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Neuropsychological results and neuropathological findings at autopsy in a case of mild traumatic brain injury
Published online by Cambridge University Press: 01 September 2004
Abstract
Autopsy studies were undertaken in a 47-year-old college-educated male patient who, 7 months prior to an unexpected death, had sustained a mild traumatic brain injury (TBI) as manifested by brief loss of consciousness and an initial Glasgow Coma Scale score of 14. The patient died from cardiac arrest secondary to an undiagnosed and unknown arteriosclerotic cardiovascular disease as assessed by the coroner's office at the time of autopsy. Gross inspection of the brain at autopsy was normal; however, microscopic analysis demonstrated what were considered trauma findings of hemosiderin-laden macrophages in the perivascular space and macrophages in the white matter, particularly the section taken from the frontal lobe. The patient had partially returned to work at the time of death, but had encountered problems with diminished cognitive performance in his work as an appraiser. Neuropsychological studies were generally within normal limits although several tests of either speed of processing or short-term memory showed lower than expected performance. This case demonstrates the presence of subtle neuropathological changes in the brain of a patient who sustained a mild TBI and was still symptomatic for the residual effects of the injury 7 months post injury when he unexpectedly died. (JINS, 2004, 10, 794–806.)
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- Type
- CASE STUDY
- Information
- Journal of the International Neuropsychological Society , Volume 10 , Issue 5 , September 2004 , pp. 794 - 806
- Copyright
- 2004 The International Neuropsychological Society
INTRODUCTION
Most of our knowledge concerning the neuropathological features of traumatic brain injury (TBI) either come from clinically relevant animal models of experimental brain injury or from human post-mortem studies typically involving patients who die shortly after or within days of their injuries. There are some studies where patients have survived for longer periods of time, but these are typically individuals with severe deficits and/or coma (Adams et al., 2000; Ommaya et al., 2002; Strich, 1956, 1961), where the cause of death is either attributable to the brain injury or the combination of brain or systemic injuries. As would be expected, the majority of these neuropathological reports involve patients with moderate to severe TBI. An exception is Blumbergs et al. (1994) report involving patients with mild TBI who died not from the head injury but from complications of systemic injuries or other causes. Even though these patients had Glasgow Coma Scores (GCS; Teasdale & Jennett, 1974) in the mild range (i.e., 14–15) remarkably all were found to have axonal injury. Unfortunately, in the Blumbergs et al. (1994) study only 1 subject survived more than 4 weeks; that subject was 80 years old, no specific assessment for neurobehavioral sequelae was obtained or reported, and no neuropsychological testing was obtained.
The issue of residual neural damage in mild TBI has been controversial (Alexander, 1995), but considerable data are accumulating indicating enduring pathophysiological effects associated with mild TBI. For example, Garnett et al. (2000a, 2000b) and Brooks et al. (2000) recently demonstrated abnormal magnetic resonance spectroscopy (MRS) findings with normal structural imaging, even in cases meeting criteria for mild TBI (i.e., GCS ≥ 13). Magnetization transfer and MR signal intensity studies have similarly demonstrated abnormalities in otherwise normal appearing MR scans from individuals with mild TBI (Goetz et al., 2004; Hofman et al., 2002; Kumar et al., 2003; McGowan et al., 2000; Sinson et al., 2001; Thatcher et al., 1997). Lewine et al. (1999) in a group of mild TBI subjects, also with normal structural MR imaging findings, demonstrated significant magnetoencephalographic (MEG) abnormalities and studies using diffusion tensor MR imaging have shown white matter abnormalities following mild TBI (Arfanakis et al., 2002). Sequential quantitative MR imaging has even demonstrated progressive degenerative changes in mild TBI (MacKenzie et al., 2002).
The likelihood of significant sequelae from mild TBI and their apparent occult presentation to any macroscopic inspection also comes from the prevalence and incidence studies of dementia and neuropsychiatric outcome. For example, several studies (Guo et al., 2000; O'Meara et al., 1997; Plassman et al., 2000; Schofield et al., 1997), although not all (Mehta et al., 1999), have demonstrated an association between a history of mild TBI in individuals who presumably had fully “recovered” and later in life developed dementia (Guo et al., 2000; O'Meara et al., 1997; Plassman et al., 2000; Schofield et al., 1997). These studies support the presence of a permanent neuropathologic basis to mild TBI, even though clinical “recovery” has occurred. With regard to neuropsychiatric outcome, even patients with mild TBI have a significant increase in depression (Fann et al., 2004; Holsinger et al., 2002; Jorge et al., 2004).
Recently, we evaluated a 47-year-old patient who sustained a well-documented mild TBI and seemed to be on his way to a good recovery when he died unexpectedly at 7 months post injury. Because of the unexplained nature of his sudden death, a mandatory autopsy took place and although an exhaustive neuropathological investigation was not undertaken, gross neuropathological inspection of the brain was made at autopsy along with several tissue specimens examined microscopically.
Importantly, neuropsychological testing and behavioral information was obtained approximately 6 months after injury along with neuroimaging data shortly before the patient died. This patient had returned to work on a limited basis and was attempting to resume a normal life once again. Accordingly, post-injury behavioral, neuroimaging, and neuropsychological data were available to compare to the autopsy and neuropathological data.
CASE STUDY
History of Accident
At age 47 this otherwise healthy college educated male real estate appraiser was involved in a motor vehicle accident (MVA) when the patient's vehicle struck a large load of lumber that had come loose and across the center divide from an oncoming flat-bed semi-truck hauling lumber. The patient, as the only occupant, was the seat-belted driver traveling at freeway speed (65 mph) when, without warning, the head-on collision occurred. The collision demolished the vehicle and because of the lumber debris and other traffic factors at the time of impact, it was estimated that 1–3 min transpired before the patient was attended to by individuals at the scene of the accident. According to police reports an eyewitness considered him to be “unconscious.” Actual duration of loss of consciousness (LOC) is unknown, but when emergency medical personnel arrived on the scene, approximately 15 min post injury, his GCS was rated at 14 due to confusion. He had to be extricated from the damaged vehicle (approximately 45 min), after which he was helicopter evacuated to a Trauma I hospital. During transit his GCS was rated a 15 with a similar rating given on ER admission. The impact of lumber through the windshield, produced what the emergency medical responders recorded as “massive bleeding,” especially from one laceration extending approximately 10 cm from the forehead posteriorly. He also complained of severe neck pain. After admission to the ER, CT imaging of the brain was interpreted to be within normal limits (see Figure 1). However, cervical CT imaging demonstrated grade I C4/5 subluxation with fractures of the left C3/4 and C4/5 posterior lateral elements. Clinically, neurosurgical evaluation found him to be neurologically normal except for significant loss of left deltoid strength, left C5 sensation and diminished left triceps reflex. Neurosurgically, he was successfully treated with an anterior fusion at C3/4 and C4/5.
Day-of-injury CT scan that was interpreted as within normal limits. There is slight asymmetry of the anterior horn but this was not considered to be clinically significant. Interhemispheric fissure was at midline and there is appropriate white gray matter differentiation with no edema or blood byproducts noted (scan is in radiological perspective where left is on the viewer's right).
Injury severity classification
GCS was never reported lower than 14 and then recorded as 15 when assessed both initially and later in the ER; in addition, he exhibited no significant anterograde amnesia—all consistent with mild TBI. While some classification schemes of brain injury would potentially categorize this as “complicated mild,” or even mild–moderate because of sustaining a cervical fracture (Alexander, 1995; Varney & Roberts, 1999), he was never clinically assessed as having anything more than mild injury. Furthermore, as indicated above, he was hospitalized for only four days and that was based solely on the fact that he had undergone neurosurgical repair for the cervical fracture. Accordingly, for the purposes of this case study, for the reason given above, the patient was considered to have sustained a mild TBI.
Course of recovery
The patient had what would be described as a routine course of recovery. He was hospitalized for only 4 days. He convalesced at home and underwent physical therapy for approximately 3 months. Within 1 month post injury he attempted to return to work, but found it difficult to focus and sustain mental effort. Nonetheless, he gradually increased his workload but never succeeded in reaching his previous level of function prior to his untimely death. His subjective complaints are summarized in Table 1. Subjectively, throughout this post-injury period, he found that his endurance was diminished and that the appraisal work was more difficult. He reported taking longer to do his work with diminished accuracy and “no stamina.” He also reported that before the accident he could conceptualize, visualize and anticipate an appraisal project from “beginning to end” and that he could no longer perform these tasks like he once did. He complained of not being “creative” and lacking “enthusiasm” for his work, like he once did. His wife described him as being “slower” in his ability to process and problem solve. Also, coworkers in his office reported that the amount and accuracy of his work had diminished. These were the factors that actually precipitated the reason for the neuropsychological consultation. During this post-injury period he had numerous follow-up medical visits including examinations by the neurosurgeon, plastic surgeon, family physician, and a physiatrist who was managing his treatment. All performed standard physical exams including cardiac and blood pressure studies with no systemic abnormalities detected. When released by the neurosurgeon he resumed his physical conditioning program without incident or complication. Accordingly, it is unlikely that any of the above mentioned symptoms were due to the underlying cardiovascular disease that would soon take his life, although they cannot be ruled out. Prior to the accident he had no significant health concerns, was completely asymptomatic for any of the problems identified in Table 1, and had never been diagnosed with a pre-existing medical problem that could explain these complaints. All symptoms listed in Table 1 had their onset after this injury.
Subjective complaints based on the Adult Neuropsychological History Questionnaire (Greenberg, 1994)
Premorbid functioning
Vocationally, this patient was very successful in his line of business and had achieved considerable recognition by holding several important state association positions in his professional field. He had a bachelor's degree in finance. School records indicated that he graduated from high school with a 2.2 grade point average (on a 4.0 scale) and maintained approximately a B average in college. His high school records also indicated that on some unspecified intelligence testing he obtained an “IQ score of 109.” The patient was in excellent health at the time of the accident. Prior to the accident he was a mountain hiker, runner and biker and competitively sparred in karate. In college he was a varsity wrestler and in high school played several competitive sports. He had no known history of heart disease prior to his unexpected death and there was no family history of cardiovascular or neurological disease or disorder. Routine pre-injury physical exams were negative although minimally elevated blood pressure was noted, but never thought significant enough to treat. There was no prior head injury, other than incidental contact during competitive sport activities and no history of loss of consciousness for any reason. He was on no medication at the time of the accident and likewise was on no medication at the time of neuropsychological assessment. Nonetheless, it could not be ruled out that he had sustained a prior mild head injury from contact sports he competed in as a youth. He was not obese and his weight was appropriate for his height and age; he engaged in routine physical fitness before and after the accident and had resumed a vigorous exercise program.
Neuropsychological consultation
Due to the aforementioned symptoms, the patient was referred for neuropsychological consultation by his treating physiatrist. Results of neuropsychological testing are summarized in Table 2. For the most part, neuropsychological studies, including tests of memory were performed within normal limits. On intellectual testing with the Wechsler Adult Intelligence Scale–Revised (WAIS–R; Wechsler, 1981) he obtained a Full Scale IQ score of 116 with no difference between verbal and performance abilities. On the Wechsler Memory Scale–Revised (WMS–R; Wechsler, 1987) his General Memory Index was 123, and all other indices were within a standard deviation. He made only one error on the Benton Visual Retention Test (BVRT; Benton, 1992), no errors on the verbal component of the Warrington Recognition Memory Test (WRMT; Warrington, 1984) and only two errors on the visual component. On the Paced Auditory Serial Addition Test (PASAT, Lezak, 1995) he made only four errors. Academic performance on the Wide Range Achievement Test–Revision 3 (WRAT–3, Jastak & Wilkinson, 1993) ranged from the 53rd to the 73rd percentile. He displayed superior word fluency as reflected by the mean word fluency on the FAS of 26 and only one item not named on the Boston Naming Test (BNT; Goodglass & Kaplan, 1987). Visual–perceptual function was normal (28/30) on the Hooper Visual Organization Test (HVOT; Hooper, 1958) and normal (36/36) on the Raven Coloured Progressive Matrices test (Raven's CPM; Raven, 1947). The only hint of slightly sub-par performance came on the Digit Symbol subtest on the WAIS–R (scaled score = 9), Trial 1 (5/15) of the Rey Auditory Verbal Learning Test (RAVLT; Rey, 1964) and 15-min recall (13/36) of the Rey-Osterrieth Complex Figure Test (ROCFT; Rey, 1964).
Neuropsychological testing results
Table 2 continued
Self-reported neurobehavioral findings
Table 1 outlines the Adult Neuropsychological History Questionnaire (Greenberg, 1994) of the subjective complaints of the patient that developed after the injury. These are the common complaints associated with post-concussive syndrome as outlined in the Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM–IV; American Psychiatric Association, 1994, pp. 704–706). Table 2 summarizes the various symptom and self-report inventories. The Symptom Checklist–90–R (SCL–90–R; Derogatis, 1996) results demonstrated T scores of approximately 60 (i.e., 1 SD above the norm) on the somatic and depression scales. His Beck Anxiety and Depression Inventories (BAI and BDI, Beck, 1978, 1990) yielded scores of 5 and 9 (within normal limits) and a short-form of the Minnesota Multiphasic Personality Inventory (MMPI; Faschingbauer, 1974) yielded a T score of 60 on the depression subscale. Taken together these findings indicated his subjective symptoms represented an endorsement of mild symptomatology mostly in terms of cognitive, motivation and drive rather than affective problems at the time of neuropsychological consultation, although there was some endorsement of the latter.
Neuroimaging studies
On admission to the ER the patient underwent CT imaging of the head and the findings were negative (see Figure 1). No other cranial imaging was done acutely. As stated above, CT imaging of the neck demonstrated cervical fractures. Approximately 6 months post injury, as part of the comprehensive work-up for his ongoing symptoms, MR and single photon emission computed tomography (SPECT) studies were undertaken, using 99mTc-HMPAO radionuclide. Unfortunately, on the day neuroimaging studies were performed, technical problems were encountered during MR imaging and the procedure had to be abandoned, with no clinically interpretable images obtained. SPECT imaging was accomplished on that day, with studies reportedly within normal limits. Regrettably, the patient died 11 days later, just 3 days prior to when the MR scan had been rescheduled.
Death
In an attempt to regain his physical stamina, the patient had resumed exercising on a regular basis since about 1 month following the accident. Seven months to the day post injury, during a semi-strenuous morning jog, he collapsed and died. Because of the unexplained death occurring on public property, a full autopsy was ordered. The Office of the Medical Examiner, State of Utah, Department of Health performed the autopsy. The final pathological diagnosis for the cause of death was “ischemic heart disease” due to “arteriosclerotic cardiovascular disease.”
Pathological examination of the brain
Gross anatomic inspection of the brain and spinal cord was described as normal. Brain weight was assessed at 1,510 g. The outward appearance of the brain was normal and no residual contusions or surface abnormalities were detected (see Figure 2). The brain was routinely sectioned and inspected and no gross abnormalities were identified. Two sections of the brain were taken for microscopic analysis—one frontal lobe, the other temporal lobe at the level of the hippocampus. These sections were examined microscopically where “hemosiderin-laden macrophages” (see Figure 3) were observed in perivascular spaces along with “scattered macrophages in the white matter.” More were reported in the section taken from the frontal lobe than the temporal lobe where the pathologist described the findings as a “sprinkling of lymphocytes.” In the sections viewed, neurons appeared intact. The one section with the hippocampus was specifically examined for pyramidal cell loss, which was not observed. The spinal cord was also sectioned at several levels and no abnormalities, including no hemosiderin or macrophages, were found at any level. One histological slide was decolorized and re-stained with Elastic Van Gieson (EVG) to determine the status of the elastic lamina of vessels. The EVG stain revealed no abnormalities, such as reduplication and thickening common in hypertensive individuals, further supporting the conclusions that the abnormal neuropathological findings were trauma related.
Post-mortem gross brain at the time of autopsy demonstrating no abnormalities. Positioning of the brain was based on routine placement by the pathologist.
Histological findings of hemosiderin (arrow) in a perivascular space indicating prior hemorrhagic lesion, most likely trauma induced, according to the neuropathologist's conclusions.
DISCUSSION
In this case study of mild TBI gross brain inspection revealed no visible pathological findings. As shown in Figure 2, no old surface contusions, regions of focal atrophy or any other visible abnormality was present, confirming the generally normal gross appearance expected in mild TBI. However, at the histological level, presence of hemosiderin-laden macrophages in perivascular spaces, scattered macrophages and lymphocytes in the white matter were identified. The neuropathologist's final diagnosis was “cerebral white matter with increased perivascular hemosiderin laden macrophages” that was attributed to the prior trauma. Appearance of lymphocytes in the white matter was more prevalent in the section taken from the frontal cortex, but this has to be viewed cautiously as only select sections were reviewed as part of the coroner directed neuropathological examination and histological assessment was not based on a systematic sectioning of the brain. Nonetheless, Scheid et al. (2003) using a T2-weighted gradient-echo sequence at 3 Tesla field strength found more than double the signal abnormality consistent with prior microbleeds in the frontal region, than the temporal lobe in an MR imaging study of 66 chronic TBI patients. Although the findings of the current case study presented herein were nonspecific, and no further microscopic or ultrastructural details were available, these abnormalities were consistent with injury to brain parenchyma with concomitant immunologic and phagocytotic response to injury (Grady et al., 2003; Soares et al., 1995; Tracey, 2002). The board-certified neuropathologist who performed the examination concluded that most likely these were trauma-based findings in the brain of this individual who had sustained a mild TBI. No similar pathology was noted in spinal cord sections, even at the level where the fracture occurred.
In their review of the cellular mechanisms in brain injury, McIntosh et al. (1998) suggest that presence of macrophages may be part of progressive tissue necrosis, presumably because they release cytotoxic molecules (including oxygen free radicals and inflammatory cytokines) mediating the local inflammatory response to brain injury and to the phagocytosis of debris from dying cells. Macrophages may also be present as part of reparative responses to brain injury as well (Silver & Miller, 2004). Experimental models of brain injury that routinely demonstrate macrophages at perilesional sites (Schwab et al., 2001; Vela et al., 2002) have even shown that the degree of macrophage presence positively correlates with the severity of damage. Also, animal models have shown that where no gross detection of hemorrhaging has been identified, hemosiderin staining may be evident histologically (Adelson et al., 2001). Furthermore, the microvasculature of the brain is also susceptible to shear injury and microhemorrhaging (Dietrich et al., 1994; Scheid et al., 2003). Accordingly, presence of hemosiderin is likely a marker of parenchymal injury as well (Oehmichen et al., 2003; Raghupathi & Margulies, 2002).
By their very nature, case study reports have to be viewed cautiously and conservatively. This patient did die from what was assessed by the coroner's office as “arteriosclerotic cardiovascular disease,” even though he had never been assessed for having, or treated for, any cardiovascular condition prior to his death. Presence of occult cardiovascular disease at the time of vigorous exercise could have been the trigger for sudden death (see Albert et al., 2000). How his cardiovascular condition may have contributed to the histological findings is not known since, in a post-mortem case study such as this, there is no post-hoc method to control for these factors. On the other hand, given the nature of the injury, the timing of his symptoms and the relevant histopathological findings consistent with trauma, the likely explanation is that these findings were traumatically related. Further credence for this conclusion comes from another recent case, presented in Figure 4, with very similar clinical history (i.e., mild TBI, GCS = 14), where the gradient recalled echo MR scan (Besenski, 2002; Fazekas et al., 1999; Preul et al., 2003) over 1 yr post injury demonstrated numerous small hemosiderin deposits. Histological studies of brain injury have shown disseminated hemosiderin deposits within brain parenchyma (Oehmichen et al., 2003). Other neuroimaging studies have clearly demonstrated the increased frequency of hemosiderin deposits in frontal over temporal regions in TBI (Scheid et al., 2003). However, hemosiderin deposits of the size seen in the patient in this case study would have been under the threshold of detection by MR imaging (Wardlaw & Statham, 2000). Immunological response and presence of macrophages is indicative of a response to injury (Adelson et al., 2001; Folkerts et al., 1998; Grady et al., 2003; Medana & Esiri, 2003; Stoll et al., 1989) and it was concluded by the neuropathologist that these neuropathological findings were attributable to the trauma in question.
Frontal coronal view of MRI (gradient recalled echo) in a separate patient, but with similar history of mild TBI. At the time of this injury, the patient was a passenger in a vehicle involved in a rollover accident, following rear impact. He had apparent brief LOC and paramedic rated his GCS as 14 at the scene, but 15 on arrival to the ER. Note the scattered hemosiderin deposits (black signal) scattered throughout the frontal region bilaterally, but more so in the right frontal (scan is in radiological perspective). The patient was 16 years of age at the time of injury, 17 years old at the time of imaging and without any history of prior head trauma or any other risk factor for microhemorrhaging. He was discharged from the hospital on the day of injury following several hours of observation where his mental status did not change. He had similar subjective symptoms and complaints as the patient who is the focus of the case study, independently verified by high school teachers who knew him before and after the injury.
Neuropsychologically, this patient's studies were broadly within normal limits, yet his subjective complaints, confirmed both by his spouse and coworkers, of changes in cognitive abilities, personality and temperament were consistent with mild TBI. If a liberal interpretation of his neuropsychological studies is undertaken, comparing to either his reported pre-morbid IQ of 109 or his post-injury WAIS–R Full Scale IQ of 116, there were only three tasks where the patient performed below expectations: a speed of processing task (Digit Symbol) and two memory tasks (Trial 1 RAVLT performance and 15-min recall of the ROCFT). These slightly diminished performances levels would be fitting with the patient's subjective complaint that some of his cognitive abilities were “off.” However, these are also subtle cognitive changes that occur in individuals diagnosed with depression and/or post-traumatic stress disorder (Brandes et al., 2002).
Even if the above mentioned tests are detecting subtle abnormalities in cognitive status of this patient, the remainder of his neuropsychological studies would have to be considered entirely within normal limits, despite his subjective cognitive and neurobehavioral complaints. The ecological validity of neuropsychological testing has limitations (Silver, 2000), where the controlled environment of the laboratory does not necessarily match the cognitive challenges of the outside world. In this case, the neuropsychological studies provide minimal insight into the residual neurobehavioral effects of this head injury, but the patient's presenting complaints and alteration in job performance are most fitting with the behavioral indicators of what DSM–IV labels a post-concussive syndrome (pp. 704–706). Neuropsychologically, the patient's memory was generally within normal limits. His complaints centered more on high-level executive problems, drive and motivation. Interestingly, recent research in the area of multiple sclerosis has implicated axonal injury as a factor in fatigue (Tartaglia et al., 2004). Accordingly, the connection between white matter burden and fatigue may be associated with the white matter damage in TBI.
Unfortunately, the brain was not preserved for more complete analysis as the findings were based on a clinical autopsy and what is reported here is based entirely on the final coroner's report, where the neuropathological analysis was performed by a board certified neuropathologist. These findings are not specific, but the presence of hemosiderin laden macrophages in the white matter clearly indicate perturbation of brain parenchyma or blood vessels and the likelihood of at least some microhemorrhaging secondary to trauma (see Davis & Robertson, 1985; Graham et al., 2002; Malamud & Hirano, 1973; Yokota et al., 2002). Lastly, with regard to hemosiderin deposits, it should be pointed out that they can occur spontaneously and for a variety of non-traumatic reasons (Imaizumi et al., 2004; Johnston & Marx, 2003; Wong et al., 2003).
It should be noted that had the patient lived, litigation would have likely occurred. However, the patient was clinically referred by his treating physiatrist; he was following a rigorous physical retraining and reconditioning program in an attempt to recover and had returned to work. As indicated above, the neuropsychological test performance was generally within normal limits and all validity and measures of effort were performed normally as well. Accordingly, the issue of potential litigation had he lived, was not thought to have affected his performance on neuropsychological tests. Also, it is not known what role his latent cardiovascular status may have played with respect to his subjective complaints.
This study has definite implications for cases of mild TBI. As indicated in the introduction, there is compelling evidence that presence of prior head injury, even mild, constitutes a vulnerability factor for later in life dementia (Guo et al., 2000; Plassman et al., 2000) and long-term neuropsychiatric sequela (Fann et al., 2004; Holsinger et al., 2002; Jorge et al., 2004). Obviously since in most cases of mild TBI patients resume approximate levels of premorbid ability, the increased risk of dementia implies underlying latent neural damage. In most cases of mild TBI conventional neuroimaging studies are negative, as they were in this case. However, recent studies have clearly demonstrated quantitative, MR signal, and biochemical markers of injury to the white matter in mild TBI where seemingly conventional imaging detects no abnormality (Bigler, 2001, 2002; Brooks et al., 2000; Garnett et al., 2000a, 2000b; McGowan et al., 2000; Sinson et al., 2001; Thatcher et al., 1997; Zhang et al., 2003). Furthermore, MacKenzie et al. (2002) in a longitudinal study have demonstrated degenerative changes that accompany even mild TBI. This case histologically demonstrates markers of injury present in the white matter below conventional methods of detection using contemporary neuroimaging methods, more so in the frontal region. Furthermore, behaviorally the patient presented with classic post-concussive symptomatology that had persisted until his unexpected death 7 months post injury. Slowed neural transmission or disrupted integration of neural pathways due to white matter injury (Adams et al., 2000; Gennarelli et al., 1998; Mathias et al., 2004; Povlishock & Christman, 1995; Smith & Meaney, 2000), particularly in the frontal region, could certainly be at the basis of the patient's complaints following this mild TBI.
In summary, the post-mortem findings in a case of mild TBI (brief LOC; initial GCS of 14) are presented that documents neuropathology under the threshold of detection by CT or SPECT imaging and even direct visual inspection of the gross brain. Markers of previous trauma were identified in the white matter under microscopic analysis. At a minimum these findings demonstrated the likelihood of perturbation of white matter, and presence of microhemorrhagic lesions in mild TBI, in both frontal and temporal lobe regions. The connection between sustaining a mild brain injury, the persistence of neurobehavioral symptoms and problems in this patient, most of which were not observed in standardized neuropsychological testing, and the histopathology of white matter injury is made.
ACKNOWLEDGMENTS
Parts of the ongoing traumatic brain injury (TBI) research have been supported by funds from the Ira Fulton Foundation. The reviews of Tracy McIntosh, Ph.D., of earlier revisions of this manuscript are gratefully acknowledged as is the manuscript assistance of Jo Ann Petrie.
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Day-of-injury CT scan that was interpreted as within normal limits. There is slight asymmetry of the anterior horn but this was not considered to be clinically significant. Interhemispheric fissure was at midline and there is appropriate white gray matter differentiation with no edema or blood byproducts noted (scan is in radiological perspective where left is on the viewer's right).
Subjective complaints based on the Adult Neuropsychological History Questionnaire (Greenberg, 1994)
Neuropsychological testing results
Table 2 continued
Post-mortem gross brain at the time of autopsy demonstrating no abnormalities. Positioning of the brain was based on routine placement by the pathologist.
Histological findings of hemosiderin (arrow) in a perivascular space indicating prior hemorrhagic lesion, most likely trauma induced, according to the neuropathologist's conclusions.
Frontal coronal view of MRI (gradient recalled echo) in a separate patient, but with similar history of mild TBI. At the time of this injury, the patient was a passenger in a vehicle involved in a rollover accident, following rear impact. He had apparent brief LOC and paramedic rated his GCS as 14 at the scene, but 15 on arrival to the ER. Note the scattered hemosiderin deposits (black signal) scattered throughout the frontal region bilaterally, but more so in the right frontal (scan is in radiological perspective). The patient was 16 years of age at the time of injury, 17 years old at the time of imaging and without any history of prior head trauma or any other risk factor for microhemorrhaging. He was discharged from the hospital on the day of injury following several hours of observation where his mental status did not change. He had similar subjective symptoms and complaints as the patient who is the focus of the case study, independently verified by high school teachers who knew him before and after the injury.
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