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7 NEUROLOGIC OUTCOMES This chapter discusses neurologic outcomes, such as seizure disorders, postconcussion symptoms, ocular and visual motor degeneration, neuroendocrine disorders, and the neurodegenerative diseases dementia of the Alzheimer type, dementia pugilistica, parkinsonism, multiple sclerosis, and amyotrophic lateral sclerosis. SEIZURE DISORDERS The onset of seizures has been linked to an excessive electric discharge in the brain, cortical disruption, scarring, irritability, and the release of various endogenous neurotoxins (Silver et al., 2005). Seizures can cause a wide variety of symptoms, including loss of consciousness, shaking, and changes in vision, hearing, taste, mood, and mental function. There are two main types of seizures: generalized and focal. Generalized seizures result from abnormal electric activity on both sides of the brain, and focal, or partial, seizures result from localized excessive electric activity in one portion of the brain. A number of studies have noted the presence of seizures after traumatic brain injury (TBI). Seizures that occur within the first 7 days after TBI are termed acute symptomatic or provoked. Seizures that occur more than 7 days after injury are termed remote symptomatic or unprovoked. If unprovoked posttraumatic seizures are recurrent, they are called posttraumatic epilepsy. A 5% incidence of posttraumatic seizures has been found after closed head injury and a 30â50% incidence after open head injury (Silver et al., 2005). The overall risk of seizures caused by penetrating TBI related to war injuries is as high as 53%; in civilian populations, the overall risk of seizures after closed head trauma of any severity ranges from 0.5% to 8% (Jennett, 1975; Salazar et al., 1985). The prevalence of epilepsy in the general population as estimated by the Centers for Disease Control and Prevention during the period 1986â1990 was 4.7 cases per 1,000 persons (CDC, 1994). Garga and Lowenstein (2006) note that TBI âaccounts for 20% of symptomatic epilepsy in the general population and 5% of all epilepsy.â Primary Studies The committee identified 10 primary studies that examined the association of TBI with seizures: six studies of military populations with penetrating head injuries and four of civilian cohorts with closed head injuries. See Table 7.1 for a summary of the primary studies. 197
198 GULF WAR AND HEALTH The six primary studies lack the controls that were a key part of the Rochester Epidemiology Project (discussed below), but the rate of seizures in this group was generally higher than the rate in the general population. Furthermore, in most studies it is not possible to determine how many subjects had only a single seizure within 6 months of injury and none later. Thus, the overall proportion of those classified as having post-TBI seizures, ostensibly lasting more than 6 months, might be slightly inflated. In general, the risk of unprovoked seizures after penetrating TBI is higher than the risk after even the most severe forms of closed TBI. Caveness et al. (1962) compared the number of seizures reported by others in soldiers who sustained both penetrating and nonpenetrating head injuries during World War I (WWI; Credner, 1930; Ascroft, 1941), World War II (WWII; Russell, 1951; Walker and Jablon, 1961), and the Korean War (Caveness and Liss, 1961). They found that seizures were more likely to occur after penetrating head injury (34â43%) than after blunt and blast head injury (12â24%). Of the 317 cases in the WWI cohort, 34.8% reported having seizures compared with 28% of those in the WWII cohort and 24.1% of those in the Korean War cohort. The proportion of patients who had penetrating TBI that later had seizures ranged from 42% in the Korean War cohort (Caveness and Liss, 1961) to 47% in the WWI cohort (Ascroft, 1941). A followup study was conducted by Caveness (1963) 8â11 years after initial injury. During the followup period, 356 of the original Korean War subjects participated (76.2% of the total and 87.2% of those suitable for followup). Information was collected through mailed questionnaires, physical examinations, interviews with the American Red Cross, and a review of Veterans Administration (VA) records. During the period 1957â1958, additional VA information was available on 84.6% of the participants. Questionnaires were obtained in 1961â1962 from 90.5% of the participants, personal letters from 21.6%, and telephone replies from 9.6% (Caveness, 1963). Caveness (1963) found that of the 356 men, 109 (30.6%) had postinjury seizures; 30 patients had seizures that did not persist beyond 6 months, so 79 (22%) apparently had seizures more than 6 months after injury. Of those with penetrating head wounds, 42% suffered seizures, and 16.4% of those with blunt head wounds had seizures. The authors noted that there was no significant difference in the number of seizures between the total original group and those who were followed for 8â11 years. Evans (1962) assessed the prevalence of seizures in the same 422 head-injured Korean War veterans at 3â11 years after injury. The overall prevalence was 19.7%. The prevalence was 32% in those with penetrating head injuries, 2% in those with blast wounds, and 8% in those with blunt head injuries. Phillips (1954) conducted a conditional cohort study of 500 head-injured men admitted within 3 days of injury into the Military Hospital for Head Injuries, Oxford. Information was collected on amnesia, electroencephalographic findings, personal and family history, cerebrospinal fluid (CSF) pressure, epilepsy, intracranial hemorrhage, CSF leak, infection, mental-health changes, condition on discharge, and followup after rehabilitation. The author found that 31 men (6%) developed seizures after injury; 24 had generalized seizures, 5 focal seizures, and 2 mixed seizures. Seven with seizures had focal signs after injury, of whom 5 had focal seizures and 2 had generalized seizures. All the focal seizures occurred within the first 6 days after injury, whereas generalized seizures typically did not typically for several months. It is unclear whether the head injuries were combat-related, and the time between injury and seizure
NEUROLOGIC OUTCOMES 199 is ambiguous. Thus, it was not possible to determine from the report the number of patients who had their only seizure within 6 months of injury. Russell (1968) conducted a conditional cohort study of the prevalence of epilepsy after penetrating head injury in 185 patients injured in WWII. The men were followed for 10â20 years after injury. Of the 185, 77 (41.6%) had posttraumatic grand mal epilepsy, and 40 (21.6%) were still having seizures 10 years or more after injury. The study was limited in that it did not include a control population and the cohort was not described in terms of age, sex, and nationality. It also is not clear who may have had only one seizure in the first 6 months after injury. Weiss et al. (1983) studied 1,221 head-injured Vietnam veterans enrolled in the Vietnam Head Injury Study (VHIS). Although the focus of the study was on prognostic factors in the occurrence of epilepsy, they reported that 31% of the cohort had seizures more than a week after injury. A followup study of this cohort was reported by Salazar et al. (1985) and by Rish et al. (1983). The four studies of closed TBI and seizure risk in civilians come from the Rochester Epidemiology Project (see Chapter 5). Annegers et al. (1980) reported the risk of unprovoked seizures in a cohort of 2,747 patients (1,132 children and 1,615 adults) in Olmsted County, Minnesota, who had sustained TBI in 1935â1974. An additional 4,541 patients who sustained TBI in 1975â1984 were added later (Annegers et al., 1998). As part of the Rochester Epidemiology Project, medical records containing physician diagnoses of TBI were linked to later medical records documenting unprovoked seizures in the study interval and compared with records of those who did not sustain TBI. The authors found the overall risk of unprovoked seizures after TBI to be 3.6 times (95% CI, 2.7â4.8) that in the noninjured population. That risk, also known as the standardized incidence ratio (SIR), was highest among those with severe TBI (SIR, 17.0; 95% CI, 12.3â23.6), followed by those with moderate TBI (SIR, 2.9; 95% CI, 1.9â 4.1) and mild TBI resulting in loss of consciousness (LOC) or posttraumatic amnesia (PTA; SIR, 1.5; 95% CI, 1.0â2.2). The overall unprovoked-seizure risk was found to be highest in the first year after injury (SIR, 12.7) and to fall (to 4.4) 1â4 years after injury and fall further (to 1.4) 5 years or more after injury. That pattern of seizure risk over time was also found in each TBI- severity group. Although the risk of unprovoked seizures after mild TBI was increased at all times after injury, it was significantly different from the risk in the uninjured population only during in the period 1â4 years after injury. A limitation of both Annegers et al. studies (1980, 1998) is that the authors included children in the study and in the risk estimates. It is not possible with the available data to calculate rates for adults only, and reported rates may be misleading inasmuch as seizures occur more frequently in children than adults. Therefore, the generalizability to the veteran population is unclear. Two additional published analyses of the Rochester Epidemiology Project included children but presented the post-TBI incidence of seizures in adults separately. Annegers and colleagues (1995) reported that the age-adjusted incidence of post-TBI seizures in adults ranged from 2.0/100,000 person-years in 25- to 34-year-olds to 14.0/100,000 person-years in those over 74 years old. In addition, the age-adjusted incidence of post-TBI seizures was higher in males at all ages (8.6/100,000 person-years in males and 4.8/100,000 person-years in females). Singer (2001) used data from the Rochester Epidemiology Project to compare the incidence of post-TBI seizures with the incidence of idiopathic epilepsy previously determined for Olmsted County.
200 GULF WAR AND HEALTH Singer (2001) found that the incidence was highest in the first year after head injury. Compared with the expected seizure rate in idiopathic epilepsy, seizures were 3.1 times more likely to occur during the first year after mild head injury, 6.7 times more likely after moderate head injury, and 95 times more likely after severe head injury. Overall, mild head injury resulted in 0.4 excess seizure per 1,000 per year, whereas severe head injury resulted in 10 per 1,000 per year. Secondary Studies The committee identified 19 secondary studies of the relationship between TBI and the onset of seizures. The major limitation of the studies is lack of a control or comparison population. Two secondary studies were drawn from the VHIS registry, which is described in more detail in Chapter 5. Both studies found an increase in epilepsy 15 years after injury. Rish and colleagues (1983) studied male Vietnam veterans who had had penetrating craniocerebral injuries and had survived for 1 week after injury. Of 1,127 veterans, 378 had a diagnosis of posttraumatic epilepsy (34%). Similarly, Salazar and colleagues (1985) studied the first 421 head-injured veterans to followup as part of phase II of the VHIS and found that 53% had posttraumatic epilepsy. The relative risk of epilepsy in the head-injured veterans was 580 times that in the general age-matched population in the first 6 months and fell to 25 times higher after 10 years. About 57% of patients with seizures had attacks within a year after injury; in about 18%, the first seizure occurred more than 5 years after injury; and in 7%, the first seizure came 10 years or more after injury. At 15 years after injury, 28% of all those who sustained head injuries had persistent seizures. Jennett and Lewin (1960) and Jennett (1962, 1969, 1973, 1975) conducted a number of studies of posttraumatic epilepsy in head-injured patients admitted into hospitals in Oxford, Glasgow, and Rotterdam. (A detailed description of the cohort is included in Chapter 5.) Jennett and Lewin (1960) studied 1,000 patients who sustained nonmissile head injuries and were consecutively admitted to the Radcliffe Infirmary, Oxford, in 1948â1952. In the first month after injury, 4.6% of the cohort experienced seizures. Four years after the last case was admitted, the authors followed up the series to determine the rate of seizures and found that 28 (10%) of the 275 patients who were able to be followed had one or more seizures. Jennett (1962) assessed the incidence of epilepsy in 315 patients of the above cohort. The 315 patients included 75 who were in the inclusive series with early epilepsy and 240 from the original 1,000 who did not have early epilepsy. Some 58 cases of late epilepsy were observed in this population. Jennett (1969) expanded on the original Oxford series of patients by including additional cases and cases from a hospital in Glasgow, Scotland. Seizure risk was assessed in 600 patients who had blunt head injury and depressed skull fracture. After 1 year, 9.5% of the 333 patients able to be followed up had developed seizures. Jennett (1973) studied the Oxford and Glasgow population and included an additional 250 head-injured patients from Rotterdam who had depressed fractures. The incidence of late epilepsy in the unselected series of injuries was calculated to be about 5% and about 45% in those who sustained missile injuries. Jennett (1975) provided a summary of the seizure cases identified in the Oxford, Glasgow, and Rotterdam cohorts. Several other authors reported on head-injured patients admitted into the Radcliff Infirmary. Roberts (1979) studied the subset of head-injured patients admitted with severe TBI
NEUROLOGIC OUTCOMES 201 (PTA of over a week or LOC of over a month). Of the 291 patients in this series examined 10â24 years after head injury, 25.5% developed seizures (Roberts, 1979). Lewin et al. (1979) reported that posttraumatic epilepsy was diagnosed in 28% of 479 patients admitted into the John Radcliffe Infirmary in Oxford in 1955â1969 with a head injury resulting in PTA or LOC of a week or more. Three secondary studies assessed seizure rates in veterans or military personnel who had sustained penetrating head injury. Wagstaffe (1928) studied the prevalence of epilepsy in 377 WWI veterans who had sustained a penetrating gunshot wound of the head and found that 37 had seizures and that âtraumatic epilepsy is nearly ten times more common with penetrating wounds of the dura than with other injuries to the head.â Watson (1947) studied the prevalence of epilepsy in 279 patients admitted with penetrating head injury sustained during WWII and found that 101 (36.2%) had had seizures at the 2-year followup. Russell and Davies-Jones (1969) conducted a conditional cohort study of the occurrence of epilepsy after penetrating head injury in WWII soldiers and found that 42% of 562 soldiers had had epilepsy by 5 years after the penetrating TBI. Four secondary studies assessed seizure rates in head-injured patients admitted into hospitals. Miller and Jennett (1968) studied seizure rates in 400 patients who had penetrating or puncture head wounds. Over half had brief or no LOC and PTA less than 1 hour, and late posttraumatic epilepsy occurred in 9.5%. Stevenson (1931) assessed the occurrence of epilepsy in 84 patients who sustained gunshot wounds of the head; 74% of those with penetrating and 23% of those with superficial wounds of the head had epilepsy. Sargent (1921) found that 800 of 18,000 people who had sustained gunshot wounds of the head had seizures (4.5%). And Penfield and Shaver (1945) assessed epilepsy in patients admitted into a hospital because of a head injury in 1929â1941; of the 407 patients assessed, 11 developed epilepsy, for an incidence of 2.7%. Two secondary studies assessed risk factors for posttraumatic epilepsy. Angeleri et al. (1999) conducted a prospective study of risk factors for posttraumatic epilepsy in 137 consecutively enrolled patients up to 1 year after injury. They found that the posttraumatic epilepsy group included 18 who had at least two seizures at 2â12 months; risk factors included a low score on the Glasgow Coma Scale (GCS), early seizures, and single brain lesions seen with computed tomography (CT). Englander et al. (2003) also studied risk factors for late posttraumatic epilepsy in 647 patients who had moderate or severe TBI and were admitted into trauma centers within 24 hours of injury. The patients were followed for up to 2 years, until death, or until their first late posttraumatic seizure. Sixty-six had late posttraumatic seizures, 337 had no late posttraumatic seizures during the full 24-month followup, 167 had no late posttraumatic seizures during the time they were followed, and 54 patients were given anticonvulsants and did not have late posttraumatic seizures. The authors found that the highest cumulative probabilities of late posttraumatic seizures were associated with biparietal contusions (66%), dural penetration with bone and metal fragments (62.5%), multiple intracranial operations (36.5%), multiple subcortical contusions (33.4%), subdural hematoma with evacuation (27.8%), midline shift greater than 5 mm (25.8%), and multiple or bilateral cortical contusions (25%). In addition, initial GCS score was associated with the cumulative probabilities of late posttraumatic seizures at the 24-month followup (GCS score of 3â8, 16.8%; score of 9â12, 24.3%; and score of 13â15, 8.0%).
202 GULF WAR AND HEALTH Finally, Ryan et al. (2006) assessed seizure symptoms in 127 college undergraduates who reported a history of head injury. Participants were divided into three categories on the basis of their self-reported head-injury status: students who sustained head injury with brief LOC, students who had head injury with brief alteration of consciousness (AOC), and students who had no head injury. The authors found that those in the LOC group reported a greater frequency of seizure symptoms and a greater number of clinically significant seizure symptoms (p < 0.015) than the no-head-injury group and had more clinically significant seizure symptoms than the AOC group (p < 0.09). There was no significant difference between the AOC and no-head-injury groups in frequency of seizure symptoms or number of clinically significant seizure symptoms. Summary and Conclusion The committee reviewed 10 primary studies and 19 secondary studies of TBI and seizures. The secondary studies are largely supportive of the primary studies that indicate that brain injury is associated with seizure activity. Unprovoked seizures were strongly associated with most types of TBI. The highest risk of unprovoked seizures occurred in those suffering penetrating head injury (which usually occurred during military combat): 32â53% had seizures. After blunt trauma, seizure risk varied with initial injury severity. Compared with the healthy, uninjured population, the risk of unprovoked seizures was about 17â95 times higher after severe TBI and 2.9â6.6 times higher after moderate TBI. The seizure risk after mild TBI that resulted in LOC or PTA was about 1.5 times that in the healthy, uninjured population. The risk of seizure after a blast is not clear, although one study of Korean War veterans reported that 2% suffered a seizure within 11 years of injury. In general, the seizure risk after all forms of TBI appears to be highest within the first year after trauma and to decline thereafter. Animal models confirm the presence of seizures after both penetrating and blunt TBI. Using a lateral fluid percussion model of TBI in adult rats, several authors have demonstrated both provoked and unprovoked seizures (Golarai et al., 2001; Santhakumar et al., 2001; DâAmbrosio et al., 2004; Kharatishvili et al., 2006). A single episode of severe fluid percussion injury can cause a spontaneous seizure and recurrent seizures that become chronic and become worse with time (DâAmbrosio et al., 2004). Seizures have also been demonstrated after TBI induced in rats in a penetratingâballistic-injury model (Williams et al., 2005). The committee concludes, on the basis of its evaluation, that there is sufficient evidence of a causal relationship between sustaining a penetrating TBI and the development of unprovoked seizures. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of a causal relationship between sustaining a severe TBI and the development of unprovoked seizures. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of a causal relationship between sustaining a moderate TBI and the development of unprovoked seizures. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between sustaining a mild TBI
NEUROLOGIC OUTCOMES 203 resulting in loss of consciousness or amnesia and the development of unprovoked seizures.
204 TABLE 7.1 Seizure Disorders and TBI Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations Annegers et Retrospective 2,747 patients of TBI determined by Seizures SIR; seizures in Age- and sex- Children included in al., 1980 cohort Olmsted County, health-care provider, determined from adults, children: matched controls risk estimate; results MN, with head documented in medical records < 1 year after trauma, include children, injuries sustained medical record SIR, 12.7 (95% CI, whose rates of 1935â1974 195 severe head 7.7â20); seizures may be compared with injuries: documented 1â4 years after different from age-, sex-specific brain contusion trauma, SIR, 4.4 adultsâ rates rates in general (diagnosed by (95% CI, 2.7â6.9); population; observation during 5+ years after followed for surgery,or from focal trauma, RR, 1.4 28,176 person- neurologic (95% CI, 0.7â2.5); years abnormalities), overall SIR, 3.6 Excluded deaths intracranial (95% CI, 2.7â4.8) within 1 mo, hematoma, or at least seizures before 24 h of TBI, prior unconsciousness epilepsy, second or PTA head injury, prior TBI, seizure within912 moderate head 1 week of TBI, injuries: skull febrile seizures fractures or 1,132 of 2,747 head injuries, causing patients (41%) at least 0.5 h of were children less unconsciousness than 15 years old or PTA 1,640 mild head injuries: no fracture but unconsciousness or PTA for less than 30 min Annegers et Retrospective Same as above, but Mild: LOC or Seizures Including children, Cumulative Children included in al., 1998 cohort new cases added amnesia for determined from adults: probability of risk estimate; results (4,541) for less than 30 min medical records Mild: SIR, 1.5 (95% unprovoked include children,
Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations additional 10-year Moderate: LOC CI, 1.0â2.2); seizure after TBI whose rates of period (1975â for 30 minâ24 h or moderate, SIR, 2.9 estimated with seizures may be 1984) and skull fracture (95% CI, 1.9â4.1); Kaplan-Meier different from followup of Severe: LOC or severe, SIR, 17.0 method adultsâ rates original cases amnesia for (95% CI, 12.3â23.6) Importance of (followup of more than 24 h, Mild: < 1 year, SIR, prognostic 53,222 person- subdural hematoma, 3.1 (95% CI, 1.0â factors years) or brain 7.2); 1â4 years, SIR, determined with contusion 2.1 (95% CI, 1.1â Cox proportional 3.8); 5â9 years, SIR, hazards analysis 0.9 (95% CI, 0.3â 2.6); 10 years, SIR, 1.1 (95% CI, 0.5â 2.1) Moderate: < 1 year, SIR, 6.7 (95% CI, 2.4â14.1); 1â4 years, SIR, 3.1 (95% CI, 1.4â6.0); 5â9 years, SIR, 3.0 (95% CI, 1.2â6.2); 10 years, SIR, 1.8 (95% CI, 0.8â3.6) Severe: < 1 year, SIR, 95.0 (95% CI, 58.4â151.2); 1â4 years, SIR, 16.7 (95% CI, 8.4â32.0); 5â9 years, SIR, 12.0 (95% CI, 4.5â26.6); 10 years, SIR, 4.0 (95% CI, 1.1â10.2) Singer, 2001 Retrospective Same population Mild head injury: Seizures 97 of 4,541 TBI Included children cohort as above (4,541 LOC or amnesia for determined from cases had at least one and adults patients) with TBI less than 30 min medical records seizure in 50-year 205
206 Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations diagnosed in Moderate head period Olmsted County, injury: LOC Mild head injury: MN, 1935â1984 for 30 minâ24 h or comparative Post-TBI seizure skull fracture incidence rate, 1.52 incidence rates Severe head injury: (3.1 in first PT year, compared with LOC or amnesia for 2.1 in years 1â5); expected idiopathic more than 24 h, excess event rate, 0.3 seizure rate as ratio subdural hematoma, Moderate head (comparative or brain injury: comparative incidence rate) and contusion incidence rate, 2.85 absolute difference (6.65 in first PT year, (excess event rate) 3.1 in years 1â5); per 1,000 of excess event rate, 1.1 population per year Severe head injury: comparative incidence rate, 17.0 (95 in first PT year, 16.7 in years 1â5); excess event rate, 10 Annegers et Retrospective 692 patients in Head trauma Seizures Age-adjusted Age Included children al., 1995 cohort Olmsted County, determined from incidence rates of and adults MN, who medical records; acute symptomatic developed acute acute symptomatic post-TBI seizures, symptomatic post- seizures defined as 2.0 per 100,000 TBI seizures in occurring within 7 person-years (25- to 1955â1984 days of brain 34-year-olds) to 14.0 trauma or during per 100,000 person- period of recovery years (> 74-year- from such an insult olds); incidence higher in males than females at all ages (overall age-adjusted rate, 8.6 in males vs 4.8 in females) Caveness et Five WWI: 1,990 Blunt and penetrating Seizures 38.2% had seizures None No referent group;
Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations al., 1962 retrospective German war determined at undetermined cohorts from injuries; head Hechsler whether there were WWI, WWII, trauma examined Institution preinjury seizures; Korean War 1914â1928 (> 50% inability to were > 5 years determine number after trauma) who may have had their one and only seizure within first 6 mo after TBI WWI: 317 GSW of Penetrating Seizures 34% head, 7â20 years determined at after trauma British Ministry of Pensions WWII: 820 GSWs Dural penetration Seizure determined 43% within 5 years after by postal inquiry trauma; WWII: 739 head Blunt, blast, Seizures 28% (missile, 33.9%; injured selected penetrating blunt, blast, 24.1%) from Army and VA 7â8 years after trauma Korean War: 407 âCraniocerebral Seizures 24.1% (missile, 35%; random sample 5 injury in combatâ determined by blunt, blast: 12.2%) years after trauma record review or interviews 214 missile, 52 135 with dura matter blast, 141 blunt rupture Caveness, Conditional 356 Korean War Penetrating (52%), Seizures Prevalence of No reference group; 1963 cohort veterans with head blunt (48%) determined with seizures: overall, no screening for injuries treated by Six categories: I, postal 30.6%; seizures preinjury seizure study author or two head blow without questionnaire lasting > 6 mo, 22%; disorder other NS and MS change; II, penetrating, 42.1%; Cohort may overlap assessed 7â8 years transient LOC; III, blunt, 16.4%; I, with Evans 13526 after injury focal brain injury 7.1%; II, 10.4%; III, 207
208 Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations without dural 39.0%; IV, 20.0%; penetration; IV, dural V, 51.4%; VI, 57.3% penetration without neurologic deficit; V, dural penetration with neurologic deficit; VI, dural penetration with profound complications Evans, 1962 Conditional 422 Korean War Penetrating (52%), Seizures Prevalence of No reference group; cohort veterans with head blunt (35%), blast determined with seizures: overall, no screening for injuries treated at (12%) postal 19.7%; penetrating, preinjury seizure US Naval Hospital Five categories: I, no questionnaire 32%; blunt, 8%; disorder in Yokusaka or on scalp lacerations, no blast, 2%; I, 1%; II, Cohort may overlap US hospital ships, skull fracture; II, 1.7%; III, 1.2%; IV, with Caveness 13530 assessed 3â11 scalp lacerations, no 1.7%; V, 14% Inability to years after injury skull fracture; III, Seizure prevalence determine number linear skull fracture; increased with who may have had IV, depressed skull increasing duration their one and only fracture; V, brain of LOC and PTA seizure within first 6 penetration mo after TBI Phillips, 1954 Conditional 500 adult male Blunt head trauma Seizures 6% had seizure No controls; unclear cohort âmilitary whether combat- personnelâ related; unclear admitted into interval between military hospital injury and seizures; for head injuries in inability to Oxford for head determine number injury with seizures persisting beyond 6 mo Russell, 1968 Conditional 185 patients Penetrating TBI Seizures 21.6 % had seizures No controls, but cohort followed > 10 combat-related; years after injury cohort not described
Type of TBI: Mild, Moderate, Health Outcomes Severe; Blunt, or Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations in terms of age, sex, nationality, how wounded; inability to determine number with seizures persisting beyond 6 mo Weiss et al., Prospective 1,221 head injured Penetrating TBI PT epilepsy 31% had seizures > 1 Inability to 1983 cohort (W.F. Vietnam veterans week after injury; determine number Caveness formula used to with seizures VHIS registry) describe onset of first persisting beyond 6 seizures after injury mo, but Salazar and Rish report that 43% of seizure patients in this cohort had their first seizure more than 1 year after injury NOTE: CI = confidence interval, GSW = gun shot wound, LOC = loss of consciousness, MS = mental status, NS = neurosurgeons, PT = posttrauma, PTA = posttraumatic amnesia, RR = relative risk, SIR = standardized incidence ratio, TBI = traumatic brain injury, VA = Department of Veterans Affairs, VHIS = Vietnam Head Injury Study, WWI = World War I, WWII = World War II. 209
210 GULF WAR AND HEALTH POSTCONCUSSION SYMPTOMS Numerous symptoms have been reported after TBI. Both the International Classification of Diseases, 10th Edition (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), recognize a constellation of symptoms that may occur after TBI. The ICD-10 recognizes a postconcussion syndrome (PCS), and the DSM-IV postconcussional disorder (PCD). The ICD-10 criteria used to diagnose PCS include three or more of the following eight symptoms: headache; dizziness; fatigue; irritability; subjective concentration difficulty; memory impairment; insomnia; and reduced tolerance of stress, emotional excitement, or alcohol. There is no clear requirement that the symptoms began or worsened after the head trauma although there is a statement that the syndrome occurs after head trauma. The DSM-IV criteria include the presence of three or more of the following symptoms that occur or worsen shortly after the trauma and last at least 3 months: fatigue; disordered sleep; headache; dizziness; irritability; changes in personality; apathy or lack of spontaneity; or anxiety, depression, or affective lability (Luis et al., 2003). Criteria for PCD, which is a research definition rather than a clinical definition, also include difficulty in attention or memory on the basis of neuropsychologic testing and a finding that the symptoms cause substantial impairment in social or occupational functioning and constitute a decline from a previous level of functioning. Although there were numerous studies of persistent symptoms after TBI, none looked specifically at PCS or PCD. Primary Studies Eight primary studies were identified that looked at the association of TBI with symptoms. Hoge et al. (2008) looked at symptoms reported by soldiers 3â4 months after their return from year-long deployments in Iraq and compared those who reported LOC or altered mental state with those who reported an injury that did not involve an altered mental state. Two of the studies evaluated the relationship between TBI and postconcussion symptoms in separate cohorts of people with head trauma involving brief LOC who had been seen in the emergency departments (EDs) of two hospitals in Kaunas, Lithuania (Mickeviciene et al., 2002, 2004). Masson et al. (1996) evaluated the prevalence of symptoms in patients in Aquitaine, France, 5 years after hospitalization for head injury. Stulemeijer et al. (2006a) evaluated fatigue in patients who attended the ED of a Dutch hospital. Those four studies compared the rates of symptoms in TBI patients with rates in patients who had trauma that did not involve the head. McLean et al. (1993) assessed the rate of symptom endorsement 12 months after hospitalization for head injury compared with the rate in friends who did not experience a head injury. Heitger et al. (2007) compared subjects who had mild TBI and were admitted into a New Zealand ED with uninjured controls recruited from a database of volunteers interested in participating in research studies. Gerber and Schraa (1995) conducted a prospective study of patients consecutively admitted into an ED because of mild TBI and compared them with a group that had orthopedic injuries and with uninjured controls. (See Table 7.5 for a summary of the primary studies of this outcome.) Hoge et al. (2008) studied the symptoms that were bothersome or frequent in 2,525 US Army soldiers 3â4 months after their return from year-long deployments in Iraq. They compared the 124 who reported injuries involving LOC and the 260 who reported injuries with altered mental state with the 435 who reported other injuries. Symptom rates among the 1,706 who
NEUROLOGIC OUTCOMES 211 reported no injury were also given. Soldiers were recruited from two brigades, and 59% of them completed the questionnaire. Normal transfers to other units, training, and attendance at military schools were the main reasons for not filling out the questionnaire. Of soldiers who attended recruitment briefings, 98% agreed to participate. Soldiers were classified according to their responses about injury during deployment. One group reported losing consciousness (being knocked out); another group denoted as having altered mental state reported being dazed, confused, âseeing stars,â or not remembering the injury; a third group reported an injury without altered mental state; and a fourth group reported no injury. Physical symptoms were measured by using the Patient Health Questionnaire 15-item somatic-symptom severity scale (PHQ-15). Five additional questions asked about symptoms regarded as important postconcussion symptoms that are not part of the PHQ-15. The authors tallied the number of soldiers reporting âbothered a lotâ by the symptom or the number reporting âmore than half the daysâ for fatigue, sleep disturbance, concentration problems, or irritability. Common postconcussion symptoms studied were headache, dizziness, fatigue, sleep disturbance, memory problems, balance problems, ringing in the ears, concentration problems, and irritability. All nine symptoms were reported more by those with LOC than by those with injuries that involved no alteration in consciousness (odds ratios [ORs], 1.89â3.45; each p value < 0.02). The most common problems were irritability, fatigue, and sleep disturbance, each of which was reported by over half the soldiers who had LOC. Those with altered mental state but no LOC associated with their injuries reported significantly more irritability, concentration problems, balance problems, headache, and sleep disturbance (ORs, 1.38â2.46; each p value < 0.05). The most common reported symptoms in those with altered mental state were irritability (47.6%) and sleep disturbance (44.9%) (see Table 7.2). Statistical tests comparing those who had mild TBI with those who had no injury were not presented, but the rates of symptom endorsement were lower in those without injury, and the sample was much larger. Hoge et al. (2008) also presented ORs for posttraumatic stress disorder (PTSD) and depression. PTSD was more frequent in both groups with TBI, that is, those with LOC and altered mental status; depression was more frequent in those with LOC than in those with any other injuries. After adjusting for PTSD and depression, however, headache was the only postconcussion symptom significantly more frequently reported, and that was only in the group with LOC. That raises the question of whether postconcussion symptoms are caused by mild TBI or PTSD and depression, or both. Neither Hoge et al. (2008) nor other studies reviewed present data that allow determination of which symptoms might be caused specifically by the TBI or the PTSD and depression. TABLE 7.2 Symptoms After Deployment According to Type of Injury During Deployment Injury with p Value for p Value for Injury with Altered No Injury LOC vs Altered Mental LOC (n = Mental Status Other Injury (n = 1,706), Other Status vs Other Symptoms 124), % (n = 260), % (n = 435), % % Injury Injury Headache 32.2 17.7 12.1 8.4 < 0.001 0.04 Dizziness 8.3 5.9 3.1 1.8 0.01 0.07 Fatigue 53.2 39.7 34.6 25.2 < 0.001 0.21 Sleep disturbance 53.8 44.9 37.2 24.1 0.001 0.05 Memory problems 24.6 16.2 13.7 7.4 0.005 0.38 Balance problems 8.3 6.7 2.8 1.6 0.02 0.02 Ringing in ears 23.5 17.9 14.0 5.9 0.01 0.17
212 GULF WAR AND HEALTH Injury with p Value for p Value for Injury with Altered No Injury LOC vs Altered Mental LOC (n = Mental Status Other Injury (n = 1,706), Other Status vs Other Symptoms 124), % (n = 260), % (n = 435), % % Injury Injury Concentration 31.4 26.0 18.1 10.2 0.002 0.02 problems Irritability 56.8 47.6 36.8 24.7 <0.001 0.006 NOTE: LOC = loss of consciousness. SOURCE: Hoge et al., 2008. Mickeviciene et al. (2002) studied the frequency and severity of a number of postconcussion symptomsâincluding headache, dizziness, memory problems, concentration problems, fatigue, and irritabilityâin a retrospectively identified inception cohort of 200 patients seen in the ED of Kaunas University Hospital or Red Cross Hospital in Kaunas, Lithuania, for head trauma involving LOC lasting 15 minutes or less. Patients with other major injuries or LOC over 15 minutes were excluded. The control group consisted of 200 age- and sex-matched controls with minor injuries (not involving the head or neck) who reported never having had a previous concussion and who were seen in the EDs within 2 weeks of the TBI cases. Self-report questionnaires with questions about general health and a detailed section about headaches and less extensive questioning about other symptoms were mailed to participants 22â35 months after their injuries. Subjects returned the questionnaires before they were told of the interest in the relationship between TBI and symptoms. Study participants were asked about the frequency of headache, dizziness, memory problems, and concentration problems and were asked to mark a visual analogue scale to indicate the degree of 15 symptoms on a scale ranging from 0 (ânoâ) to 100 (âmuchâ). Some 66% of TBI participants and 73% of controls returned the questionnaires. The two groups were similar in most demographic characteristics although participants with concussion reported slightly lower education and were less likely to be currently married. The authors found no significant differences between subjects who had sustained head injuries with brief LOC and controls in occurrence of any headaches during the previous month (p = 0.92) or for more than 7 days in the previous month (p = 0.95); comparative results were similar for headaches in the previous year. No significant differences were found between the TBI participants and controls in extent of self-reported dizziness, memory problems, or concentration problems. Of the 15 postconcussion symptoms marked on a visual analogue scale, only depression (p = 0.002) and alcohol intolerance (p = 0.04) were endorsed more by those with TBI. The investigators considered headache, memory problems, concentration problems, dizziness, fatigue, and irritability to be core postconcussion symptoms and looked at the numbers with PCS, which was defined as the number who endorsed all six core symptoms, including at least one to what the authors defined as a significant degree. There was no significant difference between those with TBI and controls in the number endorsing each symptom to a pronounced degree and the other five core symptoms to any degree (p = 0.06â0.87). Only one person with TBI and three controls endorsed all six core symptoms to a significant degree. The study was limited by the fact that no CT or magnetic resonance imaging (MRI) was done to rule out intracranial lesions, by the moderate response rates, and by the collection of data by mail questionnaires rather than in-person interviews. It has the advantage of having been conducted in a country where there is no financial incentive to overreport symptoms. In addition, the subjects were unaware of the reason for the study.
NEUROLOGIC OUTCOMES 213 Mickeviciene et al. (2004) conducted a prospective cohort study to investigate the relationship of posttraumatic symptoms, the influence of sociodemographic factors, and the effect of expectation on symptoms of PCS related to head injury. The study population included 300 patients seen in the ED of Kaunas University Hospital or Red Cross Hospital in Kaunas, Lithuania, for head trauma involving LOC lasting 15 minutes or less. The control group consisted of 300 sex- and age-matched people who had sustained a minor nonhead injury. Some 64% of those with TBI and 72% of controls returned the questionnaires at 1 year after injury. Subjects were given a standard self-report questionnaire with questions about postconcussion symptoms (the Rivermead Post-Concussion Symptoms Questionnaire, RPQ) and were also asked to mark a visual analogue scale to indicate the severity of symptoms on a scale ranging from 0 (ânoâ) to 100 (âmuchâ). The authors found that reports of any headaches after 1 year (p = 0.98) and frequent headaches (p = 0.15) did not differ significantly between the head-injured patients and the controls. The head-injured subjects more commonly reported some memory problems (p < 0.001), some concentration problems (p = 0.04), and some dizziness (p = 0.02). They did not differ from controls in dizziness occurring every day, constant memory problems, and constant severe concentration problems 1 year after injury. On the visual analogue scale, the subjects with TBI reported significantly more memory problems, concentration problems, and tiredness; there was no significant difference in the other 12 symptoms. No relationship was found between headache or cognitive dysfunction at 1 year and severity of concussion. The study was limited by the fact that only 51 head-injured participants had CT imaging to rule out intracranial lesions, by the moderate response rates, and by collection of data by mail questionnaires. The subjects were sent the questionnaires soon after injury and 3 months later, and this made them aware of the possibility of persistent postconcussion symptoms. It has the advantage of having been conducted in a country where there is no financial incentive to overreport symptoms. Heitger et al. (2007) used the RPQ to collect information on symptoms from 37 subjects presenting at the Christchurch, New Zealand, Hospital ED with mild TBI (GCS scores, 13â15 at first assessment with no consecutive scores below 13; PTA less than 24 hours; and no structural damage or skull fracture on head CT if obtained). The subjects and controls had no history of TBI with persisting symptoms, no central neurologic disorder or psychiatric disorder, and no regular intake of psychoactive drugs or history of drug abuse. Controls were recruited via a volunteer database made available by the Department of Psychology at the University of Canterbury, Christchurch, New Zealand, and were individually matched to the mild-TBI cases on age, sex, and years of formal education. The paper states the number who reported the symptom at all and the number who reported that it was at least a mild problem at 1 week and 3, 6, and 12 months after injury. All pairs participated in the 1-month and 6-month evaluation, and 31 (84%) in the 12-month evaluation. Most controls answered the questionnaire only once. At 6 months, the TBI subjects reported significantly higher scores on the 0â4 scale for each of headaches, dizziness, noise sensitivity, fatigue, irritability, feeling depressed, poor memory, poor concentration, slowed thinking, double vision, and restlessness (each p < 0.05) (see Table 7.3 for detailed results). At 12 months, those with mild TBI reported significantly more headaches, fatigue, poor memory, poor concentration, blurred vision, and double vision (each p < 0.05). There was no significant difference at either time in nausea, sleep disturbance, frustration, or light sensitivity. A strength of the study is that no patients were involved in litigation or were seeking compensation beyond the standard provisions of the no-blame insurance that covers all New Zealand residents. A limitation is that controls were volunteers interested in participating in research and may not have been similar to the mild-TBI subjects. Most also answered the
214 GULF WAR AND HEALTH questionnaire only once, although responses by the 10 controls who completed the questionnaire more than once were consistent. In addition, the controls were uninjured, so the effects of mild TBI cannot be separated from the effects of injury in general. TABLE 7.3 Frequency of Symptoms on RPCS Questionnaire Patients Reporting Symptoms, % Controls 6 Months 12 Months Score of 2 or Score of 2 or Score of 2 or Symptom Highera p Valueb Higher p Valueb Higher Fatigue 22 < 0.01 26 < 0.05 8 Headache 22 < 0.01 26 < 0.05 3 Dizziness 19 < 0.05 23 3 Poor concentration 27 < 0.05 26 < 0.05 5 Forgetfulness or poor 27 < 0.01 16 < 0.05 8 memory Irritability 22 < 0.05 13 8 Sleep disturbance 14 19 8 a Score of 2 or higher = subjects who reported a score of 2, 3, or 4 for this symptom (scale = 0â4), that is, symptom was at least a mild problem. b p value from Wilcoxon matched-pair test using full range of symptom scores (0â4). NOTE: RPCS = Rivermead Post-Concussion Symptoms. SOURCE: Heitger et al., 2007. Reprinted with permission from Journal of Rehabilitation Medicine, 2008. Copyright 2007 by Foundation of Rehabilitation Information. Stulemeijer and colleagues (2006a) reported on fatigue in 618 consecutive patients 18â60 years old who attended the Radboud University Nijmegen Medical Center in the Netherlands and had mild TBI (impact to the head with GCS 13â15 at admission, with no LOC or LOC less than 30 minutes, and with or without PTA). Controls were 483 people who presented at the emergency department with ankle or wrist distortion. Questionnaires were sent by mail 6 months after trauma and were returned by 299 with mild TBI (52% of the 574 delivered questionnaires) and 287 (60%) of the controls. In both groups, responders were older than nonresponders and more likely to be female. Controls were more highly educated, more likely to be female, and slightly younger, but the analysis adjusted for these characteristics. Fatigue was measured with the Checklist of Individual Strength (CIS), which asks about fatigue severity in the previous 2 weeks. A CIS fatigue score of 40 or higher was used to identify severe fatigue; 95 (32%) of the mild-TBI subjects and 35 (12%) of the controls reported severe fatigue (p < 0.001). Limitations of the study include a low response rate. Gerber and Schraa (1995) conducted a prospective study of 22 consecutively admitted patients who had mild TBI matched with orthopedically injured patients and uninjured controls to assess injury severity, symptoms, and disability. Mild TBI was defined as having sustained an impact to the head with alteration in consciousness including LOC less than 30 minutes or PTA less than 24 hours. Subjects were excluded if they had a GCS of less than 13 or a skull fracture. Orthopedically injured controls included those who had sustained an orthopedic injury of a region other than the head, neck, or upper extremity. Exclusion criteria for both groups included a maximal Abbreviated Injury Score greater than 2, pre-existing history of a learning disability, and chronic medical disorders, major psychiatric disorders, or substance-abuse disorders. An uninjured control group matched for age, sex, and education with the mild-TBI group was
NEUROLOGIC OUTCOMES 215 included. All subjects completed a structured interview with questions about demographic and socioeconomic status and preinjury medical and psychologic status. Subjects were asked about alterations of consciousness, PTA, associated injuries, and symptoms. To evaluate severity of symptoms, the subjects were first asked to describe and rate on a scale medical or psychologic symptoms that they were experiencing at the time (volunteered symptoms). They were also asked to confirm the presence or absence and rate severity of symptoms on a symptom checklist (elicited symptoms). They were contacted for followup at 6 months after injury. At the 6-month followup, 22 (79%) of the 28 mild-TBI subjects and 26 (68%) of the 38 orthopedically injured subjects completed the assessment. In an assessment of symptoms volunteered by the mild-TBI subjects at 6 months after injury, headache was the most frequent volunteered symptom and concentration difficulties (13.6%) and memory problems (13.6%) the most commonly reported cognitive symptoms. Reports of those three symptoms differed significantly among the groups. The mild-TBI group had significantly higher scores for volunteered somatic and cognitive symptom clusters than either control group (each p < 0.05). Regarding elicited symptoms at the 6-month followup, fatigue (45.5%) and headache (27.3%) were the symptoms most commonly cited by the mild-TBI group; no symptom was endorsed significantly more by the orthopedic or uninjured controls, and there were no significant differences in the scores for somatic or cognitive symptom clusters. Limitations of the study include the small sample, lack of specification of the method for recruiting community controls, and failure to use appropriate statistical tests to account for small numbers of participants endorsing individual symptoms. Strengths include the consecutive enrollment of injured subjects and careful matching. Masson et al. (1996) evaluated the prevalence of cognitive, behavioral, and somatic impairments in 231 patients who had sustained mild, moderate, or severe TBI and were hospitalized 5 years before the initiation of the study. The control group consisted of 80 lower- limbâinjured (LLI) patients. Subjects were 15â60 years old at the time of injury. One hundred eighty-two TBI patients and 64 LLI patients participated in the followup; 29 (13%) TBI patients and 1 (1%) LLI patient had died, and 20 (9%) TBI patients and 15 (19%) LLI patients were lost to followup or refused to participate. Self-reported functional status was assessed through face- to-face interviews in the hospital or home, telephone interviews, or postal questionnaires; all LLI cases were assessed with one of these methods. Status was also assessed with the European Chart for Brain Injured Patients Evaluation, and the overall outcome was assessed with the Glasgow Outcome Scale (GOS). Subjective complaints were counted regardless of whether subjects associated them with their injuries. All subjective complaints reported except fatigue and pain were more commonly reported by mild-TBI patients than by LLI patients (see Table 7.4): headache (p < 0.001), memory problems (p < 0.05), dizziness (p < 0.01), anxiety (p < 0.01), sleep disturbance (p < 0.05), depressive temper (p < 0.01), and irritability (p < 0.01). Pain was significantly more common in LLI patients (p < 0.001). Memory problems, sleep disturbance, pain, and irritability were significantly related to severity in those with TBI, and the severely injured reported them most frequently. Forty-five (39%) mild-TBI patients and 6 (9%) LLI patients complained of more than three of the eight symptoms (excluding pain) (p < 0.001) and could be considered to have PCS according to an ICD-like definition. The rate of PCS in patients with moderate or severe TBI was not reported. Limitations of the study include the lack of face- to-face interviews of LLI patients and the counting of symptoms whether or not they predated injury or were related to a different cause. Strengths include the low loss rate and the population- based nature of the sample.
216 GULF WAR AND HEALTH TABLE 7.4 Prevalence of Subjective Complaints 5 Years After Injury Lower-LimbâInjured Patients (n = 64) Head Injured Patients According to Initial Head Injury Severity Minor (n = 114) Moderate (n = 35) Severe (n = 27) Subjective Complaints No.a % pb No.a % No.a % No.a % pc Headache 10 15.6 < 0.001 50 43.9 19 54.3 12 44.4 NS Fatigue 19 30.6 NS 34 35.1 11 32.4 15 57.7 NS Memory problem 10 15.6 < 0.05 36 32.1 21 60.0 18 66.7 < 0.001 Dizziness 8 12.5 < 0.01 37 32.5 13 37.1 7 25.9 NS Sleep disturbance 8 12.5 < 0.05 32 26.3 4 11.4 18 66.7 < 0.001 Pain 38 59.4 < 0.001 38 33.3 4 11.4 13 48.1 < 0.01 Depressive temper 9 14.1 < 0.01 44 38.6 17 48.6 11 40.7 NS Anxiety 9 14.1 < 0.01 54 47.4 17 48.6 17 63.0 NS Irritability 9 14.1 < 0.01 43 37.7 21 60.0 17 63.0 < 0.05 a Prevalences were calculated among patients who answered the question. Prevalences of overall impairments (related or not related to the head injury by the patient). b Prevalences in lower-limbâinjured patients were compared with prevalence in minor-head-injury patients. c Prevalences were compared in the three groups of head-injury severity. NOTE: NS = not significant. SOURCE: Masson et al., 1996. Reprinted with permission from Brain Injury. Copyright Taylor and Francis Ltd. http://www.informaworld.com. McLean et al. (1993) assessed psychosocial recovery in 102 hospitalized patients examined at 1 and 12 months after head injury. The subjects were head-injured patients consecutively admitted into Harborview Medical Center in Seattle, Washington. Selection criteria included any LOC, PTA for at least 1 hour, and evidence of cerebral trauma; head injury requiring hospitalization; age range of 15â60 years at time of injury; and absence of history of pre-existing conditions, including central nervous system (CNS) insult, major psychiatric problems, and treatment for alcohol-related problems. The reference group consisted of 102 friend controls matched for age, education, sex, and race. Head-injury severity was assessed on the basis of GCS score and time from injury to ability to follow commands consistently. Outcomes were assessed with a battery of psychosocial measures, such as the Head Injury Symptom Checklist (HISC). The HISC includes a list of 12 symptoms that are frequently associated with head injury, for example, headache, dizziness, and concentration problems. At 12 months after injury, the head-injured patients differed significantly in seven symptoms on the HISC: dizziness (p < 0.01), blurred vision (p < 0.001), concentration problems (p < 0.001), being bothered by noise (p < 0.05), irritability (p < 0.01), temper (p < 0.01), and memory problems (p < 0.001). The median number of symptoms endorsed at 1 year was five by those with severe TBI, two by those with moderate TBI, three by those with mild TBI, and two by controls. The severely injured reported significantly more symptoms than those with moderate TBI (p < 0.05) or friend controls (p < 0.05). Limitations of the study include the inability to separate the effects of head injury and other injuries, the absence of a statement of the loss rate before the 1-month assessment, and the relatively small numbers of cases in severity subgroups. Strengths include the recruitment of consecutive cases within days of injury, the use of friend controls who are likely to be similar to those with TBI on difficult-to-measure characteristics, data collection that was primarily face-to-face and consistent in both groups, and the good retention rate between the 1-month and 12-month assessments.
NEUROLOGIC OUTCOMES 217 Secondary Studies The committee identified three secondary studies. Edna and Cappelen (1987) conducted a prospective study of 485 head-injured patients admitted into surgical and neurosurgical departments in Norway. They found that 51% of the patients reported new PCS after injury (a mean of 4 years after injury). The following new symptoms were reported at a 3- to 5-year followup by over 15% of those with TBI: headaches (23%), memory impairment (20%), dizziness (19%), fatigue (18%), and being bothered by noise or light (18%). The rate of symptoms in controls was reported to be comparable with the rate of preinjury complaints in the head-injured group. Johansson and colleagues (1991) conducted a population-based study of the incidence of TBI and a retrospective cohort study of symptoms related to head trauma in the Umea district of northern Sweden. Symptoms were collected with a mailed questionnaire 1.5â3 years after injury. Memory impairment was reported by 15% of those with concussion and 63% of those with manifest brain injury (p < 0.01, calculated by committee); dizziness by 11% and 45%, respectively (p < 0.01); headache by 22% and 45% (not significant); and sensitivity to noise or light by 13% and 36% (not significant). The study was limited by the lack of a control group, although the paper did compare severity groups. Stulemeijer and colleagues (2006b), in another report based on the primary study described above, compared those who had mild TBI alone or accompanied by other injuries with controls. They found that regardless of whether the mild TBI was isolated, those who had mild TBI had higher scores than controls on each of the physical, affective, and cognitive symptom clusters on the RPQ; each p value comparing the three groups was less than 0.0001, and post hoc comparisons showed that each mild-TBI subset had a higher score than the controls. There have also been a few studies of military populations and nonmilitary populations (e.g., Walker and Erculei, 1969; Roberts, 1979; Bryant and Harvey, 1999; Suhr and Gunstad, 2002; Luis et al., 2003; and Vanderploeg et al., 2007) that were of interest but did not meet the committeeâs selection criteria (see Chapter 4). They are not described here, but their findings are consistent with those of the selected studies with regard to postconcussion symptoms. Summary and Conclusions The committee reviewed eight primary studies and three secondary studies that assessed the relationship between TBI and self-reported postconcussion symptoms. The study populations consisted largely of patients who presented to an ED with mild TBI or who were hospitalized with a broader range of TBI severity. Six of the eight primary studies were restricted to those with mild TBI. One looked at symptoms reported by soldiers who had recently returned from Iraq and found that significantly more who had had LOC reported each of the nine common postconcussion symptoms; significantly more of those with an altered mental state but no LOC reported five of the nine symptoms (Hoge et al., 2008). Two of the studies evaluated the relationship between TBI and postconcussion symptoms in separate cohorts of people with head trauma involving brief LOC who had been seen in the EDs of two hospitals in Kaunas, Lithuania (Mickeviciene et al., 2002, 2004); one of the studies (2002) did not find significant differences between TBI participants and trauma controls in any of the seven postconcussion symptoms reported, and the other found
218 GULF WAR AND HEALTH significantly higher endorsement of some memory problems, some concentration problems, some dizziness, and extent of fatigue. Stulemeijer et al. (2006a) reported on fatigue in mild-TBI patients who went to an ED and in trauma controls and found significantly more fatigue in those with mild TBI at 12 months after injury. Heitger et al. (2007), in a smaller ED study, found significantly higher endorsement by mild-TBI patients of 8 of 10 symptoms compared with normal volunteers. Gerber and Schraa (1995), a small but well-controlled study, found higher endorsement of headache, memory problems, and concentration problems by mild-TBI patients than by orthopedic-injury patients or community members. Masson and colleagues (1996) evaluated the prevalence of symptoms in patients in Aquitaine, France, 5 years after hospitalization for head injury. They found that all subjective complaints (headache, memory problems, dizziness, sleep disturbance, and irritability) reported except fatigue were more commonly reported by TBI patients with minor injury than by patients with lower-limb injuries. Memory problems, sleep disturbance, and irritability were significantly related to severity in those with TBI, and the severely injured reported the highest rates. Similarly, McLean et al. (1993) assessed the rate of symptom endorsement by patients 12 months after hospitalization for TBI and by friends who did not experience TBI. They found that at 12 months after injury, the head-injured patients differed significantly in seven symptomsâ including dizziness, blurred vision, concentration problems, being bothered by noise, irritability, and memoryâbut did not differ in headache or fatigue. Two secondary studies evaluated symptoms in groups that included people with more severe injuries. Johansson et al. (1991) found significantly more dizziness and memory problems in those with more severe injuries than in those with concussion. Headache and sensitivity to noise or light were also endorsed by over one-third of the people with more severe injuries, but the difference was not significant. Edna and Cappelen (1987) found that over 15% of people hospitalized with TBI in surgical or neurosurgical departments endorsed new occurrence of headaches, dizziness, fatigue, memory impairment, and being bothered by noise or light. One secondary study that assessed mild TBI (Stulemeijer et al., 2006b) found that regardless of whether the mild TBI was isolated or accompanied by other injuries, those with mild TBI had higher scores than controls in each of the physical, affective, and cognitive symptom clusters on the RPQ. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between sustaining a TBI and development of postconcussive symptoms (such as memory problems, dizziness, and irritability).
TABLE 7.5 Postconcussive Symptoms and TBI Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Limitations Adjustments Mickeviciene et Retrospective 200 head injured Mild head injury Self-report Headache (during last Sex- and age- Mail questionnaire al., 2002 cohort patients; 200 non- with some LOC but questionnaire month) in TBI vs matched sent to patients and head-injured under 15 min sent by mail to controls: controls controls; self- controls (with patients and any, 61% vs 61% (p = reported symptoms minor injury); all controls 0.92); > 7 days, 23% vs only patients injured 23% (p = 0.95); any 131 (66%) head 22â35 mo before dizziness, 65% vs 63% injured patients, 146 study; identified (p = 0.84); any memory (73%) controls from EDs of two problems, 68% vs 59% returned major hospitals in (p = 0.12); any questionnaires Kaunas, Lithuania concentration Mild TBI based on problems, 66% vs 57% clinical assessment (p = 0.08) without CT scan or MRI No incentive to exaggerate symptoms, because little possibility of receiving monetary compensation for postconcussion symptoms Mickeviciene et Prospective 300 subjects with Mild head injury Questionnaires At 1 year, headache Sex- and age- Mail questionnaires al., 2004 concussion (LOC < 15 min) mailed included (during last month), matched sent to patients, matched on age, standard self- TBI vs controls: any controls controls; self- sex with controls report 65% vs 64% (p = 0.98); reported symptoms with minor questionnaire, > 7 days, 21% vs 15% only nonhead injuries, the RPSQ, VAS (p = 0.15); any Mild TBI based on followed for 1 for determining dizziness, 62% vs 50% clinical assessment; year, who symptom (p = 0.02); any memory no traumatic presented to EDs severity problems, 64% vs 47% pathologic effects of two hospitals in (p < 0.001); any found in 51 cases Kaunas, Lithuania concentration with CT scans 192 (64%) of head- problems, 71% vs 61% No incentive to 219
220 Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations injured patients, (p = 0.04) exaggerate 215 (75%) of symptoms, because controls returned little possibility of questionnaires at 1 receiving monetary year compensation for postconcussion symptoms Masson et al., Prospective 231 head injured Mild head injury, Self-reported See Table 7.4 Cohort population- 1996 cohort; with various 141; moderate head functional status based; age and sex population-based degrees of head injury, 38; severe through face-to- distribution similar study in injury; 80 controls head injury, 52; all face interview in in all groups Aquitane, with LLI hospitalized hospital or Symptom rates France, designed Over 15 to under home, telephone include symptoms to determine years old interview, or unrelated to injury incidence of all mailed After 5 years, serious injuries questionnaire; following patients resulting in self-reported not included in final hospitalization functional status analysis: lower-leg or death assessed with injury, one died, 15 European Chart lost to followup; for Brain Injured mild head injury, Patients two died, 18 lost to Evaluation; followup; two overall outcome refused to assessed with participate; GOS moderate head injury, two died; severe head injury, 25 died McLean et al., Prospective 102 hospitalized Broad range of Head Injury At 12 mo after injury, Group TBI cases, controls 1993 cohort adult head injured severity Symptom head injured vs friend matched on excluded if they had patients, 102 Checklist controls: memory age, sex, pre-existing uninjured controls problems, 39% vs 5% education, conditions; head who were friends (p < 0.001); race injured cases
Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations of head injured concentration recruited within patients; 15â60 problems, 39% vs 14% days of injury, but years old (p < 0.001); blurred loss rate before 1- vision, 19% vs 2% (p < mo assessment not 0.001); dizziness, 23% given; 93% of head vs 6% (p < 0.01); injured, 84% of irritability, 45% vs 23% controls seen at 1 (p < 0.01); temper, mo followed at 1 27% vs 12% (p < 0.01); year; controls were bothered by noise, 27% uninjured, so effect vs 13% (p < 0.05); may be related to headache, 36% vs 35%; head injury or other fatigue, 47% vs 43%; injuries bothered by light, 21% vs 10%; anxiety, 33% vs 26%; insomnia, 27% vs 15% Gerber and Prospective 22 patients with Mild Injury severity, % of MTBI patients Controls Schraa, 1995 mild TBI matched symptoms, who volunteered matched on with orthopedically disability as symptoms at followup: age, sex, injured patients, measured with headache, 13.6; education uninjured controls structured dizziness, 0; fatigue, 0; interview, concentration symptom problems, 13.6; checklist memory problems, 13.6; irritability, 0 Orthopedic controls volunteered none of listed symptoms; 9.1% of controls volunteered irritability Heitger et al., Prospective 37 patients with MTBI PCS assessed See Table 7.3 Controls 221 2007 cohort mild closed head Patients asked if head with written individually
222 Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations injury who injury occurred versions of matched to presented to within 24-h period, it RPSQ, RHIFQ, each case with Christchurch was assessed whether SF-36 Health respect to age, Hospital with acute patients remembered Survey sex, years of head injury, 37 being at scene after Patients assessed formal controls with no accident or regaining at 1 week, 3, 6, education history of head consciousness, being 12 mo after injury helped by injury others, arrival of ambulance, being in ambulance, arriving at hospital, treatment events whose times were noted on chart, being served meal All patients had PTA of 2 minâ22 h (median, 15 min); 32 had confirmed LOC (median, 2.0 min; range, 0.5â15 min) Hoge et al., 2008 Retrospective 2,525 US Army MTBI as assessed Postconcussion See Table 7.2 TBI, symptoms self- infantry soldiers with positive symptoms reported; assessed surveyed 3â4 mo responses to any of assessed with with questionnaire after return from following items on Patient Health 3â4 mo after deployment to questionnaires: Questionnaire deployment; 59% of OIF: 124 head âlosing 15-item somatic all soldiers injured with LOC, consciousness symptom deployed to OIF, on 260 head injured (knocked out),â severity scale duty completed with altered mental âbeing dazed, Five questions in questionnaire; status, 435 with confused, or âseeing addition to 7% of values for other injury, 1,706 stars,ââ or ânot questionnaire to some variables with no injury remembering the assess symptoms missing
Type of TBI: Health Mild, Moderate, Outcomes or Severe; Blunt, Outcome Comments or Reference Study Design Population Penetrating, Blast Measures Results Adjustments Limitations injuryâ related to memory, balance, concentration, ringing in ears, irritability Stulemeijer et al., Prospective 299 consecutively MTBI defined as Fatigue assessed MTBI patients reported 2006a cohort admitted patients history of impact to with Checklist significantly higher 18â60 years old head with or without Individual levels of fatigue than who presented LOC 30 min, with Strength minor-injury controls with MTBI at ED or without PTA and PCS assessed (mean score, 29.9 Â± of Radboud hospital admission with RPSQ 15.3 vs 22.1 Â± 12.5; p < University with GCS 13â15 0.0001) Nijmegen Medical Severe fatigue in MTBI Center, assessed 6 patients vs controls: mo after trauma 32% vs 12% (p < Comparison group, 0.001) 287 patients 18â60 years old who presented to ED with ankle or wrist distortion, assessed 6 mo after trauma NOTE: ED = emergency department, GCS = Glasgow Coma Scale, GOS = Glasgow Outcome Scale, LLI = lower-limb injury, LOC = loss of consciousness, MTBI = mild traumatic brain injury, OIF = Operation Iraqi Freedom, OR = odds ratio, PCS = postconcussion syndrome, PTA = posttraumatic amnesia, RHIFQ = Rivermead Head-Injury Follow-up Questionnaire, RPSQ = Rivermead Postconcussion Symptoms Questionnaire, RR = relative risk, TBI = traumatic brain injury, VAS = Visual Analogue Scale. 223
224 GULF WAR AND HEALTH OCULAR AND VISUAL MOTOR DETERIORATION Ocular and visual motor deterioration is a sensory and neuromuscular anomaly of eye movement that has been characterized by the inability to perform effective saccades, rapid ballistic movements during which there is a suppression of vision (Marr et al, 2005). Some symptoms related to ocular and visual motor deterioration are difficulty in tracking objects visually, lack of coordination, and vertigo. Primary Studies The committee identified one primary study that assessed the relationship between TBI and ocular and visual deterioration (see Table 7.6). Heitger and colleagues (2006) assessed oculomotor and upper-limb visuomotor function in 37 patients who had closed head injuries and presented at the emergency department of Christchurch Hospital in New Zealand. The patients had mild TBI with GCS scores of 13â15. All patients had experienced PTA for about 2 minutesâ 22 hours; 32 patients had confirmed LOC. The control group consisted of 37 people with no history of TBI or with persisting symptoms or complaints, no central neurologic disorder or psychiatric condition, and no regular intake of psychoactive drugs or history of drug abuse; the controls were individually matched to head-injured patients with respect to age, sex, and years of formal education. The groups were compared at 1 week, 3 months, and 6 months after injury; 31 patients and controls were assessed at 12 months after injury. All participants were evaluated on measures of saccades, oculomotor smooth pursuit, and upper-limb visuomotor function and with neuropsychologic tests. Recovery was assessed with the RPQ. At 3 and 6 months, patients with closed head injuries showed deficits in several oculomotor and upper-limb visuomotor measures and in verbal learning. At 1 year after injury, those with closed head injuries did not show signs of cognitive impairment but had residual deficits in eye and arm motor function. Secondary Studies The committee identified one secondary study that assessed the relationship between TBI and ocular and visuomotor function. Kraus et al. (2007) evaluated oculomotor function in people who had sustained TBI. They assessed 37 subjects who had a history of TBI: 20 mild TBI and 17 moderate to severe TBI. Mild TBI was defined as meeting at least one of the following criteria: any period of LOC, any loss of memory of events immediately before or after the incident, any alteration in mental state at the time of the incident, and focal neurologic deficit. Moderate to severe TBI was diagnosed if LOC was greater than 30 minutes or GCS was less than 13. The injuries were sustained at least 6 months before initiation of the study. Subjects were recruited from the University of Illinois Medical Center and through advertisements. Exclusion criteria included history of psychiatric disorder before the head injury, substance abuse, current pending litigation, and presence of another neurologic or medical condition. The control population consisted of 19 healthy people who had no history of psychiatric illness or TBI, substance abuse or dependence, or significant medical or neurologic illness. The groups were matched on age, education, and employment. Subjects underwent a number of oculomotor function and neurocognitive tests: the visually guided saccades (VGS) test, the antisaccades (AS) test, the Tower of London test, the Stroop Color-Word Test, the Paced Auditory Serial Addition Test, the
NEUROLOGIC OUTCOMES 225 Trail Making Test, Connersâ Continuous Performance Test-II, the Controlled Oral Word Association Test, the Ruff Figural Fluency Test, and the Wechsler Test of Adult Reading. The patients with moderate to severe TBI showed longer latencies and lower accuracy on the VGS test than the controls, and the patients with mild or moderate to severe TBI had more prosaccade errors on the AS test than the controls. Summary and Conclusion The committee reviewed one primary study (Heitger et al., 2006) and one secondary study (Kraus et al., 2007) that assessed the relationship between TBI and ocular and visual motor deterioration. The results showed a slight deterioration in ocular and visual motor function after a mild (closed) TBI. Heitger and colleagues (2006) found that at 6 months after injury, patients with closed head injuries showed deficits on several ocular and upper-limb visual motor measures. At 1 year after injury, those with closed head injuries did not show signs of cognitive impairment but had residual deficits in eye and arm motor function. Kraus and colleagues (2007) found that the patients with moderate to severe TBI had longer latencies and lower accuracy than controls on the VGS test; patients with mild or moderate to severe TBI had more prosaccade errors than controls on the AS test. Although the primary study found a decline in ocular and visual motor function after mild (closed) head injury, the overall body of evidence on this outcome is limited in that only two studies met the committeeâs criteria for inclusion as either primary or secondary. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between sustaining a mild TBI and the development of ocular and visual motor deterioration.
226 TABLE 7.6 Ocular and Visual Motor Deterioration and TBI Health Outcomes or Comments or Reference Study Design Population Type of TBI Outcome Measures Results Adjustments Limitations Heitger et al., Prospective 37 mild closed- Mild closed Saccades, Sustained motor Controls matched 2006 cohort head-injury head injury oculomotor smooth impairment up to 1 with respect to age, patients from ED (GCS, 13â15) pursuit, upper-limb year sex, years of at Christchurch visuomotor function, formal education Hospital, New neuropsychologic Zealand tests; recovery assessed with RPSQ NOTE: ED = emergency department, GCS = Glasgow Coma Scale, RPSQ = Rivermead Postconcussion Symptoms Questionnaire, TBI = traumatic brain injury. .
NEUROLOGIC OUTCOMES 227 ENDOCRINE DISORDERS The endocrine system consists of glands that secrete hormones that regulate a host of functions, including metabolism, growth, and development. The pituitary gland, in the base of the brain, can be damaged during TBI. The pituitary secretes hormones that regulate homeostasis and hormones that stimulate other endocrine glands. The hypothalamus, in the middle of the base of the brain, is responsible for regulating body temperature, hunger, thirst, and fatigue and for synthesizing and secreting hypothalamic releasing factors that stimulate pituitary hormone release. Clinical data suggest that TBI can cause complex hormonal responses of hypothalamoâ pituitaryâend organ axes that lead to acute and chronic hypopituitarism (Woolf, 1992; Cernak et al., 1999; Klose et al., 2007b). The most frequent dysfunctions are growth hormone (GH) deficiency (Bavisetty et al., 2008), secondary hypoadrenalism, hypogonadism (Kosteljanetz et al., 1981; Woolf et al., 1986; Cernak et al., 1997), hypothyroidism (Shutov et al., 1980; Shutov and Chudinov, 1987, 1988, 1993; Woolf et al., 1988), and diabetes insipidus (Boughey et al., 2004; Giordano et al., 2005; Tsagarakis et al., 2005; Klose et al., 2007a; Behan et al., 2008). It has been reported that the risk of pituitary insufficiency increases in patients who have severe TBI but not mild TBI. It has been hypothesized that neuroendocrine changes after TBI might be consequences of both structural and functional hypothalamo-pituitary changes (Woolf et al., 1986; Klose et al., 2007b). That hormonal alterations substantially modify the posttraumatic clinical course and the success of therapy and rehabilitation underscores the need for the identification and appropriate timely management of hormone deficiencies to optimize patient recovery from head trauma, to improve quality of life, and to avoid the long-term adverse consequences of untreated hypopituitarism. The committee reviewed several studies of damage to the pituitary gland and hypothalamus and possible adverse effects (including diabetes insipidus, hypopituitarism, and GH insufficiency); they are discussed below. Primary Studies The committee identified eight primary studies that assessed the relationship between TBI and a variety of endocrine disorders, including diabetes insipidus (DI), GH insufficiency, and hypopituitarism (see Table 7.7 for a summary of the primary studies). Agha et al. (2005b) prospectively studied the effect of TBI on posterior pituitary function, specifically DI and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in 50 consecutive patients (38 men and 12 women). The patients were admitted into a neurosurgical unit of a hospital in Dublin, Ireland, and had a median age of 35 years and an initial GCS score of 3â13; they were compared with 27 healthy controls matched for age, sex, and body-mass index (BMI). All subjects were assessed three times: during the acute phase, at 6 months after trauma, and at 12 months after trauma. Posterior pituitary function in the acute phase was assessed by determining serial daily fluid balance (serum and urine osmolalities) and serum sodium and with the standard observed 8-hour water-deprivation test; at 6 and 12 months, only the water-deprivation test was used. In the acute phase, DI was seen in 13 (26%) patients, 11 of whom received the diagnosis on the basis of hypernatremia associated with hypotonic
228 GULF WAR AND HEALTH polyuria and two on the basis of the water-deprivation test. The development of DI was associated with a lower GCS score, but the association was not significant; in the acute phase, however, there was a negative association between peak plasma osmolality and GCS scores (r, -0.39; p = 0.005) and GOS scores (r, -0.45; p = 0.001). At 6 months, nine of the patients had normal water-deprivation tests, leaving four of 48 patients with TBI and none of 27 controls with DI; at 12 months, an additional patient had recovered; no new cases were observed at either followup time. Two of the three patients with permanent DI had partial vasopressin deficiency. In the acute phase, seven (14%) patients had SIADH, and there was no association of SIADH with any patient variable. The SIADH had resolved in all patients by 6 months, and no new cases were reported. Agha et al. (2005a) used a longitudinal design to assess pituitary function in 50 consecutive patients who had severe or moderate TBI. GH deficiency was found in nine (18%) patients in the acute phase; five recovered after 6 months, and two more developed deficiency. At the 1-year followup, five (10%) had GH deficiency. In 2004, Agha et al. (2004a) prospectively studied the effect of moderate or severe TBI on anterior pituitary dysfunction in 102 consecutive patients admitted into a neurosurgical unit in Beaumont Hospital in 2000â2002. The TBI cohort did not overlap with that in the study above (Agha et al., 2005a). The control population consisted of 31 healthy people matched to cases on age, sex, and BMI. Forty-two patients had sustained moderate TBI, defined as having a GCS score of 9â13; 57 had sustained severe TBI, defined as a GCS score of 8 or less. Exclusion criteria included being over 65 years old or under 15 years old at the time of testing, having suffered a prolonged hypotensive episode, being pregnant, and being on glycocorticoid therapy. Patients were tested at 6â36 months after injury (median, 17 months). The glucagon stimulation test (GST) was used to screen for somatotrophic and corticotrophic function. Those with abnormal GH response related to GST were given the insulin tolerance test (ITT), and those with a history of heart disease or seizures were given the arginine + growth-hormoneâreleasing hormone (GHRH) test. Those with subnormal serum cortisol responses to the GST were given the ITT or, if they had heart disease or seizures, were given the 250-Î¼g short synacthen test (SST). The authors found that 18 (17.6%) of the injured patients and no controls had a GH response to the GST test of less than 5 Î¼g/L; 11 of the 18 failed the ITT or the arginine + GHRH test. In addition, 23 (22.5%) of the TBI patients, and three (9%) of the 31 controls had cortisol responses to GST of less than 450 nmol/L; 13 of these TBI patients failed the ITT or synacthen test. Agha et al. (2004b), using the same cohort (Agha et al., 2004a), prospectively studied the incidence of posterior pituitary dysfunction (including DI) in 102 consecutive patients who had sustained moderate or severe TBI and 27 healthy matched controls. Patients were evaluated 6â36 months after injury. In the acute phase, 22 (21.6%) patients developed DI. Seven (6.9%) of the patients had permanent DI compared with none of the controls. In the acute phase, 13 (12.7%) patients (95% confidence interval [CI], 7.0â20.8%) had evidence of SIADH. At followup, two patients had evidence of SIADH. Kelly and colleagues (2006) conducted a prospective cohort study of GH deficiency or insufficiency after TBI. Of 129 patients who were admitted into an intensive-care unit and who had sustained mild TBI (GCS score, 13â14), moderate TBI (GCS score, 9â12), or severe TBI (GCS score, 3â8), 44 were compared with 41 healthy controls. The subjects participated in a variety of pituitary-function tests and neurobehavioral and quality-of-life tests at 6â9 months
NEUROLOGIC OUTCOMES 229 after injury. At 6â9 months after injury, eight (18%) TBI patients had GH deficiency or insufficiency; the cutoff was defined by the lower 10% of controls (p = 0.35). Limitations of the study include a low followup rate and a small sample that yielded low power to detect a difference in rates. Herrmann and colleagues (2006) assessed the prevalence of hypopituitarism in 76 patients who had sustained severe TBI. The patients were evaluated in July 2003âMay 2004 and had been discharged from neurosurgery departments of a number of hospitals in Germany. Severe TBI was defined as having a GCS score of less than 8 (mean, 4.4 Â± 2.8); patients were injured an average of 22 Â± 10 months before the study. TBI was characterized with CT and MRI. Exclusion criteria included alcohol abuse, known pituitary deficiency or disease, apallic syndrome (vegetative state) or illness that would prevent testing, and pregnancy. Patients underwent a series of neuroendocrine tests, including GH response to GHRH + arginine, thyroid- stimulating hormone (TSH), free thyroxine, thyroxine (T4), triiodothyronine (T3), prolactin, testosterone, estradiol, sex hormoneâbinding globulin, cortisol, adrenocorticotropic hormone (ACTH), GH, and insulin-like growth factor 1 (IGF-1). Of the patients, 18 (24%) were found to have pituitary deficiency, 6 (8%) had GH insufficiency, 2 patients (3%) had partial ACTH deficiency, and 2 had TSH deficiency. Schneider and colleagues (2006) conducted a prospective longitudinal study of TBI patients to assess hypopituitarism at 3 and 12 months after injury. The study population consisted of 78 consecutively admitted TBI patients. The control group consisted of 38 healthy subjects. Inclusion criteria were TBI grades IâIII 3 as assessed according to GCS, BMI of 17â20, and age of 18â65 years. Exclusion criteria were glucocortoid treatment within 3 weeks or GH treatment within 12 months; a history of cranial irradiation or pre-existing pituitary disease; severe cardiac, renal, or hepatic disease; sepsis; and substance abuse. Subjects were evaluated with the GHRH + arginine test, the short ACTH test, and basal hormone measurements. Seventy of the patients participated in the followup at 12 months after injury. The authors found that more than 50% of the patients had impairments of at least one pituitary axis at 3 months after injury. At 12 months, 36% still had hormonal disturbances. Seven (10%) had stimulated GH less than 9 ng/mL, as did one of the 38 controls (not significant). The following axes were affected at 12 months after injury: 21% gonadotropic, 10% somatotropic, 9% corticotropic, and 3% thyrotropic. Klose et al. (2007b) conducted a 12-month prospective cohort study to assess the incidence of hypopituitarism after TBI. They assessed 46 patients hospitalized at the Copenhagen University Hospital with mild (22), moderate (9), or severe (15) TBI for hypopituitary function at 3, 6, and 12 months after injury. Mild TBI was defined as a GCS of 13â 15, moderate 9â12, and severe under 9. The control group consisted of 30 age- and BMI- matched healthy volunteers who underwent anterior pituitary testing. Another cohort of 100 healthy volunteers served as controls for the synacthen test. Anterior pituitary function was assessed initially at 0â12 days after injury for baseline information and then retested at 3, 6, and 12 months after injury. Tests included the ITT for baseline and poststimulatory hormone levels or, if this test was contraindicated, the GHRH + arginine test. A synacthen test to assess baseline hormone concentrations was conducted at 6 months. At 3 months after injury, 6 of the 46 patients had anterior pituitary deficiencies; at 12 months after injury, no additional patients had 3 A GCS of 3â8 indicates a severe TBI or a grade III, while a GCS of 9â12 indicates a moderate TBI (grade II), and a GCS of 13â15 indicates a mild TBI or grade I.
230 GULF WAR AND HEALTH deficiencies. Of the 46 patients, 5 (11%) had GH deficiencies. Patients with more severe TBI were more likely to be hypopituitary (4) than those with mild or moderate TBI (one) (p = 0.02). TBI severity appeared to be related to early endocrine changes, such as increased total cortisol, free cortisol, and copeptin and decreased thyroid and gonadal hormones (p < 0.05). Severity of TBI was not related to long-term development of hypopituitarism (p > 0.1). Secondary Studies The committee identified four secondary studies that assessed the relationship between TBI and a variety of endocrine disorders, including DI, GH insufficiency, and hypopituitarism. In a study of pituitary function in competitive boxers, Kelestimur et al. (2004) studied 11 male Turkish active or retired amateur boxers and compared them with 7 nonboxing controls matched on age and BMI. Radioimmunoassays were used to assess free T4, free T3, TSH, follicle-stimulating hormone (FSH), prolactin, cortisol, luteinizing hormone, total testosterone, free testosterone, and IGF-1. Serum GH secretory status was assessed with the GHRH plus GH- releasing peptide-6 (GHRH + GHRP-6) test. Basal hormone levels in all boxers and controls were within normal limits. However, there was a statistically significant difference in mean peak GH levels, which were 10.9 Â± 1.7 g/L in the boxers and 41.4 Â± 6.7 g/L in the controls; five (45%) of the boxers were considered to have severe GH deficiency (less than 10 g/L). Mean IFG-1 levels were significantly higher in the controls (367 Â± 18.8 ng/mL) than in the boxers (237 Â± 23.3 ng/dL). Other pituitary hormones were normal, including antidiuretic hormone. There was a significant negative correlation between peak GH and duration of boxing (r, -0.60) and bouts of boxing (r, -0.61). In a similar study, Tanriverdi et al. (2007) compared pituitary function in 22 active or retired amateur competitive Turkish kick boxers (16 men and 6 women) with that in 22 nonboxing controls (17 men and 5 women) that were matched on age and sex. The following basal hormone levels were measured: free T4, free T3, TSH, FSH, prolactin, luteinizing hormone, total testosterone, estradiol, gonadrotropin, cortisol, and IGF-1. The GHRH + GHRP-6 test was used to assess GH. As with the Turkish boxers in the previous study, the basal hormone levels in the kick boxers did not differ from those in the controls except for IGF-1 levels, which were significantly lower in the kick boxers (276.5 Â± 25.9 ng/mL) than in the controls (346.8 Â± 20.9 ng/mL). Five of the kick boxers had peak GH of less than 20 g/L and were considered to be GH-deficient; they also were older and had boxed longer and in more bouts than boxers who were not deficient, but the difference was not significant. Two boxers were also deficient for cortisol, one of whom was also GH-deficient. As with the regular boxers in the previous study, there was a significant negative correlation between IGF-1 and age, duration of boxing, and number of bouts. Bushnik and colleagues (2007) conducted an observational study of 64 people to assess neuroendocrine outcomes and fatigue after TBI. Subjects were recruited from the community with flyers. Over one-third of the study population had self-reported coma of more than 2 weeks. The subjects underwent neuroendocrine testing an average of 10 years after injury, including tests to assess thyroid, adrenal, gonadal axes function, and GH after glucagon stimulation. The authors found that 23 subjects (39%) had severe GH deficiency, 16 (27%) had moderate GH deficiency, and 20 (34%) had normal GH reserve following glucagon administration. Twelve (19%) of the 63 participants had central hypothyroidism. Forty percent (23 of 57) of the subjects
NEUROLOGIC OUTCOMES 231 were deficient in one anterior pituitary axis, 44% (25 of 57) were deficient in two, and 9% (5 of 57) were deficient in more than two. As discussed in Chapter 5, Roberts (1979) assessed patients for disordered hypothalamic and pituitary function. Results indicated that anterior hypopituitarism did not increase in frequency because of head trauma; at the time of the study, only one patient (a 10-year-old boy) had that diagnosis. The incidence of DI (diagnosed on the basis of polyuria) in the consecutive series was 8 of 291 patients (3%). Hypothalamic hyperphagia was diagnosed in 16 of 291 (6%) in the consecutive series and 6 of 40 (15%) in the selected series. Lower age and greater severity of injury seem to contribute to increased rates of DI and hyperphasia in the injured. Summary and Conclusions Changes in the endocrine system after TBI have been reported. The committee identified eight primary and four secondary studies that assessed the relationship between TBI and a number of endocrine disorders, including hypopituitarism, DI, and GH insufficiency. Hypopituitarism Regarding hypopituitarism, the committee identified one primary study (Agha et al., 2005b) and four secondary studies (Roberts, 1979; Kelestimur et al., 2004; Bushnik et al., 2007; Tanriverdi et al., 2007) that assessed the relationship between TBI and hypopituitarism. Many of the reported disturbances appear acutely and eventually resolve, but several studies reviewed by the committee demonstrate some long-term effects of hypopituitarism (Kelestimur et al., 2004; Agha et al., 2005b; Tanriverdi et al., 2007). The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and endocrine dysfunction, particularly hypopituitarism. Diabetes Insipidus The committee identified two primary studies (Agha et al., 2004b, 2005b) that evaluated the relationship between TBI and DI. Agha et al. (2005b) prospectively studied the effects of TBI on posterior pituitary function, including DI, and found that the development of DI was associated with lower GCS score, but the association was not statistically significant. In the acute phase, there was a negative association between peak plasma osmolality and GCS and GOS scores. At followup, four (8%) TBI subjects and no controls had DI. Agha et al. (2004b) prospectively studied the incidence of posterior pituitary dysfunction (including DI) in consecutive patients who had sustained moderate or severe TBI and healthy matched controls. Seven percent of patients who had moderate or severe TBI and no controls had permanent DI. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between moderate or severe TBI and diabetes insipidus. Growth Hormone Insufficiency The committee identified five primary studies (Agha et al., 2004a, 2004b, 2005a, 2005b; Kelly et al., 2006) that assessed the relationship between TBI and GH insufficiency.
232 GULF WAR AND HEALTH In 2004, Agha et al. (2004a) prospectively studied the effect of moderate or severe TBI on anterior pituitary dysfunction in 102 consecutive patients and found that 18 had a GH response to the GST test of less than 5 Î¼g/L; 11 of these patients failed the ITT or the arginine + GHRH test. In addition, 23 TBI patients had cortisol responses to GST of less than 450 nmol/L; 13 of these failed the ITT or synacthen test. Similarly, Agha et al. (2005a) assessed pituitary function in the same population of 50 consecutive patients with severe or moderate TBI. GH deficiency was found in 9 (18%) subjects in the acute phase; 5 recovered after 6 months, and 2 more patients developed deficiency. At the 1-year followup, 5 were GH-deficient. Kelly et al. (2006) conducted a prospective cohort study of GH deficiency or insufficiency after TBI and found that at 6â9 months after injury, 8 (18%) TBI patients had GH deficiency or insufficiency when the cutoff was defined by the value in the lower 10% of controls. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and growth hormone insufficiency.
TABLE 7.7 Endocrine Disorders and TBI Health Outcomes Study or Outcome Comments or Reference Design Population Type of TBI Measures Results Adjustments Limitations Agha et al., Cohort 102 patients, Severe or GH, ACTH Controls: normal Matched on age, Inclusion criteria: 2004a including 85 males; moderate (GCS assessed with response to GST was sex, BMI severe or moderate median age, 28 score, 3â13) GST; ITT or stimulated peak of > 5 TBI, age 15â65 years; range, 15â65 arginine + GHRH Î¼g/L, cortisol peak > years, 6 mo or longer years; TBI survivors test for GH 450 nmol/L (16 Î¼g/dL) after injury, admitted into assessment; ITT or 18 TBI patients discharged alive neurosurgical unit in 250-Î¼g short (17.6%), 0 controls had from neurosurgical Beaumont Hospital synacthen test for GH response to GST unit in 2000â2002; ACTH reserve test of < 5 Î¼g/L, 11 of 29% had history of examined at median whom failed ITT or seizure disorder of 17 mo (range, 6â arginine + GHRH test GH or ACTH 36 mo) after event; 23 patients (22.5%), deficiency not 31 matched healthy three of 31 (9%) of related to age, GCS controls controls had cortisol score, or presence of responses to GST of < other pituitary 450 nmol/L, 13 of hormone whom also failed ITT abnormalities or synacthen test Agha et al., Prospective Same population as Moderate, defined WDT; plasma, In acute phase, 22 Matched on age, Inclusion criteria: 2004b cohort Agha et al., 2004a as GCS score of urine osmolalities; (21.6%) patients sex, BMI severe or moderate 9â13 urine volume; developed DI TBI, age 15â65 Severe TBI thirst score; blood Seven of 102 patients years, at least 6 mo defined as GCS pressure; weight; who sustained after injury score of 8 or less plasma sodium moderate or severe TBI Exclusion criteria: had permanent DI pregnant women, (6.9%) vs 0 of 27 patients with controls established renal In acute phase, 13 disease, patients with subjects (12.7%; 95% raised creatinine, CI, 7.0%â20.8%) had patients on lithium evidence of SIADH; at of other medication followup, two patients known to cause renal had evidence of insensitivity to AVP, SIADH patients with diabetes mellitus and 233
234 Health Outcomes Study or Outcome Comments or Reference Design Population Type of TBI Measures Results Adjustments Limitations hemoglobin A1C greater than 6.5%, patients with hypokalemia or hypercalcemia Agha et al., Prospective 50 patients with Severe or Pituitary function; 13 patients (26%) had Matched on age, Posterior pituitary 2005b cohort severe or moderate moderate; posttraumatic DI; DI in acute phase, of sex, BMI dysfunction seen in TBI; studied acutely, GCS score 3â13 SIADH whom 9 recovered by 6 acute phase after TBI at 6, 12 mo after mo, additional patient but most patients TBI; 27 healthy recovered by 12 mo; 0 recover over long controls of 27 controls had DI term Three patients had permanent DI, including two with partial vasopressin deficiency Seven patients had SIADH in acute phase, but none at 6 or 12 mo Agha et al., Prospective 50 patients with Severe or Pituitary function GH deficiency found in Matched on age, 2005a cohort severe or moderate moderate; 9 subjects (18%) in sex, BMI TBI; studied acutely, GCS score 3â13 acute phase; 5 at 6, 12 mo after recovered after 6 mo; 2 TBI; 27 healthy more patients controls developed deficiency; at 1-year followup, 5 had GH deficiency Herrmann et Cohort 76 patients with Severe, defined as Neuroendocrine 18 of 76 had pituitary No control group, no al., 2006 severe TBI, GCS score < 8; tests, including GH deficiency indication of discharged from mean, 4.4 Â± 2.8; response to GHRH Six of 76 had GHD percentage of neurosurgery patients injured + arginine; TSH; (GH peak range normals outside departments in average of 22 Â± free T4, T4, T3; [GHRH + arginine], reference range Germany 10 mo before prolactin; 2.8â6.3 Î¼g/L; GH peak study testosterone; range [ITT], 1.5â2.2 estradiol; SHBG; Î¼g/L; IGF-I range, 62â cortisol; ACTH; 174 Î¼g/L)
Health Outcomes Study or Outcome Comments or Reference Design Population Type of TBI Measures Results Adjustments Limitations GH; IGF-I Two of 76 had partial ACTH deficiency Two of 76 had TSH deficiency Kelly et al., Prospective 44 patients, 14â80 Mild, moderate, Pituitary function; Eight of 44 (18%) had After complicated 2006 years old, with mild, severe (GCS neurobehavioral, GHD/GHI vs 10% of mild, moderate, or moderate, or severe score 3â14) QOL testing controls; 6â9 mo after severe TBI, 18% of TBI with GHD or performed 6â9 mo injury, TBI patients patients develop GH insufficiency; 41 after injury with GHD/GHI had chronic GHD/GHI, healthy controls higher rates of at least which is associated one marker of with depression, depression (p < 0.01) poor QOL TBI patients with GHD/GHI had decline in QOL (by SF-36 Health Survey) due to physical health (p = 0.02); energy and fatigue (p = 0.05); emotional well-being (p = 0.02); pain (p = 0.01); general health (p = 0.05) Klose et al., Prospective 46 consecutive Mild, GCS 13â Pituitary 3 mo after trauma, 6 of Age, BMI Exclusion criteria: 2007b patients with mild 15; moderate, insufficiency 46 had anterior inconclusive (22), moderate GCS 9â12; assessed at 3, 6, 12 pituitary deficiencies diagnosis, chronic (nine), or severe (15) severe, GCS < 9 mo 12 mo after trauma, 1 alcohol or drug TBI hospitalized in patient recovered; no abuse, prior severe Copenhagen Baseline, additional patients head trauma or University Hospital; stimulated found to have apoplexies, chronic 30 healthy volunteer hormone deficiencies use of controls; another 100 concentrations; Five of 46 had GH glucocorticoids healthy volunteer Synacthen-test deficiency at 12 mo Mean GH not controls for (acute + 6 mo); Four of 15 patients significantly Synacthen test ITT, GHRH + with severe TBI had different from arginine test (used hypotituitarism vs 1 of controls at 3, 12 mo; 235
236 Health Outcomes Study or Outcome Comments or Reference Design Population Type of TBI Measures Results Adjustments Limitations if ITT was 31 patients with mild or number of controls contraindicated at moderate TBI with hormone 3, 12 mo) deficiency not given Schneider et Prospective 78 consecutively Grade IâIII as Subjects evaluated 3 mo after trauma, 56% Exclusion criteria al., 2006 longitudinal admitted patients assessed with at 3, 12 mo after had impairments of at included with TBI of whom GCS inury with GHRH least one pituitary axis glucocorticoid 70 were tested at 12 + arginine test, with axes being treatment within 3 mo; 38 healthy short ACTH test, affected as follows: weeks or growth controls basal hormone gonadotropic, 32%; hormone treatment measurements corticotropic, 19%; within 12 mo; somatotropic, 9%; history of cranial thyrotropic, 8% irradiation, pre- 12 mo after trauma, existing pituitary 36% still had diseases; severe impairments; affected cardiac, renal, or following axes: hepatic disease; gonadotropic, 21%; sepsis; substance somatotropic, 10%; abuse corticotropic, 9%; Except for thyrotropic, 3%; 7 of stimulated GH, no 70 had stimulated GH indication of < 9 ng/mL vs 1 of 38 percentage of controls (not normals outside significant) reference range NOTE: ACTH = adrenocorticotropic hormone, AVP = arginine vasopressin, BMI = body-mass index, CI = confidence interval, DI = diabetes insipidus, FSH = follicle-stimulating hormone, GCS = Glasgow Coma Scale, GH = growth hormone, GHD = growth-hormone deficiency, GHI = growth-hormone insufficiency, GHRH = growth-hormone releasing hormone, GST = Glucagon Stimulation Test, IGF-1 = insulin-like growth factor-1, ITT = insulin-tolerance test, QOL = quality of life, SHBG = sex-hormone binding globulin, SIADH = syndrome of inappropriate antidiuretic hormone secretion, TBI = traumatic brain injury, TSH = thyroid-stimulating hormone, WDT = water-deprivation test.
NEUROLOGIC OUTCOMES 237 NEURODEGENERATIVE DISEASES Neurodegenerative diseases refer to a variety of nervous system disorders that result from the deterioration of neurons or their myelin sheath. Such deterioration can lead to a number of debilitating diseases. The committee members focused specifically on dementia of the Alzheimer type, parkinsonism, and multiple sclerosis (MS) because those were the neurodegenerative diseases that were identified during the TBI literature searches. Neurodegenerative disorders are commonly categorized into ones that primarily affect memory and lead to dementia, such as Alzheimer disease (AD), and ones that affect movement, such as ataxia, including Parkinson disease (PD) and MS. DEMENTIA OF THE ALZHEIMER TYPE AD is a progressive neurodegenerative illness that is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. Advanced age is an important risk factor for AD inasmuch as it is most commonly observed in people 65 years old and older. It has been estimated that about 4.5 million people in the United States suffer from AD and that about 5% of men and women 65â74 years old have it; nearly 50% of those 85 years old and older may have AD (NIH, 2006). Symptoms of AD vary widely with the stage of the illness. In the early stages, symptoms commonly include memory impairment, which can progress to severe cognitive decrements and an inability to perform daily functions. Symptoms also include difficulty with language and poor judgment. The duration of the disease is estimated to be 5â20 years. Genetics may play a role in the development of AD: researchers have found that the presence of the APOE gene is a risk factor for such diseases as cardiovascular disease, atherosclerosis, and dementia (including AD). Because pathologic confirmation of the clinical diagnosis of AD was not reported in most of the studies reviewed, the committee limited its conclusions to the evaluation of the relationship of TBI and dementia of the Alzheimer type, rather than AD. The committee identified one primary study that investigated the association between TBI and dementia of the Alzheimer type. Plassman et al. (2000) investigated the relationship between nonpenetrating head injury and the risk of AD and other dementias in WWII veterans (see Table 7.8). Primary Study Plassman et al. (2000) conducted a population-based retrospective cohort study of male WWII Navy and Marine Corps veterans to assess the relationship between nonpenetrating TBI and the risk of AD and other dementias. Subjects included 548 veterans who served during 1944â1945 and were hospitalized during military service with diagnosis of nonpenetrating head injury; 1,228 subjects matched on education and age who had unrelated injuries served as controls. Medical records were abstracted in 1996 and 1997 to document details of the closed head injuries. Subjects were considered to have had a closed head injury if it was documented in medical records; if the injury produced LOC, PTA, or skull fracture; and if the injury did not result in marked cognitive impairment or neurologic sequelae more than 3 months after injury. Subjects who had a head injury that penetrated the dura mater were excluded from the study. TBI
238 GULF WAR AND HEALTH was designated as mild (LOC or PTA for less than 30 minutes with no skull fracture), moderate (LOC or PTA for more than 30 minutes but less than 24 hours and/or skull fracture), or severe (LOC or PTA for more than 24 hours). The authors identified men with dementia by using a three-stage screening and assessment process, including a telephone interview, a dementia questionnaire, and a clinical assessment for those whose scores indicated dementia. Proportional- hazards methods were used to estimate the risk of AD and dementia associated with head injury. Multiple logistic regression was also used to assess the validity of the proportional-hazards analysis. The authors found that a history of moderate TBI increased the risk of AD (hazard ratio [HR], 2.32; 95% CI, 1.04â5.17), as did severe TBI (HR, 4.51; 95% CI, 1.77â11.47). Similarly, moderate TBI (HR, 2.39; 95% CI, 1.24â4.58) and severe TBI (HR, 4.48; 95% CI, 2.09â9.63) were associated with dementia. There was no significant risk of AD (HR, 0.76; 95% CI, 0.18â 3.29) or dementia (HR, 1.33; 95% CI, 0.51â3.47) in those with mild TBI. The study is limited in that the data rely primarily on reviews of 50-year-old medical records and the authors could not rule out other factors in the development of dementia later in life. Secondary Studies The committee identified nine secondary studies that assessed the relationship between TBI and AD. Schofield and colleagues (1997) conducted a community-based longitudinal study of aging that included 271 participants in north Manhattan. The participants were screened for significant cognitive impairment. History of TBI was ascertained on two occasions, first by physicians who asked about head injury with LOC and second by an interviewer who asked about prior TBI with LOC or PTA, duration of LOC, and date of head injury. Annual evaluations for up to 5 years were conducted to determine the first occurrence of dementia. The annual examination consisted of a clinical evaluation by a physician and neuropsychologic testing, including tests of memory, abstract reasoning, language, and tests of construction. Of the 217 participants, 39 had a diagnosis of probable or possible AD. A history of TBI with LOC as reported to a physician was associated with earlier onset of dementia due to AD (relative risk [RR], 4.1; 95% CI, 1.3â12.7). However, a history of TBI with LOC or PTA as reported to an interviewer was not significantly associated with earlier onset of AD overall (RR, 2.0; 95% CI, 0.7â6.2), but those who reported LOC of over 5 minutes were at increased risk (RR, 11.2; 95% CI, 2.3â59.8). The authors also found that incident AD was significantly associated with TBI that had occurred within the preceding 30 years (RR, 5.4; 95% CI, 1.5â19.5). French and colleagues (1985) conducted a caseâcontrol study to assess risk factors related to dementia of the Alzheimer type. The study population included 78 male subjects who received a diagnosis of AD in 1979â1982 at the Veteransâ Administration Medical Center in Minneapolis, Minnesota, and controls matched to subjects on age, race, and sex. Inclusion criteria included âinsidious onset, gradual progression of dementia with an intact level of consciousness, and absence of focal neurologic signs.â Interviews were held with surrogate respondents (usually next of kin). Information ascertained during the interview included variables relevant to viral, genetic, and immunologic hypotheses; environmental and occupational exposures; drug use; psychologic stress; smoking; and alcohol use. Information about prior TBI was also ascertained. The authors found that TBI was reported significantly more frequently in subjects than in hospital controls (OR, 4.50; 95% CI, 1.44â15.69; p < 0.01), and TBI occurred before the diagnosis of dementia.
NEUROLOGIC OUTCOMES 239 Amaducci and colleagues (1986) conducted a caseâcontrol study in a population of 152 consecutive patients admitted into neurology departments of seven centers in northern Italy in 1982â1983 who had a clinical diagnosis of AD. Clinical history, a neurologic examination, and neuropsychologic and laboratory tests were used to assess other factors, including TBI. The control group consisted of 116 hospital and 92 population controls matched to the subjects on age, sex, and region of residence. The authors found that although the odds of TBI were higher in subjects than in hospital controls (OR, 3.5; p = 0.18) or population controls (OR, 2.0; p = 0.51), the differences were not significant. Broe and colleagues (1990) conducted a caseâcontrol study of 170 people who had a clinical diagnosis of AD and 170 controls matched to the cases on age, sex, and region of residence. Subjects were consecutive new referrals to dementia clinics in Sydney, Australia, who were 52â96 years old. The participants and accompanying relatives or friends were interviewed to assess cognitive or behavioral changes. A clinical examination included a Neurology of Aging Schedule, the Mini-Mental State Examination (MMSE), and a full neuropsychologic assessment. The authors defined a significant TBI as one resulting in LOC for more than 15 minutes. The estimated ORs for head injuries were relatively low, and none was statistically significant. The OR for TBI in all subjects any time before the assessment was 1.33 (p = 0.593) and for head injuries in all subjects at least 10 years before the assessment 1.60 (p = 0.405). Heyman and colleagues (1984) conducted a caseâcontrol study to assess risk factors for AD. Participants were 40 patients with onset of dementia and 80 controls matched on age, sex, and race. A structured interview was administered to acquire information about a variety of risk factors, including prior illnesses, dietary or lifestyle habits, occupational exposure, exposure to domesticated and wild animals, and family history of dementia, mental retardation, and leukemia. Both subjects and close family members or friends were interviewed. Each of the 40 patients with a diagnosis of AD was also admitted for a uniform battery of diagnostic testing. Six of the subjects had sustained TBI, and four of them reported that the incident occurred 30â40 years before the onset of dementia; in one case, the injury had occurred 19 years earlier. In all five patients, the reported TBI was severe and was associated with LOC, PTA, and multiple fractures of the limbs or trunk. The authors found that a history of TBI was reported significantly more frequently in the subjects than in the controls (15% and 3.8%, respectively). As discussed above, Lewin et al. (1979) determined the cause of death of 75 severely injured patients discharged from the John Radcliffe Infirmary in Oxford, England, 10â24 years earlier who had been in a consecutive series of 7,000 patients with severe TBI (patients had LOC for 1 week or more). The authors found that âmost patients who survived in states of decerebrate dementia died within a year after injury, and though a few lived for several years, only one from the two series survived for a decade.â In addition, frontolimbic dementia, seen in 50 cases, was observed only after the most severe form of TBI and was largely confined to adolescents and young adults who had the athetoid pseudobulbar and severe brainstem cerebellar patterns of lesion. Guo et al. (2000) conducted a caseâcontrol study to investigate the relationship between head injury and the APOE genotype and the risk of AD in participants in the MIRAGE project. The study included a total of 2,233 probands who met criteria of probable or definite AD and 14,668 controls (first-degree family members and spouses) who had participated in the MIRAGE project. Head injury was confirmed by using a structured questionnaire, interviews with multiple informants, and a thorough review of medical records. The authors used conditional logistic
240 GULF WAR AND HEALTH regression techniques to determine the relationship between head injury and the odds of developing AD. Analyses were adjusted for age, sex, and age at onset of AD. The generalized estimating equation was used to examine effects of the APOE genotype and head injury on the odds of AD. The authors found an OR of 4.6 (95% CI, 3.7â5.9) for AD associated with all types of head injury. In a comparison limited to cases and their unaffected spouses, the ORs for AD were 9.9 (95% CI, 6.5â15.1; p < 0.001) for TBI with LOC and 3.1 (95% CI, 2.3â4.0) for TBI without LOC. When subjects were compared with controls who were their parents and siblings, the ORs were 4.0 (95% CI, 2.9â5.5) for TBI with LOC and 2.0 (95% CI, 1.5â2.7) for TBI without LOC. The authors reported that head injury without LOC did not significantly increase the risk of AD in spouses (OR, 1.3; 95% CI, 0.4â4.1). The study is limited in that head injury in probands and family members was ascertained with informant interviews without independent confirmation, so there was potential recall bias. As discussed in Chapter 5, Guskiewicz et al. (2005) studied the association between recurrent concussion and long-term health outcomes, including mild cognitive impairment, AD, and risk of depression in retired professional football players. The authors found no association between recurrent concussion and AD but observed earlier onset of AD in the retired football players than in the general American male population. Shalat and colleagues (1987) conducted a caseâcontrol study to assess risk factors for AD in 98 men who had clinically diagnosed AD and 162 normal controls. Subjects were identified through the Geriatric Research, Education, and Clinical Center and the Edith N. Rogers Memorial Veterans Hospital in Bedford, Massachusetts. Controls were selected from a list of Massachusetts registered voters and were matched to cases on sex, age, and region of residence. Information was obtained with mailed questionnaires completed by spouses or next of kin at the same addresses. The authors found excess odds of severe head trauma in the subjects (OR, 2.4; 95% CI, 0.5â11.1). A meta-analysis of seven caseâcontrol studies of AD (including Amaducci et al., 1986; Broe et al., 1990; and Heyman et al., 1984) to assess the interaction of genetic and environmental risk factors, including head injury, was largely supportive of the findings described above. Van Duijn and colleagues (1994) found that âlate maternal age at birth and a history of head trauma [were] associated with a statistically significant increase in the risk for AD in the absence of a family history of dementia.â Summary and Conclusions The committee identified one primary study (Plassman et al., 2000) and nine secondary studies (Lewin et al., 1979; Heyman et al., 1984; French et al., 1985; Amaducci et al., 1986; Shalat et al., 1987; Broe et al., 1990; Schofield et al., 1997; Guo et al., 2000; Guskiewicz et al., 2005) that assessed the relationship between TBI and dementia of the Alzheimer type. Plassman et al. (2000) investigated the relationship between nonpenetrating TBI and the risk of AD and other dementias in WWII veterans. The authors found that a history of TBI increased the risk of AD (HR, 2.00; 95% CI, 1.03â3.90) and dementia (HR, 2.23; 95% CI, 1.30â3.81). Moderate TBI (HR, 2.32; 95% CI, 1.04â5.17) and severe TBI (HR, 4.51; 95% CI, 1.77â11.47) were both associated with increased risk of AD. Similarly, moderate TBI (HR, 2.39; 95% CI, 1.24â4.58) and severe TBI (HR, 4.48; 95% CI, 2.09â9.63) were both associated with dementia. There was no significant risk of AD (HR, 0.76; 95% CI, 0.18â3.29) or dementia (HR, 1.33; 95% CI, 0.51â
NEUROLOGIC OUTCOMES 241 3.47) in those with mild TBI. Except for the studies of Amaducci et al. (1986) and Broe et al. (1990), the secondary studies found an increased risk of AD after TBI. A meta-analysis of seven caseâcontrol studies supported these findings, noting that âa history of head trauma [was] associated with a statistically significant increase in the risk for AD in the absence of a family history of dementiaâ (Van Duijn et al., 1994). Taken as a whole, the studies generally found a strong association between moderate or severe TBI and dementia of the Alzheimer type. Studies suggested an association between mild TBI with LOC and dementia of the Alzheimer type, but mild TBI without LOC was not found to be strongly associated with dementia of the Alzheimer type. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and dementia of the Alzheimer type. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between mild TBI (with LOC) and dementia of the Alzheimer type. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists between mild TBI (without LOC) and dementia of the Alzheimer type.
242 TABLE 7.8 Dementia of the Alzheimer Type and TBI Type of TBI: Mild, Moderate, Health Severe; Blunt, Outcomes or Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Plassman et al., Retrospective World War Nonpenetrating AD, other AD risk with Controls matched Review of 50-year-old 2000 cohort; review of II US Navy or head injury with dementias moderate head on education, age medical recordsâ well- military hospital Marines male LOC, PTA, or Risk of dementia, injury: HR, 2.32 defined head-trauma records veterans serving skull fracture including AD, (95% CI, 1.04â group in military in that resolved through 5.17); AD risk 1944â1945, within 3 mo of verification of with severe head hospitalized injury medical records injury: during military Mild: LOC, PTA and three-stage HR, 4.51 (95% service for head < 30 min, no diagnostic CI, 1.77â11.47) injury (n = 548) skull fracture; procedure: Results similar or unrelated moderate: LOC, Telephone for dementia injury (n = PTA < 24 h, Interview for 1,228) and/or skull Cognitive Status fracture; severe:(TICSm), LOC, PTA > 24 telephone DQ, h clinical assessment of AD diagnosed according to NINCDS- ADRDA criteria NOTE: AD = Alzheimer disease, ADRDA = Alzheimerâs Disease and Related Disorders Association, CI = confidence interval, DQ = dementia questionnaire, HR = hazard ratio, LOC = loss of consciousness, NINCDS = National Institute of Neurological and Communicative Disorders and Stroke, PTA = posttraumatic amnesia, WWII = World War II.
NEUROLOGIC OUTCOMES 243 DEMENTIA PUGILISTICA Dementia pugilistica (DP) is a neurologic disorder that primarily affects boxers who are exposed to multiple head injuries. Some studies refer to DP as chronic traumatic encephalopathy (CTE) or punch-drunk syndrome. It is commonly associated with declines in mental and physical abilities, such as dementia and parkinsonism. Some authors have described the development of DP along a continuum. Mendez (1995) notes that the spectrum of CTE in professional boxers can range from mild, âsubclinicalâ brain damage to the syndrome of DP. CTE is initially characterized by motor, cognitive, and psychiatric symptoms. Mendez reports that there may be a gradual worsening to middle and late stages of CTE over the course of 7â35 years if boxing exposure continues. The end stage of progressive CTE is DP (Mendez, 1995). In mild cases of DP, the most common symptoms include slurring dysarthria, gait ataxia, disequilibrium, and headache. Clinical symptoms often occur 10â20 years after retirement from the sport. Neuropsychologic tests are often used to assess cognitive decline associated with DP. Studies of boxers who were thought to have symptoms of DP have found deterioration in tests of memory, information processing and speed, finger-tapping speed, attention and concentration, sequencing abilities, judgment, abstraction, reasoning, planning, and organization (McCrory et al., 2007). More recently, studies have also been done of soccer players since repeated heading may also cause repeated TBI. The committee focused its evaluation on the primary population that exhibits this effect: boxers. Boxers are typically subjected to repeated blows to the head. As Millspaugh (1937) reported in 1937, âthe etiology of dementia pugilistica is trauma, usually repeated frequently and varying from a comparatively insignificant abrasion, contusion or laceration to compound fracture, brain concussion, loss of consciousness, shock, coma, and death.â Repeated blows to the head can produce rotational acceleration of the brain, diffuse axonal injury, and other neuropathologic conditions (Mendez, 1995). The prevalence of DP among boxers is well discussed in the older literature. Martland (1928) was the first to identify âpunch-drunk syndromeâ in boxers. In 1936, Carroll noted that âthere is a clinical syndrome of frequent occurrence among boxers to which they refer as âpunch drunk.ââ The term dementia pugilistica was coined by Millspaugh in 1937, and in 1949, Critchley introduced the term chronic progressive posttraumatic encephalopathy of boxing. More recently, Mendez (1995) noted that âprofessional boxers with multiple bouts and repeated head blows are prone to chronic traumatic encephalopathy.â In reviewing the literature on DP in boxers, the committee recognized that there is a considerable difference between amateur boxing and professional boxing in measures to protect against head injury. In amateur boxing, bouts are usually limited to three rounds of 3 minutes each; gloves are typically larger, heavier, and more absorbent than those used by professional boxers (Stewart et al., 1994). Amateur boxers pursue âpointsâ rather than knockout blows to win a match. Also, in 1984â1986, additional safety measures were introduced into the sport, including the requirement to use headgear; and matching novice boxers with opponents of similar skill level. Bouts are stopped when boxers are at risk of head injury, and mandatory suspension rules can be used when head injuries are observed (Stewart et al., 1994). Professional boxers are not required to adhere to those safety measures, including the use of headgear. That may partially explain why DP is observed primarily in professional boxers and why findings
244 GULF WAR AND HEALTH from studies sometimes differ depending on whether the population studied consists of professional boxers or amateur boxers. The committee did not identify any studies that met the criteria for a primary study, because there was not a clear identification of TBI in the population of boxers, rather participation in boxing or soccer was used as a surrogate measure for TBI. In addition, the severity of head injury and the nature of repeated trauma were unknown. Secondary Studies The committee identified six secondary studies that evaluated the relationship between TBI and DP in boxers and soccer players. Four of them are limited by their use of boxing as a proxy for TBI. Another used soccer headings as a proxy for head injury. Some of the studies included subjects under 18 years old. One study was a pathology study of retired boxers to assess cerebral changes characteristic of DP. Drew and colleagues (1986) assessed neuropsychologic deficits consistent with DP in 19 licensed professional boxers. The 19 boxers were a subset of 87 active licensed professional boxers in an area of California. Initial contact was made with 38 potential participants; 29 agreed to participate, but 10 of them did not show up for testing, and that left 19 participants. The control group consisted of athletes identified through the Fresno Parks and Recreation Department who were active in organized basketball or baseball. The controls were comparable with the boxers in age, race, and education. Exclusion criteria for controls included history of drug abuse, boxing, or head trauma. The boxing history of the boxers was assessed and showed a range in the number of amateur bouts of 1 to 195 (mean, 52.8; SD, 55.98) and of professional bouts from 0 to 37 (mean, 13.7; SD, 13.08). The total of amateur losses and draws ranged from 0 to 15 (mean, 5.2; SD, 4.47), and the total of professional losses and draws ranged from 0 to 10 (mean, 3.8; SD, 2.88). Both groups were given various subtests of the Quick Neurological Screening Test, the Randt Memory Test, and the Halstead-Reitan Neuropsychological Test Battery. The authors found that boxers demonstrated significantly more deficits than controls in all tests except Seashore Rhythm, Finger Tapping, and Category Test. The boxers also scored worse than controls on all the summary scores of impairment. Of the 19 boxers, 15 scored in the impaired range on the Reitan Impairment Index; only 2 of the 10 controls scored in this range. As discussed in Chapter 5, Porter and Fricker (1996) conducted a neuropsychologic assessment of 20 amateur boxers, 16â25, in the six largest boxing clubs in Dublin, Ireland; 20 controls matched on age and socioeconomic status also participated in the study. Each of the amateur boxers was to have competed in a minimum of 40 amateur matches. The boxers were given a battery of neuropsychologic tests by an independent examiner initially in 1992 and again 15â18 months later. The tests included Trail-Making Tests A and B, the Finger Tapping Test (FTT), and the Paired Associate Learning Test. The authors found that the boxers performed significantly better then the controls on Trail-Making Tests A and B, but the control group's scores on the FTT were significantly higher than those of the boxers, and the boxersâ scores in the FTT (dominant hand) showed significant deterioration. The authors noted that there was no evidence of neuropsychologic impairment in the 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. Again, the subjects underwent a repeated battery of neuropsychologic
NEUROLOGIC OUTCOMES 245 tests at 18 months, 4 years, 7 years, and 9 years after an initial assessment. The boxers scored higher than the controls on Trail Making Tests A and B at all times but lower on the FTT at all times except baseline for the dominant hand. 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. Roberts (1969) examined 250 ex-professional boxers from a random sample of British boxers who first registered in 1929â1955 and had professional licenses for 3 years. The authors found that 37 exhibited symptoms characteristic of punch-drunk syndromeâevidence of lesions of the central nervous system. Of the 37, 4 had progressively deteriorated; their symptoms were not thought to be related to the normal aging process. The authors also found that âthere were eleven others with evidence of central nervous system disease whose lesions were adequately explicable on the basis of a diagnosis which bore no relation to their boxing careers.â Jordan et al. (1996) assessed chronic encephalopathy in elite soccer players. The subjects included 20 members of the US menâs national soccer team training camp and 20 age-matched male elite track athletes. Soccer players were given a questionnaire to assess symptoms of head and neck injuries, number of headings, and number of seasons played on various teams. The authors developed a heading-exposure index to assess cumulative exposure to headings. All subjects also completed a brain MRI scan. Seven soccer players reported a history of headings; five had had complete LOC. Eight runners reported that they had had head injuries; four had complete LOC. The authors found that reported head-injury symptoms, particularly in soccer players, correlated with history of acute head injuries (r = 0.63) and noted that the âfindings suggest that any evidence of encephalopathy in soccer players relates more to acute head injuries received playing soccer than from repetitive heading.â Corsellis and colleagues (1973) conducted the largest of the pathology studies, examining the brains of 15 retired boxers to assess cerebral changes characteristic of DP. The brains were collected from the Department of Neuropathology and the Institute of Psychiatry at Runwell Hospital, UK. Information about the boxers was collected retrospectively from relatives and friends by a social worker; hospital records were reviewed when available. Of the 15 men, 12 had boxed professionally and 3 as amateurs. The boxing careers extended from 1900 to 1940. The boxersâ age at death ranged from 57 to 91. Autopsies revealed cerebellar damage, cortical damage and other scarring of the brain, substantia nigral degeneration, neurofibrillary tangles in the cerebral cortex and temporal horn areas, and abnormalities of the septum pellucidum. Summary and Conclusions The committee identified six secondary studies that assessed the relationship between boxing or repeated heading in soccer and DP. Drew and colleagues (1986) assessed professional boxers and found neuropsychologic deficits consistent with DP. The remaining secondary studies found mixed results. Porter (2003) and Porter and Fricker (1996) conducted a neuropsychologic assessment of 20 amateur boxers, 16â25 years old, in the six largest boxing clubs in Dublin, Ireland, and found no evidence of neuropsychologic impairment in the boxers compared with the controls. Roberts (1969) examined 250 ex-professional boxers from a random sample of British boxers who first registered in 1929â1955 and had professional licenses for 3 years. The authors found that 37 exhibited symptoms characteristic of punch-drunk syndrome; of the 37, four had progressively deteriorated, and their symptoms were not thought to be related to the normal
246 GULF WAR AND HEALTH aging process; in the others, the authors found no evidence that neuronal degeneration, rather than age, was the cause. Jordan et al. (1996) noted that âany evidence of encephalopathy in soccer players relates more to acute head injuries received playing soccer than from repetitive heading.â Pathologic findings of DP were observed by Corsellis et al. (1973). Findings were consistent with DP in the 15 boxers who were autopsied. The autopsies revealed cerebellar damage, cortical damage, and other scarring of the brain; substantia nigral degeneration; neurofibrillary tangles in the cerebral cortex and temporal horn areas; and abnormalities of the septum pellucidum. Findings in professional boxers demonstrate an association with the development of DP; pathology study of brains of autopsied boxers also support these findings. The evidence is less clear in amateur boxing and soccer: it is difficult to know the severity, if any, of the head injury experienced. Therefore, the committee cannot draw a conclusion about TBI and DP in general and has limited its conclusions to professional boxers. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between professional boxing and development of dementia pugilistica. PARKINSONISM Parkinsonism is a neurologic condition characterized primarily by hypokinesia, rigidity, tremor, and postural instability. Parkinson disease is the primary underlying cause of parkinsonism although other factors have been associated with it, including exposure to toxicants and other metabolic conditions. PD is a neurodegenerative disorder resulting from a deficiency in dopamine. Symptoms of PD include tremor, rigidity, bradykinesia, and postural instability; these symptoms gradually progress. An important risk factor for PD is age; it affects mainly people over 50 years old. Diagnosis of PD is based on a thorough review of medical history and a neurologic examination. As with AD, pathologic confirmation of the clinical diagnosis of PD was not reported in most of the studies reviewed by the committee, so it limited its conclusions to the evaluation of the relationship between TBI and parkinsonism. Primary Studies The committee identified two primary studies that evaluated the association between TBI and parkinsonism (see Table 7.9). Bower and colleagues (2003) evaluated the association between a history of TBI and PD in a caseâcontrol study, and Goldman and colleagues (2006) conducted a caseâcontrol study of 93 male twin pairs discordant for PD. Bower and colleagues (2003) examined a history of TBI as a risk factor for PD in a caseâ control study, using the medical-records linkage system of the Rochester Epidemiology Project. Included were 196 cases of PD diagnosed in 1976â1995. Each case of PD was matched on age and sex to a general-population control also residing in Olmsted County, Minnesota. TBI (mild, moderate, or severe) was ascertained by a trained nurse abstractor who reviewed the complete medical records of cases and controls. A neurologist also abstracted the information from the records, and a second neurologist independently assessed the presence and severity of TBI. The
NEUROLOGIC OUTCOMES 247 authors defined TBI as a âhead injury with evidence of a presumed brain involvement, that is, concussion with loss of consciousness, posttraumatic amnesia, neurologic signs of brain injury, or skull fracture.â TBI was defined as severe if there was brain contusion (based on direct observation during surgery or focal neurologic symptoms), intracranial hematoma, or LOC or PTA lasting over 24 hours. TBI was defined as moderate if there was LOC or PTA lasting 30 minutes to 24 hours or a skull fracture. TBI was defined as mild if there was an absence of skull fracture and there was LOC or PTA lasting less than 30 minutes. A history of TBI was significantly more frequent in men with PD (9.9%) than in their matched controls (1.7%) (OR, 6.0; 95% CI, 1.3â26.8). A history of TBI was also greater in all cases of PD than in matched controls (OR, 4.3; 95% CI, 1.2â15.2; p = 0. 02). Mild TBI accompanied only by PTA was not associated with an increased risk of PD. The authors also considered the association between PD and a history of mild TBI with LOC, moderate TBI, or severe TBI and found a significant association (OR, 11.0; 95% CI, 1.4â85.2; p = 0.02). The authors noted that the âresults suggest an association between head trauma and the later development of PD that varies with severity.â Possible study limitations include the broad confidence intervals, the potential for underascertainment of mild TBI from medical records alone, and the possibility that patients with more severe TBI might be followed more closely in the medical system, a phenomenon that could lead to an earlier diagnosis of PD. Goldman and colleagues (2006) conducted a caseâcontrol study of 93 male twin pairs discordant for PD that were identified through the National Academy of Sciences WWII veteran twins cohort. After screening for PD in a telephone interview, twins who were thought to be likely PD cases were examined in person by a movement-disorder specialist. PD was diagnosed according to the Core Assessment Program for Intracerebral Transplantations criteria. Probable PD was characterized on the basis of â(1) the presence of at least two of the following signs, at least one of which must be either resting tremor or bradykinesia: resting tremor, cogwheel rigidity, bradykinesia, and postural reflex impairment; (2) no other cause of parkinsonism; (3) no signs of more extensive neurodegeneration indicating atypical parkinsonism; and (4) a clear-cut response to L-dopa, if treated.â Possible PD was defined in one of the following ways: â(1) meets definitions 2 through 4 above, but neither bradykinesia nor resting tremor is present; (2) meets definitions 2 through 4 above, but only resting tremor is present; (3) meets definitions 1 through 3 above, but response to L-dopa is unknown; (4) meets all of definitions above, but also has another clinical symptom or sign sometimes, but not always, found in PD (eg, prominent dementia, severe dysautonomia).â Each in-person examination was reviewed independently by a second neurologist. Controls were the unaffected twins. To assess TBI, a structured lifetime head-injury questionnaire was conducted by telephone. TBI was associated with an increased risk of PD (OR, 3.0; 95% CI, 1.2â7.6). The association between a history of TBI and later PD was stronger for two or more TBIs (OR, 4.3; 95% CI, 0.46â41) than for only one TBI (OR, 3.6; 95% CI, 1.1â12; p for trend = 0.022). The association between head injury and PD was slightly stronger in monozygotic than in dizygotic pairs. The authors also conducted a subanalysis of 18 twin pairs concordant for PD and found that the twin with earlier onset of PD was more likely to have sustained TBI. However, the authors cautioned that the number of subjects in the analysis was small.
248 GULF WAR AND HEALTH Secondary Study The committee identified one secondary study of the relationship between TBI and parkinsonism. Taylor and colleagues (1999) conducted a caseâcontrol study to assess risk factors for PD. The subjects were 140 patients of the Movement Disorder Center at Boston University Medical Center diagnosed with PD. Each subject was examined by a neurologist. The controls were 147 peopleâmatched on age, sex ratio, and socioeconomic statusârecruited through the PD patient population of the Movement Disorder Center. None of the controls had a diagnosis of PD or met diagnostic criteria for PD. Data were collected on environmental exposure, family history of illness, and comprehensive medical history, including age at onset of PD and at diagnosis, head injury, smoking, vitamin intake, and depression. Head injury was diagnosed if the trauma was âsevere enough to cause loss of consciousness, blurred or double vision, dizziness, seizures, or memory loss.â Subjects and controls were stratified into birth cohorts in 5- year intervals, and the average age at onset of PD was calculated for each birth cohort. Chi- square tests were used to test differences in ORs; univariate logistic regression was used to calculate ORs for family history. The mean period between age at reported head injury and age at onset of PD was 36.5 years. The authors found that four factors were associated with increased odds of PD: TBI (OR, 6.23; 95% CI, 2.58â15.07), family history of PD (OR, 6.08; 95% CI, 2.35â15.58), family history of tremor (OR, 3.97; 95% CI, 1.17â13.50), and history of depression (OR, 3.01; 95% CI, 1.32â6.88). Possible study limitations include recall bias related to the extensive time between head injury and onset of PD. Summary and Conclusion The committee identified two primary studies (Bower et al., 2003; Goldman et al., 2006) and one secondary study (Taylor et al., 1999) that evaluated the association between TBI and parkinsonism. The results of all three suggested an association. Bower and colleagues (2003) conducted a caseâcontrol study of PD as related to TBI by using the medical-records linkage system of the Rochester Epidemiology Project and found that the frequency of head trauma overall was significantly higher in people with PD than in controls. An increased risk was observed in patients with mild TBI and LOC or with more severe TBI. The authors noted that the âresults suggest an association between head trauma and the later development of PD that varies with severity.â Goldman and colleagues (2006) conducted a caseâcontrol study of male twin pairs discordant for PD and found that TBI with LOC or PTA was associated with an increased risk of PD. Taylor et al. (1999) conducted a caseâcontrol study to assess risk factors related to PD and found that TBI was associated with an increased risk of PD. The committee concludes, on the basis of its evaluation, that there is sufficient evidence of an association between moderate or severe TBI and parkinsonism. The committee concludes, on the basis of its evaluation, that there is limited/suggestive evidence of an association between mild TBI (with LOC) and parkinsonism.
TABLE 7.9 Parkinsonism and TBI Type of TBI: Mild, Moderate, Health Severe; Blunt, Outcomes or Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Bower et al., Case control, 196 PD patients Mild, moderate, PD, determined Any head trauma, Matched 1 to 1 Incident cases 2003 derived from REP living in severe; included by neurologist OR, 4.3 (95% CI, on age; separate reviewed, thus avoiding Olmsted County, only cases with review of medical 1.2â15.2) analyes stratified referral bias MN, with onset impairment of records, Severe trauma, on age of onset, Broad CI because PD 1976â1995 consciousness or previously OR, 11.0 (95% CI, severity of TBI, rare memory at time validated method 1.4â85.2) family history of People with mild TBI of injury Mild trauma, no PD might not have sought increased risk of medical attention, thus PD would not be in system; Men, OR, 6.0 result would be (95% CI, 1.3â26.8) underascertainment of mild TBI; if distributed Women, NS equally in PD case, Age of onset > 71 controls, bias would be years, p = 0.02 (no toward finding no OR because of lack effect of mild TBI on of data on controls) risk of PD Patients with significant head trauma might be followed more closely; this would lead to earlier or more frequent diagnosis of PD 249
250 Type of TBI: Mild, Moderate, Health Severe; Blunt, Outcomes or Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Goldman et al., Case control 93 twin pairs Mild to Screened for PD OR, 3.8 (95% CI, 2006 ascertained from moderate: head in telephone 1.3â11; p = 0.014); National injury with LOC interview; PD risk greater if Research or amnesia examined twins two or more Council WWII with likely PD; previous TBIs than Veteran Twins PD diagnosed if one (p for trend Cohort according to = 0.022) CAPIT criteria Association stronger in monozygotic twins than in dizygotic twins In subanalysis of 18 pairs concordant for PD, twin with earlier PD onset more likely to have sustained head injury NOTE: CAPIT = Core Assessment Program for Intracerebral Transplantations, CI = confidence interval, LOC = loss of consciousness, NS = not significant, OR = odds ratio, PD = Parkinson disease, REP = Rochester Epidemiology Project, TBI = traumatic brain injury, WWII = World War II.
NEUROLOGIC OUTCOMES 251 MULTIPLE SCLEROSIS MS, a chronic nervous system disorder caused by progressive deterioration of the myelin sheath, is characterized by such symptoms as muscle weakness, visual disturbances, coordination and balance problems, and cognitive and memory problems. Symptoms can range from mild to severe; severe symptoms can include an inability to speak and paralysis. The disease is more likely to affect women, and onset typically occurs at the ages of 20â40. As of 2002, the prevalence of MS in the United States was estimated to be 85/100,000 population (Noonan et al., 2002). Primary Study The committee identified one primary study of the relationship between TBI and MS (see Table 7.10). Goldacre and colleagues (2006) conducted a population-based record-linkage study to investigate the risk of MS after head injury. To ascertain those with and those without TBI, data were collected from the Oxford record-linkage study on hospital admissions for TBI in January 1963âMarch 1999. To ascertain later MS, those data were linked to death data and to hospital admissions for MS in the same period. The cohort with TBI (110,993) was compiled by using information on patients admitted with mild, moderate, or severe head injury (as defined by ICD-9 codes 850â854). The reference group (534,600) was selected by using medical records of people admitted for a wide array of health conditions in the same period. Excluded from the study were those with MS recorded before or at admission and those 85 years old or older at the time of TBI. Rates of later MS were calculated and standardized by age (in 5-year age groups), sex, calendar year of first recorded admission, and area of residence. The authors found that there was no difference in the risk of MS between people with and people without TBI (RR, 1.1; 95% CI, 0.88â1.36). When the time since TBI was examined, there was no significant increase in the risk of MS after either short or long periods. Nor was the risk of MS increased after head injury with a hospital stay of less than 2 days (RR, 1.1; 95% CI, 0.71â1.57), of 2 days or more (RR, 1.0; 95% CI, 0.68â1.45), or of 7 days or more (RR, 1.3; 95% CI, 0.64â2.34). The study has limitations with respect to the identification of mild TBI, but not moderate or severe TBI; only people hospitalized for mild TBI would have been identified. Secondary Study The committee identified one secondary study that assessed the relationship between TBI and onset of MS. Kurland (1994) used population data from the Rochester Epidemiology Project (discussed further in Chapter 5) to assess the relationship between TBI and MS. The author identified all the cases of MS diagnosed in the local population of Olmsted County, Minnesota, in 1905â1991. Also identified were people with TBI (819) and lumbar disk surgery (942). Head trauma was defined as TBI with evidence of skull fracture and/or LOC or PTA. The author found no correlation between onset or exacerbation of MS and TBI or lumbar disk surgery. Summary and Conclusion The committee identified one primary study and one secondary study of the relationship between TBI and MS. The primary study (Goldacre et al., 2006) found no association or
252 GULF WAR AND HEALTH increased risk of MS after head injury. Similarly, the secondary study (Kurland, 1994) found no correlation between onset or exacerbation of MS and head injury. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists between TBI and the development of MS.
TABLE 7.10 Multiple Sclerosis and TBI Type of TBI: Mild, Moderate, Health Severe; Blunt, Outcomes or Penetrating, Outcome Comments or Reference Study Design Population Blast Measures Results Adjustments Limitations Goldacre et al., Cohort 110,993 people Mild, moderate, MS and head OR, 1.1 (95% CI, Standardized by Takes into account 2006 (population-based with report of severe as injury as 0.88â1.36; p = age (in 5-year only those record-linkage head injury determined by identified through 0.42); mean groups), sex, hospitalized with MS study) derived (ICD-9 codes length of hospitalizations or followup, 16.7 calendar or identified at death from Oxford 850â854); ICD- hospital stay at deaths in same years year of first Mild TBI may be Record Linkage 9 534, 600 in time of injury period (1963â recorded underidentified Study reference group; (mild, < 2 days; 1999) admission, inasmuch as all TBI identified moderate, 2â7 district of identified during January 1, 1963â days; severe, > 7 residence hospitalization March 31, 1999 days) No adjustments for other potential risk factors Limitation is mixed age group; ages 0â65+ years included Strengths of study include head injury, MS diagnoses made independently, so recall bias avoided Geographically defined but otherwise unselected population Analysis of long- and short-term risk of MS after TBI NOTE: CI = confidence interval, ICD = International Classification of Diseases, MS = multiple sclerosis, OR = odds ratio, TBI = traumatic brain injury. 253
254 GULF WAR AND HEALTH AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigâs disease, is a neuromuscular disease that causes degeneration of motor neurons in the cerebral motor cortex, the brainstem, and the spinal cord, which leads to muscle weakness and atrophy. In the final stages of the disease, the muscles responsible for breathing are disrupted; patients often die from respiratory failure. It is estimated that 5â10% of ALS cases are inherited, and the causes of the remaining cases are unknown. ALS affects 20,000â30,000 people in the United States and is more prevalent in men than in women. The risk of the disease increases with age (IOM, 2006). The committee identified no primary studies and few secondary studies of the relationship between TBI and ALS, but it recognized the importance of evaluating the literature for this outcome because there has been a concern about a relationship of the disease to military service (IOM, 2006). Secondary Studies The committee identified two secondary studies related to ALS. Chen et al. (2007) conducted a caseâcontrol study of 110 ALS cases at two major referral centers in New England. The patients, recruited in 1993â1996, received a diagnosis of ALS according to the standard criteria of the World Federation of Neurology and met the following criteria: received the diagnosis within the previous 2 years, lived in New England for half the year, spoke English, and were mentally competent. The control population consisted of 270 people without a diagnosis of dementia, parkinsonism, neuropathy, postpoliomyelitis syndrome, ALS, or other motor neuron diseases. Controls were frequency-matched to cases on age, sex, and telephone area code. Information on subjects and controls was collected by using a structured questionnaire administered by trained interviewers. To determine whether people had TBI, they were asked whether they had ever been injured so severely that they required medical attention and, if so, were then asked for details about the injury to identify TBI. The authors found that a history of TBI was associated with a higher risk of ALS. Compared with those who did not have TBI, there were significantly higher odds of ALS in patients with more than one TBI (OR, 3.1; 95% CI, 1.2â8.1) and in patients who had TBI during the preceding 10 years (OR, 3.2; 95% CI, 1.0â10.2). In patients who had multiple TBIs in the preceding 10 years, the risk of ALS was more than 11 (95% CI, 1.1â114.3), but the number of cases was small. Kurtzke and Beebe (1980) conducted a caseâcontrol study to assess risk factors for ALS. They identified 504 WWII veterans whose deaths were attributed to ALS during 1963â1967. The control population consisted of 504 men matched to subjects on age, entry into military service, and branch of service. To assess the validity of the ALS diagnosis, the authors reviewed hospital records and identified 37 representative deaths attributed to ALS; 36 were found to have definite ALS. The records were also reviewed for information about physical condition on entry into the service and other medical issues, including diseases and injuries. There were eight intracranial injuries in ALS subjects compared with two in controls. The authors found that âmen dying of ALS more often had a history of injury 15 or more years before death than did the controls during the same period.â
NEUROLOGIC OUTCOMES 255 Summary and Conclusion The committee did not find any studies that met the criteria for a primary study of TBI and ALS (see Chapter 4); however, it did identify two secondary studies. Chen and colleagues (2007) found that ever having experienced a TBI was not significantly associated with a higher ALS risk. However, compared with those who did not have TBI, there were significantly higher odds of ALS risk for patients with more than one TBI (OR, 3.1; 95% CI, 1.2â8.1) and patients who had TBI during the preceding 10 years (OR, 3.2; 95% CI, 1.0â10.2). For patients with multiple head injuries in the preceding 10 years, the risk of ALS was more than 11-fold. Kurtzke and Beebe (1980) found a higher frequency of intracranial injury in ALS subjects than in controls and stated that âmen dying of ALS more often had a history of injury 15 or more years before death than did the controls during the same period.â The secondary studies generally found higher rates of ALS in the head-injured, but no studies that met the criteria of a primary study were identified. The committee concludes, on the basis of its evaluation, that there is inadequate/insufficient evidence to determine whether an association exists TBI and the development of ALS.
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