MRI was first used to investigate patients with TBI in a 1986 study of 50 patients 16. The three main findings, which have since been confirmed, were as follows: MRI identified lesions more frequently than did computed tomography; brain lesions were common after TBI; and although patients who regained consciousness rapidly had no lesions in fundamental deep brain structures, some of them had severe cortical lesions. Several descriptions of MRI lesions in TBI patients have been reported since that initial study was published (Table 1) 1718192021, although few of them focused on the prognostic value of MRI 17181920. Conventional MRI findings that strongly predicted outcome included DAI, total lesion burden and DAI in the brainstem.

DAI is the most common primary lesion in TBI patients 2223 and may be the most common cause of poor outcome 222324. DAI may be ischaemic or haemorrhagic 78. Ischaemic DAI is seen as a hypersignal on DWI or FLAIR, with no abnormality on the T2* sequence 25. The hypersignal with DWI disappears within about 2 weeks. Conversely, haemorrhagic DAI appears as a hyposignal on the T2* sequence, with normal DWI findings. It has been proposed 22 that DAI location could be classified into the following stages: stage 1, frontal and temporal white matter; stage 2, lobar white matter and posterior part of corpus callosum; and stage 3, dorsolateral midbrain and pons. With outcomes defined as Glasgow Outcome Scale 26 scores of 2 to 3 versus 4 to 5, none of the 33 patients with good outcome in another study 27 had haemorrhagic DAI (Table 1). DAI appears to be a major determinant of poor outcomes, although its use as an outcome predictor in the individual patient remains difficult. Whether the correlation between DAI and outcome is due to the total lesion burden or to DAI location remains debated.

In several prospective studies, lesion burden was associated with outcome irrespective of DAI location (Table 1) 171928. Among 40 prospectively enrolled patients with severe TBI, lesions by FLAIR and T2*-weighted sequences increased progressively with GOS score groups 1 to 2, 3, and 4 to 5 17. Similar results were obtained in a study comparing 42 patients with persistent vegetative state with 38 patients who recovered consciousness 19.

A number of studies have focused on the value of DAI location in predicting outcome 19293031. Brainstem lesions in the pons and mesencephalon appear to be the most potent markers of poor prognosis, most notably when they are bilateral and symmetrical 18192931. In a prospective study conducted in 61 patients (Table 1) who were studied within 7 days of TBI 18, all patients with bilateral pontine lesions died as compared with 9% of patients with no brainstem lesions. These results were confirmed by the same group in a prospective study of 102 comatose patients 29 using the following four-stage grading system: grade I, lesions of the hemispheres only; grade II, unilateral lesions of the brainstem at any level with or without supratentorial lesions; grade III, bilateral lesions of the mesencephalon with or without supratentorial lesions; and grade IV, bilateral lesions of the pons with or without any of the lesions of lesser grades. Mortality increased gradually from 14% with grade I lesions to 100% with grade IV lesions. These findings were corroborated by two independent studies 1931 (Table 1). We recently confirmed the prognostic value of brainstem lesions in the upper pons and lower midbrain in a study of 73 patients 32. Bilateral pontine lesions carry a high mortality rate and predict poor neurological outcomes.

Three studies showed that corpus callosum lesions were associated with poor outcomes 193031 (Table 1). However, these lesions may merely represent markers for severe initial injury. In addition to lesion burden, both total lesion volume and frontal lobe lesion volume on FLAIR images correlated significantly with clinical outcomes 30. Nevertheless, evaluating DAI lesion volume is difficult (most notably when the lesions are small), time consuming, cumbersome and subject to inter-rater variability.

The presence of severe DAI and a heavy lesion burden are associated with permanent neurological impairment. However, these factors are difficult to use in the individual patient, especially to distinguish GOS score 2 from GOS score 3. In TBI patients, brainstem lesions are easily identified by MRI. In our experience, they are associated with poor outcomes, most notably when they are posterior and bilateral. Posterior brainstem lesions in the periaqueductal grey matter are probably more relevant than anterior brainstem lesions as predictors of poor outcomes in patients with brainstem stroke 21 or TBI 19. In clinical practice, treatment limitation may deserve consideration in patients who have large bilateral lesions in the posterior part of the pons after TBI.

Several MRS studies have been conducted in TBI patients (Table 2). Some of them were purely descriptive 33, others assessed only the neuropsychological outcomes 3435, and yet others focused on global outcome as evaluated using the GOS or Disability Rating Scale 1736373839404142.

Compared with control individuals, TBI patients exhibited decreased NAA levels, decreased NAA/creatine ratios and increased choline levels (Table 2) in all brain regions evaluated 35363738394142. Increased lactate levels were seldom found in TBI patients, contrary to patients with other brain injuries 38. The NAA/creatine ratio appeared to be the best outcome predictor. Low NAA/creatine values correlated with poor outcomes when they were located in the frontal 3739, frontoparietal 43, or occipitoparietal lobes 3640; the splenium of the corpus callosum 41; the thalami 42; the pons 17; or a voxel including the corpus callosum, the white matter, and part of the hemispheric cortex 38.

These studies are heterogeneous (Table 2) in terms of patient selection, time from TBI to MRS, voxel location, method of outcome assessment and timing of outcome assessment. For instance, among studies of patients with TBI, one included only patients in a vegetative state 42, another included patients with severe TBI 17 and a third excluded patients with early initial coma 36. These differences in patient selection may be associated with differences in severity of brain oedema and in associated hypoxia and herniation, thereby introducing bias into the interpretation of the results. MRS findings vary greatly according to time since TBI. Four phases may be distinguished: an acute phase, which lasts 24 hours after TBI; an early subacute phase, which spans from the days 1 to 13; a late subacute phase, from days 14 to 20; and a chronic phase, which starts on day 21. Only two studies included patients at the acute phase 3840, and only one of these included all patients before 72 hours 38. Two studies were conducted from the early subacute phase to the first month 1737 and one began inclusion in the late subacute phase but included patients up to 11 months after TBI 43. Four studies focused on the chronic phase; in two of these studies, patients were included 3 weeks to 6 months after TBI 3639 and in the other two studies they were included 2 months to 8 months after TBI 3942.

Although NAA/creatine ratios were similar across studies, the results should be interpreted with caution because experimental in vitro and in vivo data suggest differences in the underlying pathophysiological mechanisms and in the time course of the lesions 444546. To interpret these results reliably, information on NAA values over time are needed. Experiments conducted in vitro 44 and in vivo 4546 show an early NAA decrease starting within a few minutes after TBI and reaching the trough value within 48 hours. This finding explains why spectroscopic disturbances may require 48 hours for visualization 47. NAA levels remain stable within the first month after TBI, supporting the validity of MRS assessment during the second or third week 4849. Later on, between 6 weeks and 1 year after TBI, NAA levels may decrease 937. Partial recovery of NAA levels has been suggested and may indicate recovery of mitochondrial function 41.

Another important factor that varied across studies was MRS voxel location (Table 2). Voxels were located in the hemisphere (the occipitoparietal, frontoparietal, or frontal lobes), corpus callosum, thalamus, or brainstem (the pons). Because whole brain analysis is time consuming, voxels are typically restricted to the areas most affected by DAI, namely the lobar white matter, corpus callosum and upper brainstem 50. Estimation of NAA in the whole brain may improve the prognostic value of MRS 41. A good compromise may be a voxel encompassing the corpus callosum, white matter and part of the hemispheric cortex 38.

Studies also differed in their definitions of poor and good GOS outcome groups: comparisons involved GOS score 1 to 2 versus GOS score 3 to 5 39, GOS score 1 to 4 versus GOS score 5 41, or GOS score 1 to 2 versus GOS score 4 to 5 17. Finally, the time from TBI to outcome assessment varied from 3 to 18 months (Table 2), further complicating comparisons because neurological status may improve for up to 1 year after TBI.

Although MRS has superseded conventional MRI, the combination of these two techniques may be useful 17. Variations in the NAA/creatine ratio over time have not been studied in a large TBI patient population. The above-mentioned variability in NAA levels constitutes the main limitation of this technique. To overcome this limitation, repeated studies at intervals of 1 to 2 weeks are probably needed. In our experience, variations in the NAA/creatine ratio are minimal in many patients. We agree with Sinson and coworkers 41 that whole brain NAA estimation might improve the prognostic value of MRS. Absence of dysfunction by MRS is a valuable finding; in a patient with normal results by both conventional MRI and MRS, a poor outcome is unlikely. However, we have seen a few patients with normal conventional MRI and MRS findings who had poor outcomes, probably related to white matter damage detected as DTI abnormalities.

Initial reports of DTI in TBI patients suggest that this technique may demonstrate alterations in white matter connections that are missed by conventional MRI 51. DTI provides information on the physiological status of fibre bundles, thus complementing the metabolic and biochemical information supplied by MRS. At present, little is known about the prognostic value of DTI in patients with TBI. DTI findings correlated with clinical status in patients with multiple sclerosis or neurodegenerative disease 5253. In a mouse model of TBI, DTI parameters were significantly reduced in the injured brain, whereas conventional MRI showed no significant changes 54. Furthermore, changes in relative anisotropy correlated significantly with the density of stained axons on histological sections.

In a study comparing 20 TBI patients and 15 healthy control individuals, fractional anisotropy was reduced in the internal capsule and splenium of the corpus callosum and correlated with Glasgow Coma Scale score and Rankin score at discharge in the TBI patients 55. Similar findings have been reported in children 56. Anecdotal case reports of DTI abnormalities in TBI patients have been reported 5758. In two patients who recovered partially after 6 years and 19 years, respectively, in a minimally conscious state, DTI disclosed increased anisotropy within the midline cerebellar white matter over an 18-month period 59. This anisotropy increase correlated with an increase in resting metabolism, measured using positron emission tomography, which suggests that axonal regrowth might underlie increases in anisotropy. Larger studies of DTI variations over time are needed. In our institution, comatose patients have been included in a prospective DTI study for the past 3 years. Patients with major connectivity abnormalities in both hemispheres and the brainstem were at increased risk for poor outcomes. A large multicentre prospective study is ongoing in France to assess the usefulness of combining DTI with MRS.

Magnetization transfer imaging is sensitive for detecting white matter lesions in patients with multiple sclerosis, progressive multifocal leukoencephalopathy, or wallerian degeneration 1112. Preliminary results in TBI are promising 6061. The magnetization transfer ratio was decreased in TBI patients 6061. Out of 28 TBI patients, eight had abnormal magnetization transfer ratios, and all eight had persistent neurological deficits 62. In another study, however, no correlation was found between GOS score and abnormal magnetization transfer ratio 41.