Journal of the Neurological Sciences 263 (2007) 218 – 222 www.elsevier.com/locate/jns Low signal intensity and increased anisotropy on magnetic resonance imaging in the white matter lesion after head trauma: Unrecognized findings of diffuse axonal injury Tohru Okanishi a,⁎, Yoshiaki Saito a , Shinya Fujii b , Yoshihiro Maegaki a , Chisako Fukuda c , Yutaka Tomita c , Kousaku Ohno a a Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan b Division of Radiology, Faculty of Medicine, Tottori University, Japan c Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, Japan Received 19 February 2007; received in revised form 13 June 2007; accepted 20 June 2007 Available online 31 July 2007 Abstract We report on a four-year-old girl with head trauma caused by a motor vehicle accident. She presented with delirium, oculomotor palsy and ptosis in her left eye, left hemiparesis, and pyramidal signs in all extremities. Computed tomography on the day of admission showed diffuse cerebral edema with right-sided predominance. Magnetic resonance images on day 3 of admission showed lesions of diffuse axonal injury and contusion in the corpus callosum and right occipital and bilateral temporal lobes. There was a low-intensity lesion in the white matter of the right hemisphere on T2-weighted images, fluid-attenuated inversion recovery, T2⁎-weighted images, apparent diffusion coefficient maps and diffusion-weighted images. This low-intensity lesion disappeared by day 7, and a transient brain atrophy in the right hemisphere appeared on day 28. The low signal intensity in the cerebral white matter was apparently different from that associated with contusion and typical diffuse axonal injury, and might represent a late-onset accumulation of non-heme iron and free radicals in the white matter after head trauma. © 2007 Elsevier B.V. All rights reserved. Keywords: Head trauma; Diffuse axonal injury; Low signal intensity; MRI; Free radicals; SSEP; Giant potential; Fractional anisotropy 1. Introduction White matter lesions with low-intensity signals on T2weighted (T2W) magnetic resonance imaging (MRI) are rare and have been reported in patients with Sturge–Weber syndrome, cerebral ischemia and infarction, moyamoya disease, and multiple sclerosis [1,2]. In some of these conditions, accumulation of non-heme iron and the resultant production of free radicals are proposed to cause this signal change [1,3], based on the simultaneous emergence of hypointense signals on apparent diffuse coefficient (ADC) maps [4,5] and T2⁎-weighted imaging [6]. ⁎ Corresponding author. Tel.: +81 859 38 6777; fax: +81 859 38 6779. E-mail address: oknsoknsokns@yahoo.co.jp (T. Okanishi). 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.06.048 Here, we report on a child who showed a low-intensity lesion in the cerebral white matter after head trauma, which suggested the presence of axonal flow disruption with resultant free radical production. 2. Case report A 4-year-old girl was admitted to our hospital after a motor vehicle accident, where she was sitting in the front seat but was unrestrained. Contusions were present on her face, but no major extracranial injury was noted. She was comatose with a Glasgow/Japanese coma scale score (adapted for children) of 10/II-20. She spoke only a few words repeatedly and did not engage in conversation. Moreover, she showed an irregular sleep–wake cycle and somnolence. Left hemiparesis and T. Okanishi et al. / Journal of the Neurological Sciences 263 (2007) 218–222 219 Fig. 1. Cranial CT at 2 h after the accident (A) and MRI on day 3 (B to I) of this patient. CT on admission showed diffuse brain edema with right-sided predominance (A). T1W imaging (D) showed no remarkable change. FLAIR imaging (B) showed a high-intensity lesion (arrow) in the right temporo-occipital subcortical white matter. Callosal high signal lesion (arrow) was noted on sagittal T2W imaging (C). Axial T2W (E), T2⁎-weighted (F), FLAIR (G), and diffusion-weighted (H) imaging and the ADC map (I) showed decreased signal intensity in the right parietal region. complete left oculomotor nerve palsy were noted. Deep tendon reflexes were exaggerated in all the extremities, and Babinski's sign was positive on both sides. There was no cranial bone fracture, and computed tomography (CT) and MRI revealed traumatic lesions, as described below. Phenobarbital and glycerol were administered. An electroencephalogram on day 3 of admission showed attenuated alpha waves, and sporadic high-voltage slow waves in the left frontal and central areas. Although the sleeping tendency persisted, she could sit without help on some occasions, and talked with others transiently. By day 9, the left hemiparesis had disappeared, and her sleep–wake cycle was normalized. Fluctuation of conscious level persisted with intermittent loss of integrity in the contents of her conversation. This symptom disappeared by day 20, but her speech remained slow, and a mild impairment of episodic memory was evident and persisted for three months. By day 30, she showed no left oculomotor palsy, speech disorder, memory deficit, or gross and fine motor symptoms. Irritability disappeared 4 months after the head trauma. 220 T. Okanishi et al. / Journal of the Neurological Sciences 263 (2007) 218–222 Fig. 2. ADC values of the patient's brain. ADC values of the right hemispheric low-intensity lesion on axial (A) and coronal (B) images, and the corresponding area in the contralateral hemisphere. ADC values in the right hemisphere were lower than those in the left hemisphere. Fig. 3. T2W imaging MRI on day 7 (A), day 28 (B), and day 56 (C), SPECT on day 22 (D), and fractional anisotropy (FA) map on day 56 of this patient (E). Low signal intensity disappeared on day 7 (A). Atrophy of the right cerebral hemisphere appeared on day 22 (B), and by day 56 (C). SPECT (D) showed diffuse hypoperfusion in the right hemispheric cortex. FA map on day 56 (E), slightly inferior to the lesion in Fig. 1E to I, showed increased anisotropy in the subcortical white matter of the right parietal cortex relative to the other side (red/blue color represents high/low anisotropy, respectively). Diffusion-weighted imaging was performed by using single-shot spin-echo echo-planar imaging. The parameters were as follows: data matrix = 96, field of view = 29 cm, section thickness = 3 mm without gap, TE = 73.7 ms, TR = 1000 ms, ASSET factor = 2; number of acquisitions = 4; b = 1000 s/mm2 with 6 directions. The FA map was generated on the Functool using Advantage Windows (General Electric, Milwaukee, WI, USA). T. Okanishi et al. / Journal of the Neurological Sciences 263 (2007) 218–222 221 Fig. 4. Short-latency somatosensory evoked potentials recorded from the patient. (A) Evolution of the amplitude (μV) of short-latency somatosensory evoked potentials (SSEPs), elicited by median nerve stimulation, on days 20 and 35. Recording electrodes were placed on C3' and C4' (2 cm posterior to C3 and C4) and reference electrodes were placed on the auricles. (B) Right median nerve SSEPs on day 20. 2.1. Neuroimaging Cranial CT (Fig. 1A) at 2 h after the accident showed diffuse cerebral edema, predominantly in the right hemisphere, and a high-intensity lesion, which suggested subdural hematoma, in the occipital interhemispheric fissure. Brain MRI on day 3 revealed high-intensity lesions, indicating brain contusion, in the right temporo-occipital (Fig. 1B) and bilateral temporal (not shown) subcortical white matter on fluid-attenuated inversion recovery (FLAIR) images. A high-intensity lesion was present in the corpus callosum, which suggested diffuse axonal injury, on a T2W image (Fig. 1C). In addition, a white matter lesion was noted in the right parietal area, with a hypointense signal on T2W (Fig. 1E), T2⁎-weighted (Fig. 1F) and FLAIR (Fig. 1G) images, diffusion-weighted image (DWI) (Fig. 1H), and ADC maps (Figs. 1I, 2A and B). T1-weighted images showed no abnormality (Fig. 1D). The ADC value of this lesion was low (Fig. 2A), compared to the corresponding area in the contralateral hemisphere (Fig. 2B). On day 7, the low-intensity lesion in the right hemisphere had disappeared on MRI (Fig. 3A), and magnetic resonance angiography revealed no abnormality in the intra- and extracranial arteries (not shown). MRI on day 28 showed subdural effusion over the right hemisphere, predominantly in the frontal region, and diffuse atrophy of the right hemisphere (Fig. 3B). On day 56, subdural effusion and right hemispheric atrophy had partially disappeared, but the shifted midline persisted (Fig. 3C). On day 22, single photon emission computed tomography (SPECT) images revealed hypoperfusion in the right hemisphere (Fig. 3D) and thalamus. On day 63, the cerebral perfusion had mostly recovered, but thalamic hypoperfusion persisted (not shown). Fractional anisotropy (FA) mapping on day 56 (Fig. 3E) showed increased anisotropy in the right parietal area relative to the other side, slightly inferior to the preceding lesion with low signal intensity. 2.2. Electrophysiological analysis On day 20, the brainstem auditory evoked potentials were normal. Short-latency somatosensory evoked potentials (SSEPs) with median nerve stimulation showed a markedly enhanced amplitude of N20–P25 (7.6 μV) in the left hemisphere (Fig. 4B) and attenuated N20–P25 (2.2 μV) in the right (damaged) hemisphere (Fig. 4A). By day 35, this interhemispheric difference had decreased (left cortex, 5.2 μV; right cortex, 3.4 μV) (Fig. 4A). 3. Discussion The distribution of lesions in the corpus callosum and the subcortical white matter with high signal intensity on FLAIR images was compatible with the changes in diffuse axonal injury (DAI) and accompanying parenchymal contusion [7]. Microbleeding in the white matter, with spotty appearance with multiple, small foci of hemorrhage, is also common in DAI 222 T. Okanishi et al. / Journal of the Neurological Sciences 263 (2007) 218–222 [7–9]. In contrast, the low signal intensity of the deep white matter on each MRI modality (T2W, T2⁎-weighted, and FLAIR images, and ADC map) has only been recorded in head trauma very rarely. This signal change may have a common mechanism with other types of lesion that show similar signal changes; namely, accumulation of free radicals and/or iron [1,2]. These chemicals change the magnetic susceptibility of the tissue by their paramagnetic effect [2], resulting in the appearance of lowintensity signals on T2W [1–3,10], T2⁎W [2], and FLAIR [1– 3,10] images, and ADC maps [4,5]. Low signal intensity of DWI may be attributed to the dark-through effect of the low signal on T2W images [1]. Indeed, induction of oxidative stress has been confirmed in experimental head trauma, by demonstrating (1) the release of non-heme iron and other metals from the disrupted axonal flow, (2) activation of nitric oxide synthase, and (3) dysregulation of electron transport [11]. These mechanisms lead to the production of free radicals, which could be at least partly responsible for the brain edema [11] in the damaged hemisphere of the present patient. Increased anisotropy was found in the white matter in the vicinity of the low signal lesion later in the course of the illness. This change may have been due to disruption of selective intersectioning fibers in the right hemisphere [12], or regrowth of axons [13] and suggests that axonal damage extended to larger areas beyond the signal change visible on routine MRI. Such difficulty in identification of exact tissue damage is common in cases with DAI, as has been demonstrated by postmortem examination [8]. Furthermore, the lack of detection of the low signal lesions in most cases of head trauma may be related to the rapid clearance of free radicals and iron, or the lateonset and short-lasting response of nitric oxide production that peaks at 48 h after brain injury [14]. The two types of unusual findings in the present patient, i.e. the low signal intensity and the increased anisotropy, are probably underestimated in MRI of many injured brains. We propose that these findings can be regarded as subtypes of axonal damage in DAI. Since immature brains are more vulnerable to oxidative stress [11], age-related propensity to these types of lesions needs to be clarified. Interestingly, the SSEP was enhanced in the somatosensory cortex contralateral to the white matter lesion. This may have resulted from reduced inhibition from the damaged cortex [15], suggesting a functional disruption of the undamaged cortex after traumatic brain injury. In conclusion, this case of traumatic brain injury involved a white matter lesion that showed low signal intensity on MRI. Repeated examination of MRI during the acute phase, and careful observation for a decreased signal change, may improve the detection of such lesions in patients following head trauma. The significance of this unique finding should be further explored in terms of functional correlates and prognosis. References [1] Lee JH, Na DG, Choi KH, Kim KJ, Ryoo JW, Lee SY, et al. 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