Diagnostic approaches to predict persistent post-traumatic symptoms after mild traumatic brain injury - a literature review.

Just Accepted by International Journal of Neuroscience

Diagnostic approaches to predict persistent posttraumatic symptoms after mild traumatic brain injury – a literature review Aline M. Studerus-Germann, Jean-Philippe Thiran, Alessandro Daducci, Oliver P. Gautschi doi:10.3109/00207454.2015.1033620

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ABSTRACT Mild traumatic brain injury (mTBI) is one of the most frequently diagnosed neurological disorder in emergency departments. Although there are established recommendations for the diagnosis and treatment in the acute stage, there is an ongoing debate which diagnostic methods and risk factors predict unfavourable long-term outcome after mTBI. This literature review addresses the question, which diagnostic approaches may best predict persistent posttraumatic symptoms (pPTS). A literature search for experimental studies from January 2000 to September 2014 evaluating the following diagnostic approaches (1) susceptibility-weighted imaging (SWI), (2) diffusion tensor imaging (DTI), (3) magnetic resonance spectroscopy (MRS), (4) functional magnetic resonance imaging (fMRI), as predictive factors of pPTS or unfavourable cognitive outcome in adult populations with mTBI was performed. DTI has been proved to be a valuable tool to identify diffuse axonal injury (DAI) after mTBI. Additionally, some studies showed associations between DAI and unfavorable cognitive outcome. SWI has shown to be a highly sensitive imaging method to identify microbleeds. The presence and quantity of microbleeds in this imaging technique can further provide etiological evidence for pPTS. MRS provides information about local neurons metabolism and preliminary data show that creatine-phosphocreatine levels measured after mTBI are predictive of cognitive outcome and emotional distress. The results of one study have shown fMRI as a useful tool to differentiate mTBI patients with pPTS from controls and mTBI patients without pPTS in a resting-state condition. From the evaluated diagnostic approaches to predict pPTS after mTBI, DTI, SWI, MRS, and fMRI seem to have adequate sensitivity and specificity as predictive diagnostic tools for pPTS. Large longitudinal clinical trials are warranted to validate the prognostic applicability and practicability in daily clinical practice.

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Publisher: Informa Healthcare Journal: International Journal of Neuroscience DOI: http://dx.doi.org/10.3109/00207454.2015.1033620

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Diagnostic approaches to predict persistent posttraumatic symptoms after mild traumatic brain injury – a literature review

Aline M. Studerus-Germann1,2, Jean-Philippe Thiran3, Alessandro Daducci3, Oliver P.

Division of Neuropsychology, Department of Neurology, State Hospital St.Gallen,

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1

Switzerland

2

Department of Psychopathology and Clinical Intervention, University of Zurich, Switzerland 3

Signal Processing Laboratory (LTS5), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

4

Department of Neurosurgery, Geneva University Medical Center, Faculty of Medicine, University of Geneva, Switzerland

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Correspondence to:

Dr. med. Oliver P. Gautschi

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Neurochirurgien FMH

Département des Neurosciences cliniques Service de Neurochirurgie

Hôpitaux Universitaires de Genève Rue Gabrielle-Perret-Gentil 4

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Gautschi4,*

1211 Genève 14

Phone: +41 22 372 52 87 Mobile: + 41 79 55 33 777 Fax: +41 22 372 82 25 Email: [email protected]

1

Key words: mild traumatic brain injury; diffusion tensor imaging; susceptibility-weighted imaging; diffuse axonal injury; persistent posttraumatic symptoms

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Conflict of Interest: The authors report no conflict of interest.

ABSTRACT

disorder in emergency departments. Although there are established recommendations for the

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diagnosis and treatment in the acute stage, there is an ongoing debate which diagnostic methods and risk factors predict unfavourable long-term outcome after mTBI. This literature

review addresses the question, which diagnostic approaches may best predict persistent posttraumatic symptoms (pPTS). A literature search for experimental studies from January 2000 to September 2014 evaluating the following diagnostic approaches (1) susceptibilityweighted imaging (SWI), (2) diffusion tensor imaging (DTI), (3) magnetic resonance

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spectroscopy (MRS), (4) functional magnetic resonance imaging (fMRI), as predictive factors of pPTS or unfavourable cognitive outcome in adult populations with mTBI was performed.

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DTI has been proved to be a valuable tool to identify diffuse axonal injury (DAI) after mTBI. Additionally, some studies showed associations between DAI and unfavorable cognitive outcome. SWI has shown to be a highly sensitive imaging method to identify microbleeds. The presence and quantity of microbleeds in this imaging technique can further provide

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Mild traumatic brain injury (mTBI) is one of the most frequently diagnosed neurological

etiological evidence for pPTS. MRS provides information about local neurons metabolism and preliminary data show that creatine-phosphocreatine levels measured after mTBI are predictive of cognitive outcome and emotional distress. The results of one study have shown fMRI as a useful tool to differentiate mTBI patients with pPTS from controls and mTBI patients without pPTS in a resting-state condition. From the evaluated diagnostic approaches to predict pPTS after mTBI, DTI, SWI, MRS, and fMRI seem to have adequate sensitivity 2

and specificity as predictive diagnostic tools for pPTS. Large longitudinal clinical trials are warranted to validate the prognostic applicability and practicability in daily clinical practice.

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Introduction Mild traumatic brain injury (mTBI) is one of the most frequently diagnosed neurological

disorder in emergency departments worldwide. Historically, the diagnosis of mTBI has been

diagnosis is dependent on the patient’s subjective self-report (2). This self-report of deficits

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may be underreported by the patient’s reduced awareness of limitations. Moreover, the desire

to return to play or duty, cultural issues that discourage symptom report, symptoms that are not immediately apparent but develop or worsen over days to weeks, and finally potential costs of urgent medical care in some countries for symptoms which the patient or family do

initially not feel life-threatening or worrisome, among others, are also factors that may lead to

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underreporting (3).

Persistent posttraumatic symptoms (pPTS), including neuropsychological impairments,

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persisting physiological complaints and psychiatric symptoms, are often summarized as postconcussion syndrome (PCS). The usefulness of PCS in the assessment of mTBI remains unclear due to the non-specificity of these symptoms and the fact that a given percentage of the normal population report these symptoms even in the absence of a traumatic event (4).

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very challenging, due to the continuing debate over the clinical definition (1) and because the

Recently, Wäljas et al. reported that 31% of their healthy control sample met PCS criteria (5). According to their results, significant predictors of PCS at one month were pre-injury mental health problems and the presence of extra-cranial bodily injuries. Also, being symptomatic at one month was a significant predictor of still being symptomatic at one year, and depression was significantly related to PCS at both one month and one year. Additionally, the incidence of PCS after mTBI varies widely, partially because of the difference in diagnostic criteria for 3

PCS (6). Recent findings suggest that in mTBI patients, 64% using ICD-10 criteria and 11% using DSM-IV criteria have PCS three months post-injury (6). The long-term prevalence of PCS after mild brain trauma is estimated between 15 and 30% (7). These persisting

and

work-related

activities

(8).

mTBI

patients

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complaints may disrupt the patients’ social relationships and their ability to resume leisure with

pPTS

may

have

greater

neuropsychological impairments than those without pPTS (9). Studies of Sheedy et al. and

to predict PCS with a sensitivity of 80%, respectively 71.4%, and a specificity of 76%,

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respectively 64.2% in an Australian and Canadian population (10, 11). The assumption for the

development and persistence of PCS is that metabolic and structural changes in the brain of

mTBI patients have not returned to homeostasis (12). There is a trend that earlier intervention (e.g. psychosocial intervention) is more likely to improve outcome (13-15). Therefore, the identification of patients who might continue to have pPTS and who should be offered early

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treatment is of paramount importance.

Though computed tomography (CT) is the gold standard to detect intracranial abnormalities

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in the emergency setting, it is not a tool for prognostication of short- or long-term nonneurosurgical sequelae such as PCS (16). Additionally, magnetic resonance imaging (MRI) is more sensitive than CT in detecting traumatic lesions during the acute phase of injury (17). Nevertheless, the correlation between focal structural lesions detected by conventional MRI

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Faux et al. found that immediate verbal recall and quantitative recording of headache was able

and long-term patient outcome is controversial since T1- or T2-weighted MRI sequences may not be sensitive to microstructural neuropathology of milder injuries (18). Another study showed, however, that an approach to identify and count individual patho-anatomic features on MRI such as brain contusions and foci of hemorrhagic axonal injury could be predictive of a poorer 3-months outcome in mTBI (19). One or more brain contusions on MRI, and 4 foci of hemorrhagic axonal injury on MRI, were each independently associated with poorer 34

months outcome as measured with the Extended Glasgow Outcome Scale (GOS-E) (19). Recently, susceptibility-weighted imaging (SWI) has been found to be useful to detect microbleeds after mTBI as a marker of diffuse axonal injury (DAI). It has been shown to

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provide etiological evidence for some post-traumatic neurological deficits that were unexplainable in conventional MRI (20). Furthermore, the quantity and volume of SWI-

detected bleeds suggestive of haemorrhagic DAI seem to be an important factor determining

can be obtained immediately after injury and may provide prognostic information regarding

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long-term outcome (23). Another promising, more recent MRI-technique, is diffusion tensor

imaging (DTI), which can be used to detect alternations in the white matter ultrastructure

allowing the generation of three-dimensional reconstructions of white matter tracts and brain structural connectivity (24). DTI has been shown to be more sensitive for DAI than conventional MRI (25). A third evolving MRI-technique is magnetic resonance spectroscopy (MRS), which provides information about metabolism in small regions of the brain.

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Preliminary data show that Creatine-Phosphocreatine (Cr) levels measured with MRS in the subacute stage after mTBI are predictive of cognitive outcome and emotional distress (26).

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Another imaging method, the functional magnetic resonance imaging (fMRI) analyses regional changes in hemodynamic activity, most frequently using the blood oxygenation level-dependent (BOLD) signal. The role of fMRI in the management of mTBI is still limited (27).

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long-term cognitive and neuropsychiatric disability following TBI (21, 22). This assessment

This literature review addresses the questions which of the named diagnostic approaches (SWI, DTI, MRS, and fMRI) may predict pPTS in adults with mTBI.

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Methods A thorough literature for experimental studies focused on mTBI and neuroimaging published from January 2000 up to September 2014 was performed on PubMed on the 30th of

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September 2014. The search included the following keywords: (1) “mild traumatic brain injury” and (2) “susceptibility-weighted imaging” or “diffusion tensor imaging” or “magnetic resonance spectroscopy” or “functional magnetic resonance imaging”, and (3) / “post-

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criteria were identified from the reference lists of included articles.

Inclusion criteria: Articles were included if they evaluated one of the following diagnostic approaches (1) SWI, (2) DTI, (3) MRS, and/or (4) fMRI as predictive factors of pPTS or

cognitive outcome in adult populations with mTBI. The search was limited to English language studies. Exclusion criteria: Studies focussing merely on paediatric patients were excluded because of the on-going brain development of children and adolescents and the

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variability in the pattern of PCS depending on age. Also excluded from the present review were studies with a focus only on blast-related mTBI as the injury mechanism is not fully

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understood yet. Studies that mixed mTBI with moderate or severe TBI or where the severity of injury was not clearly specified in the full article were excluded. Studies focusing on other MRI-sequences as the ones specified in the inclusion criteria were excluded. Finally case reports, interventional studies and reviews were excluded.

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concussion symptoms” / or “cognitive outcome”. Further studies meeting the inclusion

Results

Search Results Overall, the literature search identified 127 articles trough database searching plus three articles trough the reference sections of those articles addressing diagnostic approaches to predict pPTS after mTBI (Fig. 1). After removal of duplicates 104 titles and abstracts were 6

screened, of which 61 were excluded because they met one or more of the above exclusion criteria. Of the retrieved and assessed 43 relevant full papers 18 were removed because they met one or more of the above exclusion criteria. A total of 25 studies were finally included in

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the qualitative synthesis, 1 focusing on SWI and DTI, 1 on MRS and fMRI, 2 merely on SWI, 16 merely on DTI, 2 merely on MRS and 3 merely on fMRI.

Traumatic cerebral microbleeds have shown characteristic regional distributions and

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associations with initial neurological status and prognosis after mTBI (20). Microbleeds in

mTBI were found to be located more frequently in white matter than in deep nuclei compared to a control group (20). The presence and quantity of microbleeds in mTBI patients were closely related with lower scores on the Glasgow Coma Scale (GCS) on the day of trauma and on the Glasgow Outcome Scale (GOS) one year post-injury (20). Toth et al. did not find microhaemorrhages in their mTBI patients with SWI and did not perform any questionnaires

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or assessments to measure pPTS (28). Contra wise, Kou et al. found in three of nine patients with mTBI intracranial haemorrhages on SWI, all of them had very high glial fibrillary acidic

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protein (GFAP) levels (29).

Diffusion Tensor Imaging (DTI)

DTI has demonstrated that mTBI is associated with wide-spread structural changes in cortical

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Susceptibility-weighted imaging (SWI)

white matter tracts and the integrity of those have been shown to correlate with behavioural and cognitive measures (25, 30-36). According to recent literature, changes in diffusivity indexes may indicate different types of white matter abnormality and different stages postinjury after mTBI (1, 37). Higher fractional anisotropy (FA) in mTBI compared to controls may reflect an inflammatory response such as axonal swelling or cytotoxic edema (38-40). Decreased FA in mTBI compared to controls may indicate axonal degeneration and 7

discontinuities with excess water between tracts or in perivascular spaces (1, 32). These findings have been confirmed by Kou et al. who reported that DTI FA values could both increase or decrease in the acute setting (29). DTI findings of the first week post-injury

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provide evidence that in the acute state FA normally increases and/or radial diffusivity (RD) decrease and/or apparent diffusion coefficient (ADC; also referred to as mean diffusivity (MD)) decreases (28, 39-43). More than 2 weeks post injury either a decrease in FA or an

suggested that decreased FA probably indicates the original damage to the axon and the

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increased one indicates recovery, and that an increase in FA may indicate more severe TBI correlated with poor clinical outcomes (48). Unfortunately the time difference between studies more than 2 weeks post-injury is very heterogeneous, ranging from a mean of 17 days to 35 months (49, 50).

By means of more recent DTI analysis techniques such as automated region of interest (ROI)

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analysis, tract-based voxel-wise analysis and quantitative tractography, frontal and temporal association white matter pathways have been found to be the most frequently damaged (37).

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Messé et al. found damage to long association fasciculi connecting frontal, parietal, and temporal cortices to represent the main pathological substrate of PCS (50). Patients with persistent PCS had significantly higher mean RD values in long association white matter fibre tracts. They also found changes in MD following mTBI and interpreted that MD is the most

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increase in MD or a combination of both is seen more common (44-47). Recently, Zhu et al.

sensitive diffusion variable to measure the early occurrence of DAI following mTBI and to predict the clinical outcome. Chu et al. found a decrease in MD and RD and an increase in FA scores in mTBI-patients with increased pPTS scores at a range of 1 to 6 days post-injury (39). They suggest that damage to white matter and its interconnectivity by means of mTBI may be associated with pPTS. On the other hand, however, Bouix et al. reported an abnormally low FA in white matter and an increased gray matter FA in patients with pPTS following mTBI 8

(51). The authors explain this novel in-vivo finding in gray matter FA with an animal model of brain trauma that associates increased FA in gray matter with pathologies such as gliosis. Lange et al. did not find any significant differences in white matter integrity in the corpus

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callosum between mTBI patients who met the criteria for PCS and the ones who did not meet them 2 months post-injury (52).

50, 53, 54). The largest published DTI study with mTBI patients (n= 43) and cognitive

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assessment concluded that microstructural white matter lesions detected by DTI correlate with

persistent cognitive deficits in mTBI (33). Kinunnen et al. found that the location of white

matter damage measured with DTI potentially predicts cognitive function (46). Associative learning and memory was related to the structure of the fornices in the way that patients with increased FA performed better on memory testing. Executive function was related to frontal lobe connections, patients with high MD in the left superior frontal white matter showed

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worse performance in executive function. Whilst Kinunnen et al. did not find a relationship between their measures of executive function and FA, Niogi et al. reported a correlation

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between attention control as a measure of executive function and FA in the left hemisphere anterior corona radiata in mTBI patients (33, 46). Additional to that memory performance of mTBI patients was correlated with FA in the uncinate fasciculus in the study of Niogi et al. (33). Interestingly, Fakhran et al. found sex differences in white matter abnormalities after

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A growing number of studies compare DTI findings with cognitive status (31, 33, 40, 43, 46,

mTBI (55). The authors found a relative sparing of the uncinate fasciculus in female compared with male patients after mTBI. The authors concluded that gender and uncinate fasciculus FA values are independent risk factors for pPTS after 3 months and stronger predictors of time to symptom resolution than initial symptom severity. Wu et al. found a correlation between FA and memory performance, specifically they found that increased FA of the left cingulum bundle correlated with poorer memory performance in mTBI patients 9

tested approximately 3 days post-injury (43). Miles et al. reported a trend toward a significant correlation between baseline MD measured at an average of 4 days post-injury and response speed at 6 months follow-up as well as a positive correlation between baseline FA and a

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measure of executive function (53). Niogi et al. found that the number of damaged white matter structures measured by DTI was significantly correlated with mean reaction time on a

cognitive task (54). Kraus et al. found that in a sample tested at a mean of 92.55 months post-

in executive function, attention, and memory (31). They found reduced FA in the cortico-

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spinal tract, sagittal stratum, and superior longitudinal fasciculus. They concluded that white

matter changes might be primarily due to axonal damage rather then myelin damage. In a study of Mayer et al. a significantly greater FA as a result of reduced RD in the corpus

callosum and several left hemisphere tracts within 21 days post-injury was not correlated with poor neuropsychological test performance (40).

cognitive

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The exact mechanisms that cause changes in DTI measures and lead to correlations with impairment

are

still

not

fully

understood.

Unfortunately

different

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neuropsychological tests were used to characterize the cognitive domains that seem most prone to white matter injury – executive function, memory and attention/information processing speed – which makes a comparison between studies difficult.

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injury a greater number of regions with reduced FA predicted greater cognitive impairments

Magnetic Resonance Spectroscopy (MRS) MRS-detectable N-acetyl aspartate (NAA) levels reflect both axonal integrity and independent cellular processes, such as mitochondrial disturbances (56). With MRS, lower levels of white matter NAA have typically been found in mTBI patients compared to healthy controls or to the uninjured brain side in the acute phase after injury (41, 57). These results have been interpreted to reflect neuronal loss, metabolic dysfunction or myelin repair (26). 10

Recovery from NAA/creatine (Cr) was found 30 days after injury by Vagnozzi et al. (58). The initially reduced NAA returned to a nearly normal level by 2 months post-injury (57). Since NAA was sampled from areas, which showed white/grey pericontusional lesions on CT, the

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recovery rate might be faster in patients with normal CT findings. Chen et al. additionally found reduced NAA/Cr in 13 cases and increase of lactic acid (Lac) in 7 cases of 19 examined

mTBI patients (41). Gasparovic et al. found higher levels of white matter creatine-

compared to healthy controls and the Cr levels were predictive of executive function and

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emotional distress (26). In mTBI patients the combined glutamate and glutamine signal (Glx) were significantly lower and the Cr levels significantly higher compared to healthy controls

(26). Similarly, Henry et al. showed a significant decrease in glutamate in the primary motor cortex (M1), as well a significant decrease in NAA in the prefrontal and primary motor cortices in a group of 12 concussed athletes (59). At the late subacute (> 1 month post-injury) and chronic (> 6 months post-injury) stages of mTBI George et al. found decreases in choline-

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to-creatine ratio (Cho/Cr) measured in the thalamus and centrum semiovale (CSV) (60). Their results from the early sub-acute phase (within 10 days post-injury) showed positive

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associations between Cr measurements in the CSV with performance on cognitive assessment in immediate and delayed code substitution as a measure of visual search and learning respectively recognition and memory by means of Automated Neuropsychological Assessment Metrics (ANAM).

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phosphocreatine in mTBI patients in the early sub-acute phase (3 to 19 days post-injury)

The findings of these three studies including MRS and cognitive assessment, respectively emotional measure, show that metabolic measures can potentially serve as diagnostic and prognostic markers of mTBI. Also the study from Henry et al. including 10 concussed and 10 non-concussed athletes confirmed cortical neurometabolic changes in the acute post-

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concussion phase as well as recovery and continued metabolic abnormalities in the chronic phase (61).

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Functional magnetic resonance imaging (fMRI) Chen et al. designed a study to define the relationship between self-reported PCS,

neuropsychological performance and fMRI activation in a group of concussed athletes with

grouped according to their PCS score showed reduced task related activation patterns in the

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dorsolateral prefrontal cortex for both low and moderate PCS groups during a working memory task. The authors reported that the severity of PCS predicted the fMRI BOLD signal

changes in cerebral prefrontal regions. By comparing the brain activation maps a clear difference could be seen between the control group and concussed athletes with an additional activation peak in left temporal lobe during verbal working memory task in the concussed individuals. Additionally, they found an inverse relationship between PCS scores and

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cognitive performance on several subtests of a computerised cognitive test battery. Their result support the use of the PCS scale as diagnostic measure after mTBI and the use of brain

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activation maps to differentiate between athletes with and without concussion. Similarly, Slobounov et al. performed an fMRI study evaluating spatial memory including 15 athletes suffering from mTBI, however, without persisting PCS (62). The quantitative analysis of BOLD signal revealed that concussed individuals had a significantly larger cluster size during

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persisting PCS (4). This study including 28 male athletes with and without concussion

encoding at parietal cortex, right dorsolateral prefrontal, and right hippocampus. Messé et al., on the other hand, investigated 17 mTBI patients with persistent PCS at 6 months post-injury compared with 38 mTBI patients with no PCS and 34 healthy controls using a resting-state fMRI (63). The authors could demonstrate an increased connectivity in temporal regions and decreased connectivity in frontal regions in mTBI patients with PCS.

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In summary the results of the above fMRI studies show that concussed individuals show additional activation peaks (4) and larger cluster size (61) compared to healthy controls during cognitive task conditions. The results of the study of Messé et al. have shown fMRI as

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a useful tool to differentiate mTBI patients with PCS from controls and mTBI patients without PCS in a resting-state condition by means of changed connectivity (63).

The lack of consistency of criteria to define mTBI and the diversity of populations leads to a

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wide heterogeneity among the included subjects (64). The methods and questionnaires used to measure pPTS varied between studies and with it the criteria chosen for PCS, which made a comparison of PCS difficult. This was an initial reason for us to choose pPTS instead of PCS as outcome variable for the purpose of this review. An open question for all mentioned diagnostic approaches is how many hours, days or weeks post-injury should mTBIs be examined that pPTS can be predicted best. Cortical changes across the human lifespan have

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rarely been taken into consideration when interpreting imaging results of mTBI studies, though it is known that the brain in healthy adults changes during lifespan. All diagnostic

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measures based on MRI have weaknesses in availability, capacity and costs. Diagnostic measures based on MRI vary greatly on MRI characteristics, such as spatial resolution, magnetic field strength, sequence parameters, and image post-processing. This has to be taken into account when comparing and interpreting study results.

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Discussion

Susceptibility-weighted imaging (SWI) The detection of traumatic cerebral microbleeds seems to be predictive of the prognosis after mTBI. The strength of SWI is that it can be analysed efficiently by a neuro-radiologist in clinical setting. Future studies should investigate if adult patients with a higher number of microbleeds measured with SWI are at risk for specific neuropsychological impairments, as 13

could be shown in a study with paediatric patients when the number of microbleeds exceeded 7 or more regions (65). It should, moreover, be investigated if the size of microbleeds is predictive of pPTS. However, microbleeds can also be found in cerebrovascular disease,

to the traumatic incidence but to pre-existing diseases.

Obviously, DTI is a very promising tool to quantify mTBI in the acute, subacute, and chronic

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phase. The time difference between (m)TBI and DTI scanning is an important factor in the interpretation of DTI results (51). In some studies mTBI patients with a very wide range of

different times post-injury ranging from some months to several years are examined with DTI and compared with each other in one group (32, 36, 54). We believe that this leads to biased data as the DTI values change over time, as can be seen in studies which compared several time-points (25, 40, 50, 53). More knowledge is needed on the best time window to scan

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mTBI patients with DTI to predict pPTS. A major limitation of past DTI-studies on mTBI is their small sample sizes (32, 42, 43, 50, 53). This leads to limited statistical power of the

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statistical analysis of DTI and cognitive data. For example for voxel-based morphometric analysis, the statistical power is largely influenced by the sample size (50). In ROI analysis of DTI data the small sample sizes prevent from investigating regional differences in focus regions. In the study of Wu et al. the small sample size of 12 mTBI patients did not permit an

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Diffusion Tensor Imaging (DTI)

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dementia, and in normal ageing, therefore their occurrence in mTBI patients might not be due

investigation of regional differences within the cingulum bundles (43).

The methods of analysis of DTI data varies between studies and their comparability should be further studied. There is no agreement as to which analysis method is the best for mTBI patients in clinical and research setting. The regional approach to discriminate controls and mTBI is thought to be the better method than the whole-brain white matter approach and 14

might be a better predictor of cognitive outcome according to Benson et al. (49). So far, ROIanalysis is used most often in mTBI-studies and it is said to be appropriate for individual analysis (54). A limitation of it is that it only samples a pre-defined, restricted number of

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regions, ignoring the diffusivity of axonal damage and the placement of ROI is dependant on the analyst. Another approach is the voxel-based analysis, which is independent from the analyst, fast, and suited for group analysis, whilst its suitability for individual analysis has yet

normalization and co-registration processes (54). A voxel-wise approach reduces potential

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biases by standardizing the analysis and improves sensitivity by minimizing partial volume

effects (32). Kinnunen et al. were the first to evaluate the relationship between white matter damage measured with tract-based spatial statistics (TBSS), a new voxel-based technique, and cognitive impairment following TBI (46). Toth et al. also used TBSS in their recent study and

concluded that the semi-automated method is suitable for clinical practice (28). Equally using a TBSS approach, Zhu et al. observed a loss of structural integrity in multiple brain domains

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in acute symptomatic mTBI patients, who presented decreased FA values in widespread regions specially located in frontal lobe, limbic system, and sublobar areas compared with a

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healthy control group (48). So far analysis of DTI data is quite time consuming and therefore difficult to handle in the clinical setting. Automated analysis would reduce time and costs and therefore would make it more valuable in clinical setting.

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to be evaluated and there are concerns about errors that may occur from the requires spatial

Normative data with which DTI data of single mTBI patients can be compared, respectively, criteria which allow to decide if the DTI data of a patient predicts a negative outcome in terms of pPTS, are needed for clinical use. An example of the use of a criterion in DTI data is that of Kraus et al., who defined reduced anisotropy as 1 SD below the mean FA of control subjects (31). Another criterion to define DAI was set by Niogi et al. (54). They defined DAI as FA values 2.5 SD below the region average, based on a control group with healthy adults. 15

The exact mechanisms that cause changes in DTI measures such as FA are still not fully understood. Authors who have looked into which specific brain regions are affected in mTBI

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stated future studies should examine additional brain regions and determine whether there are brain regions more susceptible to the injury (42). More results from comparisons between DTI and neuropsychological findings respectively work status would be beneficial for clinical

should be collected and considered as part of an unfavourable long-term outcome. Adequate

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assessment methods of daily life functioning should be defined (e.g. health questionnaires).

The relations between structural lesions in MRI / DTI and long-term outcome in mTBI patients are still controversially discussed. Longitudinal studies with larger sample sizes with objective and sufficient sampling of white matter regions are needed to better understand the relationship between brain tissue damage as measured by DTI and neuropsychological

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dysfunction, respectively pPTS, in patients with mTBI and to allow better assessment of the time course of DTI changes in mTBI. Such studies should ascertain whether DTI can serve as

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a predictive measure for an unfavourable long-term cognitive outcome after mTBI and as such can triage patients with pathological DTI imaging into rehabilitation measures.

Magnetic Resonance Spectroscopy (MRS)

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treatment. In general we believe that data on impairments in daily life functioning after mTBI

Cr levels in mTBI patients were predictive of executive function and emotional distress in the study of Gasparovic et al. (26). Their study provides preliminary evidence for the sensitivity of MRS to detect subtle disruptions in neurometabolism following mTBI and shows correlations with pPTS. Similarly, Kirov et al. found that PCS-positive patients (patients indicating at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficit or blurred vision) had lower white matter NAA than the 16

controls (n=12; 7.0±0.6 versus 7.9±0.5mM; p=0.0007) (56). Global white matter NAA, therefore, showed sensitivity to the TBI sequelae associated with PCS in patients with mostly normal neuroimaging as well as GCS scores. Moreover, mTBI patients who did not report

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PCS were indistinguishable from controls in all markers in both tissue types (56). The same study group previously reported in a group of 20 mTBI patients and 17 age and gender matched healthy controls mTBI-induced thalamic metabolite concentration changes under

concentrations in the controls (66). The authors concluded, therefore, that MRS could serve as

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an objective laboratory indicator for differentiating “mild” from more severe categories of

TBIs regardless of the presence or absence of clinical symptoms. Further studies are needed to evaluate MRS as predictive factor of persistent posttraumatic symptoms or cognitive outcome.

Functional magnetic resonance imaging (fMRI)

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Resting-state fMRI allows an indirect evaluation of the intrinsic neuronal activity trough its metabolic and hemodynamic sequelaes providing critical insights into the pathophysiology of

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brain function (63). Messé et al. demonstrated PCS-specific alterations in the topological connectivity pattern following mTBI and their evolution over time (63). Other authors, however, found no significant fMRI differences after multiple sports-related concussions (67).

These authors explained the lack of long-term fMRI differences with the relative plasticity of

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±13.0% for NAA, ±13.5% for Cr and ±18.8% for Cho relative to their corresponding

younger adults’ cognitive abilities following mTBI.

Conclusions From the evaluated diagnostic approaches to predict pPTS after mild traumatic brain injury, DTI, SWI, MRS and fMRI (resting-state condition) seem to have adequate sensitivity and specificity as predictive diagnostic tools according to the current literature. However, the 17

number of studies to evaluate MRS and fMRI as diagnostic measures to predict pPTS is yet very small. Large longitudinal clinical trials are requested to validate the prognostic applicability and practicability in daily clinical practice. Future studies could compare

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different imaging modalities such as DTI versus SWI versus MRS versus fMRI in the same patient sample to compare the advantages and predictive strength of the different modalities.

At present a lot of effort goes into evaluation of diagnostic measures in mTBI, we hope

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research about therapeutic measures for mTBI patients will soon grow too.

18

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and evolving resting-state network alterations in post-concussion syndrome following mild traumatic brain injury. PloS one. 2013;8(6):e65470. PubMed PMID: 23755237. Pubmed Central PMCID: 3675039.

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66. Kirov I, Fleysher L, Babb JS, Silver JM, Grossman RI, Gonen O. Characterizing 'mild' in traumatic brain injury with proton MR spectroscopy in the thalamus: Initial findings. Brain injury : [BI]. 2007 Oct;21(11):1147-54. PubMed PMID: 17882630.

fMRI differences after multiple sports-related concussions. Brain injury : [BI].

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2012;26(13-14):1684-96. PubMed PMID: 23163249.

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67. Terry DP, Faraco CC, Smith D, Diddams MJ, Puente AN, Miller LS. Lack of long-term

28

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Identificatio

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Screening

Records after duplicates removed (n = 104) )

Records screened (n =104)

Eligibility

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Full-text articles assessed for eligibility (n =43)

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Included


Additional records identified through other sources (n =3)

Records identified through database searching (n = 127)

Studies included in qualitative synthesis (n =25)

Fig 1 Flow diagram of literature search.

29

Records excluded (n =61) )

Full-text articles excluded, with reasons (n =18)

Persistent vertigo and dizziness after mild traumatic brain injury.

Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury.

Neuroimaging after mild traumatic brain injury: review and meta-analysis.

Association of symptoms following mild traumatic brain injury with posttraumatic stress disorder vs. postconcussion syndrome.

Do Children and Adolescents With Mild Traumatic Brain Injury and Persistent Symptoms Benefit From Treatment? A Systematic Review.

Occult retinal detachment after mild traumatic brain injury: case report and literature review.

Occupational needs and intervention strategies for military personnel with mild traumatic brain injury and persistent post-concussion symptoms: a review.

Symptoms of Persistent Behavior Problems in Children With Mild Traumatic Brain Injury.

Autonomic Dysfunction after Mild Traumatic Brain Injury.

Persistent Sleep Disturbances Independently Predict Poorer Functional and Social Outcomes 1 Year After Mild Traumatic Brain Injury.

Persistent problems 1 year after mild traumatic brain injury: a longitudinal population study in New Zealand.

Evaluation of White Matter Injury Patterns Underlying Neuropsychiatric Symptoms after Mild Traumatic Brain Injury.

Mild traumatic brain injury.

Mild traumatic brain injury.

Treating prolonged symptoms of mild traumatic brain injury: neuropharmacology.

Mild traumatic brain injury and ADHD: a systematic review of the literature and meta-analysis.

Neurobehavioral Outcomes of Mild Traumatic Brain Injury: A Mini Review.

Cervical Spine Involvement in Mild Traumatic Brain Injury: A Review.

Systematic review of return to work after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis.

Hippocampal Neurophysiologic Changes after Mild Traumatic Brain Injury and Potential Neuromodulation Treatment Approaches.

A preliminary study to identify locomotor-cognitive dual tasks that reveal persistent executive dysfunction after mild traumatic brain injury.

Nonsurgical interventions after mild traumatic brain injury: a systematic review. Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis.

Concussion: A Systematic Review.

Traumatic brain injury and posttraumatic stress disorder.