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High Prevalence of Insomnia in an Outpatient Population With HIV Infection
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Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology:Volume 19(3)1 November 1998pp 260-265
Rubinstein, Mark L.; Selwyn, Peter A.
AIDS Program, Yale School of Medicine, New Haven, Connecticut, U.S.A.
"....(73%) respondents were classified as having a sleep disturbance....Anxiety, depression, self-reported sleep disturbance, and signs of cognitive impairment as already defined were significant predictors of insomnia..... One of the most striking findings in our study was that 100% of patients with cognitive impairment had sleep disturbances.....HIV enters the central nervous system (CNS) shortly after initial infection and may involve the brain before onset of any other physical manifestations of the disease (22,23)....CNS infections often lead to hypersomnolence but may also present with insomnia or sleep-wake cycle disruptions..... As proposed by Norman et al. (15), a possible explanation for the observed relationship between HIV infection and sleep disorders in this and previous studies, may lie in the relationship between immune mediators and sleep. Elevated levels of interferon, tumor necrosis factor, and interleukin-1 (IL-1) have been detected in HIV-seropositive patients (1). These substances have all been shown to affect sleep physiology by enhancing slow wave sleep (SWS) and thereby disrupting normal rapid eye movement and non-rapid eye movement (REM/NREM) sleep cycles (16). Research on animal models also offers support for an immune-mediated association; Fewer than 45% of patients with insomnia, surprisingly, had any mention of sleep disturbance in their clinic records..... clinicians need to be more aware of the high prevalence of insomnia in HIV-seropositive outpatients. Prompt diagnosis and treatment of insomnia may improve quality of life and feelings of well-being in HIV-seropositive ambulatory populations."
From a different study:
Sleep disturbances in HIV-infected homosexual men.
(CNS involvement, immune defense mobilization)
AIDS. 1990 Aug;4(8):775-81.
Norman SE, Chediak AD, Kiel M, Cohn MA.
Sleep Disorders Center, Mount Sinai Medical Center, Miami Beach, Florida 33140.
To provide a better understanding of the etiology of subjective sleep complaints in HIV-infected individuals, a study to evaluate sleep/wake disturbances in 10 healthy HIV-infected male volunteers was performed. All subjects were HIV-infected but had no history of AIDS-related infections, and considered clinically asymptomatic. Interviews and sleep questionnaires revealed sleep complaints in nine subjects. Five healthy HIV-seronegative male subjects, with no history of sleep complaints, were also evaluated. Sleep architecture analyses detected that, in comparison to published normative data and to negative controls, there was a significant increase in the total percentage of slow wave sleep (SWS) and an increase in the percentage of SWS in the later sleep cycles. When compared with normative data, an increase in stage 1 shifts, rapid eye movement (REM) periods, and arousals were also observed in the HIV-infected group. Significant decreases in sleep latency, total percentage stage 2 sleep, and average REM durations were also observed in the HIV-infected group compared with normative data. These sleep architecture abnormalities could not be attributed to known sole primary sleep disorders, first night effect, medications, anxiety or depression. This study indicates that sleep disturbances occur early in the course of HIV infection and suggests that the observed alterations of sleep physiology may be a consequence of central nervous system involvement and/or immune defense mobilization in the early phases of HIV infection.
High Prevalence of Insomnia in an Outpatient Population With HIV Infection
Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology:Volume 19(3)1 November 1998pp 260-265
Rubinstein, Mark L.; Selwyn, Peter A.
AIDS Program, Yale School of Medicine, New Haven, Connecticut, U.S.A.
Abstract
Objective: To determine the prevalence, characteristics, and clinical recognition of insomnia in HIV-seropositive outpatients.
Design: Systematic sample of patients attending an outpatient HIV/AIDS clinic at an urban teaching hospital.
Methods: Patients were recruited for standard interviews including Pittsburgh Sleep Quality Index (PSQI); Mini Mental State Exam (MMSE); Trail Making Test A and B, and Hospital Anxiety and Depression Scale. Abstraction of medical records was used to assess clinician identification of insomnia.
Results: 115 of 127 (91%) patients who were approached agreed to be interviewed for the study. Of these, 79 (69%) were male, 36 (31%) female; 38 (33%) black, 64 (56%) white, 12 (10%) Hispanic, 1 (1%) native American; 45 (39%) were injection drug users. Eighty-four (73%) respondents were classified as having a sleep disturbance according to the PSQI. Patients with cognitive impairment had a higher prevalence of insomnia (100% versus 70%; p = .034). A trend was shown for drug-using patients to report a higher prevalence of insomnia than nondrug users (86% versus 69%; p < .07). Using multivariate analysis, cognitive impairment (odds ratio [OR] = 1.4) as defined by the neuropsychiatric test battery and depression (OR = 1.2) were the best predictors of insomnia (p < .05). Only 28 (33%) patients with insomnia had any documentation of sleep disturbance in their clinical medical records.
Conclusions: Insomnia is widespread and underdiagnosed in HIV-seropositive ambulatory patients. Insomnia is especially prevalent among those with cognitive impairment. These findings suggest the importance for clinicians to inquire specifically about sleep disorders in HIV-seropositive patients. Prompt diagnosis and treatment may improve the quality of life in patients living with HIV.
Studies of sleep disturbances in HIV-seropositive populations report an increase in insomnia among HIV-seropositive subjects compared with HIV-seronegative populations (1-7). However, several of these studies have selected for patients with sleep disorders, and none have been performed in representative outpatient populations with adequate sampling of women and injection drug users. In addition, no previous studies have explored provider recognition of sleep disturbance. We therefore chose to undertake an investigation into this clinically significant aspect of HIV infection using a large sample of ambulatory patients with HIV/AIDS.
The intent of this paper is to report on the prevalence, characteristics, and clinical recognition of insomnia in HIV-seropositive outpatients. By examining comorbid anxiety, depression, cognitive impairment, illicit drug use, and the side effects of medication, we wished to explore the characteristics of insomnia in this patient group. We also reviewed clinic medical records to determine how often clinicians detected and treated sleep disorders in this HIV-seropositive population.
MATERIALS AND METHODS
Clinical Data
The study design was a systematic, cross-sectional sample of HIV-infected outpatients in an HIV clinic at an urban teaching hospital during July and August, 1994. Every third patient at the outpatient HIV clinic was approached for an interview during the normal waiting period before clinic visits. Informed consent was obtained from patients agreeing to be interviewed. To exclude patients with recent or acute serious illness, patients were excluded from this study if they had been hospitalized within 30 days before the time of interview. All interviews were confidential and conducted in a private room by one interviewer (M.R.). Subjects received $5.00 U.S. for their participation.
Data were collected on patterns of sleep using the Pittsburgh Sleep Quality Index (PSQI) (8). Depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS) (9). In addition, a medical history was taken with a focus on HIV-related illnesses and symptoms. Baseline cognitive status was assessed using both the Folstein Mini Mental State Exam (MMSE) (10) and the Trail Making Test A and B (11). Information concerning alcohol and illicit drug use was also collected by questionnaire.
Patients' medical charts were used to obtain data on CD4+ T-lymphocyte counts, current medications, the clinical staging of the HIV infection, and to assess clinician identification of insomnia. The study was approved by the Human Investigation Committee of the Yale School of Medicine.
Case Definitions
Insomnia was defined as having a global score >5 on the PSQI, which has been determined to yield a diagnostic sensitivity of 89.6% and a specificity of 86.5% in identifying insomnia (8). Cognitive impairment was defined by a score of <24 on the MMSE, or a score of >39 seconds on the Trail Making A test, or a score of >91 seconds on the Trail Making B test (12). Depression was defined by a mean score of >10 on the depression subset of the HADS. Anxiety was like-wise defined as a mean score of >10 on the anxiety component of the HADS (9).
Statistical Analysis
Comparison of subjects with and without insomnia as defined by the PSQI was performed using Pearson ƒÔ2 and Fisher's exact tests. Multivariate analysis was conducted with linear and stepwise regression models. All statistics were generated using SYSTAT software (SYSTAT, Inc., Evanston, IL, U.S.A.).
RESULTS
Subjects
Of 127 patients approached, 119 (94%) agreed to participate in the study; eight (6%) respondents refused or were unavailable. All of those refusing to participate reported time constraints as the reason for refusal. Four additional patients were dropped from the study. One had a diagnosed case of sleep apnea, two were excluded because of abnormal sleep-wake cycles because of night-shift work, and a fourth withdrew before completing the interview. The final sample consisted of 115 patients (Table 1): 79 (69%) were men and 36 (31%) women, 64 (56%) white, 38 (33%) black, 12 (10%) Hispanic and 1 (1%) Native American. The median age of the study group was 37.6 years (range, 21.2-63.3 years). In this sampling, 45 (39%) patients admitted to using drugs by injection, 29 (25%) within 6 months of the interview. The CD4+ T-lymphocyte counts among subjects ranged from 0 to 1640 cells/mm3 (median, 200 cells/mm3). The median U.S. Centers for Disease Control and Prevention (CDC) HIV/AIDS classification stage among all patients was 2B (range, 1A-3C) (13).
Insomnia
Of these patients, 84 (73%) were classified as having a sleep disturbance according to the PSQI. Patients classified as having insomnia reported needing over 1 hour to fall asleep compared with less than 15 minutes for the patients without insomnia (mean, 61.5 minutes versus 12.7 minutes; p < .001). In addition, those with insomnia slept approximately 2 fewer hours per night than the noninsomnia comparison group (5.7 hours versus 7.8 hours; p < .001).
No statistically significant difference was found in the prevalence of insomnia by race or gender. Of 29 patients who admitted to illicit drug use over the 6 months before being interviewed, 86% were classified as having insomnia, versus 69% of nondrug users (p < .07) No significant differences were found between those groups with and without insomnia in the prevalence of alcohol, caffeine, heroin, or cocaine use within the previous 30 days (Table 2). No patients in either group reported any stimulant use other than cocaine, which finding did not exceed 10% in either group.
From Jules: in table 2 associated with insomnia were anxiety (<.001, 65% vs 26% with insomnia had anxiety), depression (.002), 40% with insomnia had depression vs 10% without insomnia had depression).
Clinical Variables
No statistically significant difference in mean CD4+ counts between patients with and without insomnia (320 versus 263 cells/mm3; p = .4) was determined, nor were there differences by CDC classification category. Of patients with insomnia, 49 (58%) thought HIV-related symptoms interfered with their sleep. The most frequently mentioned of these were night sweats (28%), headache (25%), chills (20%), and diarrhea (8%).
Thirty-seven (32%) patients were depressed and 63 (55%) had anxiety based on the HAD scale; 29 (25%) were considered both anxious and depressed. Among patients with insomnia, 41% were classified as depressed, compared with only 10% of those without insomnia (p < .005; Table 2). Of patients with insomnia, 65% had clinically significant anxiety, compared with 26% of those without insomnia (p < .001).
Eleven (10%) patients were classified as having cognitive impairment according to the MMSE (defined as a score of <24 of 30; for this group, mean score, 21.6; range, 20-23); 100% of this group had insomnia. Comparing the groups with and without insomnia, those with insomnia were more likely to have MMSE scores <24 and Trial Making A and B tests >39 and 91 seconds, respectively (p < .001) (i.e., the cutoffs for cognitive impairment for those tests).
Medication Use
From the entire study group, 45 (39%) patients reported taking medication for sleep three or more times per week. Of those taking sleep medications, 55% reported benefit from their medication when taken. Insomnia was not associated with current use of any of the major AIDS-related antiretroviral and prophylactic agents. This study was conducted before the advent of the protease inhibitors. Serotonin reuptake inhibitors (SSRI) were not widely used among our respondents. Only 10 patients reported SSRI use, including nine of those with insomnia (11%) and one (3%) of those without insomnia (p = .206). Prescribed benzodiazepine use was more common among those subjects with insomnia (40% versus 3%; p < .01); in 30 of 34 patients (88%) within the group with insomnia who received benzodiazepines, this reflected the prescription of such medication for sleep.
Multivariate Analysis of Predictors of Insomnia
On the basis of preliminary analysis, all statistically significant predictors of insomnia were used in the linear regression analysis (Table 3). We chose not to include benzodiazepine use in the final models, in that this variable clearly seemed to indicate a consequence of insomnia rather than a meaningful predictor. Anxiety, depression, self-reported sleep disturbance, and signs of cognitive impairment as already defined were significant predictors of insomnia. By stepwise, multiple-regression analysis on these categories, the best predictors of insomnia were self-reported sleep disturbance, depression, and score of <24 on the MMSE (adjusted OR: 1.58, 1.17, and 1.35 respectively; p < .001; Table 4).
Sixty patients who reported having a sleep problem on interview stated that they had previously informed their health care provider of their sleep disturbance. Of these patients, 18 (30%) had a treatment plan instituted by their clinician and noted in their clinic charts. Only 35 (42%) patients classified with clinically significant insomnia by the PSQI had any record of sleep disturbance documented in their clinic record by their health care provider.
DISCUSSION
Approximately 10% to 35% of the general population complains of frequent sleep quality disturbance (14). The 73% of patients classified as having insomnia by the PSQI in this study sample of HIV-seropositive outpatients is well above this range and can be compared with a prevalence of 13% reported in a nondepressed population in a previous study using this instrument (8). Although previous studies indicated the clinical significance of insomnia in patients with HIV, to our knowledge this is the first study to document such a high prevalence of insomnia in unselected HIV-seropositive outpatients.
However, regarding the use of the PSQI in this study to classify insomnia, this instrument relies on patients' subjective assessments of their own sleep. In another report first describing the use of this intervention, no significant differences between PSQI estimates and laboratory findings for sleep latency were demonstrated in polysomnographic studies; moreover, the PSQI tended to overestimate sleep duration and efficiency (8).
As proposed by Norman et al. (15), a possible explanation for the observed relationship between HIV infection and sleep disorders in this and previous studies, may lie in the relationship between immune mediators and sleep. Elevated levels of interferon, tumor necrosis factor, and interleukin-1 (IL-1) have been detected in HIV-seropositive patients (1). These substances have all been shown to affect sleep physiology by enhancing slow wave sleep (SWS) and thereby disrupting normal rapid eye movement and non-rapid eye movement (REM/NREM) sleep cycles (16). Research on animal models also offers support for an immune-mediated association; Toth and Krueger describe alterations in the sleep stages of rabbits after microbial inoculation (17). Given the possible link between immune function and sleep, it was of interest that no significant difference was found in our study in mean CD4+ counts or CDC HIV/AIDS stage between patients with and without sleep disturbances, although patients with HIV-related symptoms did frequently note that they interfered with sleep.
Another notable finding in our study was the lack of association between insomnia and recent illicit drug or alcohol use. Despite the known effects of cocaine, other stimulants, and alcohol on sleep, these factors did not reach statistical significance, although trends in the data, especially for injection drug use, suggest that a larger sample may have yielded significant findings.
Two factors found to be strongly associated with insomnia in our study were anxiety and depression. The association between depression and sleep disturbances has been well documented, and insomnia is a common indicator of depression (8,18,19). Some studies among the elderly report that insomnia appeared to precede depression, including one that found that sleep disorders in the elderly were the best predictor of future depression (18). However, using patients with narcolepsy and sleep apnea, other researchers have shown that even massive sleep deprivation does not necessarily lead to depressive syndromes (20). Because we did not collect data on sleep performance before diagnoses of depression in our patients, we are not able to make inferences about the temporal relationship between insomnia and depression in our patients.
The association between insomnia and anxiety has been equally well documented (19). As with depression, insomnia is included in the clinical diagnosis of anxiety and yet symptoms of anxiety have also been demonstrated by sleep deprivation (21). Anxiety was identified in roughly three quarters of our HIV-seropositive patients with insomnia, although as with depression, we were unable to determine the relative timing of onset for these two conditions with respect to coexisting sleep disturbances.
One of the most striking findings in our study was that 100% of patients with cognitive impairment had sleep disturbances. Moreover, patients with insomnia took considerably longer to complete both the Trail Making A and Trail Making B exercises. Some studies have shown that HIV enters the central nervous system (CNS) shortly after initial infection and may involve the brain before onset of any other physical manifestations of the disease (22,23). We therefore wondered whether or not HIV itself could cause insomnia through direct interaction with the central nervous system. CNS infections often lead to hypersomnolence but may also present with insomnia or sleep-wake cycle disruptions (22,24). Some such sleep-wake cycle disruptions are identical to those experienced by our patients (i.e., prolonged sleep latency and increased number and duration of nighttime awakenings).
It is also possible, however, that the cognitive impairment observed in our patients might itself be a consequence of chronic sleep disturbance. Although relatively sensitive tests for mild cognitive impairment like the Trail Making Test or the MMSE may be negatively affected by sleep deprivation, this would be unlikely to affect scores substantially to produce a classification of "impaired," which is reserved for obvious clinical impairment. We strongly doubt that the observed scores on the MMSE were, in effect, themselves the result of sleep deprivation.
Although many major medications used to treat patients with HIV such as zidovudine, dapsone, and interferon-α (IFN-α), have been shown to be associated with insomnia (25), we found no statistically significant increase in sleep disturbance associated with their use. This finding is supported by White et al. who found no significant differences in sleep parameters between those patients who were taking zidovudine and those who were not (26). The observed higher prevalence of benzodiazepine use in the group with insomnia most likely reflected the higher likelihood of receiving prescriptions for this class of medications to treat insomnia in this group; however, the possibility of benzodiazepine-induced disruptions in REM sleep patterns cannot be excluded.
Fewer than 45% of patients with insomnia, surprisingly, had any mention of sleep disturbance in their clinic records. Most patients with sleep complaints noted that they had reported these concerns to their health care provider, and only 30% of these patients had charted evidence of this noted in their clinical records. That at least half the patients who were receiving sleep medications reported benefit, as well as the likelihood that other techniques may also be effective (e.g., meditation, relaxation exercises), suggest that clinicians need to be more aware of the high prevalence of insomnia in HIV-seropositive outpatients. Prompt diagnosis and treatment of insomnia may improve quality of life and feelings of well-being in HIV-seropositive ambulatory populations.
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