Handbook of Clinical Neurology, Vol. 127 (3rd series) Traumatic Brain Injury, Part I J. Grafman and A.M. Salazar, Editors © 2015 Elsevier B.V. All rights reserved

Chapter 19

Resting functional imaging tools (MRS, SPECT, PET and PCT) J. VAN DER NAALT* Department of Neurology, University Medical Center Groningen, University of Groningen, The Netherlands

MAGNETIC RESONANCE SPECTROSCOPY Magnetic resonance spectroscopy (MRS) provides a noninvasive technique to assess neuronal injury and inflammation following traumatic brain injury (TBI) with various metabolites such as N-acetylaspartate, choline, and lactate. Of particular importance is N-acetylaspartate (NAA), synthesized in mitochondria, that is considered as a marker of neuronal loss. A reduction in NAA is caused by a failure in mitochondrial energy production. Choline (Cho) is a marker for membrane synthesis or repair. An increase of choline is related to membrane degradation following cellular damage or inflammation. Creatinine (Cr) is a marker for intact brain energy metabolism. Lactate (Lac) accumulates as result of anaerobic glycolysis and in the setting of TBI, may be a response to the release of glutamate (Glu), an excitatory amino acid released after injury (Marino et al., 2011). Results of most studies are represented by the ratio of creatinine (Cr), used as an internal standard. Table 19.1 gives an overview of the most common molecules.

Technique MRS provides a noninvasive measure of various metabolites that can also easily be applied in children. Abnormal metabolites are represented in a spectrum with peaks whose positions and intensities reflect the structure of the molecule. The interpretation, however, is hindered by reliance upon (peak) ratios in various brain regions and nonquantitative results. Furthermore, MRS has a poor resolution with only partial brain coverage, and its use is limited in the acute phase of TBI.

Mild traumatic brain injury MRS detects abnormalities in otherwise normalappearing tissue in mild TBI. In the subacute phase after injury an early reduction of the NAA and an increase of the choline component is demonstrated, which correlates with injury severity (Garnett et al., 2000b; Sinson et al., 2001). The NAA ratio is low in areas of pericontusional edema. Moreover, the lactate ratios were high in these areas, suggestive of ischemic damage (Son et al., 2000). Decreased ratios are apparent within 1 week after injury in normal-appearing white matter near cortical contusions, with normalization at 1 month after injury (Nakabayashi et al., 2007). In clinically asymptomatic athletes decreased ratios were found in the genu of the corpus callosum (Johnson et al., 2012). Decreased NAA in the prefrontal cortex correlated with postconcussive symptoms (Henry et al., 2010). Similarly, in a prospective study of concussed athletes the most significant alterations of metabolites occurred at the third day after injury, with complete recovery within 4 weeks postinjury. Notably, these patients were asymptomatic within 2 weeks after injury, underlining the sensitivity of MRS in accurately measuring metabolic changes beyond clinical presentation of patients (Vagnozzi et al., 2010). The association of spectroscopic imaging with injury severity and outcome is weak despite widespread metabolic changes in normal appearing MRI (Govindaraju et al., 2004). On the other hand, in patients with good recovery as measured with the Glasgow Outcome Scale, high NAA ratios were found (Sinson et al., 2001). MRS studies show furthermore an inconsistent relation of abnormal NAA ratios and neuropsychological outcome. Primary findings include decrease of glutamate and NAA, particularly in the frontal lobes (Govind et al., 2010). Another group reported decrease of glutamate

*Correspondence to: J. van der Naalt, MD, PhD, Department of Neurology, University Medical Center Groningen, University of Groningen, The Netherlands. E-mail: [email protected]

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Table 19.1 Most common molecules in magnetic resonance spectroscopy Molecule

Role, location

Significance in TBI Reduced NAA in acute phase up to 2 weeks after traumatic brain injury Marker for neuronal and axonal damage Increased Cho is related to membrane degradation In TBI related to diffuse axonal injury

N-acetylaspartate

NAA

Involved in energy metabolism Synthesized in mitochondria

Choline

Cho

Creatinine

Cr

Membrane synthesis or repair Synthesized in phospholipid layer of cell membranes Cellular energy metabolism

Lactate

Lac

Glutamate Glutamine

Glu Glx

Involved in anaerobic metabolism End product of glycolysi Excitatory amino acid in neurons (Glu) or glial cells (Gln)

Used as internal reference for measurement of other peaks in TBI Increased in hypoxic-ischemic injury Increased in hypoxic-ischemic injury

TBI, traumatic brain injury.

without a concomitant reduction of NAA that was not related to neuropsychological performance. This inconsistent finding is probably related to group samples with varying severity and the measurement of absolute values instead of ratios (Yeo et al., 2011). MRS studies suggest evidence of diffuse injury contributing to the pathology of mild TBI. Decreased levels of NAA were found in the corpus callosum and thalamus in patients with varying severity of injury (Cecil et al., 1998; Kirov et al., 2007). Furthermore, decreased NAA levels were demonstrated in the white matter of patients with postconcussive complaints several days to months after injury (Kirov et al., 2013).

Severe traumatic brain injury In severe TBI several markers have been related to severity of injury and outcome (Ross et al., 1998; Friedman et al., 1999; Brooks et al., 2001; Shutter et al., 2004; Marino et al., 2007). Reduced NAA is apparent within the first 24 hours after injury and several studies have revealed decreased NAA up to 1 month after injury (Condon et al., 1998; Ross et al., 1998; Brooks et al., 2001) (Fig. 19.1). Regarding the predictive value of spectroscopy studies, NAA has been related to duration of post-traumatic amnesia and outcome (Garnett et al., 2000a, b; Marino et al., 2007). Decreased NAA in white matter has been demonstrated in patients with neuropsychological impairment. An increase occurred between 3 and 6 months in those patients with better outcomes (Brooks et al., 2001; Signoretti et al., 2008). In addition, Friedman also reported a relation between impaired neuropsychological testing and changes in

choline and NAA, underlining the concordance between neurometabolic levels and behavioral function. Diffuse axonal injury has been stated to be an important contributor to brain dysfunction after severe TBI (Friedman et al., 1999). In addition, the NAA/Cr ratio in the corpus callosum was noted as most useful for outcome prediction (Holshouser et al., 2006). NAA levels have been used to discriminate patients who recovered from coma from those who died or remained vegetative. Reduced NAA ratios within the thalamus and brainstem could differentiate patients who recovered awareness from those who remained in a vegetative state (Ricci et al., 1997; Uzan et al., 2003; Carpentier et al., 2006). Choline levels are less frequently used for outcome prediction due to more variable results (Brooks et al., 2001; Shutter et al., 2004; Marino et al., 2007). Early MRS within 24 hours after injury can detect increased lactate with a variable time course of clearance (Condon et al., 1998). Elevated choline and glutamate determined within the first week after injury predicted long-term outcome (Marino et al., 2007) with high accuracy (97%) in combination with the GCS (Shutter et al., 2004). Brooks and colleagues demonstrated an elevated choline in the gray matter of patients with poor cognitive outcome at 3 months after injury compared to patients with favorable outcome. Increased lactate in the first hours postinjury was also related to outcome and severity of injury (Marino et al., 2007). This close relationship between clinical scores and brain parenchymal levels of lactate had not been reported before in MRS studies, probably because of the tendency to perform MRS studies in the subacute and chronic phase.

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Fig. 19.1. MRS imaging. MRS and conventional MRI showing the volume of interest for a normal control (left panel) and two TBI patients (central and right panel). Spectra show decreases of N-acetylaspartate (NAA) and increases of choline (Cho) and lactate (La) in patients with TBI compared to the normal control. Metabolic abnormalities are evident in normal-appearing brain of the patient in the central panel (a and b). (Reproduced from Marino et al., 2007, with permission from BMJ Group.)

Summary In general, widespread injury after TBI is consistent with decrease in NAA/Cr ratio and increase of Cho/Cr ratios. MRS studies can be easily done in children and are equally performed in all categories of severity of injury. Because NAA is a metabolite with activity both in neurons and axons, NAA decrease within the gray matter is associated with neuronal injury and NAA decrease within the white matter is related to axonal injury. Only a few studies with early MRS in severe TBI have found a relation with outcome. However, MRS studies can not be used to predict to outcome in individual patients as in most studies only group comparison is done. Most MRS studies contain small patient groups, with varying times after injury in the subacute and chronic phase after injury. The precise time of imaging after injury and anatomic localization has yet to be determined.

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY Single photon emission computed tomography (SPECT) is a nuclear medicine imaging technique. Several tracers are available, with technetium-labeled hexamethylpropyleneamine oxide (99Tc-HMPAO) being the most

commonly used tracer in TBI. This tracer passes through the blood–brain barrier and undergoes metabolism within the brain. The uptake within the brain remains constant for several hours and is proportional to the cerebral blood flow (CBF). Unlike PET, SPECT measures flow, but not regional metabolism, and acutely damaged brain areas appear as regions of decreased regional CBF (Fig. 19.2).

Technique SPECT is a relatively simple and inexpensive imaging modality that can be used to assess cerebral perfusion. In practice, relative perfusion maps are created by comparing data within a region of interest (ROI) to data obtained from a comparable ROI within normalappearing brain. Disadvantages of SPECT include the nonquantitative results and relatively low resolution of the images. The development of anatomic standardization with voxel-based analysis and statistical parametric mapping has increased sensitivity to abnormalities in TBI (Koenraad et al., 2002; Shin et al., 2006). This technique cannot be used in the acute or subacute TBI setting when patients are agitated and confused, since patients must be cooperative and able to remain still during the entire procedure.

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Fig. 19.2. SPECT imaging. Iomazenil SPECT images acquired in the acute stage after trauma (upper row) showing decreased uptake in the left frontal lobe and the temporal lobe (arrows). Delayed iomazenil SPECT acquired 2 months after trauma (lower row) shows marked recovery of uptake at the sites of reduced uptake although areas of decreased uptake persist. (Reproduced from Koizumi et al., 2010.)

Mild traumatic brain injury In general, HMPAO SPECT is more sensitive than CT in the detection of brain abnormalities, with a larger area of involvement seen on SPECT. Abnormal SPECT findings are found in 40–70% of patients with TBI, especially in the first 3 months after injury (Gray et al., 1992; Ichise et al., 1994; Jacobs et al., 1996; Kant et al., 1997; Abdel-Dayem et al., 1998; Hofman et al., 2001). Most patients show hypoperfusion, predominantly located in the frontal and temporal region. Abnormalities are not equally distributed, as one in three lesions on SPECT were not demonstrated with CT whereas one in four lesions on CT did not correspond with SPECT abnormalities (Roper et al., 1991). Furthermore, some types of cerebral contusions are associated with decreased CBF while others are not. As early as 12 hours after injury, Lorberboym et al. (2002) demonstrated decreased CBF among 75% of mild TBI patients, mostly in the frontal and temporal regions. In the subacute phase, i.e., within 10 days after injury, several studies have demonstrated SPECT abnormalities in patients with a normal CT (Nedd et al., 1993; Gowda et al., 2006). Imaging studies assessed within 3 months after injury also showed more lesions compared to late imaging with up to 68% abnormalities in patients with a normal CT scan (Abdel-Dayem et al., 1998). Also in the chronic phase several months after injury, hypoperfusion has been demonstrated in patients with a mixture of both normal and abnormal

CT/MRI scans (Gray et al., 1992; Ichise et al., 1994; Kant et al., 1997; Umile et al., 2002). Gray and colleagues reported in 80% of patients with mild TBI SPECT abnormalities compared to 55% CT abnormalities. Another study reported even a higher incidence with 50% SPECT abnormalities compared to 12% CT/MRI documented abnormalities (Kant et al., 1997). The severity of SPECT abnormalities correlates with injury-related variables such as post-traumatic amnesia and postconcussive symptoms (Kant et al., 1997; Lorberboym et al., 2002; Bonne et al., 2003; Gowda et al., 2006) although inconsistent findings with regard to neuropsychological tests results are found (Hofman et al., 2001; Lewine et al., 2007). Bonne and colleagues (2003) reported a relation between hypoperfusion in the frontotemporal regions and neuropsychological tests. On the other hand, 70% of memory problems were found to coincide with temporal lobe abnormalities whereas 30% of patients demonstrated discordant findings, i.e., temporal lobe abnormalities without memory problems (Umile et al., 2002). In a later study, postconcussive symptoms and memory deficits assessed by neuropsychological tests were related to SPECT in 40% of patients (Lewine et al., 2007). SPECT studies can detect abnormalities in asymptomatic patients. Recently, decreased perfusion in the prefrontal and temporal lobes was found in asymptomatic professional football players compared to healthy volunteers (Amen et al., 2011).

RESTING FUNCTIONAL IMAGING TOOLS (MRS, SPECT, PET AND PCT) Few SPECT studies have been related to outcome (Jacobs et al., 1996; Hofman et al., 2001). Jacobs and colleagues examined the predictive power of SPECT in a series of 136 mild TBI patients with normal admission CT scans at 1 year after injury. Outcome was determined by a neurologic examination, postconcussive symptoms and memory tests. The positive predictive power (i.e., probability of poor outcome in the presence of initial abnormal SPECT) was 64% at 3 months, increasing to 83% at 12 months. The negative predictive power (i.e., probability of good outcome with initial normal SPECT) was 89% at 3 months, increasing to 100% at 12 months. Caution was recommended in attributing abnormal SPECT findings to postconcussive symptoms although a negative initial SPECT is highly suggestive of good clinical outcome (Mitchener et al., 1997).

Severe traumatic brain injury In the subacute phase more abnormalities were demonstrated with SPECT than with CT in patients with varying severity of injury. One in three patients shows good recovery despite lesions on SPECT or MRI, indicating that not all lesions have functional impact (Newton et al., 1992; Mitchener et al., 1997). Regarding the predictive value of SPECT imaging, a correlation was found between Glasgow Outcome Scale and the number of lesions (Newton et al., 1992). The synthesis of information from MRI and SPECT imaging increased the accuracy of outcome assessment; unfavorable outcome was demonstrated in 75% of patients with abnormalities on both imaging techniques despite a normal CT (Prayer et al., 1993). However, the relation with neuropsychological testing is found to be inconsistent (Goldenberg et al., 1992; Kesler et al., 2000; Baulieu et al., 2001). Interestingly, one study established a relation between disinhibited behavior and frontal flow, suggesting the importance of lesion location in post-traumatic behavioral disorders (Oder et al., 1992).

Summary Most studies with SPECT concern patients with mild TBI. When conducted within the first week after injury, SPECT studies show hypoperfusion mainly in the frontotemporal regions. SPECT studies in the chronic phase after injury also reveal hypoperfusion but are mainly conducted in symptomatic patients. Studies relating SPECT imaging to patient outcome are scarce. An inconsistent relation with complaints and neuropsychological testing is reported. The predictive value of SPECT for outcome is moderate although a normal SPECT is usually related to good clinical recovery. However, although

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SPECT shows more abnormalities than CT/MRI it does not indicate that it is more sensitive, because its application is still limited by its poor resolution, radiation exposure and difficulty in obtaining quantitative data. For future application, development of new ligands or studying the activation patterns during psychological tests will increase our knowledge of specific regions in the brain that are related to outcome in TBI patients. For example, the increased uptake of a benzodiazepine receptor ligand in the prefrontal regions might be a promising technique to relate postconcussive symptoms to specific brain regions (Hashimoto and Masahiro, 2009; Hattori et al., 2009; Koizumi et al., 2010).

POSITRON EMISSION TOMOGRAPHY Positron emission tomography (PET) provides tomographic images of quantitative parameters describing various features of brain hemodynamics, including cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2). The most frequently used PET tracer is fluorine-18-labeled fluorodeoxyglucose (FDG) for the detection of regional glucose consumption. FDG-PET is the only established technique to evaluate cerebral glucose metabolism. Based on the principle that regional glucose metabolism reflects the neuronal activity of the region, then focal hypometabolism would indicate an area of neuronal dysfunction. FDG-PET is assessed during rest conditions or while performing neuropsychological tasks, sometimes in combination with CBF measurements with 15-oxygen (15O). This tracer is also used to measure CBF, CBV and CMRO2.

Technique Isotopes can be administered via the intravascular or inhalation route. PET quantitative data can be obtained with a better resolution than SPECT, but the application of this technique is limited by radiation exposure and scarce availability due to high costs. It is mainly used as a research tool in a nonemergency setting. The ROI (region of interest) method has been widely used in the analysis of PET studies. With this method, a region of interest is selected and compared with the contralateral hemisphere or ROIs from a healthy volunteer. Disadvantages of the ROI method concern the subjective assessment with relatively arbitrary placement and size of ROIs, resulting in low reproducibility of results. Statistical parametric mapping (SPM) software is increasingly used in PET studies to offer more objective quantitative voxel-by-voxel analysis.

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Mild traumatic brain injury Overall, in TBI patients with varying severities of injury PET studies have demonstrated cerebral dysfunction beyond the structural abnormalities assessed by CT and MRI (Ruff et al., 1994; Alavi and New berg, 1996; Alavi et al., 1997; Newberg and Alavi, 2003). Severity of brain injury as measured by the GCS is related to decreased brain metabolism (Bergsneider et al., 2000, 2001). This period of metabolic reduction can typically persist for several weeks regardless of injury severity. One in three anatomic lesions was associated with larger and more widespread metabolic abnormalities and as many as 42% of PET abnormalities were not associated with any lesions observed on anatomic images. Epidural and acute subdural hematomas cause extensive reduction in metabolism on both the involved, adjacent, and corresponding contralateral cortex (Fig. 19.3). Global and regional metabolic rates have been found to improve as patients recover from TBI (Alavi and Newberg, 1996). In the chronic phase after mild TBI, most PET studies determine the relation of PET abnormalities with neuropsychological performance and postconcussive symptoms. In patients with postconcussive complaints but with normal CT/MRI scans, the number of complaints was found to be related to the number of PET abnormalities, although both hypo- and hypermetabolism were seen (Gross et al., 1996). Hypometabolism was more present in the frontal areas of patients with neuropsychological deficits. Furthermore, a significant relationship between attention deficits and temporal lobe abnormalities was demonstrated (Ruff et al., 1994). Notably, in patients who did not show changes in resting state metabolism with FDG-PET, an increase of CBF (with H15O PET) was found in the frontal region suggesting functional changes related to changes in network

0

50 CBF (ml/100ml/min)

connectivity (Chen et al., 2003). Recently, PET-studies have been used to determine the effects of multiple head injuries. In a study of boxers, hypometabolism was demonstrated in the frontal lobes and posterior cingulate cortex (Provenzano et al., 2010).

Severe traumatic brain injury Most severe TBI studies have examined symptomatic patients in the chronic phase and demonstrated a relationship between reduced metabolism and outcome (Yamaki et al., 1996; Umile et al., 2002; Steiner et al., 2003; Wu et al., 2004). However, PET studies have failed to find conclusive evidence of cerebral ischemia (Diringer et al., 2002; Coles et al., 2004). When comparing PET results with microdialysis values obtained within 36 hours after injury, ischemia was detected only in 1–2% of patients, whereas metabolic crisis determined by increased lactate/pyruvate (L/P) ratio was found in 25% (Vespa et al., 2005). Others concluded that this increased L/P ratio reflects a general rise in metabolism rather than a shift towards nonoxidative metabolism (Hutchinson et al., 2009). Thresholds for tissue viability and ischemia have also been defined with PET studies (Cunningham et al., 2005). The CBF threshold for irreversible tissue damage is not comparable to those reported in stroke patients. This might be explained by the reduced cerebral oxygen metabolic rate in TBI (Tenjin et al., 1990; Diringer et al., 2002; Abate et al., 2008) which is found to be related to chronic brain atrophy (Xu et al., 2010). (The cellular and neuronal plasticity are further described in Ch. 42.) Thus, blood flow and metabolism vary in different regions of the brain, requiring different therapeutic approaches (Vespa, 2006; Coles et al., 2009). PET studies have also related regional cerebral metabolism to the level of consciousness in patients.

75

0 OEF (%)

0

200 0 CMRO2 (µmol/100ml/min)

80 CMRglc (µmol/100ml/min)

Fig. 19.3. PET imaging of ischemia with display of cerebral blood flow (CBF), oxygen extraction fraction (OEF), oxygen metabolism (CMRO2), and glucose metabolism (CMRglc). Images were obtained after evacuation of a subdural hematoma (SDH) (from left to right). CT scan shows a small amount of residual SDH with minimal midline shift. The cerebral hemisphere underlying the evacuated SDH displays a marked reduction in CBF, slight fall in CMRO2 and large increase in OEF suggestive of cerebral ischemia. The substantial increase in CMFglc implies a switch to nonoxidative metabolism of glucose to meet underlying metabolic need. (Reproduced from Abate et al., 2008, with permission from Springer Science and Business Media.)

RESTING FUNCTIONAL IMAGING TOOLS (MRS, SPECT, PET AND PCT) Diffuse axonal injury may decrease neuronal activity in several brain areas, leading to widely separated areas of hypofunction. In patients with minimal conscious state/vegetative state regional hypometabolism was increased compared to severe TBI patients (Nakayama et al., 2006). With FDG-PET regional hypometabolism was demonstrated in the frontal and temporal lobes and cingulate gyrus of patients with neuropsychological deficits. This hypometabolism was related to reduced network dysfunction due to diffuse axonal injury (Kato et al., 2007; Nakashima et al., 2007). It was suggested that this hypometabolism might be related to deafferentation of neurons instead of focal neuronal loss, as additional MRI imaging did not reveal focal structural damage. This was underlined with an SPM analysis in patients with cognitive deficits years after injury demonstrating cerebral hypometabolism in multiple brain regions irrespective of the presence of structural abnormalities (Zhang et al., 2010). Therefore cognitive deficits without structural injury might be related to selective neuronal dysfunction not visible with FDG-PET studies. With oxygen-15-labeled tracers (H2O15) changes in CBF are assessed when patients are performing neuropsychological tasks. During memory tasks patients showed increased CBF in the frontal regions, which might reflect the use of altered functional networks (Ricker et al., 2001; Levine et al., 2002).

Summary Most PET studies are done in patients with severe TBI, mainly in the research setting. Besides information regarding glucose metabolism and CBF, newly developed PET tracers can provide additional insights into neuronal integrity and inflammatory changes (Jansen et al., 1996; Shiga et al., 2006; Kawai et al., 2010; Folkersma et al., 2011; Ostberg et al., 2011). Reduced binding of the central benzodiazepine receptor ligand 11 C-flumazenil as a marker of neuronal integrity is associated with neuronal loss (Heiss et al., 2001). In chronic TBI, a concomitant loss of neuronal integrity has been demonstrated in some regions of hypometabolism (Shiga et al., 2006). In addition, focal neuronal damage was detected in a small patient series with neuropsychological impairment, although the distribution and extent were different in each patient (Kawai et al., 2010). Other tracers such as R-11C-PK11195, a selective ligand for microglial activation indicative of inflammation, and MP4A, reflecting cholinergic function, might be promising ligands for future application but have not been widely used to date (Folkersma et al., 2011; Ostberg et al., 2011).

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PERFUSION COMPUTED TOMOGRAPHY Perfusion CT (PCT) is a relatively new technique that is increasingly applied in traumatic brain injury in combination with noncontrast CT (Miles, 2006). This technique is more useful in mild TBI because of the presence of frontotemporal contusions, mainly in the basal regions. Data are obtained by monitoring the first pass of an iodinated intravenous contrast bolus. Parameters of cerebral hemodynamics can be calculated containing cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) within regions of interest.

Technique Advantages perfusion CT offers are the exposure time and 24 hour availability in most hospitals. A protocol allows acquisition of two 10 mm slices of data covering a region of interest within the brain. The use is limited by this partial brain coverage although data are obtained from those regions that are frequently involved in mild TBI, namely the frontotemporal regions at the base of the skull. Radiation exposure also limits frequent application and serial scanning in the same patient. With the advanced technical systems under development, the radiation exposure is within acceptable limits, comparable with standard CT.

Mild traumatic brain injury Decreased CBF in the frontal region in the acute phase, i.e., within 6 hours after injury, was related to unfavorable outcome determined 6 months after injury. The applicability appears to be limited to patients with a normal CT scan on admission and at least a GCS of 14 (Metting et al., 2009). In addition to the predictive value, PCT was related to patient variables such as post-traumatic amnesia (PTA). When performed in patients who were still in PTA, a decreased CBF was seen in specific cortical and subcortical regions compared to those patients who were not experiencing amnesia during scanning (Metting et al., 2010). In the absence of ischemic values on perfusion CT, it was postulated that these CBF changes reflect temporary dysfunction (related to neurotransmitter release) instead of structural abnormalities.

Severe traumatic brain injury Perfusion is more sensitive than conventional unenhanced CT in the detection of cerebral contusions, featured as areas with lowered CBF and CBV and increased MTT. These PCT parameters were found to be more congruent with findings of noncontrast CT scans at 1 week (Soustiel

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J. VAN DER NAALT et al., 2008). Furthermore, perfusion CT values of CBF were lower in the immediate vicinity of epidural or subdural hematomas (Wintermark et al., 2004a). Perfusion CT assessment showed a correlation between MTT and brain tissue oxygen measures suggesting a role for detection of brain regions at risk for tissue ischemia (Hemphill et al., 2005). PCT performed during the first 48 hours from trauma showed hypoperfusion in the ischemic range in 27% of patients (Bendinelli et al., 2013), which altered clinical management. With PCT, direct and quantitative assessment of cerebral vascular autoregulation is possible and could be used to monitor the effectiveness of therapy for increased intracranial pressure (Wintermark et al., 2004b, 2006). So far, Wintermark and colleagues have performed the only prognostic study in severe TBI, demonstrating that reduced CBF on admission was predictive of outcome (Wintermark et al., 2004a) (Fig. 19.4).

Summary PCT is a relatively new technique that is increasingly applied in traumatic brain injury. The few studies so far that have been done in TBI show promising results regarding the predictive value for this patient group. The application for individual prognosis is difficult due to limitations such as the partial coverage of the brain and the various parameters that can be assessed in different regions of the brain. Future studies also have to relate PCT parameters to neurocognitive performance.

FUNCTIONAL RESTING STATE IMAGING IN CHILDREN MRS studies are more commonly performed in children due to the noninvasive measure of various metabolites and the availability of this technique in almost every hospital. However, the usefulness of assessment tools in the acute stage of brain injury is limited by signal distortion by affected brain regions. SPECT and PET studies in children are uncommon due to the need for a radioactive ligand and for sedation at very young ages. The use of this technology is limited to adults or pediatric patients for whom the clinical benefits outweigh the risk Fig. 19.4. PCT imaging of a patient with severe TBI. Conventional contrast-enhanced CT demonstrated diffuse corticomedullary dedifferentiation with diffuse edema and mass effect on the basal cisterns. A left frontoparietal fracture was also present. Perfusion-CT demonstrated major hyperemia with high regional cerebral blood flow (CBF) and cerebral blood volume (CBV) in both Sylvian territories (stars). Oligemia was observed in both occipital areas and left frontal pole. This finding suggest that different patterns of abnormalities can coexist in the same patient. (Reproduced from Wintermark et al., 2004b.)

RESTING FUNCTIONAL IMAGING TOOLS (MRS, SPECT, PET AND PCT) involved. Perfusion CT has been applied in one study so far. The application of each of these aforementioned imaging techniques in children will be described. For the clinical considerations of traumatic brain injury in children the reader is referred to Chapter 15. Magnetic resonance spectroscopy studies in children consistently demonstrate a decrease in NAA ratio and an increase in choline ratio in the subacute phase after injury. Within 3 weeks after injury recovery of ratios was seen, in particular in the anterior region comprising the frontal lobe (Yeo et al., 2006). Choline ratios were elevated in the acute but not in the chronic period (Babikian et al., 2010). In the chronic phase a reduction of NAA in the frontal region was found which correlated with severity of injury as measured by the Glasgow Coma Scale (Walz et al., 2008). Several studies have been done to assess the predictive value of MRS in determining outcome of pediatric brain injury (Sutton et al., 1995; Ashwal et al., 2000; Holshouser et al., 2000; Makaroff et al., 2005). Reduced metabolites have been related to impaired neuropsychological test performance and poor outcome (severe disability, vegetative state or death) (Yeo et al., 2006). Increased lactate ratios were present within 1–3 days after injury and related to diffuse axonal injury (Sutton et al., 1995) and outcome at discharge (Makaroff et al., 2005). Almost 90% of children showed increased lactate in the poor outcome group with an accuracy for outcome prediction of 96%. In contrast, the clinical variables alone were able to accurately predict outcome in 86% of children (Ashwal et al., 2000). In another traumatic brain injury study, metabolites in the subacute phase were also predictive for outcome. In patients with various causes for brain injury the NAA and choline ratios from normal appearing brain and visibly injured brain were predictive of poor outcome at 6 months after injury in 85% and 67% respectively (Holshouser et al., 2005). In nonaccidental coma, mean total NAA/Cr ratios in combination with age, GCS, retinal hemorrhage, and lactate on MRS scan were found to predict outcome in 100% of cases (Aaen et al., 2010). Overall results of SPECT studies are comparable to those in adults, indicating that SPECT is a more sensitive method than CT or MRI. CT findings were found to be less well defined and not as discretely localized as SPECT findings in the subacute and chronic phase after TBI (Goshen et al., 1996; Emanuelson et al., 1997). Especially in the mild TBI group, the number of lesions outlined those indicated by CT. In addition, SPECT was also a better predictor of clinical outcome on discharge and at 5 year follow-up (Emanuelson et al., 1997). One study revealed a relation between medial temporal lobe injury and postconcussive syndrome with abnormalities in 93% of symptomatic patients compared to 13% in

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asymptomatic patients (Agrawal et al., 2005). In a study comprising children and adults, in the former, most commonly hypoperfusion in the temporal lobe was found; in adults compared to frontal lobe hypoperfusion in the adults (Gowda et al., 2006). Few PET studies and case reports are available of children because of the need for exposure to radioactivity and for sedation. Worley et al. (1995) examined the effectiveness of FDG-PET in predicting outcome in a small series of children with severe TBI. Regional cerebral metabolic rates for glucose were significantly correlated with clinical outcome only when the PET was acquired within 12 weeks postinjury. Furthermore, PET results were found not to be more accurate than CT or MRI results, although the appropriate MRI sequences for detection of diffuse axonal injury were not available at that time. Another PET study in mild TBI patients comprised four adolescents and showed hypoperfusion in those with complaints and impaired neuropsychological test results (Gross et al., 1996). Perfusion CT (PCT) is a relatively new technique that is increasingly applied in traumatic brain injury in combination with noncontrast CT. Radiation exposure limits frequent application and serial scanning in the same patient although with the development of more advanced technical systems, the radiation exposure is within acceptable limits, comparable with standard CT. One study described the assessment of cerebral perfusion in a series of children, 60% of whom had traumatic brain injury. In patients with cerebral contusion, PCT disclosed abnormalities four times more frequently than a normal noncontract CT (Wintermark et al., 2005).

COMPARISON OF CLINICAL APPLICABILITYOF SPECT, PET, AND MRS The field of neuroimaging is changing. For the clinical management of TBI, besides CT and MRI new standard imaging modalities have been introduced (Newberg and Alavi, 2003; Wintermark, 2005; Metting et al., 2007). These techniques provide us with information about the extent of injury, underlying physiologic changes and anatomy. Furthermore, these imaging modalities will provide us with more information about prognosis. Research tools are providing more information about the physiologic changes leading to secondary injury, which will hopefully lead to better treatment of this disabling condition. Each technique provides advantages and limitations for clinical applicability (Table 19.2). MRS is a sensitive noninvasive technique easily applicable in children, although the interpretation of abnormalities is hindered by the various ratios in different brain regions. SPECT images are sensitive to motion and require a longer imaging time than for MRI.

Table 19.2 Comparison of properties of imaging techniques

Technique

Duration

Radiation

Contrast

Brain coverage

Quantification

MRS SPECT PET PCT

20 min 30 min 20 min 10 min

+ + +

Radio-labelled tracer Isotopes Iodinated compound

Partial Whole Whole Partial

Restricted + +

*

Mainly cognitive outcome; GR, good recovery.

Emergency setting Restricted Restricted +

Costs

Predictive value for clinical outcome

Intermediate Intermediate High Low

Moderate (early MRS in severe TBI) Low* (normal SPECT predicts GR) Low* (in severe TBI) Moderate (group comparisons)

RESTING FUNCTIONAL IMAGING TOOLS (MRS, SPECT, PET AND PCT) Furthermore resolution of SPECT is lower than PET. Clinical applicability is best in mild TBI, as abnormalities are demonstrated in 40–70% of patients despite normal CT on admission. SPECT studies specifically measure the patient’s brain at rest. Unlike PET, most applications of SPECT imaging require comparisons between the injured region and an ROI in another location presumably free of injury. A negative initial SPECT study is a reliable predictor of favorable outcome. In general, SPECT studies are more frequently performed in mild TBI whereas PET studies are more commonly done in severe TBI. FDG-PET tends to provide more accurate functional information compared to SPECT because of the enhanced spatial resolution, but PET imaging is not widely available and is primarily a research tool. Some of the techniques have been used to predict the risk of worsening symptoms after multiple TBI. This “second impact syndrome” occurs in particular after sport injuries and most imaging studies concern fMRI and DTI studies. Sport-related TBI is separately described in Chapter 10. Further advances in the development of additional neuroimaging techniques which assess functional abnormalities may improve insights in the pathophysiology of traumatic brain injury, increase the sensitivity for detecting abnormalities, and hence allow the development of better prognostic indicators for outcome and therapeutic interventions.

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