PubMed] [Google Scholar]
27.Max JE, Wilde EA, Bigler ED, et al. Psychiatric disorders after pediatric traumatic brain injury: a prospective, longitudinal, controlled study. J Neuropsychiatry Clin Neurosci. 2012;24(4):427-436. doi: 10.1176/appi.neuropsych.12060149 [DOI] [PubMed] [Google Scholar]
28.Miller JH, Gill C, Kuhn EN, et al. Predictors of delayed recovery following pediatric sports-related concussion: a case-control study. J Neurosurg Pediatr. 2016;17(4):491-496. doi: 10.3171/2015.8.PEDS14332 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Narad ME, Kennelly M, Zhang N, et al. Secondary attention-deficit/hyperactivity disorder in children and adolescents 5 to 10 years after traumatic brain injury. JAMA Pediatr. 2018;172(5):437-443. doi: 10.1001/jamapediatrics.2017.5746 [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Ornstein TJ, Sagar S, Schachar RJ, et al. Neuropsychological performance of youth with secondary attention-deficit/hyperactivity disorder 6- and 12-months after traumatic brain injury. J Int Neuropsychol Soc. 2014;20(10):971-981. doi: 10.1017/S1355617714000903 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Sinopoli KJ, Schachar R, Dennis M. Traumatic brain injury and secondary attention-deficit/hyperactivity disorder in children and adolescents: the effect of reward on inhibitory control. J Clin Exp Neuropsychol. 2011;33(7):805-819. doi: 10.1080/13803395.2011.562864 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Slomine BS, Salorio CF, Grados MA, Vasa RA, Christensen JR, Gerring JP. Differences in attention, executive functioning, and memory in children with and without ADHD after severe traumatic brain injury. J Int Neuropsychol Soc. 2005;11(5):645-653. doi: 10.1017/S1355617705050769 [DOI] [PubMed] [Google Scholar]
33.Wade SL, Kaizar EE, Narad ME, et al. Behavior problems following childhood TBI: the role of sex, age, and time since injury. J Head Trauma Rehabil. 2020;35(5):E393-E404. doi: 10.1097/HTR.0000000000000567 [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol. 2014;13(8):844-854. doi: 10.1016/S1474-4422(14)70120-6 [DOI] [PubMed] [Google Scholar]
35.Robert C, Casella G. Introducing Monte Carlo Methods With R. Springer; 2010. doi: 10.1007/978-1-4419-1576-4 [DOI] [Google Scholar]
36.Plummer M. JAGS: a program for analysis of bayesian models using Gibbs sampling. In: Proceedings of the 3rd International Workshop on Distributed Statistical Computing; Vienna, Austria; March 20, 2003. [Google Scholar]
37.R Core Team . R: A Language and Environment for Statistical Computing. The R Foundation; 2019. [Google Scholar]
38.Centers for Disease Control and Prevention . Health, United States, 2018. —data finder. October 30, 2019. Accessed May 15, 2020. https://www.cdc.gov/nchs/hus/contents2018.htm#Table_012
39.Iverson GL, Wojtowicz M, Brooks BL, et al. High school athletes with ADHD and learning difficulties have a greater lifetime concussion history. J Atten Disord. 2020;24(8):1095-1101. doi: 10.1177/1087054716657410 [DOI] [PubMed] [Google Scholar]
40.Fann JR, Leonetti A, Jaffe K, Katon WJ, Cummings P, Thompson RS. Psychiatric illness and subsequent traumatic brain injury: a case control study. J Neurol Neurosurg Psychiatry. 2002;72(5):615-620. doi: 10.1136/jnnp.72.5.615 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Liou YJ, Wei HT, Chen MH, et al. Risk of traumatic brain injury among children, adolescents, and young adults with attention-deficit hyperactivity disorder in Taiwan. J Adolesc Health. 2018;63(2):233-238. doi: 10.1016/j.jadohealth.2018.02.012 [DOI] [PubMed] [Google Scholar]
42.Dennis EL, Rashid F, Ellis MU, et al. Diverging white matter trajectories in children after traumatic brain injury: the RAPBI study. Neurology. 2017;88(15):1392-1399. doi: 10.1212/WNL.0000000000003808 [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Dennis EL, Faskowitz J, Rashid F, et al. Diverging volumetric trajectories following pediatric traumatic brain injury. Neuroimage Clin. 2017;15:125-135. doi: 10.1016/j.nicl.2017.03.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Max JE, Wilde EA, Bigler ED, et al. Neuroimaging correlates of novel psychiatric disorders after pediatric traumatic brain injury. J Am Acad Child Adolesc Psychiatry. 2012;51(11):1208-1217. doi: 10.1016/j.jaac.2012.08.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Writer BW, Schillerstrom JE. Psychopharmacological treatment for cognitive impairment in survivors of traumatic brain injury: a critical review. J Neuropsychiatry Clin Neurosci. 2009;21(4):362-370. doi: 10.1176/jnp.2009.21.4.362 [DOI] [PubMed] [Google Scholar]
46.Light R, Asarnow R, Satz P, Zaucha K, McCleary C, Lewis R. Mild closed-head injury in children and adolescents: behavior problems and academic outcomes. J Consult Clin Psychol. 1998;66(6):1023-1029. doi: 10.1037/0022-006X.66.6.1023 [DOI] [PubMed] [Google Scholar]
47.Babikian T, McArthur D, Asarnow RF. Predictors of 1-month and 1-year neurocognitive functioning from the UCLA longitudinal mild, uncomplicated, pediatric traumatic brain injury study. J Int Neuropsychol Soc. 2013;19(2):145-154. doi: 10.1017/S135561771200104X [DOI] [PubMed] [Google Scholar]

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