ORIGINAL ARTICLE
Side of pupillary mydriasis predicts the cognitive prognosis in patients with severe traumatic brain injury R. L. de Souza1–3, M. E. Thais1, G. Cavallazzi1, A. Paim Diaz1, M. L. Schwarzbold1, A. L. Nau1, G. M. Rodrigues1, D. S. Souza4, A. Hohl1 and R. Walz1,5 1
Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário (HU), Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil Unidade de Terapia Intensiva, Hospital Governador Celso Ramos (HGCR), Florianópolis, SC, Brazil 3 Unidade de Terapia Intensiva, HU, UFSC, Florianópolis, SC, Brazil 4 Serviço de Neurocirurgia, HGCR, Florianópolis, SC, Brazil 5 Departamento de Clínica Médica, HU, UFSC, Florianópolis, SC, Brazil 2
Correspondence R. Walz, Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina (UFSC), 3° andar, Campus Universitário, Trindade Florianópolis, SC 88040-900, Brazil E-mail: [email protected] Conflicts of interest The authors have no conflicts of interest. Funding Work supported by Programa de Apoio aos Núcleos de Excelência (PRONEX, NENASC Project) and Edital PPSUS, Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Submitted 3 December 2013; accepted 26 October 2014; submission 19 October 2014. Citation de Souza RL, Thais ME, Cavallazzi G, Paim Diaz A, Schwarzbold ML, Nau AL, Rodrigues GM, Santos Souza D, Hohl A, Walz R. Side of pupillary mydriasis predicts the cognitive prognosis in patients with severe traumatic brain injury. Acta Anaesthesiologica Scandinavica 2015
Background: Pupils’ abnormalities are associated to bad prognosis in traumatic brain injury. We investigated the association between the side of pupil mydriasis and the long-term cognitive performance of patients with severe traumatic brain injury (TBI). Methods: We analyzed the cognitive performance of patients admitted at the intensive care unit with isochoric pupils (IP, n = 28), left mydriasis (LM, n = 10), right mydriasis (RM, n = 9) evaluated in mean 2.5 years after the severe TBI and controls (n = 26) matched for age, sex and education level. Results: Patients and controls had similar scores in the four WAISIII investigated subtests. In comparison with controls, LM patients had lower scores in Letters and Category Fluency and IP patients in Category Fluency. Among the 10 evaluated memory tests, LM patients had lower scores than controls in eight, RM patients in two and IP in three memory tests. IP and RM were 3.5 to nine times more associated to significant impairment (cognitive scores under the percentile 10 of controls) in six of 16 investigated cognitive tests. LM was six to 15 times more associated to significant impairment in 10 of 16 cognitive tests. The association among the pupil abnormalities and cognitive performances remained significant after the multiple linear regression analysis controlling for age, gender, admission coma Glasgow scale and serum glucose, presence of associated trauma, and cranial computed tomography abnormalities. Conclusion: Side of admission pupil abnormalities may be a useful variable to improve prognostic models for long-term cognitive performance in severe TBI patients.
doi: 10.1111/aas.12447
Editorial comment: what this article tells us In this prospective clinical study in patients with traumatic brain injury, the long-term neurocognitive function in survivors was linked to early pupil abnormalities present 4 h to 14 h after the injury. This could in the future be used to improve prognostic models for traumatic brain injury. Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
PUPILS AND COGNITIVE PROGNOSIS IN SEVERE TBI
Traumatic brain injury (TBI) is a major public health problem, causing high mortality and morbidity, especially in young adults.1–3 TBI has already been named ‘silent epidemic’ because of the limited popular knowledge about the issue and of its symptoms, such as memory and abstract thinking dysfunctions, which may not be grossly evident,4 but impairs significantly the quality of life of patient and their families.4,5 Despite the high mortality, improvements in neuroimaging, neurosurgery, respiratory and hemodynamic supports have raised the survival rates of severe TBI patients, contributing to the enhancement in the prevalence of TBI-related cognitive and behavioral disturbances.1 Diagnostic and therapeutic decisions are based on patient’s prognosis. Prognostic models are statistical models that combine two or more variables of patient’s data to predict clinical outcome. The International Mission on Prognosis and Analysis of Clinical Trials in TBI study and Medical Research Council Corticosteroid Randomization after Significant Head Injury showed that age, Glasgow Come Scale, pupil abnormalities, Marshal Computed Tomography (CT) and serum glucose abnormalities are the most powerful prognostic variables for the outcome measured 6 months after the injury.2,6–9 Similar results were replicated in our population.1 The pupils’ dilatation in TBI results from uncus and hippocampal gyrus herniation through the tentorium pressing the third nerve against the sphenoid bone. In general, this process starts asymmetrically leading to a unilateral pupil dilatation that may evolve to bilateral mydriasis and, if not quickly reversed, evolves to brain death.10 In our prospective study including 748 consecutive patients with severe TBI, the mortality increased in mean three and 20 times, respectively, in patients admitted with unilateral or bilateral mydriasis in comparison to those with isochoric pupils.1 Despite transtentorial herniation is highly associated with death, aggressive neuro-intensive care and neurosurgical treatments result that around 50% may evolve relatively well according to Glasgow Outcome Scale evaluation.11 However, more detailed evaluation including neuropsychological and psychiatric assessments have demonstrated that long-term cognitive and behavioral dysfunctions are common, leading to a significant impairment in the patient’s quality of life.4,12–16
Recently, we demonstrated that after a correction for education and age distribution, the variables commonly associated with mortality or Glasgow Outcome Scale,17 including pupils’ examination, Marshal CT Classification, Glasgow Coma Scale (GCS) and serum glucose showed a limited predictive power for long-term cognitive prognosis in adult patients with severe TBI.16 In this study, the pupils’ examination in the anisochoric patients was not stratified according to the side of transtentorial herniation. Because the hemispheric lateralization for language is an important predictor for the cognitive impairment related to asymmetric brain lesion, here we investigated if the side of pupil dilatation is independently associated with specific cognitive domains dysfunction 3 years after hospitalization due to severe TBI. Methods Participants Between February 2001 and April 2009, a total of 239 consecutive patients from the metropolitan region of Florianópolis city (southern Brazil) were admitted at the intensive care unit (ICU) of Hospital Governador Celso Ramos with severe TBI and included in our prospective study protocol.1,5,12,16,18 The Human Research Ethical Committee of the Universidade Federal de Santa Catarina approved the study (Ethics committee of Universidade Federal de Santa Catarina, Protocol number 163/ 2005 – approved 30 May 2005). Informed consent was obtained from the patients and controls. The hospital is a tertiary referral center for trauma for 1 million people population of the metropolitan region of Florianópolis city. Severe TBI was defined by a GCS score ≤ 8 after the initial stabilization treatment at the emergency room admission. Because of the lower number of cases and different TBI mechanisms involved, victims of gunshot injury were not included in the present study. The sampling course for the evaluation after hospitalization is presented in Fig. 1. Attempts to contact all survivors (n = 177) were made by phone, mail and home visits in a period between 1 year and 6 years after hospitalization. Three patients died after hospitalization, one was in persistent vegetative state. Among the 177 eli-
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Fig. 1. Study flowchart for cognitive evaluation of adults consecutively admitted to an intensive care unit (ICU) due to severe non-missile traumatic brain injury (TBI).
gible patients, 118 were not localized (66.6%), and eight (4.5%) refused to participate. The remaining 51 patients (28.8%) were evaluated between March 2007 and April 2010. The sampling of patients is summarized in Fig. 1. Control subjects (n = 26) matched for gender, age and education level were recruited during the same period by convenience. They were companion persons of patients from other outpatient clinics and had no previous history of neurological or psychiatric disorders. All the evaluated patients and controls were Caucasians. Demographic and clinical variables Variables collected prospectively during hospitalization included: gender, age, admission GCS, admission pupils’ examination, admission serum glucose from peripheral blood and presence of associated trauma. Pupils were examined by an experienced physician under average lighting intensity and direct flashlight stimulus. Each eye were tested individually, and mydriasis was considered present if the pupil diameter were greater than 5 mm and no reaction to direct light stimulus was observed (paralytic mydriasis). Patients were admitted at the emergency room between 2 h and 6 h after the TBI and transferred to the ICU as soon as possible. Fourteen patients underwent neurosurgery before the intensive care admission. The pupil examination findings included in this analysis were obtained at the intensive care
admission, 4 h to 14 h after the TBI. All patients were under sedation, with stable hemodynamic and ventilation parameters. The abnormal pupil findings were sustained for at least 3 h after the initial evaluation when a second pupil evaluation was done. The subsequent evaluations or duration time of pupil abnormality after the second evaluation was not prospectively evaluated by our research protocol. Pupils were not examined in three patients, and one patient had bilateral mydriasis, and they were not included in the analysis. Patients were classified according their pupils examination as isochoric (n = 28), right mydriasis (n = 09) and left mydriasis (n = 10). The admission brain CT scans were analyzed according to the Marshall classification and presence of subarachnoid hemorrhage. The Marshall classification includes: Type I injury = normal CT; Type II injury = small lesions but visible cisterns and no midline shift; Type III injury = Diffuse swelling with nonvisible cisterns; Type IV injury = unilateral swelling with midline shift deviation higher than 5 mm; Type V injury = evacuated mass lesion; and Type VI injury = non-evacuated lesion with higher than 25 mm volume.19 Variables collected during cognitive evaluation were: hand dominance before TBI and years of education at the time of neuropsychological assessment. Neuropsychological assessment The neuropsychological assessments were done by a neuropsychologist blinded for all the clinical, radiological, neurosurgical and laboratory variables, on average 2.5 (SEM ± 0.2) years after hospitalization (range between 1 to 6 years). When necessary, the individual evaluation scores were discussed between the two examiners. Patients were evaluated individually in the TBI outcome clinic of our University Hospital. All the evaluated patients had no history of recurrent trauma or other neurologic disease. The time needed to complete the assessment was 76 (± 11) and 80 (± 18) min for controls and patients, respectively (P = 0.23). We analyzed the raw scores of the neuropsychological tests. The test battery applied was chosen based on literature and experience of neuropsychologists. The cognitive assessment included: Letters and Category Fluency,20 Rey Auditory Verbal LearnActa Anaesthesiologica Scandinavica 59 (2015) 392–405
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Table 1 Cognitive domains and the respective neuropsychological tests evaluated in patients and controls. Cognitive domain
Neuropsychological test
Reference
Memory
WMS-III Logical Memory First Recall WMS-III Logical Memory I WMS-III Logical Memory II WMS-III Visual Reproduction I WMS-III Visual Reproduction II WMS-III Visual Reproduction Recognition RAVLT – Total RAVLT – Retention RAVLT – Delayed RAVLT – Recognition WAIS-III – Digit Span Category Fluency Letters Fluency WAIS-III – Vocabulary WAIS-III – Similarities WAIS-III – Block Design
Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Lezak, 2004 Lezak, 2004 Lezak, 2004 Lezak, 2004 Wechsler, 2004 Lezak, 2004 Lezak, 2004 Wechsler, 2004 Wechsler, 2004 Wechsler, 2004
Attention, concentration, mental control Language
Abstract verbal reasoning Visuospatial and motor skills
ing Test (RAVLT),21 Wechsler Memory Scale III (WMS-III) subtests Logical Memory First Recall (LM 1st), Logical Memory I (LM I), Logical Memory II (LM II) and Visual Reproduction I (VR I), Visual Reproduction II (VR II), Visual Reproduction Recognition (VR Rec),22 Wechsler Adult Intelligence Scale III (WAIS-III) subtests Digit Span, Similarities, Vocabulary and Block Design.23 (Table 1). Statistical analysis Normality of the distribution of variables was determined the Kolmogorov–Smirnov test. We analyzed if patients who underwent the neuropsychological evaluation were comparable with the eligible patients, who were not evaluated (drop out cases) according to their clinical, demographic and hospitalization variables. Categorical variables were analyzed using chi-square, continuous variables by Mann–Whitney tests. The comparison among patients with isochoric pupils, right mydriasis and left mydriasis according to their clinical, demographic and hospitalization variables were analyzed by ANOVA or chisquare. The comparison among the controls, patients with isochoric pupils, right mydriasis and left mydriasis according to their neuropsychological performance were done by Student t-test or ANOVA followed by Bonferroni post hoc. The associations among the pupils examination,
clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance 1 year after the severe TBI were investigated by a univariate analysis using a linear regression or student t-test. The independent associations among the pupils’ examination, clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance in the chronic period after the severe TBI were analyzed by multiple linear regression. In this analysis, we included the variables showing an association with the cognitive tests with a P level lower than 0.20. The categorical variables were classified numerically to be included in the analysis: Marshal classification (Type I = 1; Type II = 2; Type III = 3; Type IV = 4; evacuated mass lesion = 5; and non-evacuated mass lesion = 6), gender (male = 1; female = 2); Sub-arachnoid hemorrhage (no = 1; yes = 2); admission pupils (isochoric or right mydriasis = 1; anisochoric or left mydriasis = 2). We also determined the association between the pupils’ examination and the low performance in the cognitive tests by binary logistic regression analysis. In this analysis, patients were grouped in isochoric/right mydriasis and left mydriasis and classified as having low cognitive performance if their score in the cognitive test was under the percentile 10 of controls. As the patients with isochoric and right mydriasis showed similar cognitive performance, they were
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grouped to increase the statistical power of the analysis. The odds ratio and 95% confidence interval for association between the pupils examination group and low score (under the percentile 10 of controls) were determined. We did not adjust for multiple tests comparisons to avoid a type II error.24 The analysis was done by SPSS 17.0 (Chicago, IL, USA). Results Most patients were male (85%), with a mean age 34 (± 13) years and 9 (± 5) years of education. The distributions of gender, age, admission glucose levels, admission CT findings by Marshall Classification, presence of subarachnoid hemorrhage, associated abdominal or thoracic trauma and admission coma Glasgow scale and pupils examination were similar (P < 0.25) between the cognitive evaluated patients and missing cases (data
not shown). Clinical, demographic, radiological and neurosurgical variables distribution according to pupil examination are presented in Table 2. There were no significant differences among the patients’ pupil subgroups according to all the clinical, demographic, radiologic, laboratorial and neurosurgical variables analyzed, except the higher prevalence of female patients in the subgroup of patients with right mydriasis. The gender, age and education levels were similar between the patients and controls (data not shown). The Fig. 2 presents the cognitive performance of controls and patients. The language tests and Wechsler Adult Intelligence Scale-III subtests are showed in Fig. 2A. There were no significant differences by ANOVA among the controls and patients subgroups according to Letters Fluency (P = 0.14), Digit Span (P = 0.18), similarities (P = 0.40) and Block Design (P = 0.21). There was a nonsignificant trend for lower scores
Table 2 Clinical, demographic, radiological and neurosurgical variables distribution according to pupil examination. Anisochoric pupils
Variables Age (years), mean (± SD) Education (years), mean (± SD) Time after TBI (months), mean (± SD) Admission glucose, mean (± SD) Gender Male Female Marshall CT classification, n (%)* Type I injury Type II injury Type III injury Type IV injury Evacuated mass lesion Non-evacuated lesion SAH, n (%)† No Yes Associated trauma, n (%) Yes No Glasgow Coma Scale, n (%) 7 or 8 5 or 6 3 or 4
Isochoric pupils n = 28 (59.6%)
Right mydriasis n = 9 (19.1%)
Left mydriasis n = 10 (21.3%)
P value
33.82 (2.5) 8.4 (0.9) 32 (3.4) 145.4 (11.7)
36.5 (4.2) 10.2 (1.7) 28 (4.8) 164.9 (67)
34.3 (13.1) 9.4 (5.2) 34 (7.6) 151.5 (15.8)
0.66 0.48 0.83 0.61
27 (96.4%) 1 (3.6%)
5 (55.6) 4 (44.4)
8 (80.0) 12 (20.0)
– 0.01
1 (3.6) 8 (28.6) 9 (32.1) 2 (7.1) 6 (21.4) 1 (3.6)
0 1 (11.1) 3 (33.3) 1 (1.11) 2 (22.2) 2 (22.2)
1 (10.0) 0 1 (10.0) 1 (10.0 6 (60.0) 1 (10.0)
– – – – – 0.23
13 (46.4) 13 (46.4)
6 (66.7) 3 (33.3)
5 (50.0) 5 (50.0)
– 0.67
16 (57.1) 12 (42.9)
6 (66.7) 3 (33.3)
5 (50.0) 5 (50.0)
– 0.76
16 (57.2) 6 (21.4) 6 (21.4)
3 (33.3) 2 (22.2) 4 (44.4)
4 (40.0) 1 (10.0) 5 (50.0)
– – 0.41
*Marshal CT Classification and †sub-arachnoid hemorrhage were not evaluated in two cases. CT, computed tomography; SAH, subarachnoid hemorrhage.
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Fig. 2. (A) Language and WAIS-III Subtests Scores of controls and patients according to their pupil examination. †Significant statistic differences from the control group (‘P’ level < 0.05); (B) Non-Verbal Memory Tests Scores of controls and patients according to the pupil examination. †Significant differences from the controls (‘P’ level < 0.0001). ‡Significant differences from the controls (‘P’ level < 0.05); (C) Verbal Memory Tests Scores of controls and patients according to their pupil examination. †Significant differences from the controls (‘P’ level < 0.0001); ‡Significant differences from the controls (P level < 0.01); §Significant differences from the controls (P level < 0.05); ¶Significant differences from the controls (P level < 0.005); ††Significant differences between right and left mydriasis groups (‘P’ level < 0.05). All data are present in mean (SE) of the raw scores of cognitive tests. Acta Anaesthesiologica Scandinavica 59 (2015) 392–405 © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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in the letters fluency (P = 0.13) and vocabulary tests (P = 0.10) in the group with left mydriasis in comparison to controls. Patients with isochoric pupils and left mydriasis showed significant lower scores than controls in the Category Fluency (P < 0.05, by Bonferroni post hoc test). Results of nonverbal memory tests are showed in Fig. 2B. There were no significant differences (ANOVA = 0.23) in the VR Rec scores among the controls and patients (ANOVA = 0.23). Patients with left mydriasis showed lower scores than controls in the VR I (P < 0.05) and VR II (P < 0.0001). In comparison to controls, the VR II was also impaired in patients with right mydriasis (P < 0.05) or isochoric pupils (P < 0.05). Results of verbal memory tests are showed in Fig. 2C. There were significant differences (ANOVA, P < 0.05) among the controls and patients groups according to RAVLT (total, retention and delayed) as well LM (first recall, immediate and late recall). Patients with isochoric pupils showed significant lower scores (P < 0.01) than controls in all the verbal memory tests except in the RAVLT Rec, LM first recall and LM I. They also showed a trend for lower performance in LM II (P = 0.07). In comparison to controls, patients with right mydriasis showed a nonsignificant trend for lower scores in the RAVLT retention, a significant impairment in RAVLT delayed (P = 0.01), but similar performance in remained five investigated verbal memory tests. Patients with left mydriasis showed a significant impairment than controls in the RAVLT total (P < 0.0001), retention (P < 0.0001) and delayed (P < 0.005) but not in RAVLT Rec. When compared with controls, the left mydriasis group also showed significant impairment in the three investigated logical memory tests with LM recall (P < 0.05), LM I (P < 0.05) and LM II (P < 0.01). There were no significant differences between patients subgroups and controls according to gender (P < 0.20), age (P = 0.25) education level (P = 0.95) and hand dominance (P = 0.35) (data not shown). Table 3 shows the association among the clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance in the cognitive tests showing significant impairment of patients in comparison to controls presented in the Fig. 2. Table 4 shows the independent negative association between the left pupil mydriasis and cog-
nitive performance in the chronic period after the severe TBI controlling the clinical, demographic, radiologic and laboratorial variables distribution by multiple linear regressions. Only the cognitive tests showing significant differences between patients and controls presented in Fig. 2 were analyzed by multiple linear regressions. Table 5 shows the odds ratio for impaired cognitive functions of patients and their pupils’ examination adjusted for age, sex and education. Cognitive impairment was defined as a raw score lower than percentile 10 of healthy controls in the respective cognitive test. Patients with isochoric pupils or right mydriasis were grouped because of their similar performance in the evaluated cognitive tests. The isochoric pupil (IP)/RM was 3.5 to 4.9 times more associated with significant impairment in five of 16 investigated cognitive tests. The LM was six to 15 times more associated with significant impairment in 10 cognitive tests. Discussion The identification of prognostic markers for cognitive and psychiatric impairments is a scientific challenge in the field of traumatic brain injury research.12,16 The pupils’ abnormalities and Marshall CT classification have been associated with a worldwide worse prognosis of TBI patients determined by death rate and Glasgow Outcome Scale.1,3,7,8,25,26 However, considering a more sensitive evaluation of long-term functional capacities by cognitive tests, when only a subset of patients with severe TBI are analyzed, the information of anisochoric pupils or CT findings without any additional reference of the hemispheric side of the lesion does not predict the cognitive impairments of patients.16 Here, we demonstrated that the side of pupil abnormality is an independent marker for specific long-term cognitive domains impairments in patients with severe TBI admitted with anisochoria. The proportion of nonverbal cognitive tests impairment in patients with right hemisphere herniation was not the same as compared with verbal tests impaired in patients with left mydriasis. This may be related to differential capacities of dominant and nondominant hemisphere recovery after the severe TBI. Differences in the sensitivity and specificity of the used cognitive tests to detect abnormalities in the severe TBI patients, Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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30 (2.6)
Time after TBI (months), mean (± SD)
© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Admission CT, n (%)* Type I injury Type II injury Type III injury Type IV injury Evacuated mass lesion Non-evacuated lesion Admission GCS 8 7 6 5 4 3
r = 0.24 r2 = 0.06 B = −0.20 P = 0.06 r = 0.59 r2 = 0.35 B = 1.3 P < 0.0001 r = 0.16 r2 = 0.02 B = 0.09 P = 0.34 r = 0.23 r2 = 0.05 B = −0.06 P = 0.34
P = 0.59 – – r = 0.18 r2 = 0.03 B = 1.1 P = 0.25
4 (8.5)
10 (19.6) 15 (29.4) 9 (17.6) 1 (2) 4 (11.8) 10 (19.6)
– – r = 0.16 r2 = 0.02 B = 0.48 P = 0.31
P = 0.34
– – r = 0.15 r2 = 0.02 B = −0.59
r = 0.44 r2 = 0.19 B = −0.19 P = 0.003 r = 0.54 r2 = 0.29 B = 0.54 P < 0.0001 r = −0.01 r2 = 0.003 B = −0.01 P = 0.74 r = 0.09 r2 = 0.009 B = −0.008 P = 0.55
Correlations by linear regression
2 (4.3) – 9 (19.1) – 13 (27.7) r = 0.09 4 (8.5) r2 = 0.007 14 (29.8) B = −0.64
150 (10)
9.0 (0.7)
Education, years (± SE)
Admission glycemia, mean (± SE)
34 (2)
All cases
Age, years, mean (± SE)
Variables
Visual Rep. II
RAVLT Total
RAVLT RAVLT Retention Delayed
– – r = 0.24 r2 = 0.06 B = 3.0 P = 0.10
P = 0.04
P = 0.10 – – r = 0.22 r2 = 0.05 B = 3.162 P = 0.14
– – r = 0.31 r2 = 0.09 B = −4.87
– – r = 0.25 r2 = 0.06 B = −4.6
– – r = 0.17 r2 = 0.03 B = 1.3 P = 0.26
P = 0.001
– – r = 0.48 r2 = 0.23 B = −4.46
P = 0.10
– – r = 0.25 r2 = 0.06 B = 0.45
– – – – r = 0.25 r = 0.40 r2 = 0.06 r2 = 0.16 B = 3.3 B = −0.95 P = 0.10 P = 0.007
P = 0.05
– – r = 0.30 r2 = 0.09 B = −5.1
– – r = 0.16 r2 = 0.02 B = −0.72 P = 0.32
P = 0.004
– – r = 0.43 r2 = 0.019 B = −2.6
LM II
– – r = 0.18 r2 = 0.03 B = 1.2 P = 0.25
P = 0.03
– – r = 0.034 r2 = 0.11 B = −9.8
– – r = 0.21 r2 = 0.04 B = 1.1 P = 0.18
P = 0.03
– – r = 0.34 r2 = 0.12 B = −2.3
r = 0.53 r = 0.54 r2 = 0.28 r2 = 0.28 B = −9.53 B = −0.39 P < 0.0001 P < 0.0001 r = 0.43 r = 0.47 r2 = 0.18 r2 = 0.22 B = 1.2 B = 0.95 P = 0.004 P = 0.002 r = 0.13 r = 0.08 r2 = 0.02 r2 = 0.006 B = 0.10 B = −0.05 P = 0.43 P = 0.63 r = 0.18 r = 0.23 r2 = 0-03 r2 = 0.05 B = −0.03 B = −0.03 P = 0.26 P = 0.15
LM 1st Recall LM I
r = 0.48 r = 0.51 r = 0.52 r = 0.31 r = 0.53 r = 0.50 r2 = 0.23 r2 = 0.26 r2 = 0.27 r2 = 0.10 r2 = 0.28 r2 = 0.25 B = −0.97 B = −0.87 B = −0.54 B = −0.59 B = −0.14 B = −0.33 P = 0.001 P < 0.0001 P < 0.0001 P = 0.04 P < 0.0001 P = 0.001 r = 0.42 r = 0.29 r = 0.51 r = 0.38 r = 0.34 r = 0.41 r2 = 0.18 r2 = 0.09 r2 = 0.26 r2 = 0.15 r2 = 0.11 r2 = 0.17 B = 2.3 B = 1.4 B = 1.45 B = 0.27 B = 0.24 B = 0.76 P = 0.004 P = 0.05 P < 0.0001 P = 0.07 P = 0.03 P = 0.006 r = 0.005 r = 0.14 r = 0.17 r = 0.23 r = 0.27 r = 0.16 r2 = 0.000 r2 = 0.02 r2 = 0.03 r2 = 0.05 r2 = 0.07 r2 = 0.03 B = 0.009 B = 0.20 B = −0.13 B = −0.04 B = −0.05 B = 0.08 P = 0.97 P = 0.45 P = 0.27 P = 0.14 P = 0.08 P = 0.31 r = 0.31 r = 0.37 r = 0.11 r = 0.19 r = 0.21 r = 0.17 r2 = 0.10 r2 = 0.14 r2 = 0.01 r2 = 0.04 r2 = 0.04 r2 = 0.03 B = −0.12 B = −0.12 B = −0.02 B = −0.07 B = −0.10 B = −0.02 P = 0.04 P = 0.01 P = 0.49 P = 0.22 P = 0.19 P = 0.31
Visual Letters Fluency Category Fluency Rep. I
Table 3 Univariated analysis showing the association among the clinical, demographic, radiologic and laboratorial variables of patients and their cognitive performance in the chronic period after the severe TBI.
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42 (82.4) 9 (17.6)
Abdominal or thoracic trauma, n (%) No Yes
15.0 (4.3) P = 0.30
19.4 (1.8)
18.6 (1.9) 18.7 (3.3) P = 0.98
19.3 (2.3) 17.2 (2.5) P = 0.53
18.2 (1.8) 20.5 (5) P = 0.61
9.1 (2.6) P = 0.45
10.7 (0.8)
10.6 (1.0) 9.1 (1.8) P = 0.50
10.6 (1.2) 8 (1.2) P = 0.65
10.2 (0.9) 11.6 (2.8) P = 0.55
49.3 (10.1) P = 0.16
62.7 (4.1)
61.1 (4.3) 55.1 (10.0) P = 0.56
64.3 (5.4) 55.9 (5.7) P = 0.29
62.6 (4) 46 (9.4) P = 0.13
Student t test or one-way ANOVA
20.3 (4.9) P = 0.04
37.7 (3.8)
35.6 (3.6) 28.0 (8.9) P = 0.39
37.7 (4.8) 31.7 (4.9) P = 0.40
36.5 (3.7) 22 (13.5) P = 0.12
21.6 (5.5) P = 0.01
34.2 (1.9)
32.2 (2.4) 29.2 (3.2) P = 0.58
5.5 (0.7) 4.5 (0.8) P = 0.36
4.8 (0.6) 5.6 (1.3) P = 0.60
3.1 (1.3) P = 0.07
5.4 (0.5)
5.1 (0.6) 4.4 (1.2) P = 0.60
5.2 (0.7) 4.8 (0.8) P = 0.70
4.84 (0.6) 5.3 (1.4) P = 0.76
3.2 (1.3) P = 0.10
5.3 (0.5)
5.1 (0.5) 4.1 (1.1) P = 0.48
9.6 (0.9) 6.3 (1.4) P = 0.05
7.5 (0.9) 10.3 (1.3) P = 0.22
11.4 (2.7) P = 0.10
17.4 (1.4)
16.3 (1.4) 16.7 (3.8) P = 0.92
18.3 (1.5) (13.8 (2.1) P = 0.09
16.5 (1.5) 15.9 (2.7) P = 0.86
18.7 (4.0) P = 0.09
28.0 (2.2)
26.5 (2.1) 26.4 (6.1) P = 1.0
29.4 (2.5) 22.6 (3.2) P = 0.10
26.7 (2.3) 25.7 (4.3) P = 0.85
7.3 (2.3) P = 0.11
13.5 (1.7)
12.7 (1.6) 11.7 (4.1) P = 0.83
14.6 (1.8) 9.5 (2.2) P = 0.08
12.5 (1.6) 12.7 (3.5) P = 0.96
*Marshal CT Classification and †Sub-arachnoid hemorrhage were not evaluated in two cases. CT, computed tomography; GCS, Glasgow Coma Scale; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.
10 (21.3)
37 (78.7)
24 (51.1) 21 (44.7)
SAH on the admission CT, n (%)† No Yes
Admission pupils, n (%) Isochoric or right mydriasis Left mydriasis
40 (85.1) 7 (14.9)
Gender, n (%) Male Female
Table 3 Continued
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Table 4 Independent negative association among the left pupil mydriasis and cognitive performance in the chronic period after the severe TBI controlling for clinical, demographic, radiologic and laboratorial variables distribution by multiple linear regressions. Cognitive tests and their predictors variables
R
R2
B coefficient
‘P’ level
Letter Fluency Constant Education Age Left mydriasis Category Fluency Constant Education Age Left mydriasis RVI Constant Education Admission glycemia Age Left mydriasis RVII Constant Education Admission glycemia Age Left mydriasis RAVLT – Total Constant Education Age Left mydriasis RAVLT – Retention Constant Education Admission glycemia Left mydriasis RAVLT – Delayed Constant Age Left mydriasis LM 1st Constant Education Age Left mydriasis LM I Constant Education Age Left mydriasis LM II Constant Education Age Left mydriasis
0.70 – – – – 0.72 – – – – 0.72 – – – – – 0.72 – – – – – 0.85 – – – – 0.58 – – – – 0.69 – – – 0.73 – – – – 0.76 – – – – 0.78 – – – –
0.49 – – – – 0.52 – – – – 0.52 – – – – – 0.52 – – – – – 0.72 – – – – 0.34 – – – – 0.48 – – – 0.53 – – – – 0.57 – – – – 0.61 – – – –
–
–
20.0 (9.2 to 30.9) 1.46 (0.91 to 2.0) −0.23 (−042 to −0.03) −6.7 (−13 to 0.03)
0.001 < 0.0001 0.04 0.05
13.5 (7.9 to 10.1) 0.7 (0.41 to 0.93) −0.2 (0.30 to −0.11) −2.0 (−5.1 to 1.1) – 97.8 (71.2 to 124.4) 2.65 (1.39 to 3.9) −0.10 (−0.20 to −0.006) −0.64 (−1.2 to −0.14) −20.3 (−35.6 to −5.0) – 77.7 (54.6 to 100.7) 1.8 (0.69 to 2.87) −0.10 (−0.18 to −0.01) −0.60 (−1.0 to −0.15) −20.7 (−33.9 to −7.5) – 53.3 (43.2 to 63.5) 1.55 (1.1 to 2.0) −0.57 (−0.75 to −0.39) −13.7 (−19.3 to −8.0) – 78.6 (52.2 to 105.0) 2.0 (0.65 to 3.3) −0.10 (−0.19 to −0.008) −23.4 (−39.6 to −7.2) – 10.3 (6.7 to 13.7) −0.15 (−0.21 to −0.08) −2.3 (−4.3 to −0.04) – 28.2 (19.9 to 36.7) 0.86 (0.45 to 1.3) 0.22 (−0.48 to −0.18) 7.5 (−12.8 to −2.3) – 45.6 (33.2 to 58.0) 1.3 (0.75 to 2.0) −0.53 (−0.74 to −0.31) −11.8 (−19.5 to −4.1) – 25.5 (16.9 to 34.0) 1.1 (0.65 to 1.5) −0.39 (−0.54 to −0.24) 8.3 (−13.6 to −2.9)
< 0.0001 < 0.0001 < 0.0001 0.21 – < 0.0001 < 0.0001 0.04 0.01 0.01 – 0.002 0.002 0.02 0.01 0.003 – < 0.0001 < 0.0001 < 0.0001 < 0.0001 – < 0.0001 0.005 0.04 < 0.006 – < 0.0001 < 0.0001 0.02 – < 0.0001 < 0.0001 < 0.0001 0.006 – < 0.0001 < 0.0001 < 0.0001 0.003 – < 0.0001 0.003 < 0.0001 0.003
All the regression models were statistically significant for a P level < 0.0001. Acta Anaesthesiologica Scandinavica 59 (2015) 392–405 © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 5 Association between cognitive impairment in the chronic period after the severe TBI and pupils examination. Cognitive tests Letters fluency Isocoric or right mydriasis Left mydriasis Category Fluency Isocoric or right mydriasis Left mydriasis WMS-III Visual Reproduction I Isocoric or right mydriasis Left mydriasis WMS-III Visual Reproduction II Isocoric or right mydriasis Left mydriasis RAVLT – Total Isocoric or right mydriasis Left mydriasis RAVLT – Retention Isocoric or right mydriasis Left mydriasis RAVLT – Delayed Isocoric or right mydriasis Left mydriasis WMS-III Logical Memory First Recall Isocoric or right Mydriasis Left mydriasis WMS-III Logical Memory I Isocoric or right mydriasis Left mydriasis WMS-III Logical Memory II Isocoric or right mydriasis Left mydriasis
Adjusted odds ratio*
95% CI
‘P’ level
9.0 NA
1.8–44.7 NA
0.007 < 0.001
4,9 9.6
1.1–19.3 1.6–57.0
0.02 0.01
3.3 6.0
0.64–17.1 1.3–32.0
0.15 0.02
4.7 9.6
1.1–18.4 1.6–57
0.03 0.01
4.9 15.3
1.2–19.3 2.4–96.1
0.02 0.004
3.9 11.0
1.1–13.8 1.9–63.2
0.03 0.007
3.5 11.2
1.0–12.3 1.8–63.1
0.05 0.007
3.8 10.2
0.9–15.3 1.5–70
0.06 0.01
3.1 7.0
0.9–11.0 1.2–46
0.06 0.02
2.4 7.3
0.7–8.7 1.2–48
0.12 0.03
*Odds ratio for impaired cognitive functions defined as a raw test score lower than the expected percentile 10 of healthy controls matched for age, sex and education. Because patients with isocoric pupils or right mydriasis showed similar cognitive performance, they were grouped to increase the statistical power of the analysis. All patients with left mydriasis showed a Letters Fluency Score lower than percentile 10, and the odds ratio could not be calculated. NA, non-applied.
including those without transtentorial herniation (isochoric pupils) also may contribute to explain our finding. As expected, memory dysfunctions were highly observed in our patients with severe TBI.27 The mesial temporal region including the cortical (parahippocampal and entorhinal cortex) and subcortical (amygdala and hippocampus) regions are susceptible to structural lesions at the skull base under the temporal lobe. The transtentorial herniation may cause a hippocampal lesion itself or interrupt its connectivity through the perforant pathway with the entorhinal cortex. The functional integrity of this circuit is crucial for memory processing including acquisition, consolidation and retrieval.27–32
Because it is methodologically difficult to objectively identify some preexisting psychosocial problems in patients with TBI, the lack of adequate control of these pre-morbid characteristics is a limitation of our study. Although our hospital is a public trauma referral center and almost all patients came from the similar socioeconomic status, those characteristics (including the education level) were not objectively controlled for the nonparticipants, and the reader needs to be aware about this study limitation. Missing (drop out) cases in the follow-up is also a worldwide limitation of TBI studies and may raise doubts whether the analyzed sample of patients adequately represents the survivor group as a whole.33,34 It is important to recognize that a Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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substantial number of variables before, during and after hospitalization were not controlled and may contribute to the cognitive prognosis. The hypoxia, hypotension, elevated intra-cranial pressure, post-traumatic amnesia (PTA) evaluation (in the acute and subacute period), brain magnetic resonance imaging findings, mood disorders and personality changes (in the chronic period) were previously found to be predictive of outcomes. We believe the inclusion of these variables in further studies may increase the predictive power of prognostic models for cognitive outcomes in severe TBI. The affected brain side and regions based on the CT evaluation were not controlled in our analysis. In fact, we considered the possibility of collinearity between the side of pupil’s abnormalities and CT lesion, but as this was not prospectively evaluated, and we are not able to investigate it retrospectively in these patients. This hypothesis are currently been tested in a large, multicentre prospective study. However, the present study clearly demonstrates the limitation of the Marshal classification of brain CT evaluation on the cognitive prognosis of severe TBI patients. To summarize, identifying premorbid, clinical, neuroradiological and laboratory (such as plasmatic and genetic) variables (biomarkers) that are independently associated with cognitive outcome remains a crucial task for the future research works with severe TBI patients. This preliminary finding suggests that the side of pupil abnormality, in anisochoric patients due to transtentorial herniation, predicts the long-term cognitive prognosis in severe traumatic brain-injured patients and may be useful to improve prognostic models for TBI. Acknowledgement We acknowledge the medical and nurses staff that collaborate in the patients care and support the our research team. References 1. Martins ET, Linhares MN, Sousa DS, Schroeder HK, Meinerz J, Rigo LA, Bertotti MM, Gullo J, Hohl A, Dal-Pizzol F, Walz R. Mortality in severe traumatic brain injury: a multivariated analysis of 748 Brazilian patients from Florianopolis City. J Trauma 2009; 67: 85–90.
2. Murray GD, Butcher I, McHugh GS, Lu J, Mushkudiani NA, Maas AI, Marmarou A, Steyerberg EW. Multivariable prognostic analysis in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007; 24: 329–37. 3. Perel P, Arango M, Clayton T, Edwards P, Komolafe E, Poccock S, Roberts I, Shakur H, Steyerberg E, Yutthakasemsunt S. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 2008; 23: 425–9. 4. Schwarzbold M, Diaz A, Martins ET, Rufino A, Amante LN, Thais ME, Quevedo J, Hohl A, Linhares MN, Walz R. Psychiatric disorders and traumatic brain injury. Neuropsychiatr Dis Treat 2008; 4: 797–816. 5. Gullo Jda S, Bertotti MM, Silva CC, Schwarzbold M, Diaz AP, Soares FM, Freitas FC, Nunes J, Pinheiro JT, Morato EF, Prediger RD, Linhares MN, Walz R. Hospital mortality of patients with severe traumatic brain injury is associated with serum PTX3 levels. Neurocrit Care 2011; 14: 194–9. 6. Marmarou A, Lu J, Butcher I, McHugh GS, Murray GD, Steyerberg EW, Mushkudiani NA, Choi S, Maas AI. Prognostic value of the Glasgow Coma Scale and pupil reactivity in traumatic brain injury assessed pre-hospital and on enrollment: an IMPACT analysis. J Neurotrauma 2007; 24: 270–80. 7. Edwards P, Arango M, Balica L, Cottingham R, El-Sayed H, Farrell B, Fernandes J, Gogichaisvili T, Golden N, Hartzenberg B, Husain M, Ulloa MI, Jerbi Z, Khamis H, Komolafe E, Laloë V, Lomas G, Ludwig S, Mazairac G, Muñoz Sanchéz Mde L, Nasi L, Olldashi F, Plunkett P, Roberts I, Sandercock P, Shakur H, Soler C, Stocker R, Svoboda P, Trenkler S, Venkataramana NK, Wasserberg J, Yates D, Yutthakasemsunt S. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 2005; 365: 1957–9. 8. Steyerberg EW, Mushkudiani N, Perel P, Butcher I, Lu J, McHugh GS, Murray GD, Marmarou A, Roberts I, Habbema JD, Maas A. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med 2008; 5: e165. doi: 101371/journal.pmed.0050165. 9. Roozenbeek B, Lingsma HF, Lecky FE, Lu J, Weir J, Butcher I, McHugh GS, Murray GD, Perel P, Maas AI, Steyerberg EW. Prediction of outcome after moderate and severe traumatic brain
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injury: external validation of the International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) and Corticoid Randomisation after Significant Head injury (CRASH) prognostic models. Crit Care Med 2012; 40: 1609–17. Plum F, Posner JP, Saper CB, Schiff ND. Plum and Posner’s diagnosis of stupor and coma. Oxford: Oxford University Press, 2007. Skoglund TS, Nellgard B. Long-time outcome after transient transtentorial herniation in patients with traumatic brain injury. Acta Anaesthesiol Scand 2005; 49: 337–40. Diaz AP, Schwarzbold ML, Thais ME, Hohl A, More M, Schmoeller R, Nunes JC, Prediger RD, Linhares MN, Guarnieri R, Walz R. Psychiatric disorders and health-related quality of life after severe traumatic brain injury: a prospective study. J Neurotrauma 2012; 29: 1029–37. Ietswaart M, Milders M, Crawford JR, Currie D, Scott CL. Longitudinal aspects of emotion recognition in patients with traumatic brain injury. Neuropsychologia 2008; 46: 148–59. Milders M, Ietswaart M, Crawford JR, Currie D. Social behavior following traumatic brain injury and its association with emotion recognition, understanding of intentions, and cognitive flexibility. J Int Neuropsychol Soc 2008; 14: 318–26. de Oliveira Thais ME, Cavallazzi G, Schwarzbold ML, Diaz AP, Ritter C, Petronilho F, Hohl A, Prediger RD, Linhares MN, Pizzol FD, Walz R. Plasma levels of oxidative stress biomarkers and long-term cognitive performance after severe head injury. CNS Neurosci Ther 2012; 18: 606–8. de Oliveira Thais ME, Cavallazzi G, Formolo DA, de Castro LD, Schmoeller R, Guarnieri R, Schwarzbold ML, Diaz AP, Hohl A, Prediger RD, Meder MJ, Linhares MN, Staniloiu A, Markowitsch HJ, Walz R. Limited predictive power of hospitalization variables for long-term cognitive prognosis in adult patients with severe traumatic brain injury. J Neuropsychol 2014; 8: 125–39. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975; 1: 480–4. Hohl A, Gullo JD, Silva CC, Bertotti MM, Felisberto F, Nunes JC, de Souza B, Petronilho F, Soares FM, Prediger RD, Dal-Pizzol F, Linhares MN, Walz R. Plasma levels of oxidative stress biomarkers and hospital mortality in severe head injury: a multivariate analysis. J Crit Care 2012; 523: e11–9. doi: 10.1016/j.jcrc.2011.06 .007.
19. Marshall LF, Marshall SB, Klauber MR, Van Bzkum Clark M, Eisenberg H, Jane JA, Luerssen TG, Marmarou A, Foulkes MA. The diagnosis of head injury requires a classification based on computed axial tomography. J Neurotrauma 1992; 9 (Suppl. 1): S287–92. 20. Lezak M, Howieson D, Loring D. Neuropsychological assessment. New York: Oxford University Press, 2004. 21. Rey A. L’éxamen clinique en psychologie. Paris: Press Universitaire de France, 1958. 22. Wechsler D. Wechsler Memory Scale, WMS-III. San Antonio: The Psychological Corporation, 1997. 23. Wechsler D. WAIS-III: manual para administração e avaliação. São Paulo: Casa do Psicólogo, 2004. 24. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–8. 25. Novack TA, Alderson AL, Bush BA, Meythaler JM, Canupp K. Cognitive and functional recovery at 6 and 12 months post-TBI. Brain Inj 2000; 14: 987–96. 26. Perel P, Edwards P, Wentz R, Roberts I. Systematic review of prognostic models in traumatic brain injury. BMC Med Inform Decis Mak 2006; 6: 1–10. 27. Markowitsch HJ, Staniloiu A. Amnesic disorders. Lancet 2012; 380: 1429–40. 28. Ferreira MB, Wolfman C, Walz R, Da Silva RC, Zanatta MS, Medina JH, Izquierdo I. NMDA-receptor-dependent, muscimol-sensitive role of the entorhinal cortex in post-training memory processing. Behav Pharmacol 1992; 3: 387–91. 29. Quillfeldt JA, Schmitz PK, Walz R, Bianchin M, Zanatta MS, Medina JH, Izquierdo I. CNQX infused into entorhinal cortex blocks memory expression, and AMPA reverses the effect. Pharmacol Biochem Behav 1994; 48: 437–40. 30. Walz R, Roesler R, Quevedo J, Rockenbach IC, Amaral OB, Vianna MR, Lenz G, Medina JH, Izquierdo I. Dose-dependent impairment of inhibitory avoidance retention in rats by immediate post-training infusion of a mitogen-activated protein kinase kinase inhibitor into cortical structures. Behav Brain Res 1999; 105: 219–23. 31. Walz R, Roesler R, Quevedo J, Sant’Anna MK, Madruga M, Rodrigues C, Gottfried C, Medina JH, Izquierdo I. Time-dependent impairment of inhibitory avoidance retention in rats by posttraining infusion of a mitogen-activated protein kinase kinase inhibitor into cortical and limbic structures. Neurobiol Learn Mem 2000; 73: 11–20. 32. Jerusalinsky D, Fin C, Quillfeldt JA, Ferreira MB, Schmitz PK, Da Silva RC, Walz R, Bazan NG, Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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Medina JH, Izquierdo I. Effect of antagonists of platelet-activating factor receptors on memory of inhibitory avoidance in rats. Behav Neural Biol 1994; 62: 1–3. 33. Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes
following traumatic brain injury. JAMA 2010; 303: 1938–45. 34. Sigurdardottir S, Andelic N, Roe C, Schanke AK. Cognitive recovery and predictors of functional outcome 1 year after traumatic brain injury. J Int Neuropsychol Soc 2009; 15: 740–50.
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Side of pupillary mydriasis predicts the cognitive prognosis in patients with severe traumatic brain injury R. L. de Souza1–3, M. E. Thais1, G. Cavallazzi1, A. Paim Diaz1, M. L. Schwarzbold1, A. L. Nau1, G. M. Rodrigues1, D. S. Souza4, A. Hohl1 and R. Walz1,5 1
Centro de Neurociências Aplicadas (CeNAp), Hospital Universitário (HU), Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil Unidade de Terapia Intensiva, Hospital Governador Celso Ramos (HGCR), Florianópolis, SC, Brazil 3 Unidade de Terapia Intensiva, HU, UFSC, Florianópolis, SC, Brazil 4 Serviço de Neurocirurgia, HGCR, Florianópolis, SC, Brazil 5 Departamento de Clínica Médica, HU, UFSC, Florianópolis, SC, Brazil 2
Correspondence R. Walz, Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina (UFSC), 3° andar, Campus Universitário, Trindade Florianópolis, SC 88040-900, Brazil E-mail: [email protected] Conflicts of interest The authors have no conflicts of interest. Funding Work supported by Programa de Apoio aos Núcleos de Excelência (PRONEX, NENASC Project) and Edital PPSUS, Fundação de Apoio à Pesquisa do Estado de Santa Catarina (FAPESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Submitted 3 December 2013; accepted 26 October 2014; submission 19 October 2014. Citation de Souza RL, Thais ME, Cavallazzi G, Paim Diaz A, Schwarzbold ML, Nau AL, Rodrigues GM, Santos Souza D, Hohl A, Walz R. Side of pupillary mydriasis predicts the cognitive prognosis in patients with severe traumatic brain injury. Acta Anaesthesiologica Scandinavica 2015
Background: Pupils’ abnormalities are associated to bad prognosis in traumatic brain injury. We investigated the association between the side of pupil mydriasis and the long-term cognitive performance of patients with severe traumatic brain injury (TBI). Methods: We analyzed the cognitive performance of patients admitted at the intensive care unit with isochoric pupils (IP, n = 28), left mydriasis (LM, n = 10), right mydriasis (RM, n = 9) evaluated in mean 2.5 years after the severe TBI and controls (n = 26) matched for age, sex and education level. Results: Patients and controls had similar scores in the four WAISIII investigated subtests. In comparison with controls, LM patients had lower scores in Letters and Category Fluency and IP patients in Category Fluency. Among the 10 evaluated memory tests, LM patients had lower scores than controls in eight, RM patients in two and IP in three memory tests. IP and RM were 3.5 to nine times more associated to significant impairment (cognitive scores under the percentile 10 of controls) in six of 16 investigated cognitive tests. LM was six to 15 times more associated to significant impairment in 10 of 16 cognitive tests. The association among the pupil abnormalities and cognitive performances remained significant after the multiple linear regression analysis controlling for age, gender, admission coma Glasgow scale and serum glucose, presence of associated trauma, and cranial computed tomography abnormalities. Conclusion: Side of admission pupil abnormalities may be a useful variable to improve prognostic models for long-term cognitive performance in severe TBI patients.
doi: 10.1111/aas.12447
Editorial comment: what this article tells us In this prospective clinical study in patients with traumatic brain injury, the long-term neurocognitive function in survivors was linked to early pupil abnormalities present 4 h to 14 h after the injury. This could in the future be used to improve prognostic models for traumatic brain injury. Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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Traumatic brain injury (TBI) is a major public health problem, causing high mortality and morbidity, especially in young adults.1–3 TBI has already been named ‘silent epidemic’ because of the limited popular knowledge about the issue and of its symptoms, such as memory and abstract thinking dysfunctions, which may not be grossly evident,4 but impairs significantly the quality of life of patient and their families.4,5 Despite the high mortality, improvements in neuroimaging, neurosurgery, respiratory and hemodynamic supports have raised the survival rates of severe TBI patients, contributing to the enhancement in the prevalence of TBI-related cognitive and behavioral disturbances.1 Diagnostic and therapeutic decisions are based on patient’s prognosis. Prognostic models are statistical models that combine two or more variables of patient’s data to predict clinical outcome. The International Mission on Prognosis and Analysis of Clinical Trials in TBI study and Medical Research Council Corticosteroid Randomization after Significant Head Injury showed that age, Glasgow Come Scale, pupil abnormalities, Marshal Computed Tomography (CT) and serum glucose abnormalities are the most powerful prognostic variables for the outcome measured 6 months after the injury.2,6–9 Similar results were replicated in our population.1 The pupils’ dilatation in TBI results from uncus and hippocampal gyrus herniation through the tentorium pressing the third nerve against the sphenoid bone. In general, this process starts asymmetrically leading to a unilateral pupil dilatation that may evolve to bilateral mydriasis and, if not quickly reversed, evolves to brain death.10 In our prospective study including 748 consecutive patients with severe TBI, the mortality increased in mean three and 20 times, respectively, in patients admitted with unilateral or bilateral mydriasis in comparison to those with isochoric pupils.1 Despite transtentorial herniation is highly associated with death, aggressive neuro-intensive care and neurosurgical treatments result that around 50% may evolve relatively well according to Glasgow Outcome Scale evaluation.11 However, more detailed evaluation including neuropsychological and psychiatric assessments have demonstrated that long-term cognitive and behavioral dysfunctions are common, leading to a significant impairment in the patient’s quality of life.4,12–16
Recently, we demonstrated that after a correction for education and age distribution, the variables commonly associated with mortality or Glasgow Outcome Scale,17 including pupils’ examination, Marshal CT Classification, Glasgow Coma Scale (GCS) and serum glucose showed a limited predictive power for long-term cognitive prognosis in adult patients with severe TBI.16 In this study, the pupils’ examination in the anisochoric patients was not stratified according to the side of transtentorial herniation. Because the hemispheric lateralization for language is an important predictor for the cognitive impairment related to asymmetric brain lesion, here we investigated if the side of pupil dilatation is independently associated with specific cognitive domains dysfunction 3 years after hospitalization due to severe TBI. Methods Participants Between February 2001 and April 2009, a total of 239 consecutive patients from the metropolitan region of Florianópolis city (southern Brazil) were admitted at the intensive care unit (ICU) of Hospital Governador Celso Ramos with severe TBI and included in our prospective study protocol.1,5,12,16,18 The Human Research Ethical Committee of the Universidade Federal de Santa Catarina approved the study (Ethics committee of Universidade Federal de Santa Catarina, Protocol number 163/ 2005 – approved 30 May 2005). Informed consent was obtained from the patients and controls. The hospital is a tertiary referral center for trauma for 1 million people population of the metropolitan region of Florianópolis city. Severe TBI was defined by a GCS score ≤ 8 after the initial stabilization treatment at the emergency room admission. Because of the lower number of cases and different TBI mechanisms involved, victims of gunshot injury were not included in the present study. The sampling course for the evaluation after hospitalization is presented in Fig. 1. Attempts to contact all survivors (n = 177) were made by phone, mail and home visits in a period between 1 year and 6 years after hospitalization. Three patients died after hospitalization, one was in persistent vegetative state. Among the 177 eli-
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Fig. 1. Study flowchart for cognitive evaluation of adults consecutively admitted to an intensive care unit (ICU) due to severe non-missile traumatic brain injury (TBI).
gible patients, 118 were not localized (66.6%), and eight (4.5%) refused to participate. The remaining 51 patients (28.8%) were evaluated between March 2007 and April 2010. The sampling of patients is summarized in Fig. 1. Control subjects (n = 26) matched for gender, age and education level were recruited during the same period by convenience. They were companion persons of patients from other outpatient clinics and had no previous history of neurological or psychiatric disorders. All the evaluated patients and controls were Caucasians. Demographic and clinical variables Variables collected prospectively during hospitalization included: gender, age, admission GCS, admission pupils’ examination, admission serum glucose from peripheral blood and presence of associated trauma. Pupils were examined by an experienced physician under average lighting intensity and direct flashlight stimulus. Each eye were tested individually, and mydriasis was considered present if the pupil diameter were greater than 5 mm and no reaction to direct light stimulus was observed (paralytic mydriasis). Patients were admitted at the emergency room between 2 h and 6 h after the TBI and transferred to the ICU as soon as possible. Fourteen patients underwent neurosurgery before the intensive care admission. The pupil examination findings included in this analysis were obtained at the intensive care
admission, 4 h to 14 h after the TBI. All patients were under sedation, with stable hemodynamic and ventilation parameters. The abnormal pupil findings were sustained for at least 3 h after the initial evaluation when a second pupil evaluation was done. The subsequent evaluations or duration time of pupil abnormality after the second evaluation was not prospectively evaluated by our research protocol. Pupils were not examined in three patients, and one patient had bilateral mydriasis, and they were not included in the analysis. Patients were classified according their pupils examination as isochoric (n = 28), right mydriasis (n = 09) and left mydriasis (n = 10). The admission brain CT scans were analyzed according to the Marshall classification and presence of subarachnoid hemorrhage. The Marshall classification includes: Type I injury = normal CT; Type II injury = small lesions but visible cisterns and no midline shift; Type III injury = Diffuse swelling with nonvisible cisterns; Type IV injury = unilateral swelling with midline shift deviation higher than 5 mm; Type V injury = evacuated mass lesion; and Type VI injury = non-evacuated lesion with higher than 25 mm volume.19 Variables collected during cognitive evaluation were: hand dominance before TBI and years of education at the time of neuropsychological assessment. Neuropsychological assessment The neuropsychological assessments were done by a neuropsychologist blinded for all the clinical, radiological, neurosurgical and laboratory variables, on average 2.5 (SEM ± 0.2) years after hospitalization (range between 1 to 6 years). When necessary, the individual evaluation scores were discussed between the two examiners. Patients were evaluated individually in the TBI outcome clinic of our University Hospital. All the evaluated patients had no history of recurrent trauma or other neurologic disease. The time needed to complete the assessment was 76 (± 11) and 80 (± 18) min for controls and patients, respectively (P = 0.23). We analyzed the raw scores of the neuropsychological tests. The test battery applied was chosen based on literature and experience of neuropsychologists. The cognitive assessment included: Letters and Category Fluency,20 Rey Auditory Verbal LearnActa Anaesthesiologica Scandinavica 59 (2015) 392–405
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Table 1 Cognitive domains and the respective neuropsychological tests evaluated in patients and controls. Cognitive domain
Neuropsychological test
Reference
Memory
WMS-III Logical Memory First Recall WMS-III Logical Memory I WMS-III Logical Memory II WMS-III Visual Reproduction I WMS-III Visual Reproduction II WMS-III Visual Reproduction Recognition RAVLT – Total RAVLT – Retention RAVLT – Delayed RAVLT – Recognition WAIS-III – Digit Span Category Fluency Letters Fluency WAIS-III – Vocabulary WAIS-III – Similarities WAIS-III – Block Design
Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Wechsler, 1997 Lezak, 2004 Lezak, 2004 Lezak, 2004 Lezak, 2004 Wechsler, 2004 Lezak, 2004 Lezak, 2004 Wechsler, 2004 Wechsler, 2004 Wechsler, 2004
Attention, concentration, mental control Language
Abstract verbal reasoning Visuospatial and motor skills
ing Test (RAVLT),21 Wechsler Memory Scale III (WMS-III) subtests Logical Memory First Recall (LM 1st), Logical Memory I (LM I), Logical Memory II (LM II) and Visual Reproduction I (VR I), Visual Reproduction II (VR II), Visual Reproduction Recognition (VR Rec),22 Wechsler Adult Intelligence Scale III (WAIS-III) subtests Digit Span, Similarities, Vocabulary and Block Design.23 (Table 1). Statistical analysis Normality of the distribution of variables was determined the Kolmogorov–Smirnov test. We analyzed if patients who underwent the neuropsychological evaluation were comparable with the eligible patients, who were not evaluated (drop out cases) according to their clinical, demographic and hospitalization variables. Categorical variables were analyzed using chi-square, continuous variables by Mann–Whitney tests. The comparison among patients with isochoric pupils, right mydriasis and left mydriasis according to their clinical, demographic and hospitalization variables were analyzed by ANOVA or chisquare. The comparison among the controls, patients with isochoric pupils, right mydriasis and left mydriasis according to their neuropsychological performance were done by Student t-test or ANOVA followed by Bonferroni post hoc. The associations among the pupils examination,
clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance 1 year after the severe TBI were investigated by a univariate analysis using a linear regression or student t-test. The independent associations among the pupils’ examination, clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance in the chronic period after the severe TBI were analyzed by multiple linear regression. In this analysis, we included the variables showing an association with the cognitive tests with a P level lower than 0.20. The categorical variables were classified numerically to be included in the analysis: Marshal classification (Type I = 1; Type II = 2; Type III = 3; Type IV = 4; evacuated mass lesion = 5; and non-evacuated mass lesion = 6), gender (male = 1; female = 2); Sub-arachnoid hemorrhage (no = 1; yes = 2); admission pupils (isochoric or right mydriasis = 1; anisochoric or left mydriasis = 2). We also determined the association between the pupils’ examination and the low performance in the cognitive tests by binary logistic regression analysis. In this analysis, patients were grouped in isochoric/right mydriasis and left mydriasis and classified as having low cognitive performance if their score in the cognitive test was under the percentile 10 of controls. As the patients with isochoric and right mydriasis showed similar cognitive performance, they were
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grouped to increase the statistical power of the analysis. The odds ratio and 95% confidence interval for association between the pupils examination group and low score (under the percentile 10 of controls) were determined. We did not adjust for multiple tests comparisons to avoid a type II error.24 The analysis was done by SPSS 17.0 (Chicago, IL, USA). Results Most patients were male (85%), with a mean age 34 (± 13) years and 9 (± 5) years of education. The distributions of gender, age, admission glucose levels, admission CT findings by Marshall Classification, presence of subarachnoid hemorrhage, associated abdominal or thoracic trauma and admission coma Glasgow scale and pupils examination were similar (P < 0.25) between the cognitive evaluated patients and missing cases (data
not shown). Clinical, demographic, radiological and neurosurgical variables distribution according to pupil examination are presented in Table 2. There were no significant differences among the patients’ pupil subgroups according to all the clinical, demographic, radiologic, laboratorial and neurosurgical variables analyzed, except the higher prevalence of female patients in the subgroup of patients with right mydriasis. The gender, age and education levels were similar between the patients and controls (data not shown). The Fig. 2 presents the cognitive performance of controls and patients. The language tests and Wechsler Adult Intelligence Scale-III subtests are showed in Fig. 2A. There were no significant differences by ANOVA among the controls and patients subgroups according to Letters Fluency (P = 0.14), Digit Span (P = 0.18), similarities (P = 0.40) and Block Design (P = 0.21). There was a nonsignificant trend for lower scores
Table 2 Clinical, demographic, radiological and neurosurgical variables distribution according to pupil examination. Anisochoric pupils
Variables Age (years), mean (± SD) Education (years), mean (± SD) Time after TBI (months), mean (± SD) Admission glucose, mean (± SD) Gender Male Female Marshall CT classification, n (%)* Type I injury Type II injury Type III injury Type IV injury Evacuated mass lesion Non-evacuated lesion SAH, n (%)† No Yes Associated trauma, n (%) Yes No Glasgow Coma Scale, n (%) 7 or 8 5 or 6 3 or 4
Isochoric pupils n = 28 (59.6%)
Right mydriasis n = 9 (19.1%)
Left mydriasis n = 10 (21.3%)
P value
33.82 (2.5) 8.4 (0.9) 32 (3.4) 145.4 (11.7)
36.5 (4.2) 10.2 (1.7) 28 (4.8) 164.9 (67)
34.3 (13.1) 9.4 (5.2) 34 (7.6) 151.5 (15.8)
0.66 0.48 0.83 0.61
27 (96.4%) 1 (3.6%)
5 (55.6) 4 (44.4)
8 (80.0) 12 (20.0)
– 0.01
1 (3.6) 8 (28.6) 9 (32.1) 2 (7.1) 6 (21.4) 1 (3.6)
0 1 (11.1) 3 (33.3) 1 (1.11) 2 (22.2) 2 (22.2)
1 (10.0) 0 1 (10.0) 1 (10.0 6 (60.0) 1 (10.0)
– – – – – 0.23
13 (46.4) 13 (46.4)
6 (66.7) 3 (33.3)
5 (50.0) 5 (50.0)
– 0.67
16 (57.1) 12 (42.9)
6 (66.7) 3 (33.3)
5 (50.0) 5 (50.0)
– 0.76
16 (57.2) 6 (21.4) 6 (21.4)
3 (33.3) 2 (22.2) 4 (44.4)
4 (40.0) 1 (10.0) 5 (50.0)
– – 0.41
*Marshal CT Classification and †sub-arachnoid hemorrhage were not evaluated in two cases. CT, computed tomography; SAH, subarachnoid hemorrhage.
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Fig. 2. (A) Language and WAIS-III Subtests Scores of controls and patients according to their pupil examination. †Significant statistic differences from the control group (‘P’ level < 0.05); (B) Non-Verbal Memory Tests Scores of controls and patients according to the pupil examination. †Significant differences from the controls (‘P’ level < 0.0001). ‡Significant differences from the controls (‘P’ level < 0.05); (C) Verbal Memory Tests Scores of controls and patients according to their pupil examination. †Significant differences from the controls (‘P’ level < 0.0001); ‡Significant differences from the controls (P level < 0.01); §Significant differences from the controls (P level < 0.05); ¶Significant differences from the controls (P level < 0.005); ††Significant differences between right and left mydriasis groups (‘P’ level < 0.05). All data are present in mean (SE) of the raw scores of cognitive tests. Acta Anaesthesiologica Scandinavica 59 (2015) 392–405 © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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in the letters fluency (P = 0.13) and vocabulary tests (P = 0.10) in the group with left mydriasis in comparison to controls. Patients with isochoric pupils and left mydriasis showed significant lower scores than controls in the Category Fluency (P < 0.05, by Bonferroni post hoc test). Results of nonverbal memory tests are showed in Fig. 2B. There were no significant differences (ANOVA = 0.23) in the VR Rec scores among the controls and patients (ANOVA = 0.23). Patients with left mydriasis showed lower scores than controls in the VR I (P < 0.05) and VR II (P < 0.0001). In comparison to controls, the VR II was also impaired in patients with right mydriasis (P < 0.05) or isochoric pupils (P < 0.05). Results of verbal memory tests are showed in Fig. 2C. There were significant differences (ANOVA, P < 0.05) among the controls and patients groups according to RAVLT (total, retention and delayed) as well LM (first recall, immediate and late recall). Patients with isochoric pupils showed significant lower scores (P < 0.01) than controls in all the verbal memory tests except in the RAVLT Rec, LM first recall and LM I. They also showed a trend for lower performance in LM II (P = 0.07). In comparison to controls, patients with right mydriasis showed a nonsignificant trend for lower scores in the RAVLT retention, a significant impairment in RAVLT delayed (P = 0.01), but similar performance in remained five investigated verbal memory tests. Patients with left mydriasis showed a significant impairment than controls in the RAVLT total (P < 0.0001), retention (P < 0.0001) and delayed (P < 0.005) but not in RAVLT Rec. When compared with controls, the left mydriasis group also showed significant impairment in the three investigated logical memory tests with LM recall (P < 0.05), LM I (P < 0.05) and LM II (P < 0.01). There were no significant differences between patients subgroups and controls according to gender (P < 0.20), age (P = 0.25) education level (P = 0.95) and hand dominance (P = 0.35) (data not shown). Table 3 shows the association among the clinical, demographic, radiologic and laboratorial variables during hospitalization of patients and their cognitive performance in the cognitive tests showing significant impairment of patients in comparison to controls presented in the Fig. 2. Table 4 shows the independent negative association between the left pupil mydriasis and cog-
nitive performance in the chronic period after the severe TBI controlling the clinical, demographic, radiologic and laboratorial variables distribution by multiple linear regressions. Only the cognitive tests showing significant differences between patients and controls presented in Fig. 2 were analyzed by multiple linear regressions. Table 5 shows the odds ratio for impaired cognitive functions of patients and their pupils’ examination adjusted for age, sex and education. Cognitive impairment was defined as a raw score lower than percentile 10 of healthy controls in the respective cognitive test. Patients with isochoric pupils or right mydriasis were grouped because of their similar performance in the evaluated cognitive tests. The isochoric pupil (IP)/RM was 3.5 to 4.9 times more associated with significant impairment in five of 16 investigated cognitive tests. The LM was six to 15 times more associated with significant impairment in 10 cognitive tests. Discussion The identification of prognostic markers for cognitive and psychiatric impairments is a scientific challenge in the field of traumatic brain injury research.12,16 The pupils’ abnormalities and Marshall CT classification have been associated with a worldwide worse prognosis of TBI patients determined by death rate and Glasgow Outcome Scale.1,3,7,8,25,26 However, considering a more sensitive evaluation of long-term functional capacities by cognitive tests, when only a subset of patients with severe TBI are analyzed, the information of anisochoric pupils or CT findings without any additional reference of the hemispheric side of the lesion does not predict the cognitive impairments of patients.16 Here, we demonstrated that the side of pupil abnormality is an independent marker for specific long-term cognitive domains impairments in patients with severe TBI admitted with anisochoria. The proportion of nonverbal cognitive tests impairment in patients with right hemisphere herniation was not the same as compared with verbal tests impaired in patients with left mydriasis. This may be related to differential capacities of dominant and nondominant hemisphere recovery after the severe TBI. Differences in the sensitivity and specificity of the used cognitive tests to detect abnormalities in the severe TBI patients, Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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30 (2.6)
Time after TBI (months), mean (± SD)
© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Admission CT, n (%)* Type I injury Type II injury Type III injury Type IV injury Evacuated mass lesion Non-evacuated lesion Admission GCS 8 7 6 5 4 3
r = 0.24 r2 = 0.06 B = −0.20 P = 0.06 r = 0.59 r2 = 0.35 B = 1.3 P < 0.0001 r = 0.16 r2 = 0.02 B = 0.09 P = 0.34 r = 0.23 r2 = 0.05 B = −0.06 P = 0.34
P = 0.59 – – r = 0.18 r2 = 0.03 B = 1.1 P = 0.25
4 (8.5)
10 (19.6) 15 (29.4) 9 (17.6) 1 (2) 4 (11.8) 10 (19.6)
– – r = 0.16 r2 = 0.02 B = 0.48 P = 0.31
P = 0.34
– – r = 0.15 r2 = 0.02 B = −0.59
r = 0.44 r2 = 0.19 B = −0.19 P = 0.003 r = 0.54 r2 = 0.29 B = 0.54 P < 0.0001 r = −0.01 r2 = 0.003 B = −0.01 P = 0.74 r = 0.09 r2 = 0.009 B = −0.008 P = 0.55
Correlations by linear regression
2 (4.3) – 9 (19.1) – 13 (27.7) r = 0.09 4 (8.5) r2 = 0.007 14 (29.8) B = −0.64
150 (10)
9.0 (0.7)
Education, years (± SE)
Admission glycemia, mean (± SE)
34 (2)
All cases
Age, years, mean (± SE)
Variables
Visual Rep. II
RAVLT Total
RAVLT RAVLT Retention Delayed
– – r = 0.24 r2 = 0.06 B = 3.0 P = 0.10
P = 0.04
P = 0.10 – – r = 0.22 r2 = 0.05 B = 3.162 P = 0.14
– – r = 0.31 r2 = 0.09 B = −4.87
– – r = 0.25 r2 = 0.06 B = −4.6
– – r = 0.17 r2 = 0.03 B = 1.3 P = 0.26
P = 0.001
– – r = 0.48 r2 = 0.23 B = −4.46
P = 0.10
– – r = 0.25 r2 = 0.06 B = 0.45
– – – – r = 0.25 r = 0.40 r2 = 0.06 r2 = 0.16 B = 3.3 B = −0.95 P = 0.10 P = 0.007
P = 0.05
– – r = 0.30 r2 = 0.09 B = −5.1
– – r = 0.16 r2 = 0.02 B = −0.72 P = 0.32
P = 0.004
– – r = 0.43 r2 = 0.019 B = −2.6
LM II
– – r = 0.18 r2 = 0.03 B = 1.2 P = 0.25
P = 0.03
– – r = 0.034 r2 = 0.11 B = −9.8
– – r = 0.21 r2 = 0.04 B = 1.1 P = 0.18
P = 0.03
– – r = 0.34 r2 = 0.12 B = −2.3
r = 0.53 r = 0.54 r2 = 0.28 r2 = 0.28 B = −9.53 B = −0.39 P < 0.0001 P < 0.0001 r = 0.43 r = 0.47 r2 = 0.18 r2 = 0.22 B = 1.2 B = 0.95 P = 0.004 P = 0.002 r = 0.13 r = 0.08 r2 = 0.02 r2 = 0.006 B = 0.10 B = −0.05 P = 0.43 P = 0.63 r = 0.18 r = 0.23 r2 = 0-03 r2 = 0.05 B = −0.03 B = −0.03 P = 0.26 P = 0.15
LM 1st Recall LM I
r = 0.48 r = 0.51 r = 0.52 r = 0.31 r = 0.53 r = 0.50 r2 = 0.23 r2 = 0.26 r2 = 0.27 r2 = 0.10 r2 = 0.28 r2 = 0.25 B = −0.97 B = −0.87 B = −0.54 B = −0.59 B = −0.14 B = −0.33 P = 0.001 P < 0.0001 P < 0.0001 P = 0.04 P < 0.0001 P = 0.001 r = 0.42 r = 0.29 r = 0.51 r = 0.38 r = 0.34 r = 0.41 r2 = 0.18 r2 = 0.09 r2 = 0.26 r2 = 0.15 r2 = 0.11 r2 = 0.17 B = 2.3 B = 1.4 B = 1.45 B = 0.27 B = 0.24 B = 0.76 P = 0.004 P = 0.05 P < 0.0001 P = 0.07 P = 0.03 P = 0.006 r = 0.005 r = 0.14 r = 0.17 r = 0.23 r = 0.27 r = 0.16 r2 = 0.000 r2 = 0.02 r2 = 0.03 r2 = 0.05 r2 = 0.07 r2 = 0.03 B = 0.009 B = 0.20 B = −0.13 B = −0.04 B = −0.05 B = 0.08 P = 0.97 P = 0.45 P = 0.27 P = 0.14 P = 0.08 P = 0.31 r = 0.31 r = 0.37 r = 0.11 r = 0.19 r = 0.21 r = 0.17 r2 = 0.10 r2 = 0.14 r2 = 0.01 r2 = 0.04 r2 = 0.04 r2 = 0.03 B = −0.12 B = −0.12 B = −0.02 B = −0.07 B = −0.10 B = −0.02 P = 0.04 P = 0.01 P = 0.49 P = 0.22 P = 0.19 P = 0.31
Visual Letters Fluency Category Fluency Rep. I
Table 3 Univariated analysis showing the association among the clinical, demographic, radiologic and laboratorial variables of patients and their cognitive performance in the chronic period after the severe TBI.
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42 (82.4) 9 (17.6)
Abdominal or thoracic trauma, n (%) No Yes
15.0 (4.3) P = 0.30
19.4 (1.8)
18.6 (1.9) 18.7 (3.3) P = 0.98
19.3 (2.3) 17.2 (2.5) P = 0.53
18.2 (1.8) 20.5 (5) P = 0.61
9.1 (2.6) P = 0.45
10.7 (0.8)
10.6 (1.0) 9.1 (1.8) P = 0.50
10.6 (1.2) 8 (1.2) P = 0.65
10.2 (0.9) 11.6 (2.8) P = 0.55
49.3 (10.1) P = 0.16
62.7 (4.1)
61.1 (4.3) 55.1 (10.0) P = 0.56
64.3 (5.4) 55.9 (5.7) P = 0.29
62.6 (4) 46 (9.4) P = 0.13
Student t test or one-way ANOVA
20.3 (4.9) P = 0.04
37.7 (3.8)
35.6 (3.6) 28.0 (8.9) P = 0.39
37.7 (4.8) 31.7 (4.9) P = 0.40
36.5 (3.7) 22 (13.5) P = 0.12
21.6 (5.5) P = 0.01
34.2 (1.9)
32.2 (2.4) 29.2 (3.2) P = 0.58
5.5 (0.7) 4.5 (0.8) P = 0.36
4.8 (0.6) 5.6 (1.3) P = 0.60
3.1 (1.3) P = 0.07
5.4 (0.5)
5.1 (0.6) 4.4 (1.2) P = 0.60
5.2 (0.7) 4.8 (0.8) P = 0.70
4.84 (0.6) 5.3 (1.4) P = 0.76
3.2 (1.3) P = 0.10
5.3 (0.5)
5.1 (0.5) 4.1 (1.1) P = 0.48
9.6 (0.9) 6.3 (1.4) P = 0.05
7.5 (0.9) 10.3 (1.3) P = 0.22
11.4 (2.7) P = 0.10
17.4 (1.4)
16.3 (1.4) 16.7 (3.8) P = 0.92
18.3 (1.5) (13.8 (2.1) P = 0.09
16.5 (1.5) 15.9 (2.7) P = 0.86
18.7 (4.0) P = 0.09
28.0 (2.2)
26.5 (2.1) 26.4 (6.1) P = 1.0
29.4 (2.5) 22.6 (3.2) P = 0.10
26.7 (2.3) 25.7 (4.3) P = 0.85
7.3 (2.3) P = 0.11
13.5 (1.7)
12.7 (1.6) 11.7 (4.1) P = 0.83
14.6 (1.8) 9.5 (2.2) P = 0.08
12.5 (1.6) 12.7 (3.5) P = 0.96
*Marshal CT Classification and †Sub-arachnoid hemorrhage were not evaluated in two cases. CT, computed tomography; GCS, Glasgow Coma Scale; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.
10 (21.3)
37 (78.7)
24 (51.1) 21 (44.7)
SAH on the admission CT, n (%)† No Yes
Admission pupils, n (%) Isochoric or right mydriasis Left mydriasis
40 (85.1) 7 (14.9)
Gender, n (%) Male Female
Table 3 Continued
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Table 4 Independent negative association among the left pupil mydriasis and cognitive performance in the chronic period after the severe TBI controlling for clinical, demographic, radiologic and laboratorial variables distribution by multiple linear regressions. Cognitive tests and their predictors variables
R
R2
B coefficient
‘P’ level
Letter Fluency Constant Education Age Left mydriasis Category Fluency Constant Education Age Left mydriasis RVI Constant Education Admission glycemia Age Left mydriasis RVII Constant Education Admission glycemia Age Left mydriasis RAVLT – Total Constant Education Age Left mydriasis RAVLT – Retention Constant Education Admission glycemia Left mydriasis RAVLT – Delayed Constant Age Left mydriasis LM 1st Constant Education Age Left mydriasis LM I Constant Education Age Left mydriasis LM II Constant Education Age Left mydriasis
0.70 – – – – 0.72 – – – – 0.72 – – – – – 0.72 – – – – – 0.85 – – – – 0.58 – – – – 0.69 – – – 0.73 – – – – 0.76 – – – – 0.78 – – – –
0.49 – – – – 0.52 – – – – 0.52 – – – – – 0.52 – – – – – 0.72 – – – – 0.34 – – – – 0.48 – – – 0.53 – – – – 0.57 – – – – 0.61 – – – –
–
–
20.0 (9.2 to 30.9) 1.46 (0.91 to 2.0) −0.23 (−042 to −0.03) −6.7 (−13 to 0.03)
0.001 < 0.0001 0.04 0.05
13.5 (7.9 to 10.1) 0.7 (0.41 to 0.93) −0.2 (0.30 to −0.11) −2.0 (−5.1 to 1.1) – 97.8 (71.2 to 124.4) 2.65 (1.39 to 3.9) −0.10 (−0.20 to −0.006) −0.64 (−1.2 to −0.14) −20.3 (−35.6 to −5.0) – 77.7 (54.6 to 100.7) 1.8 (0.69 to 2.87) −0.10 (−0.18 to −0.01) −0.60 (−1.0 to −0.15) −20.7 (−33.9 to −7.5) – 53.3 (43.2 to 63.5) 1.55 (1.1 to 2.0) −0.57 (−0.75 to −0.39) −13.7 (−19.3 to −8.0) – 78.6 (52.2 to 105.0) 2.0 (0.65 to 3.3) −0.10 (−0.19 to −0.008) −23.4 (−39.6 to −7.2) – 10.3 (6.7 to 13.7) −0.15 (−0.21 to −0.08) −2.3 (−4.3 to −0.04) – 28.2 (19.9 to 36.7) 0.86 (0.45 to 1.3) 0.22 (−0.48 to −0.18) 7.5 (−12.8 to −2.3) – 45.6 (33.2 to 58.0) 1.3 (0.75 to 2.0) −0.53 (−0.74 to −0.31) −11.8 (−19.5 to −4.1) – 25.5 (16.9 to 34.0) 1.1 (0.65 to 1.5) −0.39 (−0.54 to −0.24) 8.3 (−13.6 to −2.9)
< 0.0001 < 0.0001 < 0.0001 0.21 – < 0.0001 < 0.0001 0.04 0.01 0.01 – 0.002 0.002 0.02 0.01 0.003 – < 0.0001 < 0.0001 < 0.0001 < 0.0001 – < 0.0001 0.005 0.04 < 0.006 – < 0.0001 < 0.0001 0.02 – < 0.0001 < 0.0001 < 0.0001 0.006 – < 0.0001 < 0.0001 < 0.0001 0.003 – < 0.0001 0.003 < 0.0001 0.003
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Table 5 Association between cognitive impairment in the chronic period after the severe TBI and pupils examination. Cognitive tests Letters fluency Isocoric or right mydriasis Left mydriasis Category Fluency Isocoric or right mydriasis Left mydriasis WMS-III Visual Reproduction I Isocoric or right mydriasis Left mydriasis WMS-III Visual Reproduction II Isocoric or right mydriasis Left mydriasis RAVLT – Total Isocoric or right mydriasis Left mydriasis RAVLT – Retention Isocoric or right mydriasis Left mydriasis RAVLT – Delayed Isocoric or right mydriasis Left mydriasis WMS-III Logical Memory First Recall Isocoric or right Mydriasis Left mydriasis WMS-III Logical Memory I Isocoric or right mydriasis Left mydriasis WMS-III Logical Memory II Isocoric or right mydriasis Left mydriasis
Adjusted odds ratio*
95% CI
‘P’ level
9.0 NA
1.8–44.7 NA
0.007 < 0.001
4,9 9.6
1.1–19.3 1.6–57.0
0.02 0.01
3.3 6.0
0.64–17.1 1.3–32.0
0.15 0.02
4.7 9.6
1.1–18.4 1.6–57
0.03 0.01
4.9 15.3
1.2–19.3 2.4–96.1
0.02 0.004
3.9 11.0
1.1–13.8 1.9–63.2
0.03 0.007
3.5 11.2
1.0–12.3 1.8–63.1
0.05 0.007
3.8 10.2
0.9–15.3 1.5–70
0.06 0.01
3.1 7.0
0.9–11.0 1.2–46
0.06 0.02
2.4 7.3
0.7–8.7 1.2–48
0.12 0.03
*Odds ratio for impaired cognitive functions defined as a raw test score lower than the expected percentile 10 of healthy controls matched for age, sex and education. Because patients with isocoric pupils or right mydriasis showed similar cognitive performance, they were grouped to increase the statistical power of the analysis. All patients with left mydriasis showed a Letters Fluency Score lower than percentile 10, and the odds ratio could not be calculated. NA, non-applied.
including those without transtentorial herniation (isochoric pupils) also may contribute to explain our finding. As expected, memory dysfunctions were highly observed in our patients with severe TBI.27 The mesial temporal region including the cortical (parahippocampal and entorhinal cortex) and subcortical (amygdala and hippocampus) regions are susceptible to structural lesions at the skull base under the temporal lobe. The transtentorial herniation may cause a hippocampal lesion itself or interrupt its connectivity through the perforant pathway with the entorhinal cortex. The functional integrity of this circuit is crucial for memory processing including acquisition, consolidation and retrieval.27–32
Because it is methodologically difficult to objectively identify some preexisting psychosocial problems in patients with TBI, the lack of adequate control of these pre-morbid characteristics is a limitation of our study. Although our hospital is a public trauma referral center and almost all patients came from the similar socioeconomic status, those characteristics (including the education level) were not objectively controlled for the nonparticipants, and the reader needs to be aware about this study limitation. Missing (drop out) cases in the follow-up is also a worldwide limitation of TBI studies and may raise doubts whether the analyzed sample of patients adequately represents the survivor group as a whole.33,34 It is important to recognize that a Acta Anaesthesiologica Scandinavica 59 (2015) 392–405
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substantial number of variables before, during and after hospitalization were not controlled and may contribute to the cognitive prognosis. The hypoxia, hypotension, elevated intra-cranial pressure, post-traumatic amnesia (PTA) evaluation (in the acute and subacute period), brain magnetic resonance imaging findings, mood disorders and personality changes (in the chronic period) were previously found to be predictive of outcomes. We believe the inclusion of these variables in further studies may increase the predictive power of prognostic models for cognitive outcomes in severe TBI. The affected brain side and regions based on the CT evaluation were not controlled in our analysis. In fact, we considered the possibility of collinearity between the side of pupil’s abnormalities and CT lesion, but as this was not prospectively evaluated, and we are not able to investigate it retrospectively in these patients. This hypothesis are currently been tested in a large, multicentre prospective study. However, the present study clearly demonstrates the limitation of the Marshal classification of brain CT evaluation on the cognitive prognosis of severe TBI patients. To summarize, identifying premorbid, clinical, neuroradiological and laboratory (such as plasmatic and genetic) variables (biomarkers) that are independently associated with cognitive outcome remains a crucial task for the future research works with severe TBI patients. This preliminary finding suggests that the side of pupil abnormality, in anisochoric patients due to transtentorial herniation, predicts the long-term cognitive prognosis in severe traumatic brain-injured patients and may be useful to improve prognostic models for TBI. Acknowledgement We acknowledge the medical and nurses staff that collaborate in the patients care and support the our research team. References 1. Martins ET, Linhares MN, Sousa DS, Schroeder HK, Meinerz J, Rigo LA, Bertotti MM, Gullo J, Hohl A, Dal-Pizzol F, Walz R. Mortality in severe traumatic brain injury: a multivariated analysis of 748 Brazilian patients from Florianopolis City. J Trauma 2009; 67: 85–90.
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