Diffuse Axonal Injury

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104.1 Clinical Features

and Laboratory Findings

Head trauma, especially in motor vehicle accidents, can lead to a wide spectrum of cerebral and intracra- nial lesions, with usually different clinical presenta- tions (epidural and subdural hematomas, subarach- noid and intracerebral hemorrhages, cerebral contu- sions, generalized cerebral edema, and secondary phenomena, such as hydrocephalus, raised intracra- nial pressure, and tentorial herniation), and different findings on CT and MRI.

About 50% of patients with traumatic accelera- tion–deceleration injuries are diagnosed with diffuse axonal injury (DAI), also called shearing injury. Clin- ically, DAI is characterized by loss of consciousness following the accident, usually without a lucid inter- val, a very low score on the Glasgow Coma Scale, and discrepantly subtle abnormalities on CT scans. When lesions are seen on CT, they consist mainly of pe- techial hemorrhages at the cortico-subcortical junc- tion, in the body or splenium of the corpus callosum, and/or in the basal ganglia and brain stem.

Intracranial pressure measurements in patients with DAI are, at least in the beginning, normal, in con- trast to the case with most of the other brain injuries.

DAI may result in death. It is unclear how often death occurs in DAI, but one may assume that it oc- curs in a high percentage of the patients. When it comes to a correct estimation of the frequency of death, the problem is that numbers provided by dif- ferent specialists – neurologists, traumatologists, and neuropathologists – are not consistent. In some re- ports (by neurologists) it is stated that DAI rarely re- sults in death, whereas others (neuropathologists) claim that DAI is an important cause of death in accel- eration–deceleration trauma. This difference is at least partly due to the different populations they en- counter.About 90% of patients with a clinical diagno- sis of DAI, however, will remain in a vegetative condi- tion.

In the first episode patients with DAI stay in the in- tensive care unit, in many cases artificially ventilated.

During this period it would be important for the management of these patients to have a reliable pre- diction of outcome, most importantly to maintain the option to discontinue treatment that will not further improve the condition of the patient. Clinical and neurophysiological data are important in that re-

spect. EEG will reflect the seriousness of the function- al disturbance of the brain, and will provide impor- tant information. MRI, in particular with more recent MR techniques, such as diffusion-weighted imaging, perfusion imaging, and MRS, may be helpful in pre- dicting outcome.

104.2 Pathology

Pathological findings depend heavily on the time be- tween the initial accident and the postmortem analy- sis. Because of the many secondary reactions that occur after the initial trauma, histological findings may be different in different stages. Unfortunately, very often the time between the accident and death is not reported.

In general, macroscopic findings may be normal or reveal focal atrophy, either cortical or in the rostral part of the brain stem. In early cases brain edema may be severe and tentorial herniation may be present.

Microscopic examination may demonstrate that axons are torn completely, but more often the damage is incomplete. Focal alterations in the axoplasmic membrane may result in impairment of the axoplas- mic transport. Swelling ensues and the axon is dis- sected. Early damage to the axons is shown by the presence of large numbers of eosinophilic and argy- rophilic bulbs on nerve fibers, forming the so-called retraction balls, the pathological hallmark of shear- ing injury. Macroscopically, lesions in DAI are usually ovoid or elliptical, following the long axis of the injured axons. Their distribution is not uniform or symmetrical, but they occur particularly at the junc- tion of gray and white matter, in the corpus callosum, septum, fornix, internal capsule, deep gray matter, tegmentum, and cerebellar foliae dorsal to the dentate nuclei. The lesions are often hemorrhagic; the hemor- rhages occur in a linear pattern, following the distor- tion of layers. In later stages, atrophy dominates the picture. Of the basal ganglia, the lateral and ventral nuclei of the thalamus are most atrophic, usually with sparing of the anterior and dorsomedial nuclei, the pulvinar, the centromedian nuclei, and lateral genicu- late bodies. Cholinergic neurons have been found to be more susceptible than neurons belonging to other categories of neurotransmitters. Immunocytochemi- cal staining for b-amyloid precursor protein (b-APP) detects with great sensitivity axons that have im-

Diffuse Axonal Injury

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paired fast axonal transport. In normally functioning axons b-APP is transported with fast axonal trans- port and never builds up to a concentration that al- lows its detection in tissue samples. When this fast axonal transport system is damaged, b-APP rapidly accumulates in the disrupted segment. This accumu- lation occurs before morphological methods detect the axonal damage. It is not known whether axonal damage thus detected is potentially reversible. The b-APP staining technique has demonstrated that even in apparently minor head trauma damage may occur to axons. In animal experiments there is a good correlation between the amount of axonal damage and the clinical outcome.

104.3 Pathogenetic Considerations

DAI is a shearing injury. It has been found experi- mentally that shearing injury is not induced by linear or translational forces but rather by rotational forces.

A sudden acceleration–deceleration impact can pro- duce rotational forces. Where the lesions occur de- pends on the distance to the rotational center, the arc of rotation, and the duration and intensity of the force. Because of the relative fixation of certain parts of the brain to the rigid skull, the deep and superficial portions may not move at the same rate and can even move in different directions. This will result in shear strain that manifests across the axons and results in axonal injury and rupture. Different brain parts have different consistencies depending on cell composi- tion and cell density. Injuries to the brain will be most prominent at their junction, where differences in tis- sue densities are greatest. One such vulnerable site is the gray–white matter junction, involved in 60–70%

of patients with DAI. Other vulnerable sites are the corpus callosum, corticospinal tracts, basal ganglia, and the brain stem. The initial damage to the brain is followed by secondary reactions related to hemor- rhage, edema, changes in local perfusion, and trigger- ing of biochemical cascades. Swelling of the brain may lead to tentorial herniation; swelling of the brain stem may lead to hydrocephalus. Disruption of neu- ronal and axonal connections leads to wallerian de- generation and atrophy.

It is probably the extent of the lesions and the in- volvement of the rostral brain stem that leads to the vegetative state in many of the patients. It is thought that damage to the rostral part of the brain is the cause of a reduction in dopamine turnover. In the first few hours after the traumatic brain injury, cate- cholamines in the CSF are raised. Soon the cate- cholamine production is chronically decreased and the levels in the CSF drop. Plasma norepinephrine levels have been shown to correlate with the Glasgow Coma Score and may correlate with the outcome of

brain injury. Homovanillic acid, a breakdown product of the adrenergic neurotransmitter systems, is signif- icantly decreased soon after brain injury, and the level correlates with the depth of coma.

104.4 Therapy

Dopamine, one of the catecholamines, is an important neurotransmitter in the CNS. In DAI a reduction of dopamine turnover has been found. This observation has prompted the introduction of amantadine (Sym- metrel) therapy in DAI. Amantadine is a drug known from treatment of Parkinson disease. Amantadine causes release of dopamine from central neurons, facilitates dopamine release by nerve impulses, and delays the uptake of dopamine by neural cells. It may also have a profound N-methyl-

D

-aspartate receptor antagonist effect, which may contribute to the neuro- protective effects after injury, by decreasing gluta- mate concentrations and thus excitotoxicity. In a randomized crossover design study in DAI patients, there was a consistent trend toward more rapid func- tional improvement with amantadine treatment, regardless of when during the first three months after injury the amantadine treatment was started (Meythaler et al. 2002). From these findings it is also clear that medication that results in dopaminergic blockade is contraindicated in the early stage of recovery from DAI.

104.5 Magnetic Resonance Imaging

In emergency departments CT is usually the first imaging modality used in cases of head trauma. In most presentations of head trauma CT is capable of producing a correct diagnosis. CT has the advantage over MRI of more clearly showing skull fractures. In DAI there is usually a discrepancy between the depth of the coma as expressed in the Glasgow Coma Score and the lack of or subtle findings on CT (Fig. 104.1).

White matter abnormalities develop over time (Fig. 104.1).

MRI is the best imaging modality by which to con- firm the diagnosis and to classify the lesions, usually employing the grading scale of Gennarelli. This scale divides the findings into three groups: lesions with and without hemorrhage at the gray–white matter junction, especially in the temporal and frontal areas (type 1), combined with lesions in and around the corpus callosum (type 2), and with lesions in the basal ganglia and the rostral brain stem (type 3). The scale roughly correlates with outcome.

Conventional MRI with T

1

-weighted, T

2

-weighted, T

2*

-weighted, and FLAIR images is more sensitive in depicting tissue changes than is CT (Figs. 104.2–

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104.5). The role of T

2

*-weighted images in establish- ing the diagnosis is considerable. Even early on he- mosiderin deposits depict the linear nature and mul- tiplicity of lesions (Figs. 104.2 and 104.5). The role of MR is even more pronounced when newer tech-

niques, such as diffusion-weighted images with Trace and ADC maps, tensor diffusion imaging with frac- tional anisotropy and fiber tracking, perfusion imag- ing, and magnetization transfer ratio maps are added to the protocol. These techniques allow assessment of

Fig. 104.1. A 36-year-old man with severe head trauma. The first row of images, obtained on admission, shows evidence of white matter shearing in the frontal subcortical region, corpus callosum, basal ganglia, and thalami with presence of small hemorrhages. The second row of images, obtained 1 week later, shows the hemorrhages to be more pronounced.There is

a developing leukoencephalopathy in the frontal region. The third row shows the images obtained 6 weeks after the acci- dent. The hemorrhages have now disappeared. The frontal cortex seems intact, whereas the frontal white matter is hypo- dense, related to wallerian degeneration

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Fig. 104.2.

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the presence and extent of lesions at an early stage, of the loss of structural integrity, and of changes in brain perfusion.

Diffusion-weighted imaging, commonly using a combination of Trace diffusion-weighted images and

ADC maps, is extremely sensitive in depicting post- traumatic changes at a very early stage. Most of the lesions show a high signal on the Trace diffusion- weighted images. Many of these lesions show a lower than normal ADC value (Figs. 104.3 and 104.6). It re- mains to be seen whether, as suggested, lower ADC values correspond with poorer outcome.

It is too early to describe the potential role of diffu- sion tensor imaging in combination with fiber track- ing. One can imagine that fiber tracking may illus- trate the disrupted connections in the brain and pre- dict the loss of local functionality.

MRS has been repeatedly mentioned as capable of better predicting the functional outcome of brain in- juries. The MR parameter used in these studies is the N-acetylaspartate concentration. The N-acetylaspar- tate concentration is thought to reflect the quantity and integrity of axons and neurons in the voxel. Since axonal damage is a good predictor of outcome, there is obviously a role for MRS. The drawback here is that

Fig. 104.3. A 14-year-old girl was the victim of a traffic acci- dent. The FLAIR images on the left (first column) show some subdural blood in the left occipital region and a lesion in the left frontal lobe.There are lesions in the basal ganglia and thal- ami. Diffusion-weighted Trace images (second column) show

the lesions with greater conspicuity, especially those in the basal ganglia, thalami, and the medial parts of the occipital lobes. ADC values (third column) are low (<40–50 % of normal values) in the affected areas

Fig. 104.2. A 43-year-old female, hit by a car, remained co- matose with low Glasgow Coma Scale values. The FLAIR im- ages (first and second rows) show small lesions at the cortico- subcortical junction in both frontal lobes, a small hemorrhagic lesion in the posterior corpus callosum, contusions in the right frontal operculum and the left putamen, blood around the parieto-occipital lobes on the right,a contusion in the right temporal lobe, and bilateral lesions in the midbrain, pons, and left superior cerebellar peduncle. Gradient echo images (third and fourth rows) show hemosiderin deposits in some of the le- sions, especially in the cortico-subcortical lesions in the frontal lobes

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in most studies MRS is postponed until the patient is in a stable condition, which means a considerable time interval between the accident and the per- formance of MRS, varying between 3 and 35 days.

The most important patient management decisions should ideally be made in the first 2 weeks, when pa- tients are still in the intensive care unit and ventilator- dependent.

Fig. 104.4. Series of transverse proton density images of a 32-year-old man who was involved in a frontal collision show lesions at the cortico-subcortical junction, in the truncus and splenium of the corpus callosum, basal ganglia, thalamus, pos-

terior limb of the internal capsule, and in the rostral brain stem.

All three types of the Gennarelli scale are present in this patient (see also Fig. 104.7)

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Fig. 104.5. Gradient-echo (FLASH) images of the same patient as in Fig. 104.4 show the hemorrhagic component in each of the lesions. Blood has also leaked into the ventricles

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Fig. 104.6.

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Fig. 104.6. Diffusion-weighted Trace images of the same pa- tient as in Figs. 104.4 and 104.5 (first and second rows, b = 1000) show high signal intensity in nearly all lesions. ADC maps (third and fourth rows) show very low values (as low as 0.53 ¥ 10^–3mm²/s, normal 0.85–0.95 ¥ 10^-3mm²/s) in some of the lesions

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Fig. 104.7. The three types according to Gennarelli are all pre- sent in this patient and shown in this figure.The images on the left (first column) show the cortical lesions. The middle images

(second column) reveal the corpus callosum lesions. The im- ages on the right (third column) demonstrate the brain stem lesions