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6 NEUROCOGNITIVE OUTCOMES This chapter highlights studies that examined outcomes related to alterations in neurocognition. Traumatic brain injury (TBI) can result in changes in neurocognitive performance as measured by tests of sensory integrity, motor speed and coordination, attention, working memory, episodic memory, processing speed, language processing, visual-spatial processing, and executive functions (such as higher-order planning, initiating and directing, monitoring, problem-solving, and inhibitory control). Findings of alterations in neurocognitive performance were carefully examined by the committee; there were over 430 studies of TBI and neurocognitive outcomes in the committeeâs database. The committee chose studies that specifically answered the question related to its charge, that is, what long-term outcomes (lasting longer than 6 months) might be associated with a penetrating or closed head injury in adults and meet the general criteria for inclusion described in Chapter 4. The term neurocognitive outcome as used in this chapter refers to cognitive impairment while the word neuropsychologic refers to the kinds of measurements most studies utilized to determine the level of impairment. With regard to penetrating brain injury, it has been determined that the location of a brain injury and the volume of brain tissue lost affect the type and extent of neurocognitive deficits. Many scholarly articles and textbook chapters have described the relationship of localization of brain injury with specific outcomes (Damasio et al., 1994; Haas, 2001; Ratiu et al., 2004; Silver et al., 2005; Raymont et al., 2008), so it will not be discussed here. The chapter first discusses outcomes related to penetrating head injury and then outcomes related to closed head injury. Conclusions follow each section; the conclusions that follow the closed head injury section are further delineated by the severity of the injury. PENETRATING BRAIN INJURY Studies of penetrating brain injuries have been conducted primarily in military populations and are useful because they have long-term followup and preinjury neurocognitive- test information. Primary studies are presented first, followed by secondary studies, a summary and conclusion, and finally a table (Table 6.1) with information abstracted from the primary studies. Chapter 5 provides a detailed overview of many of the studies of military populations who have been injured during war. Some of the studies inform the discussion of long-term outcomes; others were not designed to answer the question posed to the committee regarding long-term sequelae of brain injury. The committee included the military studies that fit its task best; some of the studies are primary and others secondary, but they are all described in Chapter 5. The committee identified five primary studies of penetrating brain injury, and they are discussed below. 173
174 GULF WAR AND HEALTH Primary Studies Teuber and Weinstein (1954) (see cohort description in Chapter 5) studied 35 World War II veterans selected from 185 veterans who had penetrating missile injuries and loss of brain tissue and 12 controls from 101 veterans who had missile injuries of peripheral nerves but no brain injury. All veterans had sustained their injuries 5â8 years before the study. The 35 brain- injured were selected by identifying equal numbers of men with injuries in the anterior or posterior one-third of the brain and in the right or left hemisphere. The control group consisted of nine men with arm injuries and three with leg injuries. All the men were tested with the Seguin- Goddard Formboard Test, which was administered with the men blindfolded first in its normal position and then after a 180-degree rotation. Men with brain injuries took more time, made more errors, and recalled fewer forms than the controls. Another study by Weinstein and Teuber (1957b) examined two groups of men: 62 who had loss of cerebral tissue due to penetrating head injury and 50 who had trauma of peripheral nerves. Preinjury Army General Classification Test (AGCT) scores, which had been administered on induction into the Army 13â15 years before the study, were available for all the men. Preinjury education level was determined by interview and from case records. The civilian edition of the AGCT was administered to all the study participants 10â12 years after their injuries. The findings indicate clearly that the change in AGCT score was significantly worse in the penetrating-injury group than in the peripheral-nerveâinjured group. Furthermore, although the primary aim of the study was to investigate the connection between preinjury education and intelligence and intellectual deterioration after brain injury, the authors note that the findings were independent of any effects of differences in preinjury education or preinjury AGCT score. Corkin et al. (1989) conducted a 30-year longitudinal study of 84 World War II veterans to determine the cognitive effects of penetrating head injury: 57 veterans who had penetrating head injury and 27 veterans who had peripheral nerve injury who were matched with respect to age and premorbid intelligence and education. The veterans were examined in the 1950s and in the 1980s. The veterans selected were those who had been seen by Teuber and Weinstein in New York (see Chapter 5 for Teuberâs cohort of World War II veterans). Both groups of veterans had received an average of 12 years of education before injury and were tested with the AGCT before injury. Total scores of 42 veterans were available from military records. Review of the preinjury AGCT total scores showed no differences between the two groups. Both groups were given two cognitive tests after injury: the AGCT and the Hidden Figures Test. The AGCT contains three subscalesâvocabulary, arithmetic, and block-countingâand the Hidden Figures Test measures the ability to discriminate figures from background. Ten years after the end of the war, in the 1950s, the penetrating-injury group showed poorer performance on both cognitive tests than the peripheral-nerveâinjured controls. Forty years after the war, in the 1980s (when the study was conducted), the penetrating-injury group exhibited even poorer performance on every cognitive measure except vocabulary, which remained constant. When the data were examined by brain region with computed tomography, the site of the injury exerted an even stronger effect. Veterans with injuries of the left parietal lobe had a significantly greater decrease on the vocabulary and arithmetic subscales, and those with lesions in other brain regions showed a greater decrease on other subscales or on the Hidden Figures Tests. Penetrating-injury subjects lost an average of 7.9 points from the 1950s to the 1980s, and those with peripheral nerve injury gained an average of 0.4 point. The decline was most pronounced in older subjects. The results suggested accelerated aging in those with penetrating head injury.
NEUROCOGNITIVE OUTCOMES 175 As part of the Vietnam Head Injury Study (VHIS; see Chapter 5 for description of the study and the cohort), Grafman et al. (1988) studied the nature of intellectual function after penetrating missile wounds. The cohort consisted of 263 men who had penetrating brain injuriesâ96 with lesions in the right hemisphere, 78 in the left hemisphere, and 89 in bothâand 64 uninjured controls who met the inclusion criteria: they served in Vietnam during the same years as the brain-injured, and they were stratified according to preinjury Armed Forces Qualification Test (AFQT) to be matched with the brain-injured. There were no significant differences between the groups in age, education, or preinjury AFQT percentile scores. Although Grafman and colleagues stratified head-injured subjects by location of brain injury, the study data clearly indicate that the head-injured showed worse change than the controls in performance on the AFQT. The authors also assessed whether brain-volume loss correlated with changes in cognitive function. As expected, greater total brain-volume loss correlated with greater declines in AFQT scores from before to after injury (p < 0.0001). The authors examined whether lesion location was associated with cognitive decline. No significant effects on AFQT scores by lesion location (right, left, or bilateral) were observed. Preinjury education level also did not correlate with AFQT. The results indicated several factors that influence cognitive decline after brain injury as measured with the AFQT: preinjury intelligence was the strongest predictor of postinjury intelligence scores, followed by the size of the lesion, and then the location of the lesion. Preinjury education level did not correlate with cognitive decline. Raymont et al. (2008) examined 182 Vietnam veterans as part of phase 3 of the VHIS. All were identified from the VHIS registry and had a history of penetrating head injury although an additional 17 patients who were assessed for phase 3 had not participated in phase 1 or 2. Controls were 32 veterans who had participated in phase 2 and an additional 23 who were recruited through advertisements in veteran publications; none of the controls had a history of head injury. All the veterans were assessed over 5â7 days at the National Naval Medical Center in Bethesda, Maryland. There were no significant differences between cases and controls with regard to age, years of education, or preinjury induction intelligence level (as measured with the AFQT). Brain lesions were identified with computed tomography. The median AFQT score in the entire sample was 65.0; in the penetrating-injury group, it was 54.0, and in the controls, 74.0. The penetrating-injury veterans had a significantly greater decrease in AFQT score than controls from phase 2 to phase 3 and from before injury to phase 3. The scores of the controls improved from before injury to phase 2 compared to those with penetrating head injuries. If officers were excluded from the sample, the AFQT scores of those with penetrating head injuries decreased significantly more than the scores of the controls over the entire period from before injury to phase 3. Those with penetrating injuries had lower AFQT scores at phase 3 (mean, 52.58) than the controls (mean, 68.50). The authors examined several risk factors for AFQT outcome at followup and for declining AFQT scores, including dementia, location of brain lesion, and genetic markers. They found that preinjury intelligence was the most consistent predictor of cognitive outcome at all followup times and of decline over time. There was no evidence that laterality of the lesion affected overall intelligence or decline. Specific brain regions, the degree of local and global atrophy, and some genetic markers were found to be associated with exacerbated decline. Thus, the long-term followup of Vietnam veterans with penetrating head injury found that exacerbated decline in intelligence is a significant risk.
176 GULF WAR AND HEALTH Secondary Studies Like the primary studies, the secondary studies of penetrating TBI have been conducted in military cohorts (see Chapter 5), but they have methodologic limitations that prevented the committee from including them as primary studies. For example, many of the studies examined differences in specific cognitive domains as a function of the location of the brain injury or did not compare brain-injured people with a non-brain-injured control group. Weinstein and Teuber (1957a) examined the effects of penetrating brain injury on intelligence-test scores in patients who had stable, localized brain injury. The investigators obtained preinjury AGCT scores for 62 men who later sustained penetrating brain injury and for 50 controls who incurred arm or leg nerve injuries. All the men had been injured during World War II 1â3 years after the initial AGCT. A comparable AGCT was administered about 10 years after the men were injured. The preinjury scores of the brain-injured and control groups were almost identical: means, 105.0 and 106.4, respectively. Scores on the postinjury test showed some gain: 48 of the 50 controls increased their mean score to 119.4. The 62 brain-injured men were divided into groups according to the location of their injuries: frontal, temporal, parietal, or occipital, in the left, right, or both hemispheres. The investigators found that lesions in frontal and occipital lobes were not associated with a significant decrease in scores, but lesions in the parietal and temporal lobes of the left hemisphere were associated with a significant decrease. Weinstein et al. (1956) studied spatial orientation in 62 men who had loss of cerebral tissue because of penetrating head injury and 18 men who had leg peripheral nerve injuries. All the men had been injured during World War II (see cohort description in Chapter 5). The authors focused on a particular task of spatial orientation: finding a route on a map. Men with parietal lobe lesions (in either hemisphere) did more poorly than all the brain-injured men who did not have parietal lesions, and the men with brain damage, other than in the parietal lobe, did not perform more poorly than controls. The VHIS has resulted in numerous publications of long-term outcomes associated with penetrating head injury (see Chapter 5). Salazar et al. (1986) found that Vietnam veterans who had penetrating injuries of the basal forebrain had worse outcomes than uninjured controls with regard to episodic memory, reasoning, and arithmetic but not on tests of intelligence, attention, and language. Several studies by Grafman et al. (for example, 1986, 1990) provided evidence of the detrimental effects of penetrating head injuries on facial discrimination (1986) and examined neurocognitive performance on the Wisconsin Card Sorting Test, noting that brain-damaged Vietnam veterans made more errors than controls (1990). Although there have been additional studies in the VHIS series, many were not designed to answer the question specifically posed to the committee regarding long-term health outcomes. The studies that do shed light on long-term outcomes, other than neurocognitive effects, are discussed elsewhere in this volume. Summary and Conclusion The committee reviewed five primary studies (Teuber and Weinstein, 1954; Weinstein and Teuber, 1957b; Grafman et al., 1988; Corkin et al., 1989; Raymont et al., 2008) and five secondary studies (Weinstein et al., 1956; Weinstein and Teuber, 1957a; Grafman et al., 1986, 1990; Salazar et al., 1986) of penetrating head injury in military populations. The primary and secondary studies are consistent in pointing toward a decline in neurocognitive function after penetrating head injury.
NEUROCOGNITIVE OUTCOMES 177 With regard to increased errors on the formboard test, Teuber and Weinstein (1954) showed that veterans who had penetrating head injury took more time, made more errors, and recalled fewer forms than the controls. A later study by Weinstein and Teuber (1957b) examined the change in AGCT score from before injury to after injury and found that subjects who had penetrating head injury had a greater decline in score than the group who had peripheral nerve injury independently of preinjury education and preinjury AGCT scores. Grafman et al. (1988) found cognitive decline after brain injury as measured the AFQT. However, preinjury intelligence score was the most predictive factor in postinjury intelligence score, followed by the size of the lesion; the location of the injury was the least important. In contrast, preinjury education level did not correlate with cognitive decline. The study of World War II veterans by Corkin et al. (1989) demonstrated poorer performance on cognitive tests in veterans who had penetrating head injury than in controls and continued decline over 30 years in the brain-injured veterans on every cognitive measure except vocabulary, which remained constant. It was noted that the site of the injury exerted a strong effect on the type of deficits. Finally, the study of Vietnam veterans by Raymont et al. (2008) demonstrated that exacerbated decline in intelligence over 30â40 years is a significant risk for veterans with penetrating head injury. The five secondary studies also showed long-term deficits in neurocognition including intelligence (Weinstein and Teuber, 1957a); spatial orientation (Weinstein et al., 1956); memory, reasoning, and arithmetic (Salazar et al., 1986); facial discrimination (Grafman et al., 1986); and neurocognitive decline as measured with the Wisconsin Card Sorting Test (Grafman et al., 1990). Those studies, particularly the secondary studies, suffer from various limitations, including small samples, a focus on injury sites and localization of functional outcomes (which were outside the committeeâs charge), incomplete description of how subjects and controls were selected, and apparent high rates of loss of the original sample at followup times. However, the studies had advantages not seen in studies of civilian injury, including the availability of baseline cognitive test scores and the long-term nature of followup (in some cases, 40 years or more). The overall body of evidence demonstrates poor neurocognitive outcomes in people who suffer penetrating head injury. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of a relationship between sustaining a penetrating TBI and decline in neurocognitive function associated with the affected region of the brain and the volume of brain tissue lost.
178 TABLE 6.1 Penetrating Head Injury and Neurocognitive Outcomes Type of TBI: Mild, Health Moderate, Severe; Outcomes or Blunt, Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Teuber and Cohort 35 men with brain Penetrating missile Form Board Test Brain-injured Subjects, controls Weinstein, injury selected injuries of head or subjects took more sustained injuries 5â 1954 from 185 with peripheral nerves time, made more 8 years before testing missile wounds of errors, recalled head, 12 controls fewer forms than Subjects grouped on with peripheral controls basis of location of nerve injury lesions wounds of head controls chosen from 101 with missile wounds of peripheral nerves Weinstein and Cohort 62 men with loss Penetrating head AGCT Controls had mean Eliminated Preinjury AGCT Teuber, 1957b of cerebral tissue trauma or peripheral administered 13â increase of 13.0 men with score available for 53 due to penetrating nerve trauma 15 years before AGCT points from aphasic subjects head trauma, 50 injury (on preinjury to difficulties that controls with induction into postinjury testing prevented them Preinjury educational peripheral nerve Army) from reading level determined by injury Brain-injured practice-test interview and from AGCT group, excluding questions case records administered aphasics, had again 10â12 years average increase of after injury 5.2 points; total brain-injured group had increase of 1.6 points Education before injury did not influence extent to which performance on intelligence test was affected after injury
Type of TBI: Mild, Health Moderate, Severe; Outcomes or Blunt, Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Corkin et al., Cohort 84 World War II Penetrating head AGCT (including 10 years after end Matched with Existence of baseline 1989 veterans: 57 with injury; injury severity Total, of war (in 1950s), respect to age, performance, (This population penetrating head determined by Vocabulary, TBI group had premorbid retesting at 10 and 40 was first seen in injury, 27 with number of cortical Arithmetic, Block poorer intelligence, years after Teuberâs NY peripheral nerve lobes involved, counting performance on premorbid penetrating brain laboratory) injury presence of tantalum subscales), figure- both cognitive education injury compared with plate, history of ground tests appropriate controls 18â34 years old at seizures, use of discrimination are strengths of time of injury, first anticonvulsant (measured with 30 years after war, study; testing 10 years medication Hidden Figures TBI veterans, as a possible limitation is after injury Test) group, exhibited how representative (1950s), and even poorer the subjects were of testing 40 years performance on all those injured in after injury (1980s) every cognitive World War II; measure except subsamples selected vocabulary, which from 314 studied by was constant Teuber and Weinstein (1956, 1957); age, performance correlated only in brain-injured subjects, so age- related factors might have contributed to exacerbated decline Grafman et al., Prospective, long- 263 brain-injured Penetrating head Cognitive- Preinjury AFQT ANOVAs, 1988 term followup of veterans, 64 injury outcome, AFQT score was most multiple Vietnam War uninjured controls predictive factor regression veterans (Part of matched on for postinjury analysis VHIS) preinjury AFQT intelligence scores, performed to scores followed by brain- assess volume loss, association location of injury; between size preinjury and location of 179
180 Type of TBI: Mild, Health Moderate, Severe; Outcomes or Blunt, Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations education level not brain lesions associated with predicted cognitive decline cognitive function after injury Raymont et Prospective, long- Subjects drawn Penetrating head Cognitive- At phase 3, no ANOVAs, Those with al., 2008 term followup of from VHIS injury outcome, AFQT significant linear logistic penetrating head Vietnam War registry; 92% had differences and stepwise injury had lower Veterans penetrating head between head- multiple AFQT scores at (part of VHIS injury; of 520 from injured and regressionphase 3 than phase 3) phase 2, 484 are controls in age, procedurescontrols, still alive, and 182 education, preformed to significantly greater 2,000 patients attended phase 3 intelligence assess impact decrease in AFQT entered in registry of demographic score than controls in 1967â1970 The more global factors, from phase 2 to the cognitive test, preinjury phase 3 and from the greater the intelligence, preinjury to phase 3; effect of brain- brain-volume when impact of volume loss loss, lesion education, preinjury location, intelligence, brain genetic volume loss, lesion markers onlocation on cognitive postinjury ability 36â39 intelligence was years after examined, most injury important determinant of postinjury intelligence was preinjury performance as measured by AFQT NOTE: AFQT = Armed Forces Qualification Test, AGCT = Army General Classification Test, ANOVA = analysis of variance, TBI = traumatic brain injury, VHIS = Vietnam Head Injury Study.
NEUROCOGNITIVE OUTCOMES 181 CLOSED HEAD INJURY This section focuses on studies of closed (nonpenetrating) head injuries. These injuries are typically categorized as mild, moderate, or severe TBI. One of the problems encountered by the committee in evaluating studies of closed TBI is the difficulty in comparing severity of TBI among studies. Papers are inconsistent in the measurement of severity, particularly of moderate TBI. As in the previous section, primary studies are presented first and followed by secondary studies, a summary and conclusions, and finally a table (Table 6.2) with information abstracted from the primary studies. Primary Studies The committee selected six primary studies of closed head injury. They differ from the studies of penetrating head injury in that they examined civilian populations with TBI resulting from motor-vehicle crashes, falls, assaults, or sports activities. A study by Dikmen et al. (1986), using a cohort from the trauma center at Harborview Medical Center in Seattle, Washington (previously described in Chapter 5), examined neurocognitive outcomes after mild TBI. The head-injured, drawn from a larger cohort, were 20 consecutive patients 15â60 years old who had mild TBI. The 19 controls were friends of the TBI patients from the larger head-injured group (see Chapter 5) who were matched with regard to age, education, and sex; exclusionary criteria included evidence of preinjury central nervous system (CNS) disease or alcoholism. Neuropsychologic tests were administered at 1 month and 12 months after injury; controls were tested at the same intervals. The Halstead-Reitan Neuropsychological Test Battery and additional measures of memory were administered. The head-injured group performed slightly less well than the uninjured group on 2 of the 21 measures (the Seashore Rhythm Test and the Selective Reminding Test) at 1 month after injury. At 1 year, none of the neuropsychologic measures showed significant differences. Thus, although subtle neuropsychologic effects were found at 1 month after a mild TBI, they could no longer be detected at 1 year. In another study by Dikmen et al. (1987) (see Chapter 5), the relationship between injury severity and memory was examined in 102 consecutive head-injured patients admitted into Harborview Medical Center. All patients had sustained blunt head injury; most of the cases were mild or moderate. The uninjured comparison group consisted of 102 friends of the head-injured matched on age, education, race, and sex. Head-injury severity was measured with the Glasgow Coma Scale (GCS), assessed within 24 hours of injury to determine the depth of coma; time from injury to consistent ability to follow simple commands (TFC), used as an index of coma length; and posttraumatic amnesia (PTA), used to determine the length of impaired consciousness. The Wechsler Memory Scale (WMS) and the Selective Reminding Test (SRT) were used at 1 and 12 months after injury. The head-injured group performed more poorly than the uninjured controls (p < 0.001) on each of the subscales of the WMS and the SRT. Similarly, at 1 year, there was significant impairment on most subscales of the tests administered. However, head-injured patients performed better at 1 year than at 1 month. With regard to severity of
182 GULF WAR AND HEALTH injury, only those with deep or prolonged impaired consciousness (TFC over 1 day, PTA at least 14 days, and GCS less than 8) were performing significantly worse at 1 year than the controls. Dikmen et al. (1995) conducted a prospective study of 436 adults with mild, moderate, or severe TBI recruited at the time of injury from Harborview Medical Center, a level 1 trauma center (see Chapter 5). The study included English-speaking adults who had TBI with loss of consciousness for any period or PTA for at least 1 hour or with objective evidence of TBI (such as hematoma) and who were hospitalized and survived at least 1 month after injury. Most TBI patients (74%) had sustained their injuries in motor-vehicle crashes (car or motorcycle drive, pedestrian, or bicyclist), 11% in falls, 8% in fights or assaults, and the remaining 6% in other activities. Controls were 121 patients admitted into the emergency room at Harborview Medical Center after injury to any part of the body except the head and matched to the TBI cases on age, sex, and education. Subjects and controls received a neuropsychologic assessment at 1 year after injury, which included the Halstead-Reitan Neuropsychological Test Battery and additional measures of attention and memory. The battery evaluated various neuropsychologic functions, including sensory and motor skills, attention, concentration, memory, verbal and visuospatial intellectual skills, and executive function, such as problem solving and flexibility of thinking. A year after injury, the TBI group performed significantly worse than controls on 18 of the 21 measures used for comparison. There was a doseâresponse relationship: longer coma (from time of injury to consistently following commands) was associated with greater neurocognitive impairment. Fifty percent of the subjects with the most severe TBI (those with TFC of 29 days or longer) were cognitively too impaired even to be formally tested. Tate et al. (1991) studied a consecutive series of 87 of 100 patients who had severe TBI and were admitted into a rehabilitation facility in Australia. The patients, 15â45 years old, were compared with sibling controls on 15 factors related to various neurobehavioral impairments. Of the TBI patients, 70% had current and clinically significant impairments. Disorders of learning and memory were the most common findings 6 years after injury and differed between TBI patients (56.5%) and controls (5%). Disturbances in basic neurocognition (such as orientation, visual perception, dyspraxia, and language) were least frequent (16.5% in TBI patients and 2.5% in controls). Slowness in information processing was found in 34.1% of the TBI patients and 2.5% of the controls, and posttraumatic personality changes were found in 40% of the TBI patients, while only 7.5% of the controls exhibited personality changes. The differences appear large, but the authors did not provide tests of their significance. Lannoo et al. (1998) examined neurocognitive outcomes in 85 consecutive patients who had moderate to severe head injury and were admitted into the intensive care unit (ICU) of the University Hospital of Ghent in Belgium from September 1993 to February 1996 with a GCS score of 3â12. The patients were 15â65 years old and had no previous history of CNS disease or mental retardation. The control group consisted of 32 trauma patients who had injuries of the body but not the head and were admitted into the ICU during the same study period. The controls were also 15â65 years old and had no previous history of CNS disease or mental retardation. Neuropsychologic testing was completed at 6 months after injury in 79 of the TBI patients (93%) and 22 of the controls (69%). The neuropsychologic test battery consisted of measures of attention and information processing, visual reaction time, memory and learning, verbal fluency, and mental flexibility. A multivariate analysis of variance on neuropsychologic test performance revealed that the TBI group performed significantly below the control group at 6 months after injury on most of the test measures.
NEUROCOGNITIVE OUTCOMES 183 Heitger et al. (2006) studied 37 patients who had mild TBI and presented to Christchurch Hospital, New Zealand, and compared them with 37 controls individually matched to each case with respect to age, sex, and years of formal education. The controls were volunteers recruited through a database at the Department of Psychology of the University of Canterbury, Christchurch, New Zealand. Patients and controls were assessed at 1 week, 3 months, and 6 months injury; and 31 pairs were at 12 months after injury. Neurocognitive assessments included tests of attention, working memory, episodic memory, and speed of information processing and used the Paced Auditory Serial Addition Test, the California Verbal Learning Test-I (CVLT-I), the Symbol Digit Modalities Test, and the Trail Making Test. General cognitive performance was evaluated with the vocabulary and matrix-reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Results at 3 and 6 months showed deficits in verbal learning in the mild- TBI group, but results of neurocognitive tests at 12 months showed no deficits except for a marginal difference on the CVLT total standard score (p < 0.07). Secondary Studies The committee chose 17 secondary studies for review. The studies discussed here did not meet the committeeâs criteria for primary studies as described in Chapter 4. In this discussion, the studies are grouped as follows: TBI associated with sports and then mild TBI, moderate or severe TBI, and varied severity typically in populations other than athletes. Traumatic Brain Injury Associated with Sports People involved in various sports may suffer repeated head injuries, including concussions and mild TBIs. It is often difficult to determine whether the outcome of an injury is related to a single incident or to repeated incidents. When TBI is determined retrospectively by self-report, especially after a period of months or years, it is difficult to be certain about the reliability and validity of the report; this is the case particularly in sports injuries. Studies of TBI associated with sports have found some evidence of long-term cognitive dysfunction (Matser et al., 1998, 1999, 2001; Guskiewicz et al., 2005; Moser et al., 2005; Wall et al., 2006), but the findings are not entirely consistent (Straume-Naesheim et al., 2005). Moser et al. (2005) studied 223 high school athletes (13â19 years old) who participated in a variety of sports (primarily ice hockey, football, field hockey, lacrosse, and soccer). The authors sought to identify the long-term effects of self-reported concussion on neuropsychologic functioning by determining whether there were any differences among four groups of athletes: the recently concussed (within 1 week of neuropsychologic testing), those with no concussion history, those with one concussion sustained at least 6 months previously, and those with two or more concussions sustained at least 6 months previously. The results indicated significant differences among the groups in attention (p = 0.012) and cognitive flexibility and executive functioning (p = 0.006). Post hoc analysis demonstrated that recently concussed athletes perform worse on the attention measure than athletes with no concussion history or a history of one concussion and worse on the cognitive-flexibility measure than those with no concussion history. There were no differences between those with recent concussions and those with two or more concussions on any measures; the authors suggest that this indicates long-term neuropsychologic effects in those with multiple concussions. However, the authors do not report significant differences between athletes with two or more concussions and those with no concussion or one concussion, so their conclusions are uninterpretable.
184 GULF WAR AND HEALTH Matser et al. (1998, 1999, 2001) have conducted a series of studies to determine the effects of heading on neurocognitive outcomes in soccer players. They assessed neurocognitive impairment in 53 active professional soccer players and compared it with that in 27 elite non- contact-sports athletes matched on age (Matser et al., 1998). Professional soccer players performed worse than controls on neurocognitive tests of planning, memory, and visuoperceptual tasks. In another study (Matser et al., 1999), they examined 33 amateur soccer players and compared them with 27 amateur swimming and track athletes. The soccer players demonstrated poorer outcomes than the controls in planning (39% vs 13%; p = 0.001) and memory (27% vs 7%; p = 0.004). The number of concussions was inversely related to neurocognitve performance on six of the tests. Finally, Matser et al. (2001) assessed 84 active professional soccer players with respect to the number of lifetime concussions and headers (calculated as the product of the number of headers in a single match and the number of matches in the last season). The number of headers in one season was inversely related to scores on tests of focused attention and memory. The number of concussions was inversely related to scores on tests of sustained attention and visuoperceptual processing. However, it is possible that soccer players and people who participate in other sports are different before their participation, so those results do not clearly indicate that soccer-playing affects neurocognitive performance. In contrast, Straume-Naesheim et al. (2005) studied the effect of self-reported previous concussions and heading on performance of 271 Norwegian football (soccer) players on neuropsychologic tests and did not find a relationship. Concussion was defined as loss of consciousness or amnesia after a head injury. One hundred thirty-seven players reported having one or more previous concussions, and 112 of them reported that the concussion was football- related. The results showed no relationship between total number of previous concussions or number of headings and results on neuropsychologic subtests. Furthermore, there was no difference in neuropsychologic test scores between players with the lowest heading frequency and those with the highest frequency. When those who reported never having a concussion were compared with those who reported three or more previous concussions, there were no differences in neuropsychologic performance. Thus, the authors found that lifetime heading exposure was not associated with neuropsychologic test performance. Wall et al. (2006) studied the effects of self-reported single and repeated concussions on neurocognitive outcomes in jockeys. Data were collected on 698 jockeys licensed in the United Kingdom, and 627 participated in the study. Time from concussion ranged from 4 months to 27 years (mean, 6.45 years; standard deviation [SD], 6.33 years). Test results were compared for no concussion, single concussion, and multiple concussions. Jockeys with multiple concussions did worse than jockeys with a single concussion on a test of attention and executive functioning (Stroop Test), and younger athletes had a high risk of such decrements. Guskiewicz et al. (2005) studied the association between repeated concussion and long- term cognitive impairment in retired professional football players (average age, 53.8 years). General health questionnaires were mailed to 3,683 retired players, and 2,552 were completed. About 61% of the players reported at least one concussion and 24% reported three or more concussions. Of more than half the players reporting a concussion, 54% reported loss of consciousness or memory loss associated with their concussions. A second questionnaire focusing on memory and issues related to mild cognitive impairment (MCI) was sent about 4 months after the initial questionnaire and was completed by a subset of 758 retired players; the same questionnaire was also sent to a spouse or close relative of each. On the basis of statistical
NEUROCOGNITIVE OUTCOMES 185 analysis of the data, the authors concluded that there is an association between recurrent concussion and clinically diagnosed MCI (p = 0.02) and self-reported memory problems (p = 0.001). Furthermore, a fivefold prevalence of MCI diagnosis and a threefold prevalence of memory problems were found in retired players who had three or more reported concussions compared with retired players who had no concussion history. Studies conducted to examine whether boxing is associated with chronic brain damage have typically compared neurocognitive functioning between boxers and other sports groups. The results have generally not found evidence of neuropsychologic impairment in boxers. For example, Murelius and Haglund (1991) examined 50 Swedish former amateur boxers, 25 soccer players who had reported heading during their careers, and 25 track and field athletes with no previous head injury. Boxers who had taken part in many bouts had slightly lower scores on a motor measure (finger-tapping) than soccer players and track and field athletes, but overall the boxers did not have significant cognitive impairment. Butler et al. (1993) studied 86 active amateur boxers (mean age, 16.7 years), 31 amateur water polo players, and 47 rugby players matched for age but not education. Neurocognitive function was assessed before competition (or before a bout for boxers), immediately after competition, and up to 2 years later. The results before competition found significant differences on 8 of the 12 tests, all indicating that boxers performed less well than the controls. Further analysis indicated that the results were not due to impairment associated with a prior history of boxing. The authors considered the findings as possibly due to uncontrolled-for differences in educational level or verbal functioning between the groups. The results soon after competition and at followup showed no evidence of neurocognitive dysfunction in amateur boxers compared with water polo and rugby players. Porter and Fricker (1996) conducted a neuropsychologic assessment of 20 amateur boxers and compared them with 20 controls matched for age and socioeconomic status. To be eligible to enroll in the study, each amateur boxer had to have competed in at least 40 amateur matches. The subjects were evaluated initially in 1992 and then 15â18 months later. The baseline assessment showed that the boxers performed significantly worse than the controls on a motor measure with the nondominant hand and significantly better than the controls on a test of attention (Trails A) and on a test of cognitive flexibility and executive functioning (Trails B). The results remained the same at followup except that the boxers also performed significantly worse than controls on a motor measure using the dominant hand. The authors concluded that there was no evidence of neuropsychologic impairment in the amateur boxers compared with the controls, and they found no association between boxing and performance on any of the neuropsychologic tests. Porter (2003) conducted a followup study of the same population of 20 amateur boxers and 20 matched controls at 4, 7, and 9 years after the baseline evaluation. The results remained the same as reported at the 18-month evaluation. The authors found no evidence of neuropsychologic impairment over the 9-year period. In fact, the boxers improved on some of the tests in comparison with the controls. As in much of the sports literature discussed above, a diagnosis of TBI was generally based on self-reports of exposure (for example, questionnaires that asked about number of concussions in the past or number of headings in previous matches) or surrogates of exposure (such as number of games played). Reliance on self-reports of exposure may introduce recall bias, and this should be considered in evaluating the results of the studies. An additional problem is the appropriateness of the control groups used. Typically, the controls have been selected from participants in other sports or from healthy persons with unknown comparability of cognitive
186 GULF WAR AND HEALTH functioning before injury or before exposure. The problem here is that demographic differences between the groups may have predated the exposures and potential TBIs, and this would make interpretation of results difficult. Mild Traumatic Brain Injury Vanderploeg et al. (2005) examined long-term neurocognitive outcomes of self-reported mild TBI in a nonreferred sample of male veterans. The study was a cross-sectional cohort of veterans derived from the Vietnam Experience Study (see Chapter 5). Veterans were questioned about health-related events that may have occurred any time in the roughly 16 years from military discharge to the time of the study. A subsample of veterans (excluding 40 who were hospitalized after injury and the 38 for whom data were incomplete) were categorized into three groups based on subjectsâ responses on a questionnaire: no history of motor-vehicle accident (MVA) and no history of TBI (normal controls, n = 3,214), injured in an MVA but no history of TBI (MVA controls, n = 539), and TBI with altered consciousness (mild TBI, n = 254). A 15- measure neuropsychologic battery and neurologic tests of tandem gait and peripheral visual attention were administered. Results revealed no statistically significant difference in any of the neuropsychologic measures among the three groups. However, on the basis of further exploratory analyses of the data, the authors concluded that the mild-TBI group showed more proactive interference on the verbal-learning measure and a tendency to give up more than controls on difficult attention tasks. The results of the study are limited by the long retrospective, self-reporting nature of the data, which could introduce considerable error. Moderate or Severe Traumatic Brain Injury Ruff et al. (1986) assessed neurocognitive functioning after TBI in 15 patients who had moderate TBI (GCS, 9â12), 20 patients who had severe TBI (GCS, 3â8), and 50 healthy controls. All patients were tested at least 6 months after injury; mean duration between injury and assessment was 1 year in patients with moderate TBI and 2 years in those with severe TBI. The subjects were given a battery of neuropsychologic tests, including IQ, motor, memory, attention, and fluency measures. Although the moderate-TBI group performed worse on all measures than the healthy control group, differences were significant only on the fluency measures. In contrast, the severe-TBI group was significantly different from the healthy controls on almost all measures. The severe-TBI group performed significantly worse than the moderate- TBI group in IQ, attention, and fluency measures. Zec et al. (2001) compared long-term memory impairment in 32 severe-TBI patients living independently or in an intermediate-care facility at least 2 years after injury, 15 spinal- cordâinjury patients, and 27 uninjured controls. The TBI patients were in coma or had altered consciousness for at least 3 days. Of the TBI patients, 25 (78%) had either hemiplegia (15) or quadriplegia (10), 19 (59%) had premorbid histories of at least mild alcohol or drug use, and 8 (25%) were intoxicated or under the influence of drugs at the time of injury. Spinal-cordâinjury patients were recruited from the same facilities as the TBI patients, had sustained a severe spinal- cord injury, and were at least 2 years after injury. Of that group, 13 (87%) were quadriplegic, and 2 (13%) were paraplegic. The 27 healthy controls were matched for premorbid socioeconomic background and had no statistically significant differences in age and education from the other groups. A comprehensive neuropsychologic battery was administered to assess intelligence,
NEUROCOGNITIVE OUTCOMES 187 achievement, general cognitive functioning, and memory. The TBI group scored significantly worse than the spinal-cordâinjury and control groups on almost all the tests. Bate et al. (2001) studied 35 consecutive patients admitted into an outpatient rehabilitation center over a 3-year period to identify discrete deficits of attention. All patients had severe TBI as defined by a GCS under 8 or PTA over 24 hours. Thirty-five controls were matched on age, premorbid IQ, and education. Participants and controls were given an attention test and an auditory language task. The TBI participantsâ reaction times were significantly longer than those of the controls, but TBI participants and controls oriented their visual attention in a similar manner. TBI participants made significantly more errors on the auditory language task than controls when they were performing under dual-task conditions; this suggested a deficit in auditory-verbal attention. Incoccia et al. (2004) studied reaction time in 18 people who had severe TBI (GCS, under 8 for at least 6 hours), a mean interval since injury of 39 months (SD, 38 months), and an average coma duration of 20 days (SD, 12.8 days); their mean age was 32 years (SD, 12.6 years). All TBI participants had good motor recovery as evaluated clinically and had good recovery on the Glasgow Outcome Scale. The controls were 36 people who were closely matched in age and schooling. Simple visual stimuli (alertness condition) and the go-no-go tests (which require response inhibition under particular conditions) were administered. In the test with simple visual stimuli, the TBI group and the controls performed similarly; in the go-no-go tests, the TBI group performed more slowly. The authors noted that the findings indicate that people with TBI show deficits in motor programming despite good motor recovery as evaluated clinically. Studies of Varied Severity: Mild, Moderate, or Severe Traumatic Brain Injury Novack et al. (2000) prospectively examined 72 patients who had TBI to assess cognitive and functional recovery. Inclusion criteria involved loss of consciousness (any duration), skull fracture, PTA (any duration), and objective neurologic findings. Most subjects (49, 68%) sustained a severe TBI (GCS no higher than 8). Subjects were evaluated at 6 and 12 months after injury with a battery of neuropsychologic tests to assess orientation, speed of information processing, concentration, memory, constructional abilities, and verbal skills. Test scores were transformed to standard scores by using norms that account for age and education effects, if available. Change in performance from 6 to 12 months after injury was analyzed. Although participants with severe TBI continued to perform worse than participants with mild to moderate TBI, both groups recovered at a similar rate. Summary and Conclusions The committee reviewed 6 primary studies and 17 secondary studies. Primary and secondary studies are consistent in demonstrating sufficient evidence of an association between severe brain injury and neurocognitive deficit. Neurocognitive impairments result in a host of difficulties in people who sustain severe TBI, ranging from attention, memory, information- processing speed, and executive functions to even more robust functions, such as language and visuospatial constructional skills. Such deficits are likely to affect psychosocial outcomes, such as the ability to drive, return to work, and adjust successfully to societal demands (see Chapter 9).
188 GULF WAR AND HEALTH However, there is limited/suggestive evidence that moderate TBI is associated with neurocognitive deficits. Assessment of outcomes in moderate TBI is complicated by the use of many criteria for categorizing âmild,â âmoderate,â and âsevereâ injuries. Thus, in some studies, persons with âmoderateâ injuries had significantly greater indications of injury (more similar to other categorizations of âsevereâ injuries), whereas in other studies, persons with âmoderateâ injuries had significantly smaller indications of injury (more similar to other categorizations of âmildâ injuries). The lack of consensus about what constitutes a âmoderateâ injury complicates understanding of the effects of such injuries. There is inadequate and insufficient evidence of association between mild TBI and neurocognitive deficits more than 6 months after injury. Although there are known to be subjective neurocognitive complaints in some persons with mild TBI after 6 months, the studies show inconsistent results with regard to objective measures of neurocognitive performance in this group. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between severe TBI and neurocognitive deficits. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between moderate TBI and neurocognitive deficits. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists between mild TBI and neurocognitive deficits.
TABLE 6.2 Closed Head Injury and Neurocognitive Outcomes Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations Dikmen et al., Prospective 436 adults, Minimal severity Subjects assessed At 1 year after injury: Controls Study subjects 1995 cohort head-injured patients criteria: any period 1 mo, 1 year afterhead-injured matched on age, included 85% of recruited at time of of LOC, PTA for injury significantly worse sex, education 514 subjects injury in one of three at least 1 h, or than controls (p < recruited from prospective other objective Neuropsychologic 0.01) on Results represent three longitudinal longitudinal studies: evidence of head tests included neuropsychologic tests weighted studies behavioral outcome trauma Halstead Reitan except difference on averages that of head injury, Neuropsycho- Category Test adjust for patient characteristics Head-injury logical Test (p < 0.05) differences and head-injury severity assessed Battery; motor between studies outcome, Dilantin with GCS, number function assessed Nonsignificant in inclusion prophylaxis of of nonreactive with finger- differences on two criteria posttraumatic pupils, mass tapping, name- memory measures seizures lesions requiring writing for craniotomy, TFC dominant, Severely head-injured 121 general TCs nondominant (TFC 29 days or enrolled as part of Coma from < 1 h hands; attention, greater) had patient- to more than 4 concentration, significant characteristics study weeks flexibility, impairments on all quickness measures (p < 0.001) measured with except WMS-LM (p < Seashore Rhythm 0.01), WMS-VR (p < Test, TMT A and 0.05) TMT B, Stroop Color and Word Clear doseâresponse Test Parts 1 and relationship between 2; memory length of coma (TFC), evaluated with level of performance WMS, WMS-LM, on neuropsychologic WMS-VR, SR; measures; for verbal skills example, median II measured with for TC = 0.1; TFC < 1 WAIS VIQ; h = 0.1, 1â24 h = 0.3, performance 25 hâ6 days = 0.4, 7â 189 skills measured 13 days = 0.4, 14â28
190 Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations with WAIS PIQ, days = 0.7, 29 days Tactual = 1.0 Performance Test; reasoning measured with Category Test; overall performance measured with Halstead Impairment Index Dikmen et al., Prospective 20 hospitalized Mild; subjects met Motor, 1 mo after TBI, mild Matched on age, Exclusion criteria: 1986 cohort subjects with mild following criteria: psychomotor neuropsychologic education, sex subjects with prior head injury; 19 coma not over 1 h skills (finger- effects found, none head injury, uninjured friend or, if no coma, tapping speed); significantly different; alcoholism, controls PTA of at least 1 h; attention, at 1 year after TBI, cerebral disease, GCS 12 on flexibility, similar post-TBI mental retardation, 19 of 20 seen at 1 admission; no quickness symptoms reported in significant year clinical evidence (Speech Sounds TBI, non-TBI subjects psychiatric of cortical or Perception, disorder brainstem Seashore Rhythm, contusion TMT A, TMT B); 15â60 years old memory and learning (WMS, Healthy friend SR); reasoning controls may not (Category Test); control for general health status in effects of trauma terms of sickness (Sickness Impact Small sample Profile); symptoms frequently reported as part of TBI (Head Injury Symptom
Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations Checklist); resumption of major activities, including work, school, homemaking (Function Status Index) Dikmen et al., Prospective 102 people with Mild, moderate, Memory (WMS, At 1 mo after TBI, Matched on age, Exclusion criteria: 1987 cohort closed head injury severe SRP) head-injured group education, race, prior CNS injury, admitted into performed sex significant Harborview Medical Subjects met significantly worse on neuropsychiatric Center, Seattle; 102 following criteria: both memory tests (p difficulties friend controls LOC or PTA over < 0.001); at 1 year 1 h or evidence of after TBI, most 15â60 years old 97 of 102 head- cerebral trauma subscales still show injured, 88 of 102 significant impairment controls evaluated at 30% GCS 3â8, 1 year after injury 12% GCS 9â11, Memory performance 59% GCS > 12 a function of head- injury severity, length 23% PTA < 24 h, of coma at 1 mo; 25% PTA 1â6 weaker relationship at days, 20% PTA 7â 1 year after TBI 13 days, 32% PTA > 14 days 77% moving- vehicle accidents, 10% falls, 8% fights or assaults, 5% other Tate et al., 1991 Cohort Consecutive series of Severe, blunt TBI: Subjects 70% of head-injured Controls Australian first 100 admissions sustained open examined by showed impairments: matched on age, rehabilitation into adult head-injury head injury, initial trained clinical 56.5% of head-injured sex, education, population 191
192 Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations rehabilitation unit closed head injury neuropsychologist had disorders of SES later required learning, memory vs 82 of 100 subjects Followed average of neurosurgery Neuropsychologic 5% in sibling control completed 6.3 years after impairment group; neuropsychologic trauma Head-injured evaluated with 16.5% of head-injured tests group sustained MMS, Incomplete had disturbances in Eligible: 66 males, severe injuries: Letters, basic neurocognitive 15â45 years old 21 females, sibling 98% had PTA over ideomotor praxis skills vs 2.5% in controls 1 week, 74% over tasks, ROCF, sibling control group; Crude ORs 1 mo WAIS-R Digit 34.1% of head-injured Span and had slowness in Vocabulary information subtests, Schonell processing vs 2.5% in Reading Test, sibling control group; TMT, SR, AM, 40% of head-injured Corsi test of had posttraumatic recency memory, personality change vs WCST, TT, Word 7.5% in sibling Fluency Test of control group Thurstone and Thurstone, DF, BCT Lannoo et al., Cohort 85 patients Moderate to severe Administered MANOVA on Inclusion criteria 1998 consecutively TBI neuropsychologic neuropsychologic test for patients and admitted into the (GCS score 3â12) test battery at 6 battery indicated controls: ages 15â ICU of University mo after injury, significant difference 65 years, no Hospital of Gent including tests of: between groups (p < history of CNS in September 1993â attention, 0.05); univariate disease or mental February 1996 information analyses showed retardation processing; visual significant differences 32 TCs (traumatic reaction time; (p < 0.05) on almost injuries of parts of memory, all tests, with TBI body other than learning; verbal group performing head) admitted into fluency; mental worst ICU during same flexibility
Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations study period Heitger et al., Prospective 37 patients with mild Mild Neurocognitive At 12 mo, no Controls Exclusion criteria 2006 cohort head injury, 37 testing: PASAT, neurocognitive matched on age, included alcohol controls; patients TMT A and TMT deficits remained sex, education or drug use; CNS recruited from ED of B, WASI disorder; Christchurch Marginal group psychiatric Hospital, New differences on CVLT conditions; Zealand; controls total standard score structural brain recruited from damage or database of interested hematoma on CT students scan; oculomotor or somatomotor deficits; strabismus, poor visual acuity, skull fracture, or history of prior TBI NOTE: AM = Austin Maze, BCT = Booklet Category Test, CNS = central nervous system, CT = computed tomography, CVLT = California Verbal Learning Test, DF = Design Fluency Test, ED = emergency department, GCS = Glasgow Coma Scale, ICU = intensive care unit, LOC = loss of consciousness, MANOVA = multivariate analysis of variance, MMS = Mini Mental Status, OR = odds ratio, PASAT = Paced Auditory Serial Addition Test, PIQ = performance intelligence quotient, PTA = posttraumatic amnesia, ROCF = Rey-Osterrieth Complex Figure Test, SES = socioeconomic status, SR = Selective Reminding Test, SRP = Selective Reminding Procedure, TBI = traumatic brain injury, TC = trauma control, TFC = time to follow commands, TMT A and TMT B = Trail Making Test A and B, TT = Tower of London Test, VIQ = Verbal Intelligence Quotient, WAIS = Wechsler Adult Intelligence Scale, WAIS-R = Wechsler Adult Intelligence ScaleâRevised, WASI = Wechsler Abbreviated Scale of Intelligence, WCST = Wisconsin Card Sorting Test, WMS = Wechsler Memory Scale, WMS-LM = Wechsler Memory Scale, Logical Memory, WMS-VR = Wechsler Memory Scale-Visual Reproduction. 193
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