| | Cognitive Impairment in Patients With Traumatic Brain Injury and Obstructive Sleep ApneaPresented in part to the International Neuropsychological Society, February 2006, Boston, MA. Abstract Wilde MC, Castriotta RJ, Lai JM, Atanasov S, Masel BE, Kuna ST. Cognitive impairment in patients with traumatic brain injury and obstructive sleep apnea. ObjectiveTo examine the impact of comorbid obstructive sleep apnea (OSA) on the cognitive functioning of traumatic brain injury (TBI) patients. DesignA case-control study. Neuropsychologic test performances of TBI patients with OSA were compared with those who did not have OSA. The diagnosis of OSA was based on standard criteria using nocturnal polysomnography. SettingThree academic medical centers with level I trauma centers, accredited sleep disorders centers, and rehabilitation medicine programs. ParticipantsThirty-five TBI patients who were part of a project that assessed the effect of sleep disorders in a larger sample of consecutively recruited TBI patients. There were 19 patients with TBI and OSA. They were compared with 16 TBI patients without OSA who were comparable in terms of age, education, severity of injury (when available), time postinjury, and Glasgow Coma Scale scores (when available). InterventionsNot applicable. Main Outcome MeasuresThe Psychomotor Vigilance Test, Rey Complex Figure Test, Rey Auditory Verbal Learning Test, digit span test from the Wechsler Memory Scale–Revised, and finger-tapping test. ResultsThe TBI patients with OSA performed significantly worse than the non-sleep disordered TBI patients on verbal and visual delayed-recall measures. The groups performed comparably on motor, visual construction, and attention tests. The TBI patients with OSA made more attention lapses (reaction times ≥500ms), but showed comparable fastest and slowest reaction times on a measure of sustained attention. ConclusionsOSA is associated with more impairment of sustained attention and memory in TBI patients. It is possible that early identification and treatment of OSA may improve cognitive, and thus potentially functional, outcomes of TBI patients with this disease. THERE IS AN APPARENT increased incidence of obstructive sleep apnea (OSA) and other sleep disorders in traumatic brain injury (TBI) patients.1, 2, 3, 4, 5 A wide range of cognitive deficits, most commonly involving vigilance, attention, arousal, memory, and executive functions, have been associated with OSA.6 Additionally, continuous positive airway pressure (CPAP), the first line treatment for OSA, has been associated with improvements in some cognitive functions in some placebo-controlled trials with patients who have OSA.6 Conversely, it is well established that significant cognitive impairment is associated with TBI, and that the degree of cognitive impairment is associated with the severity of the injury.7, 8 More specifically, deficits in information-processing speed, attention, memory, and executive function are commonly reported.9 TBI patients with a mild level of injury severity (Glasgow Coma Scale [GCS] score of 13–15 and an negative computed tomography [CT] scan of the brain) generally have a complete recovery, while those with more severe injuries have less complete recoveries and may be left with some degree of disability.9, 10 Rehabilitation appears to benefit people with significant TBI.11 It is likely, however, that other comorbid disorders contribute to less optimal cognitive outcomes in this patient population. Although sleep disorders appear to be common in TBI, the literature is sparse concerning their potential impact on the TBI patient’s cognitive functioning and outcome.1 Masel et al3 found no significant differences between sleepy and nonsleepy TBI subjects on measures of intellectual functioning, attention, memory, or executive function. Our goal in this study was to evaluate the degree to which the cognitive functioning of TBI patients is associated with the comorbid OSA. We hypothesized that TBI patients with OSA would show more impaired memory and attention than would those without OSA. Methods  Participants The analysis reported herein was based on 35 TBI patients who were participating in a multicenter study of the relation between sleep disorders and TBI. Subjects who were more than 18 years old and at least 3 months post-TBI were prospectively recruited from rehabilitation services at 3 academic medical centers: Memorial Hermann Hospital, Houston, TX, Transitional Learning Center, Galveston, TX, and Philadelphia Veterans Administration Medical Center, Philadelphia, PA. The study was approved by the committees for the protection of human subjects or the institutional review boards of all participating institutions. Eighty-seven TBI patients underwent the initial nocturnal polysomnography (NPSG). Forty-six patients (53%) had no sleep disorder. The other sleep-disorder diagnoses included post-traumatic hypersomnia, periodic limb movements during sleep, and narcolepsy. The 19 patients who were diagnosed with OSA were compared with 16 patients who had no sleep disorders, as confirmed by NPSG and the Multiple Sleep Latency Test (MSLT). Because of our small sample size, it was impossible to match the groups so that they would be equivalent in age, education, time postinjury, and injury severity variables. Thus, we attempted to equate the groups by eliminating control patients by age and time postinjury until the groups were as similar as possible in the characteristics listed above. All patients had a diagnosis of TBI that was based on a history of positive loss of consciousness and all were at least 3 months postinjury. We made every effort to collect injury severity data on all patients, but this was not possible in all cases. When the relevant data were available, we classified TBI severity by considering both emergency department GCS and computed tomography (CT) scan findings according to traditional criteria.12 Patients were classified as having a severe injury if their GCS was less than 9, irrespective of their CT scan findings. Patients were classified as having a moderate injury if they had a GCS of 9 to 12, again irrespective of CT findings, or if they had a GCS of 13 to 15 and a positive CT scan.9, 13 Patients were classified as having a moderate-to-severe injury if they had a positive CT scan but there was no GCS score available with which to make a finer characterization. Patients were classified as having a mild TBI if their GCS was 13 to 15 and the CT scan was negative. Sleep Disorder Diagnosis All patients underwent a history and physical examination and NPSG. An Epworth Sleepiness Scale14 questionnaire was completed on each subject on the night of the polysomnography. Nocturnal polysomnograms were performed in sleep laboratories in each center. Using standard techniques,15, 16 a computer data acquisition and analysis system recorded the following signals: electroencephalogram (EEG) (C3A2, C4A1, O1A2, O2A1), bilateral electroculogram, submental and bilateral anterior tibialis electromyogram, thoracic and abdominal excursion by piezocrystals, oral and nasal airflow by thermistor and breath sounds, body position, oxygen saturation by pulse oximeter, and electrocardiogram. Throughout the study, subjects were monitored with an infrared video camera and a 1-way intercom that connected the bedroom with the monitoring room. Polysomnographic technologists scored all studies using 30-second epochs with the Rechtschaffen and Kales criteria17 and each study was reviewed and interpreted by a physician certified by the American Board of Sleep Medicine. During the day subsequent to the sleep study, we used the MSLT to assess objective, physiologic sleepiness. The test was performed using standard techniques.18 Each patient took 5 naps of 20 minutes duration at 2-hour intervals. The following signals were recorded during the naps: EEG (C3A2, C4A1, O1A2, O2A1), bilateral electrooculograms, submental electromyogram, and electrocardiogram. A urine sample was collected after the NPSG and during the MSLT for analysis for possible opiates, benzodiazepines, cannabinoids, amphetamines, or adrenergic drugs. Obstructive apnea was defined by cessation of breathing lasting 10 seconds or longer and accompanied by continuous respiratory effort. Hypopnea was defined as more than 50% decreases in airflow for 10 seconds or longer, with 4% or more oxygen desaturation by pulse oximetry and/or electroencephalographic arousal. The diagnosis of OSA was made if there were 5 or more apneas per hour of sleep and/or 10 or more apneas plus hypopneas per hour of sleep. Rapid eye movement (REM)–related OSA was defined as 5 or more apneas per hour of REM sleep and/or 10 or more apneas plus hypopneas per hour of REM sleep, with less than 5 apneas per hour of total sleep and less than 10 apneas plus hypopneas per hour of total sleep. Table 1 shows the sleep data for each group. Measures Each patient underwent a brief neuropsychologic evaluation. The measures used are described below. Psychomotor Vigilance Test Sustained attention was evaluated with the Psychomotor Vigilance Test (PVT).a The PVT was chosen because it is sensitive to the effects of sleepiness on cognitive functioning, as well as cognitive deficits associated with OSA and its treatment.19, 20, 21, 22 The PVT is administered via a small, handheld computerized device with a 3-digit millisecond light-emitting diode counter and display window.a Patients undergo a 10-minute trial in which they press a response button when the see a number counting up from 0. Once the response button is pressed, the counter stops and feedback is given on the subjects’ reaction times for a 15-second interval. The amount of time between stimulus presentations varies between minimum and maximum interstimulus intervals of 2000 and 10,000ms. Performances are recorded in the PVT device and downloaded into a database after the testing bout. We selected the average of the fastest 10% of reaction times, the average of the slowest 10% reaction times, and the number of lapses (reaction times ≥500ms) from the PVT for this analysis because these variables are sensitive to sustained attention under conditions of sleep deprivation and in sleep disorders.20, 23 Normally, the PVT is given in several testing bouts across time. Because of time constraints, each patient in this study was exposed to the PVT once. Wechsler Memory Scale–Revised digit span test The patients underwent the digit span test from the Wechsler Memory Scale–Revised.24 On this test, subjects are asked to repeat numbers of increasing length forward after the examiner speaks them. They are then administered another condition in which they repeat another series of numbers of increasing length backward. The patient receives 1 point for each series correctly repeated. The maximum score for each trial is 12. We examined each trial independently for the purposes of this analysis. Rey Complex Figure Test On the Rey Complex Figure Test (RCFT),25 a well-known test of visual constructional skill and visual memory, patients are asked to copy a complex geometric figure and then draw it from memory 30 minutes later without warning. The maximum score for the RCFT is 36 for both the immediate and delayed recall trials. In this study, there was no immediate recall trial. Rey Auditory Verbal Learning Test The Rey Auditory Verbal Learning Test (RAVLT)25 is a well-known measure of verbal learning and recall in which a subject is read a list of 15 words and asked to recall them after the examiner finishes reading the list. Subjects are given 5 learning trials. They are then read a new 15-word list and are again asked to recall the words after the examiner finishes reading the list. Subjects are exposed to the second list once, after which they are asked to recall as many words as he/she can from the first list. After a 30-minute delay, subjects are again asked to recall the words from the first list; they subsequently participate in a recognition trial in which he/she determines whether the word he/she heard was in the first list. The following measures from the RAVLT were used for this study: (1) total recall over the 5 learning trials; (2) short delay recall (the number of words recalled from the first list after exposure to the second); (3) long delay recall (the number of words recalled after a 30-minute delay); and (4) the Rey percent retained (the percent of words recalled on trial 7 that were also recalled on the last learning trial, allowing for a measure of retention that controls for general learning efficiency [trial 7/5×100]). Finger tapping test The finger tapping test (FTT)26 is a test of fine motor speed in which a subject taps on a counter with the index finger as fast as possible in 10 seconds. The test is administered until the subject completes 5 trials that are within 5 taps of one another or until they have completed 10 trials. Both the dominant and nondominant hand is tested. The score is the average number of taps per 10-second trial. Procedures All neuropsychologic testing was done after the second MSLT nap. Group comparisons were analyzed using t tests for independent samples. For group comparisons relevant to the key hypotheses of this study, we calculated effect sizes using the Cohen d statistic.27 Results Table 2, Table 3 present the demographic and neuropsychologic data for the 2 groups. On average, the patients were studied 94.3±152.1 months postinjury. As expected, there were no significant group differences for age, education, injury severity, time postinjury, or ethnicity. | | |  | Characteristic | Non-OSA | OSA | |
|---|
| N | 16 | 19 | | | Sex | | |  Male | 12(75) | 17(90) | | | Female | 4(25) | 2(10) | | | Race | | | White | 13(81) | 13(68) | | | African American | 2(12) | 3(16) | | | Hispanic | 1(6) | 3(16) | | | Cause of injury | | | Assault | 1(6) | 1(5) | | | Auto/vehicle | 12(76) | 10(53) | | | Construction | 1(6) | 0(0) | | | Fall | 1(6) | 4(21) | | | Hit by falling object | 1(6) | 4(21) | | | CT scan findings | | | Unknown | 8(50) | 16(53) | | | Negative | 1(6) | 0(0) | | | Positive | 7(44) | 9(47) | | | Brain injury severity | | | Unknown | 8(50) | 10(53) | | | Moderate | 2(12) | 3(16) | | | Moderate/severe | 3(19) | 1(5) | | | Severe | 3(19) | 5(26) | | | | |
Patients performed comparably on the dominant-handed FTT (t35=.42, P=.68), nondominant-hand FTT (t35=1.02, P=.31), the digit span test forward (t35=.91, P=.37) and backward (t35=.32, P=.75), the copy administration of the RCFT (t35=.26, P=.79), and the total recall from the RAVLT list A total (t35=1.45, P=.16). The OSA and TBI patients, however, performed significantly worse on memory recall measures, including: RCFT delayed recall (t35=2.05, P=.048), RAVLT short delay free recall (t35=2.71, P=.01), RAVLT long delay free recall (t35=2.27, P=.03), and the RAVLT percent retention (t35=2.42, P=.02). The TBI patients with OSA made a greater number of PVT lapses (t35=−2.59, P=.01). The average of the 10% of slowest (t35=−1.49, P=.14), and the average of the 10% of fastest response times (t35=.75, P=.44), were similar between the 2 groups. The effect sizes associated with all of the statistically significant group differences were moderate-to-large by Cohen’s criteria26 (see table 2). Because TBI severity is a significant predictor of cognitive outcome, the fact that data on severity of injury were missing for some patients is a weakness of this study. To address this, the analysis was repeated on a subset of 21 patients whose injury severity was known. The groups were equated for age, education, and time postinjury, using the same method used in the previous analysis. There were 9 and 12 patients with and without OSA, respectively. Table 4 shows the data from this study, including means, standard deviations, and effect sizes. There were no differences between the groups on age, education, time postinjury, sex, severity of injury, or race. Analysis of cognitive variables with this small subsample with complete data on injury severity did not significantly change the findings. Discussion OSA appears to be associated with additional decreased sustained attention and impaired memory function in TBI patients. We compared a group of TBI patients with OSA with a group of TBI patients without a sleep disorder. Both groups were equated on relevant demographic and injury-related variables to the best possible degree, given the limitations in our data. TBI patients with OSA performed significantly worse on measures of delayed recall and retention of verbal and visual information and had more attention lapses on a vigilance task. Because cognitive deficits appear to be associated with functional outcome and employment, this increased level of cognitive impairment may have an impact on functional outcome if OSA is not recognized and treated.28, 29, 30 To our knowledge, this is the first study that has compared the cognitive functioning of TBI patients with and without OSA and the first to find a possible link between increased cognitive impairment and OSA in TBI patients. At present, however, these findings are only correlational and thereby do not imply causality. Furthermore, this study lacked complete data on acute indices of injury severity, such as GCS and brain CT findings, for the entire sample. Thus, we are unable to confirm whether both groups were indeed equivalent in terms of severity and it could be argued that it is possible that our findings resulted from heretofore unrecognized differences in injury severity between the 2 groups. When we repeated the analysis with a smaller group of patients with known severity data, the results did not change significantly. Many studies have shown memory dysfunction in otherwise healthy patients with OSA.6 Thus, it is not surprising that we found greater memory impairment in TBI patients with OSA. This analysis, however, is preliminary and a study with a larger sample of well-characterized TBI patients is needed. Study Limitations The small sample size could be considered a significant weakness of this study. While we would agree that a study with a larger sample size would be optimal, the effect sizes for the significant differences we found ranged from medium to large. This increases our confidence in the differences with a small sample size. In fact, more statistically significant differences would have likely emerged with a larger sample size. Conclusions Our findings are intriguing in that they point to a possible avenue for improving the functional and cognitive outcomes of these patients. Thus, our data would suggest that the early identification and treatment of comorbid OSA could potentially have a meaningful impact on the functional recovery of these patients if they are able to comply with CPAP treatment. This finding needs to be authenticated with a more carefully characterized sample of patients. Additionally, further research is needed into cognitive deficits in OSA and TBI and their impact on day-to-day functioning. Supplier References 1. 1Guilleminault C, Yuen KM, Gulevich MG, Karadeniz D, Leger D, Philip P. Hypersomnia after head-neck trauma: a medicolegal dilemma. Neurology. 2000;54:653–659. MEDLINE 2. 2Castriotta RJ, Lai JM. Sleep disorders associated with traumatic brain injury. Arch Phys Med Rehabil. 2001;82:1403–1406. Abstract | Full Text |
Full-Text PDF (38 KB)
|
CrossRef
3. 3Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime sleepiness in adults with brain injuries. Arch Phys Med Rehabil. 2001;82:1526–1532. Abstract | Full Text |
Full-Text PDF (104 KB)
|
CrossRef
4. 4Webster JB, Bell KR, Hussey JD, Natale TK, Lakshminarayan S. Sleep apnea in adults with traumatic brain injury: a preliminary investigation. Arch Phys Med Rehabil. 2001;82:316–321. Abstract | Full Text |
Full-Text PDF (74 KB)
|
CrossRef
5. 5Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med. 2007;3:349–356. 6. 6Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc. 2004;10:772–785. MEDLINE 7. 7Dikmen S, Reitan RM, Temkin NR. Neuropsychological recovery in head injury. Arch Neurol. 1983;40:333–338. MEDLINE 8. 8Dikmen S, McLean A, Temkin NR, Wyler AR. Neuropsychologic outcome at one-month postinjury. Arch Phys Med Rehabil. 1986;67:507–513. MEDLINE 9. 9Dikmen S, Machamer J, Temkin N. Mild head injury: facts and artifacts. J Clin Exp Neuropsychol. 2001;23:729–738. MEDLINE |
CrossRef
10. 10Binder LM, Rohling ML, Larrabee J. A review of mild head trauma (Part I: Meta-analytic review of neuropsychological studies). J Clin Exp Neuropsychol. 1997;19:421–431. MEDLINE |
CrossRef
11. 11High WM, Roebuck-Spencer T, Sander AM, Struchen MA, Sherer M. Early versus later admission to postacute rehabilitation: impact on functional outcome after traumatic brain injury. Arch Phys Med Rehabil. 2006;87:334–342. Abstract | Full Text |
Full-Text PDF (188 KB)
|
CrossRef
12. 12Levin HS. Neurobehavioral recovery. J Neurotrauma. 1992;9(Suppl 1):S359–S373. 13. 13Williams DH, Levin HS, Eisenberg HM. Mild head injury classification. Neurosurgery. 1990;27:422–428. 14. 14Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14:540–545. MEDLINE 15. 15American Sleep Disorders Association Report (Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research). Sleep. 1999;22:667–689. MEDLINE 16. 16Practice parameters for the indications for polysomnography and related procedures (Polysomnography Task Force, American Sleep Disorders Association Standards of Practice Committee). Sleep. 1997;20:406–422. MEDLINE 17. 17Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington (DC): Public Health Service; 1968;. 18. 18Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep. 1986;9:519–524. MEDLINE 19. 19Kribbs NB, Pack AI, Kline LR, et al. Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea. Am Rev Respir Dis. 1993;147:1162–1168. MEDLINE 20. 20Dinges DF, Weaver TE. Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP. Sleep Med. 2003;4:393–402. Abstract | Full Text |
Full-Text PDF (165 KB)
|
CrossRef
21. 21Sforza E, Haba-Rubio J, de Bilbao F, Rochat T, Ibanez V. Performance vigilance task and sleepiness in patients with sleep-disordered breathing. Eur Respir J. 2004;24:279–285. MEDLINE |
CrossRef
22. 22Phipps-Nelson J, Redman JR, Dijk DJ, Rajaratnam SM. Daytime exposure to bright light, as compared to dim light, decreases sleepiness and improves psychomotor vigilance performance. Sleep. 2003;26:695–700. MEDLINE 23. 23Dinges DF, Pack F, Williams K, et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep. 1997;20:267–277. MEDLINE 24. 24Wechsler D. The Wechsler Memory Scale Revised. San Antonio: The Psychological Corp; 1989;. 25. 25Lezak MD. Neuropsychological assessment. 3rd ed.. New York: Oxford Univ Pr; 1995;. 26. 26Heaton RK, Grant I, Matthews CG. Comprehensive norms for an extended Halstead-Reitan battery: demographic corrections, research, findings, and clinical applications. Odessa: Psychological Assessment Resources; 1991;. 27. 27Cohen J. Statistical power analysis for the behavioral sciences. 2nd. ed.. Hillsdale: Lawrence Earlbaum; 1988;. 28. 28Sherer M, Novack TA, Sander AM, Struchen MA, Alderson A, Thompson RN. Neuropsychological assessment and employment outcome after traumatic brain injury: a review. Clin Neuropsychol. 2002;16:157–178. 29. 29Boake C, Millis SR, High WM, et al. Using early neuropsychologic testing to predict long-term productivity outcome from traumatic brain injury. Arch Phys Med Rehabil. 2001;82:761–768. Abstract | Full Text |
Full-Text PDF (58 KB)
|
CrossRef
30. 30Dikmen SS, Machamer JE, Powell JM, Temkin NR. Outcome 3 to 5 years after moderate to severe traumatic brain injury. Arch Phys Med Rehabil. 2003;84:1449–1457. Abstract | Full Text |
Full-Text PDF (371 KB)
|
CrossRef
a University of Texas Health Science Center, Houston, TX b Memorial Hermann Hospital Sleep Disorders Center, Houston, TX c University of Texas Medical Branch, Galveston, TX d Transitional Learning Center, Galveston, TX e University of Pennsylvania School of Medicine, Philadelphia, PA f Philadelphia Veterans Affairs Medical Center, Philadelphia, PA.  Reprint requests to Richard J. Castriotta, MD, Div of Pulmonary, Critical Care and Sleep Medicine, University of Texas Health Science Center, 6431 Fannin St, MSB 1.274, Houston, TX 77030
Research supported by the Moody Foundation and Cephalon Inc. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. PII: S0003-9993(07)01283-X doi:10.1016/j.apmr.2007.07.012 © 2007 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. | |
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