Acute thalamic connectivity precedes chronic post-concussive symptoms in mild traumatic brain injury.

Chronic post-concussive symptoms are common after mild traumatic brain injury (mTBI) and are difficult to predict or treat. Thalamic functional integrity is particularly vulnerable in mTBI and may be related to long-term outcomes but requires further investigation. We compared structural MRI and resting state functional MRI in 108 patients with a Glasgow Coma Scale (GCS) of 13-15 and normal CT, and 76 controls. We examined whether acute changes in thalamic functional connectivity were early markers for persistent symptoms and explored neurochemical associations of our findings using PET data. Of the mTBI cohort, 47% showed incomplete recovery 6 months post-injury. Despite the absence of structural changes, we found acute thalamic hyperconnectivity in mTBI, with specific vulnerabilities of individual thalamic nuclei. Acute fMRI markers differentiated those with chronic post-concussive symptoms, with time- and outcome-dependent relationships in a sub-cohort followed longitudinally. Moreover, emotional and cognitive symptoms were associated with changes in thalamic functional connectivity to known serotonergic and noradrenergic targets, respectively. Our findings suggest that chronic symptoms can have a basis in early thalamic pathophysiology. This may aid identification of patients at risk of chronic post-concussive symptoms following mTBI, provide a basis for development of new therapies and facilitate precision medicine application of these therapies.

Lessons from traumatic head injury for assessing functional status after brain tumour.

Assessment of global functional status plays a central role in describing outcome after traumatic head injury, but has played a relatively minor role as an endpoint in brain tumour studies. Advantages of functional status as an outcome include simplicity, objectivity, and interpretability, and it is particularly useful in conditions where cognitive impairment is common. Work in the field of traumatic brain injury, specifically on the Glasgow Outcome Scale (GOS), provides lessons in how the validity and reliability of global outcome assessment can be improved. Functional status is conceptually and empirically distinct from cognition and health-related quality of life, and neither of these can adequately substitute for it as an outcome. The strongest candidate for a global outcome measure in brain tumour work is the Karnofsky Performance Status (KPS). Many of the lessons from the GOS could be applied to improvement of KPS assessment. However, the KPS has additional limitations, particularly that it is not brain injury specific. Global functional status is potentially a useful outcome for brain tumour studies, but there is a gap in the tools currently available.

Observer variation in the assessment of outcome in traumatic brain injury: experience from a multicenter, international randomized clinical trial.

OBJECTIVE: Accurate and consistent outcome assessment is essential to randomized clinical trials. We aimed to explore observer variation in the assessment of outcome in a recently completed trial of dexanabinol in head injury and to consider steps to reduce such variation. METHODS: Eight hundred sixty-one patients with severe traumatic brain injury who were admitted to 86 centers were included in a multicenter, placebo-controlled, Phase III trial. Outcome was assessed at 3 and 6 months postinjury using the extended Glasgow Outcome Scale; standardized assessment was facilitated by the use of a structured interview. Before initiation of trial centers, outcome ratings were obtained for sample cases to establish initial levels of agreement. Training sessions in outcome assessment were held, and problems in assigning outcome were investigated. During the trial, a process of central review was established to monitor performance. Interobserver variation was analyzed using the kappa statistic. RESULTS: Substantial observer variation was found in the rating of sample cases (weighted kappa, 0.72; confidence interval, 0.68-0.75) and in assigning outcome based on completed structured interviews (weighted kappa, 0.61; confidence interval, 0.57-0.64). In the early stages of the trial, a relatively large number of discrepancies (29-37%) were identified on central review. This number declined as the trial progressed and coincided with investigator training and feedback from central review. Centers with higher enrollment rates showed better performance. CONCLUSION: Observer variation in outcome assessment is a significant problem for head injury trials. Consistency can be improved by standardizing procedures, training assessors, and monitoring the quality of assessments and providing feedback to interviewers.

Premorbid intelligence and brain injury.

OBJECTIVES: To determine whether NART scores are associated with severity of brain injury and therefore presumably affected by brain injury. In addition, to compare the Cambridge Contextual Reading Test (CCRT) with injury severity in head-injured individuals. DESIGN AND METHODS: Participants were 55 survivors of traumatic head injury, who completed the NART and the CCRT. The scores on these premorbid measures were then compared with indices of injury severity from their initial neurosurgical admission. RESULTS: The NART was significantly correlated with Glasgow coma scale, with greater severity of injury associated with poorer performance. Poorer NART performance was also significantly more likely amongst those whose injury resulted in coma. The CCRT was preferred by patients, though it was also significantly associated with Glasgow coma scale and presence of coma. CONCLUSIONS: The data suggest that performance on both the NART and the CCRT are affected by brain injury severity and thus may underestimate true premorbid ability in these individuals. Similar findings would be likely with the conceptually identical WTAR measure. These measures should be used with appropriate caution and may be usefully supplemented by predictions based on demographic information.

Reliability of the modified Rankin Scale across multiple raters: benefits of a structured interview.

BACKGROUND AND PURPOSE: The modified Rankin Scale (mRS) is widely used to assess global outcome after stroke. The aim of the study was to examine rater variability in assessing functional outcomes using the conventional mRS, and to investigate whether use of a structured interview (mRS-SI) reduced this variability. METHODS: Inter-rater agreement was studied among raters from 3 stroke centers. Fifteen raters were recruited who were experienced in stroke care but came from a variety of professional backgrounds. Patients at least 6 months after stroke were first assessed using conventional mRS definitions. After completion of initial mRS assessments, raters underwent training in the use of a structured interview, and patients were re-assessed. In a separate component of the study, intrarater variability was studied using 2 raters who performed repeat assessments using the mRS and the mRS-SI. The design of the latter part of the study also allowed investigation of possible improvement in rater agreement caused by repetition of the assessments. Agreement was measured using the kappa statistic (unweighted and weighted using quadratic weights). RESULTS: Inter-rater reliability: Pairs of raters assessed a total of 113 patients on the mRS and mRS-SI. For the mRS, overall agreement between raters was 43% (kappa=0.25, kappa(w)=0.71), and for the structured interview overall agreement was 81% (kappa=0.74, kappa(w)=0.91). Agreement between raters was significantly greater on the mRS-SI than the mRS (P<0.001). Intrarater reliability: Repeatability of both the mRS and mRS-SI was excellent (kappa=0.81, kappa(w) > or =0.94). CONCLUSIONS: Although individual raters are consistent in their use of the mRS, inter-rater variability is nonetheless substantial. Rater variability on the mRS is thus particularly problematic for studies involving multiple raters. There was no evidence that improvement in inter-rater agreement occurred simply with repetition of the assessment. Use of a structured interview improves agreement between raters in the assessment of global outcome after stroke.

Differential responses in three thalamic nuclei in moderately disabled, severely disabled and vegetative patients after blunt head injury.

In vivo imaging techniques have indicated for many years that there is loss of white matter after human traumatic brain injury (TBI) and that the loss is inversely related to cognitive outcome. However, correlated, quantitative evidence for loss of neurons from either the cerebral cortex or the diencephalon is largely lacking. There is some evidence in models of TBI that neuronal loss occurs within the thalamus, but no systematic studies of such loss have been undertaken in the thalamus of humans after blunt head injury. We have undertaken a stereological analysis of changes in numbers of neurons within the dorsomedial, ventral posterior and lateral posterior thalamic nuclei in patients assessed by the Glasgow Outcome Scale as moderately disabled (n = 9), severely disabled (n = 12) and vegetative (n = 10) head-injured patients who survived between 6 h and 3 years, and controls (n = 9). In histological sections at the level of the lateral geniculate body, the cross-sectional area of each nucleus and the number and the mean size of neurons within each nucleus was quantified. A statistically significant loss of cross-sectional area and number of neurons occurred in the dorsomedial nucleus in moderately disabled, and both the dorsomedial and ventral posterior thalamic nuclei in severely disabled and vegetative head-injured patients. However, there was no change in neuronal cell size. In the lateral posterior nucleus, despite a reduction in mean cell size, there was not a significant change in either nuclear area or number of neurons in cases of moderately disabled, severely disabled or vegetative patients. We posit, although detailed neuropsychological outcome for the patients included within this study was not available, that neuronal loss in the dorsomedial thalamus in moderately and severely disabled and vegetative patients may be the structural basis for the clinical assessment in the Glasgow Outcome Scale. In severely disabled and vegetative patients, loss of neurons from the ventral posterior thalamic nucleus may also reflect loss of response to afferent stimuli.

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage.

OBJECTIVES: To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Neuropsychological assessments were conducted with 70 SAH survivors derived from a consecutive series of neurosurgical admissions. Outcomes, including cognitive tests, health questionnaires and Glasgow Outcome Scale at a mean of 16 months after SAH, were compared with presence or absence of the epsilon4 allele. RESULTS: There was no evidence that SAH survivors possessing the epsilon4 allele had poorer outcome. The only suggestion of an association between the epsilon4 allele and outcome was in a subgroup of patients with a Fisher grade 4 haemorrhage, although this trend did not reach statistical significance. CONCLUSIONS: Overall, possession of the APOE epsilon4 allele is not significantly associated with neuropsychological outcome following SAH. However, there may be an effect amongst those with a Fisher grade 4 haemorrhage.

Anxiety and depression after spontaneous subarachnoid hemorrhage.

OBJECTIVE: Relatively little attention has been paid to emotional outcome after subarachnoid hemorrhage (SAH). This study assessed levels of anxiety and depression among SAH survivors and related these to clinical indices. METHODS: Seventy SAH patients from a consecutive series of neurosurgical admissions participated in semistructured assessments of functional outcome; 52 of the patients also returned standardized measures of emotional outcome. These data were compared with clinical indices collected during the initial hospital admission. RESULTS: Moderate to severe levels of anxiety were present in approximately 40% of patients 16 months after hemorrhage, with approximately 20% experiencing moderate to severe levels of depression. Although anxiety was more likely to be reported at interview by those with an SAH of Fisher Grade 4, the standardized measures of anxiety and depression were not associated with severity of hemorrhage or any other clinical variables. Both anxiety and depression were significantly associated with outcome indices such as return to work and engagement in social activities. CONCLUSION: Anxiety is a significant and lasting problem for approximately 40% of survivors of SAH. It is suggested that measures taken to prevent or treat such anxiety among survivors of SAH may serve to significantly improve functional outcome.

Reliability of ratings on the Glasgow Outcome Scales from in-person and telephone structured interviews.

OBJECTIVE: To determine test-retest reliability and interrater reliability for structured interviews for the Glasgow Outcome Scale (GOS) using in-person and telephone contact. METHODS: Study 1: Thirty head-injured patients were interviewed face-to-face and then reinterviewed by telephone a few days later by the same rater. Study 2: Fifty-six head-injured patients were interviewed by telephone and then face-to-face interviews were carried out by a different person up to 1 month later. Agreement between ratings on the GOS and the extended GOS (GOSE) in each of the studies was assessed using the kappa statistic weighted with quadratic weights. RESULTS: Values of kappa(w) for the test-retest reliability study were.92 for both GOS and GOSE, and for interrater reliability study were.85 for the GOS and.84 for the GOSE. CONCLUSIONS: The findings indicate good test-retest and interrater reliability for the structured interviews. In most circumstances a structured interview over the telephone can provide a reliable assessment of the GOS, and can safely be substituted for in person contact.

Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale.

BACKGROUND AND PURPOSE: The modified Rankin Scale is widely used to assess changes in activity and lifestyle after stroke, but it has been criticized for its subjectivity. The purpose of the present study was to compare conventional assessment on the modified Rankin Scale with assessment through a structured interview. METHODS: Sixty-three patients with stroke 6 to 24 months previously were interviewed and graded independently on the modified Rankin Scale by 2 observers. These observers then underwent training in use of a structured interview for the scale that covered 5 areas of everyday function. Eight weeks after the first assessment, the same observers reassessed 58 of these patients using the structured interview. RESULTS: Interrater reliability was measured with the kappa statistic (weighted with quadratic weights). For the scale applied conventionally, overall agreement between the 2 raters was 57% (kappa(w)=0.78); 1 rater assigned significantly lower grades than the other (P=0.048). On the structured interview, the overall agreement between raters was 78% (kappa(w)=0.93), and there was no overall difference between raters in grades assigned (P=0.17). Rankin grades from the conventional assessment and the structured interview were highly correlated, but there was significantly less disagreement between raters when the structured interview was used (P=0.004). CONCLUSIONS: Variability and bias between raters in assigning patients to Rankin grades may be reduced by use of a structured interview. Use of a structured interview for the scale could potentially improve the quality of results from clinical studies in stroke.

SPECT imaging in head injury interpreted with statistical parametric mapping.

UNLABELLED: This study investigated regional cerebral blood flow in head-injured patients using statistical parametric mapping (SPM) to detect hypoperfusion on (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) SPECT scans. METHODS: Acute and follow-up SPECT and MRI scans from 61 patients who were admitted to a regional neurosurgical unit were examined. Patients had acute MRI and SPECT at 2-18 d after injury and on follow-up between 130 and 366 d after injury. Thirty-two scans from non-head-injured patients were used as a SPECT control group. The SPECT images were first aligned to the Talairach-Tournoux atlas and then analyzed statistically with SPM. RESULTS: SPECT detected more extensive abnormality than MRI in acute and follow-up stages. This effect was more pronounced on follow-up of patients with diffuse injury. Examination of a focal injury group indicated the involvement of frontal and temporal lobes and the anterior cingulate. Blood flow abnormalities persist, to a lesser extent, on follow-up scans. The diffuse group displayed low blood flow in the frontal and temporal lobes, including cingulate involvement, which persists at follow-up with additional involvement of the thalamus. CONCLUSION: SPM has a role in SPECT image interpretation because it allows better visualization than other methods of quantitative analysis of the spatial distribution of abnormalities in focal and diffuse head injury. Frontal lobe blood flow abnormality (particularly anterofrontal regions and mesiofrontal areas) is common after head injury.