http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, Early Online: 1–8 ! 2015 Informa UK Ltd. DOI: 10.3109/02699052.2014.1002421

ORIGINAL ARTICLE

Clinical correlates of retrograde amnesia in mild traumatic brain injury Teemu M. Luoto1, Grant L. Iverson2,3, Heidi Losoi1, Minna Wa¨ljas1, Olli Tenovuo4, Anneli Kataja5, Antti Brander5, & Juha O¨hman1 Department of Neurosciences and Rehabilitation, Tampere University Hospital, Tampere, Finland, 2Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA, 3Red Sox Foundation and Massachusetts General Hospital Home Base Program, Boston, MA, USA, 4Department of Rehabilitation and Brain Trauma, University of Turku and Turku University Central Hospital, Turku, Finland, and 5 Medical Imaging Centre, Department of Radiology, Tampere University Hospital, Tampere, Finland Brain Inj Downloaded from informahealthcare.com by University of Connecticut on 04/01/15 For personal use only.

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Abstract

Keywords

Primary objective: The purpose of this study was to examine the clinical significance of retrograde amnesia (RA) in patients with acute mild traumatic brain injuries (MTBI). Methods and procedures: An emergency department sample of patients (n ¼ 75), aged 18–60 years, with no pre-morbid medical or psychiatric conditions, who met the WHO criteria for MTBI were enrolled in this prospective, descriptive, follow-up study. This study examined the presence and duration of RA in relation to socio-demographics, MTBI severity markers including neuroimaging (CT, MRI) and clinical outcomes (Rivermead post-concussion symptoms questionnaire, post-concussion syndrome (PCS) diagnosis and return to work (RTW) status) at 2 weeks, 1 month and 6 months post-injury. Main outcomes and results: GCS scores and duration of post-traumatic amnesia (PTA) were related to RA. Those with GCS scores of 14 vs. 15 were more likely to have RA (2(1) ¼ 13.70, p50.0001) and a longer duration (Mann-Whitney U ¼ 56.0, p50.0001, d ¼ 1.15) of RA. The duration of RA and PTA correlated positively (Spearman (75) ¼ 0.42, p50.0001) and those with RA had longer durations of PTA (Mann-Whitney U ¼ 228.5, p ¼ 0.001, d ¼ 1.21). During the follow-up, the presence and duration of RA were not significantly associated with PCS diagnosis or time to RTW. Conclusions: In this study, the presence and duration of RA was not associated with outcome.

Concussion, head injury, post-concussion syndrome, retrograde amnesia, return to work, traumatic brain injury

Introduction Retrograde amnesia (RA) refers to the inability to recall information acquired prior to the onset of a cerebral pathology [1] as described by psychologist The´odule Ribot in 1881. In the context of TBI, RA is defined as a memory loss for events occurring before the injury [2, 3]. Based on both human and experimental animal studies, RA is believed to originate from structural and functional impairment in the anterior temporal regions and the severity of amnesia is correlated with the extent and bilaterality of tissue damage [4]. Also, interaction with the prefrontal cortex plays a role in the storage and retrieval of remote episodic and semantic memories [5–8]. However, the physiological and psychological processes underlying RA have been widely debated [4, 9–11]. Various aetiologies of RA have been presented including simulated, functional, dissociative, psychogenic and organic amnesia, but differential diagnosis and reliable assessment have proven difficult [9, 12–14]. Brief autobiographic amnesia is the sub-type of RA that is typically encountered in patients with mild TBI (MTBI) [2, 9, 15, 16]. To date, RA in MTBI has received relatively little Correspondence: Dr. Teemu M. Luoto, Tampere University Hospital, P. Box 2000, FI-33521, Tampere, Finland. E-mail: [email protected]

History Received 28 March 2014 Revised 18 November 2014 Accepted 20 December 2014 Published online 16 March 2015

attention in well-controlled, systematic studies. In contrast, RA has been more widely examined in moderate-to-severe TBI [1, 4, 5, 7, 10, 11, 16, 17]. The consistent conclusion from these reports has been that the clinical importance of RA is minor. This possibly partly explains the lack of recent RA-focused MTBI studies. Another, maybe a more crucial, drawback is that a valid and reliable method for measuring the duration of RA is not available. Nevertheless, the assessment of RA is routinely included in the management of patients with head injury [18–21]. Usually, the applied assessment method is a brief interview of events preceding the injury. It is unclear from the literature (and clinical practice) whether the true duration of TBI-induced RA can be estimated reliably. Conceptually, this task seems difficult or even impossible. If one attempts to interview a person with TBI early after injury, how can the assessor know whether the apparent last memory before the injury is accurate or whether this reflects postinjury confusion rather than true retrograde memory impairment? Furthermore, attempts to interview persons with TBI long after injury can be confounded by a logical reconstruction of what might have occurred rather than what actually occurred. Aside from methodological concerns, numerous factors can contribute or even cause remote memory loss [22] and these confounding factors should be

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considered when assessing RA in MTBI. Such confounders include: pre-morbid psychiatric and neurological problems [22], alcohol and substance abuse/intoxication [23, 24], psychological stress [25] (e.g. psychogenic amnesia), medication (e.g. glucocorticoids [26], benzodiazepines [27] and opioids [28]), cognitive reserve [29, 30], time of assessment [31] and malingering [32]. The purpose of this study is to examine the incidence, duration and clinical relevance of clinically interviewed RA in an homogenous MTBI sample that was carefully screened for pre-injury medical, psychiatric and neurological problems. First, this study examined the relations between pre- and postinjury background and clinical factors and RA. Second, the inter-relationships between RA and other clinical signs of MTBI (LOC, PTA, GCS and traumatic abnormalities in neuroimaging) were evaluated. Finally, RA was examined as a predictor of the time to return to work (RTW) and postconcussion symptomology at 2 weeks, 1 month and 6 months post-injury. There were three hypotheses: (i) the time between injury and clinical assessment would have a significant effect on the duration of RA; (ii) the duration of RA and PTA would correlate positively; and (iii) the presence and duration of RA would be associated with post-concussion syndrome (PCS) diagnosis.

Methods Study framework and ethics This study is part of a broader research program, the Tampere Traumatic Head and Brain Injury Study. Participants were enrolled from the Emergency Department (ED) of the Tampere University Hospital between August 2010 and July 2012. The ED provides health services for a joint municipal authority of 22 municipalities (both urban and rural), with a total of 470 000 residents. All consecutive patients who underwent head computed tomography (CT) due to acute head trauma (n ¼ 3023) formed the initial patient pool for this study. Referral criteria for acute head CT were based on the Scandinavian guidelines for initial management of minimal, mild and moderate head injuries [33]. All consecutive patients undergoing head CT due to acute head injury were screened to obtain a sample of working aged adults without pre-injury medical or mental health problems who had sustained a ‘pure’ MTBI. The enrolment protocol included three inclusion criteria and nine exclusion criteria. Subjects were included in the study if they: (i) met MTBI criteria of the World Health Organization’s Collaborating Centre for Neurotrauma Task Force [34], (ii) were aged between 18–60 years and (iii) were residents of the hospital district. Subjects were excluded if they had: (i) pre-morbid neurological problems, (ii) prior psychiatric problems, (iii) past TBI, (iv) regular psychoactive medication use, (v) neurosurgery, (vi) problems with vision or hearing, (vii) first language was not Finnish, (viii) the time interval between injury and arrival to the ED was over 72 hours and/or (ix) they declined to participate in the study. The major causes of exclusion were: (i) age criteria not met (n ¼ 1552, 51.3%), (ii) MTBI criteria not met (n ¼ 942, 31.2%), (iii) psychiatric problems (n ¼ 860, 28.4%) and/or (iv) neurological problems (n ¼ 744, 24.6%). Notably, there was major overlap in the causes of exclusion, because some

Brain Inj, Early Online: 1–8

patients had multiple reasons. Patient enrolment details are discussed thoroughly in a previous publication [35]. For the final enrolled sample of 75 patients, who met all the study criteria, a detailed prospective data collection was conducted which included socio-demographics, injury-related data and clinical information from the ED. Within 2 weeks from the injury, a magnetic resonance imaging (MRI) of the head was performed (see ‘Neuroimaging’ below). Also, a 2-week, 1-month and 6-month follow-up assessment of post-concussion symptoms was completed (see ‘Clinical assessment’ below). Ethics approval for the study was obtained from the Ethical Committee of Pirkanmaa Hospital District, Finland. Participants Of the 75 patients with MTBI, 45 (60.0%) were men and 30 (40.0%) were women. Their mean age was 37.2 years (SD ¼ 12.0, median ¼ 36.0, Range ¼ 18.0–60.0) and their average education was 14.2 years (SD ¼ 3.1, median ¼ 14.0, Range ¼ 9.0–22.0). The mechanisms of injury were as follows: sports (n ¼ 13, 17.3%), car accidents (n ¼ 12, 16.0%), falls from a height (n ¼ 12, 16.0%), bicycle accidents (n ¼ 11, 14.7%), ground-level falls (n ¼ 10, 13.3%), motorcycle accidents (n ¼ 5, 6.7%), violence-related injuries (n ¼ 5, 6.7%) and other (e.g. object striking the head) (n ¼ 7, 9.3%). Based on the injury circumstance or a clinical interview, 13 patients were suspected of being under the influence of alcohol. A breathalyser test was administered to these patients in the ambulance and/or the ED. Ten of these patients were under the influence of alcohol (breathalyser, Range ¼ 0.07– 2.43%) at the time of injury. Of the patients, 49 (65.3%) were transported by ambulance from the injury site to the ED. Clinical assessment A broad clinical assessment of the patients was performed by the first author. The mean time interval between injury and acute clinical assessment was 48.1 hours (median ¼ 41.0, SD ¼ 45.4, Range ¼ 2.0–241.0). The assessment included a thorough interview of past health including diagnosed medical conditions, medication use, head injury history, alcohol consumption according to the Alcohol Use Disorders Identification Test (AUDIT) [36] and drug and narcotics abuse history. Injury-related data consisted of time of injury, mechanism of injury and alcohol intoxication at the time of injury. Presence and duration of possible LOC and disorientation was evaluated using information given by eyewitnesses and ambulance personnel where available. The presence and duration of RA and PTA was assessed using the Galveston Orientation and Amnesia Test (GOAT) [37]. All the patients scored 80 points or greater (out of a maximum of 100) on the GOAT. One question on the GOAT assesses recall of the last event preceding the injury (The question: Can you describe the last event you can recall before the accident?). This question is scored dichotomously, 0 or 5 error points. The score 0 indicates that the patient is able to describe the last event prior to the injury. Of the 17 patients with RA, three (17.6%) patients had an intact memory of the accident according to the GOAT question. However, these three patients had retrograde memory deficits encompassing day-of-injury events prior to the injury event itself. The Rivermead PTA protocol [38] was

Retrograde amnesia in MTBI

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DOI: 10.3109/02699052.2014.1002421

used to measure the duration of PTA. It has reasonable reliability for monitoring the duration of amnesia in clinical practice [38]. In the protocol, patients discuss the events after the accident in a free-flowing and open-ended manner. Care is taken to distinguish between what the patient actually remembers vs. what he or she has garnered from other sources. Unfortunately, eye-witnesses or relatives were not interviewed to clarify which memories were truly experienced. Persistent PTA was screened using the Revised Westmead PTA scale [39] and all the patients scored a flawless 12 points at the time of assessment. The duration of RA was evaluated using a free-flowing and open-ended interview of the events preceding the accident, similarly to the Rivermead PTA protocol. RA was defined as a memory gap between the patient’s recall of the last events before the accident and the injury itself. The pre-injury moment when the patient reported not having chronological and continuous memories of events was defined as the initiation time of RA. The time of injury was assessed using a patient interview and by reviewing hospital and ambulance records. RA was recorded in minutes using the best estimate. Glasgow Coma Scale (GCS) [40] scores were collected from ambulance forms (if applicable) and the ED records (the lowest scores were recorded). The clinical assessment included a complete neurological examination (cranial and spinal nerves, co-ordination, balance, pronator drift and diadochokinesis). Injury Severity Scores (ISS) [41] were gathered. Also, administration of opioid medication in the ambulance and/or ED was recorded. As part of routine treatment, four different opioids were used: oxycodone (n ¼ 4), fentanyl (n ¼ 1), codeine (n ¼ 3) and alfentanil (n ¼ 14). Information relating to clinical findings in the ED is presented in Table I. Neuroimaging In the ED, a non-contrast head CT was performed with a 64row CT scanner (GE, Lightspeed VCT, Milwaukee, WI) for

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all consecutive patients with head injury. MRI of the brain was done with a 3 Tesla Siemens Trio (Siemens AG Medical Solutions, Erlangen, Germany). The MRI protocol included sagittal T1-weighted 3D IR prepared gradient echo, axial T2 turbo spin echo, conventional axial and high resolution sagittal FLAIR (fluid-attenuated inversion recovery), axial T2*, axial SWI (susceptibility weighted imaging) and DWI (diffusion weighted imaging) series. Head CT was performed in the ED within 72 hours and head MRIs were done within 14 days after injury. Mean time between injury and head CT was 11.4 hours (SD ¼ 13.0, median ¼ 5.8, Range ¼ 1.0–60.0) and between injury and MRI it was 5.8 days (SD ¼ 2.5, median ¼ 5.4, Range ¼ 1.4–13.9). All head CT scans and MRIs were analysed and systematically coded by two neuroradiologists (A.B., A.K.). Gross findings on conventional neuroimaging are also summarized in Table I. Clinical follow-up The patients filled out the Rivermead Post-concussion Symptoms Questionnaire [42] (RPQ) as part of a larger internet-based questionnaire at 2 weeks (mean time between injury and questionnaire ¼ 10.2 days, SD ¼ 3.1), 1 month (mean time between injury and questionnaire ¼ 26.5 days, SD ¼ 9.3) and 6 months post-injury (mean time between injury and questionnaire ¼ 185.5 days, SD ¼ 11.3). If a reply to the questionnaire was not received, the RPQ was completed at an outpatient clinic follow-up visit (1 and 6 months postinjury). The overall response rate at 2 weeks was 82.7% (n ¼ 62), at 1 month it was 98.7% (n ¼ 74) and at 6 months it was 92.0% (n ¼ 69). The cumulative participation rates in follow-ups were 82.7% (n ¼ 62), 82.7% (n ¼ 62) and 78.7% (n ¼ 59), respectively. With regard to outcome classification, participants were determined to have met ICD-10 diagnostic criteria for Post-concussion Syndrome (PCS) at follow-up if they endorsed symptoms on the RPQ in at least three of the ICD-10 symptom categories [43]. The criteria consist of six

Table I. Acute clinical findings (n ¼ 75). Presence, n (%) Yes Injury Severity Score AUDIT Loss of Consciousness (min)a Post-Traumatic Amnesia (h) Retrograde Amnesia (min) Galveston Orientation and Amnesia Test Glasgow Coma Scale, 15 points Glasgow Coma Scale, 14 points Acute traumatic lesion on CTb Acute traumatic lesion on MRI Diffuse axonal injury Diffuse axonal injury and subdural haemorrhage Subdural haemorrhage Subdural effusion Subarachnoid haemorrhage Contusion and subdural haemorrhage Contusion Acute opioid medication administered Alcohol intoxication a

No

28 (37.3) 69 (92.0) 17 (22.7)

47 (62.7) 6 (8.0) 58 (77.3)

69 6 7 15 7 1 1 1 1 2 2 22 10

6 69 68 60

(92.0) (8.0) (9.3) (20.0) (9.3) (1.3) (1.3) (1.3) (1.3) (2.7) (2.7) (29.3) (13.3)

Mean

Md

SD

Range

3.9 4.8 0.9 2.7 25.7 94.9

2.0 4.0 0 1.5 0 95.0

3.2 3.0 2.2 3.4 99.5 5.2

1.0–12.0 0–10.0 0–15.0 0–20.0 0–720.0 80.0–100.0

(8.0) (92.0) (90.7) (80.0)

53 (70.3) 65 (86.7)

In 25 patients, the injury was not witnessed and, therefore, the presence of LOC was unverified. These cases were coded as not having LOC. All traumatic lesions were also visible on MRI. AUDIT, Alcohol Use Disorders Identification Test.

b

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symptom categories: (i) headaches, dizziness, general malaise, excessive fatigue or noise intolerance; (ii) irritability, emotional lability, depression or anxiety; (iii) subjective complaints of concentration or memory difficulty; (iv) insomnia; (v) reduced tolerance to alcohol; and (vi) preoccupation with these symptoms and fear of permanent brain damage. The first four symptom categories were attainable using the RPQ. Two thresholds of symptom endorsement were considered—mild or greater severity (2–4 points) and moderate or greater severity (3–4 points); hereafter abbreviated as mild PCS and moderate PCS, respectively. Based on the RPQ, three additional outcome variables were constructed at all three follow-up points (2 weeks, 1 month and 6 months): (i) RPQ total score, (ii) the number of symptoms endorsed on the RPQ in mild or greater severity and (iii) the number of symptoms endorsed on the RPQ in moderate or greater severity. RTW was defined as the time point when sick leave ended and the patient returned to normal work. The capacity (full former, lighter duty, accommodations, reduced hours, etc.) in which the patient returned was not documented, however. The date of return was confirmed by interview on follow-up visits performed at 1 and 6 months post-injury. MTBI was the primary reason for time off work in 81.5% (n ¼ 53) and an orthopaedic injury in 18.5% (n ¼ 12). Ten (13.3%) patients with MTBI did not take time off work following their injuries. Four (5.3%) of the patients were unemployed at the time of recruitment. Post-graduate studies were considered as work. Statistical analyses Kolmogorov-Smirnov tests were used to determine variable distributions. The analysed variables were mainly skewed and truncated, therefore non-parametric tests were used. MannWhitney U-tests were computed for continuous variables (duration of RA, PTA and LOC, time interval between injury and RA assessment, education, age, AUDIT, ISS, RPQ score and RTW) and Pearson’s Chi-square-tests for categorical variables (presence of RA, PTA and LOC, gender, alcohol use at the time of injury, mechanism of injury, acute analgesic medication with opioids, method of transportation to healthcare, traumatic lesion on MRI, traumatic lesion on CT and PCS diagnosis). SPSS 19.0 (SPSS Inc., Chicago, IL) was used to perform all statistical analyses. The general statistical significance level was set to p50.05 for all analyses. This alpha was Bonferroni-adjusted, however, based on groups of analyses addressing specific hypotheses (i.e. 0.05 divided by the number of comparisons).

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and RA assessment, mechanism of injury, acute analgesic medication with opioids, method of transportation to healthcare (with or without ambulance) or co-morbid orthopaedic injuries (ISS score) (p40.11 in all analyses). The duration of RA was not significantly correlated with age, AUDIT score or time interval between injury and RA assessment or ISS score (p40.22 in all analyses). Gender, alcohol use at the time of injury, mechanism of injury, acute analgesic medication with opioids and method of transportation to healthcare were not associated with the duration of RA (p40.12 in all analyses). Relations between RA and clinical signs of MTBI Co-existence of RA and clinical signs of acute MTBI are shown in Table II. Those who had RA, vs. those who did not, had lower GCS scores (14 vs. 15 points, 2 (1) ¼ 13.70, p50.0001) and greater duration of PTA (mean ¼ 5.4 vs. 1.8 hours, Mann-Whitney U ¼ 228.5, p ¼ 0.001, d ¼ 1.21). Lower GCS scores (14 vs. 15 points) were significantly associated with longer duration of RA (mean ¼ 126.7 vs. 16.9 minutes, Mann-Whitney U ¼ 56.0, p50.0001, d ¼ 1.15). There was a significant positive medium correlation between the duration of RA and PTA [Spearman (75) ¼ 0.42, p50.0001]. In contrast to duration, the presence of PTA was not related to the presence (p ¼ 0.71) or duration (p ¼ 0.61) of RA. Acute traumatic lesions on head CT or MRI and LOC were not significantly associated with the presence or duration of RA. A detailed characterization of the 17 patients with RA is presented in Table III. RA, return to work and post-concussion symptomatology at 2 weeks, 1 month and 6 months post-injury The rates of post-concussion syndrome diagnoses and descriptive statistics for the RPQ are presented in Table IV. The presence of RA was not associated with mild or moderate PCS diagnoses at 2 weeks, 1 month or 6 months after injury (p40.13 in all analyses). In addition, the presence of RA was studied in relation to RPQ scores and the number of symptoms endorsed as mild or greater or moderate or greater on the RPQ at 2 weeks, 1 month and 6 months post-injury. In these analyses, there was a trend (i.e. medium effect size) toward a greater number of mild symptoms on the RPQ at Table II. Co-existence of RA and the clinical signs of acute MTBI.

RA+, n (%)

Results Relations between RA and background variables Those with RA had more years of education than those without RA (mean ¼ 13.8 years for those without RA vs. 15.8 years for those with RA, Mann-Whitney U ¼ 311, p ¼ 0.024, Cohen’s d ¼ 0.68). There was also a small positive correlation between the duration of RA and years of education (Spearman (74) ¼ 0.28, p ¼ 0.017). Those with vs. without RA did not differ in age, gender, long-term alcohol use (AUDIT score), alcohol use at the time of injury, time interval between injury

LOC+ LOC PTA+ PTA GCS 15 GCS 14 CT CT+ MRI MRI+

4 (5.3) 13 (17.3) 16 (21.3) 1 (1.3) 12 (16.0)* 5 (6.7)* 17 (22.7) 0 45 (60.0) 2 (2.7)

RA, n (%) 24 34 53 5 57 1 51 7 15 13

(32.0) (45.3) (70.7) (6.7) (76.0)* (1.3)* (68.0) (9.3) (20.0) (17.3)

Duration of RA (min), mean (SD) 5.6 (23.1) 37.7 (123.4) 27.9 (103.5) 0.3 (0.8) 16.9 (91.3) 126.7 (140.8) 28.3 (104.2) 0 15.1 (52.1) 68.0 (196.2)

*p50.0001, Pearson chi-square test. RA, Retrograde amnesia; LOC, Loss of Consciousness; PTA, Posttraumatic Amnesia; GCS, Glasgow Coma Scale.

Retrograde amnesia in MTBI

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Discussion

1 month post-MTBI being associated with the presence of RA (mean ¼ 4.5 vs. 2.8 symptoms, Mann-Whitney U ¼ 333.0, p ¼ 0.048, d ¼ 0.48). However, this association was not statistically significant after Bonferroni adjustment. There was no significant association between the duration of RA and mild or moderate PCS diagnosis at 2 weeks, 1 month and 6 months after injury (p40.21 in all analyses). Moreover, at 2 weeks, 1 month and 6 months post-MTBI, the duration of RA was not related to the RPQ scores or the number of mild or moderate symptoms endorsed on the RPQ (p40.07 in all analyses). The median time between injury and RTW was 15.0 days (mean ¼ 55.0, SD ¼ 139.1, Range ¼ 0–841.0). Within 3 months post-injury, 90.7% had returned to work. The presence (Mann-Whitney U ¼ 454.5, p ¼ 0.62) and duration (Spearman (75) ¼ 0.05, p ¼ 0.68) of RA were not significantly associated with the time to RTW. The patients (n ¼ 53) with MTBI as the primary reason for being off work were analysed separately in regards to RTW. There was no statistically significant association between RA and RTW in this sub-group.

The purpose of this study was to examine the clinical correlates of RA in an homogenous MTBI sample. The duration of RA was mainly assessed using a clinical interview to enable general applicability of the results. Education was the only preinjury factor that was related to RA and no peri-injury factors were clearly related to the presence or duration of RA. In regard to MTBI severity indices, lower GCS scores and PTA were associated with RA. RA was unrelated to neuroimaging findings. RA did not predict 6-month functional outcome of MTBI. The majority (n ¼ 15, 88.2%) of the MTBI patients with RA had no signs of structural brain damage on conventional MR imaging. Contrary to expectations [22, 25, 44], factors that presumably induce psychological stress (high-velocity injury, ambulance transportation or co-morbid injuries) did not affect the presence or duration of RA. Alcohol [22, 23] and opioids [28] can have an effect on memory functioning. In this sample, both of these factors were unrelated to RA presence or duration. These somewhat

Table III. Characteristics of the patients with RA (n ¼ 17). Time between Duration Duration injury and of LOC Alcohol of RA Duration Years of Mechanism assessment (min) intoxication (min) of PTA (h) (h) GCS Patient Age education AUDIT of injury M1 M2 M3 M4 W1 W2 W3 M5 W4 W5 M6 M7 W6 M8 M9 M10 M11

26.0 28.0 31.0 19.0 48.0 48.0 40.0 36.0 21.0 47.0 30.0 28.0 23.0 58.0 37.0 25.0 31.0

17.0 17.0 18.0 12.0 14.0 17.0 14.0 20.0 12.0 22.0 17.0 12.0 16.0 10.0 17.0 17.0 16.0

10.0 7.0 10.0 7.0 2.0 2.0 1.0 5.0 1.0 3.0 7.0 6.0 4.0 7.0 2.0 10.0 8.0

Fall Motorcycle Sport Car Car Car Fall Sport Bicycle Fall Violence Sport GFL Car Car Sport Motorcycle

8.0 50.3 20.0 66.8 28.0 3.3 20.6 14.8 236.7 18.5 46.8 44.5 21.1 47.0 51.8 71.7 27.1

14.0 15.0 14.0 14.0 14.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 14.0 15.0 15.0

120.0 1.0 30.0 300.0 10.0 15.0 5.0 720.0 2.0 90.0 240.0 30.0 2.0 30.0 300.0 30.0 2.0

7.0 2.0 12.0 20.0 1.5 3.5 0.1 4.0 6.0 6.5 9.0 2.0 0.0 5.0 5.0 4.5 4.0

1.0 0.0 0.0 0.0 0.0 0.0 5.0 0.0 1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.17 0.0

Yes No No No No No No No No No Yes No Yes No No No No

CT

MRI

Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal

Normal Normal Normal DAI Normal Normal Normal DAI Normal Normal Normal Normal Normal Normal Normal Normal Normal

RTW ISS (days) 2.0 3.0 6.0 3.0 2.0 2.0 5.0 1.0 6.0 2.0 6.0 1.0 3.0 9.0 9.0 1.0 3.0

0.0 0.0 30.0 60.0 4.0 17.0 429.0 30.0 42.0 10.0 7.0 14.0 3.0 64.0 27.0 8.0 7.0

M, Man; W, Woman; AUDIT, Alcohol Use Disorders Identification Test; GCS, Glasgow Coma Scale; RA, Retrograde amnesia; PTA, Post-traumatic amnesia; ISS, Injury Severity Score; RTW, Return to work; GLF, Ground-level fall; DAI, Diffuse axonal injury.

Table IV. PCS diagnosis and RPQ findings at 2 weeks, 1 month and 6 months follow-ups. Whole sample, n ¼ 75 Variable

2 weeks

1 month

6 months

RA+, n ¼ 17 2 weeks

1 month

RA, n ¼ 58 6 months

2 weeks

1 month

6 months

Mild PCS (n, %) 26 (34.7) 23 (30.7) 18 (24.0) 6 (46.2) 8 (47.1) 3 (17.6) 20 (40.8) 15 (26.3) 14 (26.9) Moderate PCS (n, %) 6 (8.0) 5 (6.7) 4 (5.3) 1 (7.7) 2 (11.8) 1 (5.9) 4 (8.2) 2 (3.5) 2 (3.8) RPQ score (mean, SD) 14.2 (10.1) 10.5 (9.6) 7.3 (9.3) 15.2 (9.0) 13.7 (9.7) 7.5 (9.3) 13.9 (10.4) 9.6 (9.4) 7.3 (9.4) 4.9 (3.8) 3.2 (3.6) 2.4 (3.3) 5.7 (3.6) 4.5 (3.8) 2.4 (3.5) 4.7 (3.9) 2.8 (3.5) 2.4 (3.3) Number of symptoms endorsed on the RPQ in mild or greater severity (mean, SD) 1.4 (2.2) 0.8 (2.0) 0.6 (2.2) 1.8 (1.9) 1.4 (2.7) 0.8 (2.7) 1.3 (2.3) 0.6 (1.8) 0.5 (2.0) Number of symptoms endorsed on the RPQ in moderate or greater severity (mean, SD) RPQ, Rivermead Post-concussion Symptoms Questionnaire.

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surprising findings can partly be explained by the small number of RA patients with alcohol intoxication (n ¼ 3, 17.6%) or opioid analgesia (n ¼ 4, 23.5%) at the time of injury. Additionally, the breathalyser or blood alcohol levels were not recorded systematically; therefore, the level of alcohol in individual subjects could not be examined. Furthermore, three different types of opioids (alfentanil, codein, and fentanyl) were used in the ED with patients with RA. Therefore, a statistically meaningful comparison could not be performed between the small opioid sub-groups. Past researchers have reported that the duration of RA shrinks as time since injury elapses [31, 45]. The findings did not support this. However, the study design was not appropriate to thoroughly assess the temporal gradient of RA because the intervals between injury and the clinical examination were brief and repetitive longitudinal RA assessments were not performed. Higher education is generally linked to better cognitive functioning, including memory [46, 47]. In this study, those with greater education had a trend towards a longer duration of RA. This might be a spurious finding as there was no statistically significant association between RA (presence: binary logistic regression model; and duration: linear regression model) and education in a post-hoc regression analysis with MRI lesion, duration of LOC and duration of PTA as covariates (results not shown). Consistent with the theory of a confusional state [48] following MTBI, PTA, RA and disorientation (measured with the GCS) were largely concurrent. Five out of six patients who had a GCS score of 14 also had some degree of RA. RA was significantly related to PTA (i.e. a medium correlation). In addition, 94.1% (n ¼ 16) of patients with RA also had PTA. Of the 69 patients with PTA, 23.2% (n ¼ 16) also had RA. Overall, 22.7% of the patients with MTBI had RA. This result is in line with prior reports [49, 50]. The MTBI diagnosis was solely based on RA in only one patient. This patient had no structural brain damage on imaging and the MTBI was sustained in a ground-level fall under the influence of alcohol. Thus, the MTBI diagnosis might have been a false positive— although the person seemed to fit the operational criteria for MTBI at the time of assessment. This individual patient returned to work 3 days post-injury and suffered from mild post-concussion symptoms (dizziness, sleep disturbance, impatience and poor memory) up to 1 month after injury. Based on these results, RA can be considered to have little incremental value compared to the traditional severity indices (PTA, LOC, GCS and CT lesions) in the acute identification of clinically significant MTBI. In this sample, no patient with an intracranial abnormality on CT and only 2/15 patients with an intracranial abnormality on MRI had some degree of RA. In contrast, three evidence-based and widely used head CT guidelines (Canadian CT Head Rule [21], National Institute of Clinical Excellence [20] and Scottish Intercollegiate Guidelines Network [51]) indicate RA of 30 minutes or longer as a sign for an immediate emergency CT. The discrepancy between these findings and the aforementioned CT guidelines can be the result of differences in the operational criteria for MTBI/minor head injury and RA measurement methodology. A more recent, evidence-based, CT rule has scaled down the significance of RA [52].

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There was no significant relationship between RA and later post-concussion symptoms. RA did not predict the diagnosis of post-concussion syndrome at 2 weeks, 1 month or 6 months following injury. Functionally, RA was not associated with duration of time off work. Therefore, RA, in the present study, was not related to functional outcome. Previous literature on the relationship between RA and functional outcome (i.e. symptoms or RTW) in civilian MTBI is limited. Bazarian et al. [49] showed that RA was predictive of 1-month and 3-month PCS using a stepwise, multivariate regression model. Nolin and Heroux [53] reported that RA was not related to time of RTW in a logistic regression analysis. In the sporting venue, Collins et al. [54] reported (using chi-square test) that athletes with poor presentation at 2 days post-injury were over 10-times more likely to have exhibited RA following concussive injury when compared with athletes exhibiting good presentation. Additionally, Collins et al. concluded that athletes with RA were 4-times more likely to experience PTA than athletes without RA. Asplund et al. [55] reported similar findings using chi square testing. The presence of RA was also investigated among National Football League players using simple independency testing and a multivariate logistic regression analysis [56]. Manifesting RA was related to a greater number of days out of play. In that study, the presence of any of the five following signs/symptoms: (i) LOC 1 minute, (ii) fatigue, (iii) photophobia, (iv) not oriented to time or (v) retrograde amnesia correctly identified 72% of the players with delayed recovery. In this study, the duration of RA was measured using a clinical interview. The GOAT was used in parallel to the interview. From a practical perspective, the GOAT gave minimal additional value in the assessment of RA compared to the sole use of a chronological interview. The GOAT [37] is focused on the recall of the last event leading to the accident, whereas other day-of-injury events are not included. The measurement of RA based on a free-flowing, non-structured, format can be criticized as being unreliable [38]. However, this method is most widely used in everyday clinical practice. The study setting gave substantial time to assess RA thoroughly. Therefore, this approach may have been more sensitive in the detection of RA compared to routine ED management. The strength of this study is the carefully selected, homogenous and well documented study sample. To minimize confounding factors in RA assessment, patients with premorbid neurological and/or psychiatric problems were excluded from the study. Also, all the patients were evaluated by the same physician and, therefore, inter-evaluator bias was eliminated. Moreover, the follow-up questionnaire response rate can be considered high (82.7–98.7%). This study has several limitations. First, the study sample was highly selected because of numerous inclusion/exclusion criteria and the results cannot be generalized without caution to all patients with MTBI. Additionally, the number of patients with RA was relatively low. Second, unfortunately this study did not examine the severity of pain experienced at the time of RA assessment as a possible confounding factor. Third, the RPQ is a gross outcome measure, which grades common symptoms that are not specific to MTBI and it is susceptible to distorting effects. Fourth, this study did not interview relatives or eyewitnesses to confirm the memories

DOI: 10.3109/02699052.2014.1002421

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and events reported by the patients with RA. As is always the case when individually assessing memory following a brain injury, the duration of RA can be over- or under-estimated because the patients’ recall of events can be inaccurate. Fifth, the clinical assessment in the ED did not include a systematic alcohol breathalyser or blood level test for all patients enrolled into the study. Finally, although no secondary gain aspects came across in the follow-up, one cannot rule out the possibility of malingering and its effects on the duration of RA. In addition, the limitations of conventional MR imaging in detecting axonal injuries should be taken into account in the interpretation. In conclusion, the clinical relevance of RA in the evaluation of acute MTBI seems minor. In regards to MTBI outcome, RA was not associated with post-concussion symptoms or time to RTW in this study.

Acknowledgements The authors thank research assistants Anne Simi and Marika Suopanki-Ervasti for their contribution in data collection. This study was done as part of the first author’s PhD thesis research program. A portion of this study was presented at the 9th World Congress on Brain Injury in Edinburgh, Scotland, in March 2012. This study has been supported by the Medical Research Fund of Tampere University Hospital.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Grant Iverson, PhD, has been reimbursed by the government, professional scientific bodies and commercial organizations for discussing or presenting research relating to mild TBI and sport-related concussion at meetings, scientific conferences and symposiums. He has a clinical practice in forensic neuropsychology involving individuals who have sustained mild TBIs (including athletes). He has received honorariums for serving on research panels that provide scientific peer review of programs. He is a co-investigator, collaborator or consultant on grants relating to mild TBI funded by several organizations. The other authors report no competing or conflicts of interest. GLI notes that this work was supported in part by the INTRuST Posttraumatic Stress Disorder and Traumatic Brain Injury Clinical Consortium funded by the Department of Defense Psychological Health/Traumatic Brain Injury Research Program (X81XWH-07-CC-CSDoD).

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