Original Article
A Controlled Study of Early Neurologic Abnormalities in Men with Asymptomatic Human Immunodeficiency Virus Infection
N Engl J Med 1990; 323:864-870September 27, 1990
- Abstract
- Abstract
Background.
Although neurologic complications are frequent in the acquired immunodeficiency syndrome, their incidence and progression in early human immunodeficiency virus (HIV) infection remain controversial. The goal of this study was to assess neurologic manifestations in asymptomatic carriers of HIV.
Methods.
We studied 29 HIV-seropositive homosexual men and 33 seronegative homosexual controls by means of neurologic and neuropsychological examinations, magnetic resonance imaging (MRI), and electrophysiologic tests (electroencephalography, multimodal evoked-potential tests, and otoneurologic tests). After six to nine months, the tests were repeated in 27 seropositive men and 30 controls. The investigators were blind to the serologic status of the subjects.
Results.
The seropositive subjects had a mean CD4+ lymphocyte count of 635×106 per liter. Neurologic and neuropsychological examination, MRI, and measurements of pattern visual evoked potentials did not show significant differences between the two groups. The latencies of the median-nerve somatosensory evoked potentials were slightly prolonged in the seropositive men. The initial electroencephalogram was judged abnormal in 8 of 27 of the seropositive subjects (30 percent) as compared with none of the controls, with a slowing of fundamental activity, poor anterior spread of alpha rhythm, subnormal reactivity, and unusual anterior theta activities. These findings were confirmed by computerized spectral analysis. The second electroencephalogram was abnormal in 10 of 25 of the seropositive men (40 percent). The otoneurologic evaluation identified abnormalities in the central auditory or vestibulo-ocular pathways in 34 percent of the seropositive men (10 of 29), as compared with 6 percent of the controls (2 of 33), on the first examination and in 44 percent (12 of 27) and 7 percent (2 of 30), respectively, on the second examination. Altogether, electrophysiologic abnormalities were found in 67 percent of the seropositive men (18 of 27) and 10 percent of the controls (3 of 30) (P<0.00005).
Conclusions.
In persons with asymptomatic HIV infection, electrophysiologic tests may be the most sensitive indicators of subclinical neurologic impairment. Electrophysiologic abnormalities are far more common in asymptomatic carriers of HIV than in controls and tend to progress over time. (N Engl J Med 1990; 323: 864–70.)
Article Activity
- Article
DESTRUCTION of the brain is one of the most fearsome consequences of infection with the human immunodeficiency virus (HIV). Many patients with the acquired immunodeficiency syndrome (AIDS) become demented, and at autopsy more than 90 percent have abnormalities of the nervous system.1 , 2 Some of these are due to opportunistic infections; others, described as AIDS dementia complex,3 , 4 vacuolar myelopathy, or polyneuropathy, may be caused by HIV itself, possibly acting through the production of cytokines, interference with tropic factors, or inhibition of neurotransmission (reviewed by Ho et al.5). If these are indeed the pathogenic mechanisms, it should be possible to identify functional abnormalities of the nervous system before irreversible structural damage becomes evident.
There are many ways to explore the function of the nervous system in HIV-seropositive patients. Previous studies of asymptomatic carriers and patients with generalized lymphadenopathy have examined neuropsychological function, cerebrospinal fluid, and magnetic resonance imaging (MRI) scans of the brain. Opinions diverge about the extent of neuropsychological impairment in asymptomatic carriers of HIV,6 7 8 9 10 and the interpretation of early white-matter abnormalities shown in magnetic resonance imaging is still unsettled.11 Prospective studies of cerebrospinal fluid have not revealed any predictive factors for late neurologic complications,12 13 14 15 not even the isolation of HIV from the cerebrospinal fluid, which was possible in 30 to 60 percent of seropositive subjects who had no neurologic symptoms.13 , 16
Electrophysiologic examination (by electroencephalography, measurement of evoked potentials, and otoneurologic testing) seemed more promising to us. If subtle functional alterations are indeed early signs of HIV infection in the nervous system, electrophysiologic methods may detect them more efficiently. Others have already explored similar ideas17 18 19 20 21 22 23 and have shown that electrophysiologic abnormalities are frequent in seropositive subjects. None of the studies have attempted, however, to correlate electrophysiologic methods with neuropsychological evaluation and MRI. The sensitivity and relative lack of specificity of many of these tests require that the findings in asymptomatic seropositive subjects be compared with those in a carefully matched control group. In addition, the exclusion of factors creating potential bias, such as drug use, head trauma, or neuropsychiatric illness, is a mandatory prerequisite for such a study. Therefore, we organized a prospective study of clinical, neuroradiologic, and electrophysiologic measures in a group of asymptomatic seropositive homosexual men, which we compared with the same measures in a group of seronegative homosexual men serving as controls.
Methods
The study was approved by the ethics committee of the Department of Medicine of the Geneva University Medical School. To ensure objective evaluation, observers were blinded with regard to the HIV serologic status of the subjects and all other data except age. Twenty-nine asymptomatic HIV-seropositive homosexual men (among whom 20 had generalized lymphadenopathy) and 33 seronegative homosexual men volunteered to participate in this study. They were recruited through advertisements in the local press and at a dermatology-venereal disease clinic. All were white, and none reported excessive alcohol consumption. All were asked not to take any sleeping pills during the three days before the examination. In a preliminary interview, men with neuropsychiatric illness, those using psychotropic or recreational drugs other than cannabis, and those with symptomatic HIV-related disease were excluded from the study. The groups were comparable with regard to age and education.
After they had given informed consent, the subjects completed a standardized questionnaire about sociologic variables and the use of sedatives, alcohol, and cannabis. A general medical examination was performed by the principal investigator, and a neurologic examination by two experienced neurologists. All the examinations were repeated after an interval of six to nine months.
Blood Tests
Tests for HIV antibodies and p24 antigen were performed with commercial kits (Abbott Diagnostics, Abbott Park, III.). Standard methods were used in serologic testing for syphilis (Venereal Disease Research Laboratory, fluorescent treponemal antibody, and Treponema pallidum hemagglutination tests). For the polymerase chain reaction, constant sequences of the polymerase gene were used as primers.24
Neuropsychological Examinations
The neuropsychological-test battery lasted approximately 1 1/2 hours and included tests of verbal fluency (listings of words beginning with the letter P and of names of animals), recognition of synonyms and antonyms (Test BV 4),25 memory (French adaptation of Form 1 of the Wechsler memory test),25 reasoning, as evaluated with drawings (Test B 53),26 recognition of identical figures among 10 items (Test BG 9),25 and attention and mental speed, as shown in marking the letter D when it had two dots above or below it among other Ps or Ds with fewer or more dots (Test D 2).27 The results of the neuropsychological-test battery were scored as abnormal if performance on at least one of these six tests was more than 2 SD below the mean of the control group and performance on at least one other test was between 1 and 2 SD below the mean, or if performance on at least three tests was 1 to 2 SD below the mean.
Electroencephalography
Electroencephalography was performed with the international 10–20 system. The tracings were interpreted by three specialists using a standardized system of interpretation with 30 criteria. The 14 criteria listed in Table 1Table 1
Criteria and Scoring System for Electroencephalographic Evaluation. were eventually retained, on the basis of our experience in patients with advanced HIV infection28 and after a preliminary analysis of the first examination. Recordings corresponding to sleep patterns or to wide-amplitude medication-related beta activity were excluded from analysis. At the first examination, 27 seropositive men and 30 controls were evaluated; 25 seropositive men and 28 controls were examined again six to nine months later.Electroencephalographic Mapping
Electroencephalographic computerized spectral analysis by fast Fourier transform was performed on a Cartovar system (Alvar, Montreuil, France) as described by Le Guen and Debouzy.29 The frequencies studied were those from 3.5 to 7.5 Hz, corresponding to the theta band. The recordings were analyzed statistically to detect interhemispheric asymmetry and locate differences in the theta band between the two groups.30 For technical reasons, only 30 of 62 electroencephalograms (EEGs) (those of 15 seropositive men and 15 seronegative men) could be analyzed spectrally after the first examination, and only 28 of 57 (representing 14 men in each group) after the second.
Somatosensory Evoked Potentials
Both median nerves were stimulated at the wrist, and the signal was registered at Erb's point (supraclavicular notch) (N-10), at the level of the spinal process of the second cervical vertebra (N-14), and in parietal areas of the scalp (2 cm behind and 7 cm lateral to the reference electrode Cz)(N-20). Two recordings were made for each median nerve to study the stability of the response. Abnormality was defined as the presence of a latency >2.5 SD above the mean of a normal male population.
Visual Evoked Potentials with Pattern Stimuli
Visual evoked potentials were recorded with the projection of a pattern-reversal checkerboard onto a 39-by-48-cm screen with a mean luminosity of 75 candelas per square meter. Checked stimuli with a 60-degree arc and a 60 percent contrast were presented with an alternation rate of 1.5 Hz. The summation of visual evoked responses was based on 64 presentations of the stimulus. The tests were performed monocularly and binocularly in each subject. Abnormality was defined as a latency of >2.5 SD above the mean of a normal male population.
Otoneurologic Examination
In addition to a clinical ear, nose, and throat assessment, the patients underwent audiologic and vestibular examination. Detailed descriptions of the techniques of recording and evaluation of results are given in Häusler et al.31 and Häusler.32 The criteria used in the evaluation of abnormalities in the results of the otoneurologic tests are listed in Table 2Table 2
Criteria for Abnormalities Detected on Otoneurologic Testing.; they are in accordance with the criteria in standard references.33 MRI
The subjects were evaluated with MRI using a 0.35-tesla super-conducting magnet (Diasonics, San Francisco). The cuts were performed in the axial plane with the spin—echo technique with T2-weighted images (repetition time, 2000 msec; echo time, 30 and 60 msec) and T1-weighted images (repetition time, 500 msec; echo time, 30 msec). The thickness of the slices was 10 mm. In some cases we completed the examination with cuts in the frontal and sagittal planes, using the same criteria.
Statistical Analysis
We used the chi-square test with Yates' correction or Fisher's two-tailed exact test for small numbers, the Wilcoxon two-sample test, and Hotelling's T2 test.
Results
The CD4+ lymphocyte count, the ratio of CD4+ cells to CD8+ cells, and the results of the syphilis tests are shown in Table 3Table 3
Demographic Characteristics and Serologic Results.*. As expected, the seropositive men had lower CD4+ cell counts than the seronegative men, but no seropositive men had CD4+ cell counts under 200 × 106 per liter, a level commonly associated with opportunistic infections. The results of the polymerase chain reaction and serologic testing were concordant. There was a tendency toward increased seropositivity for syphilis in the HIV-seropositive men, but it did not reach statistical significance. All these infections were old and inactive and had already been treated correctly.Ninety-three percent of the seropositive men (27 of 29) and 91 percent of the seronegative men (30 of 33) returned after six to nine months for the second examination. All the seropositive men remained asymptomatic, and none of the seronegative men became seropositive for HIV. Mean CD4+ cell counts fell slightly in both groups, but this decline did not reach statistical significance. The results of serologic testing for syphilis were unchanged.
The neuropsychological tests showed no significant differences between the two groups at base line (P = 0.54 by Hotelling's T2 test); nor did such differences appear on the follow-up examination (P = 0.66). According to our criteria, 38 percent of the seropositive men (11 of 29) and 24 percent of the seronegative men (8 of 33) had abnormal results on the first examination. On the follow-up examination, only 22 percent of the seropositive men (6 of 27) remained below the criteria for abnormality, whereas 13 percent of the seronegative men (4 of 30) did, suggesting a strong practice effect in both groups. Twelve seropositive men and two controls reported memory problems during the course of the study that were not correlated with the results of the neuropsychological tests. Neurologic testing revealed a slightly diminished sense of vibration in the legs in 14 percent of the seropositive men and 9 percent of the seronegative men, which was observed in the same subjects in both the initial and follow-up examinations.
At the initial examination, MRI scans were abnormal in 7 percent of the seropositive men (2 of 29), showing slight atrophy in one and a small, clinically silent infarction in the putamen of another. Abnormal findings were reported in 9 percent of the seronegative men (3 of 33): arteriovenous malformation in one, an old infarction in another, and two small hyperintensities of the white matter, of unknown importance, in the third. For financial reasons, MRI was performed a second time only in the seropositive group. The second examination showed the persistence of the anomalies noted previously and in one subject, the appearance of some hyperintensities of the periventricular white matter. The differences between the seropositive and the seronegative subjects on MRI did not reach statistical significance. The same was true of the results of the pattern visual evoked potentials, which were normal in all subjects, both seropositive and seronegative, with no significant differences in mean latencies and amplitudes.
The latencies of the somatosensory evoked potentials are shown in Table 4Table 4
Median-Nerve Somatosensory Evoked Potentials.*. Total latency of N-20 (between the wrist and the contralateral parietal cortex) and central conduction time from N-20 to N-14 (between the second cervical vertebra and the contralateral parietal cortex) were slightly prolonged in the seropositive group, suggesting that central sensory conduction was slowed, but the mean latencies were within the normal range in both groups. Three seropositive men (and no seronegative men) had prolonged latencies of the somatosensory evoked potential more than 2.5 SD above the mean of a healthy male reference population. At the follow-up examination, the latencies in the seropositive men did not increase as compared with those in the controls (P = 0.3 by Hotelling's T2 test). Abnormalities of the wave forms were rare and were not taken into account.The results of otoneurologic testing (Table 5Table 5
Abnormalities Detected on Otoneurologic Testing.) were abnormal at the first examination in 34 percent of the seropositive men (10 of 29), as compared with 6 percent of the seronegative men (2 of 33) (P<0.01 by Fisher's exact test). At the second examination, three additional seropositive men had abnormal results, but one man formerly found to have positive stapedial-reflex decay did not have this anomaly again, raising the percentage of persons with abnormal results to 44 percent (12 of 27) and indicating the presence of subclinical lesions of the auditory, vestibulo-ocular, and ocular pathways. No changes were found in the control group (P<0.002 by Fisher's exact test).In addition, the spontaneous and positional nystagmic reactions (recorded in the dark) were abnormal (>1 Hz) in many seropositive subjects. In contrast to the other results reported in this paper, however, the nystagmic reactions observed during the first examination were often no longer present at the follow-up examination; the opposite was true for other patients, who had normal results at first. Because of this lack of reproducibility, we decided to disregard spontaneous and positional nystagmic reactions in the statistical analysis, although as shown in Table 5, abnormalities were clearly more frequent in the seropositive than in the seronegative subjects.
Figure 1Figure 1
Electroencephalographic Scores at the First and Second Examinations. shows the results of our global electroencephalographic evaluation as scored according to the system shown in Table 1. During the first examination, the EEG was considered abnormal in 8 of 27 seropositive men who could be evaluated (30 percent), as compared with none of the 30 seronegative men. The second EEG was abnormal in 10 of 25 seropositive subjects evaluated (40 percent), but none of the controls. The second examination showed that the results were reproducible; for all subjects who had an abnormal (Type III) first EEG, the second EEG showed similar features. Finally, the EEGs of two HIV-seropositive men became abnormal at the second examination. Electroencephalographic scores were higher in the seropositive subjects than in the controls at base line (P<0.0001 by the Wilcoxon two-sample test) and increased further during follow-up (P = 0.04). The main abnormal findings were slowing of posterior activity, anterior spread of posterior rhythms, absence of reactivity, polymorphic theta activities (located mostly in frontal areas and at the vertex), and diffuse slow theta dysrhythmia of low amplitude.Computerized spectral analysis (electroencephalographic mapping) of the theta band showed more theta activities anteriorly in the seropositive men; the differences between the seropositive and seronegative men were significant (P<0.0001 at both examinations), and they confirmed the qualitative analysis shown in Figure 1. Electroencephalographic mapping did not show any interhemispheric differences with respect to the theta band in each group.
In summary, Figure 2Figure 2
Abnormalities Detected on Electrophysiologic Testing. shows that 48 percent of the asymptomatic seropositive men (14 of 29) had one or more abnormal electrophysiologic tests, as compared with 6 percent of the seronegative controls (2 of 33) (P<0.0005 by Fisher's exact test). At the second examination, the percentages were 67 percent (18 of 27) for the seropositive men and 10 percent (3 of 30) for the controls (P<0.00005).Discussion
In the evaluation of the results of tests that are sensitive but not very specific, the importance of a proper control group and unbiased assessment cannot be overemphasized. Our HIV-seropositive subjects and our controls were all homosexual men with no history of neurologic or psychiatric disease and no reported use of psychoactive drugs or alcoholism. They were closely matched in age, education, and sociocultural background; indeed, many of the seronegative subjects were friends and sexual partners of the seropositive subjects.
Because subjects had to be asymptomatic to be included in the study, the absence of significant abnormalities in the neurologic examination was an expected result. In accordance with recent studies,9 , 10 we did not detect significant neuropsychological differences between the seropositive men and the controls. The performance on neuropsychological tests was better in both groups at the follow-up examination, perhaps because of a practice effect.34 This emphasizes the need for caution in the use and interpretation of neuropsychological tests in asymptomatic subjects, especially if the tests are repeated at relatively short intervals in small groups of patients. Likewise, as has been reported in other controlled studies, MRI11 and the measurement of visual evoked potentials17 were of no use in the detection of subclinical differences between our two groups. Although the mean latencies of somatosensory evoked potentials were within the normal range in both groups, there was a slight slowing that was of borderline statistical significance (P<0.04 by the t-test), when the seropositive subjects were compared with the controls.
Figure 2 shows the results of electrophysiologic testing. We were surprised to find that at the end of the study, 67 percent of the asymptomatic seropositive men had abnormalities, as compared with 10 percent of the seronegative men (P<0.00005). This high incidence was mainly due to the findings on otoneurologic testing and electroencephalography. Otoneurologic abnormalities have been observed previously in patients with AIDS with or without neurologic symptoms.18 , 35 , 36 In asymptomatic seropositive men, prolonged latencies of the brain-stem auditory evoked potentials have been present in 17 to 38 percent17 18 19 — close to the percentages observed in this study. Likewise, nonspecific electroencephalographic changes have been described in patients with AIDS, with and without neurologic symptoms,28 , 37 and in asymptomatic seropositive subjects, in whom electroencephalographic abnormalities have been reported with a frequency of 25 to 30 percent.19 , 20 Our findings suggest cerebral dysfunction, as shown by the occurrence of slow electrical activity (theta rhythms), located mostly in anterior regions, and abnormal spatial distribution of fundamental activities (alpha and theta rhythms). We tried to standardize our methods by using a score (Table 1), which could be useful in comparing our results with those of other centers, and we noted excellent reproducibility between the first and second examinations (Fig. 1). The differences between seropositive subjects and controls on electrophysiologic testing were significant, and in the seropositive subjects there was a tendency for abnormalities to progress.
Several trivial explanations for our findings should be discussed. First, when many examinations are performed, a finding of statistical significance in just one of them may be spurious. Many of our tests, however, revealed differences between the seropositive subjects and the controls, and the statistical significance of the summary evaluation was very clear (P = 0.00005) (Fig. 2). Second, it is unlikely that an undetected opportunistic infection of the nervous system was present, because all our subjects were asymptomatic during a period of observation lasting at least six months, and they were not severely immunosuppressed, having CD4+ lymphocyte counts that ranged from 222 to 1395×106 per liter. There was no correlation between the electrophysiologic abnormalities and the CD4+ lymphocyte count or the presence of syphilis, as determined by serologic evidence or a review of the subject's history. Third, our method of selecting the study subjects made it appear unlikely that an unrecognized nutritional deficiency, such as occurs in severe alcohol abuse, could have been present. We therefore propose that infection by HIV itself (or possibly by another, as yet undiscovered agent in close association with HIV) may be responsible for our findings. In the brain, HIV has been detected in microglial cells derived from the monocyte—macrophage lineage, in multinucleated giant cells,2 and in endothelial cells.38 At present, there is no formal proof of the infection of neurons, astrocytes, or oligodendrocytes.39 Frequently, there is a discrepancy between clinical signs of AIDS dementia complex and autopsy findings.40
This suggests that indirect mechanisms could explain the cerebral pathogenicity of HIV infection — for instance, the production of cytokines, the inhibition of neurotransmission, or the antagonism of tropic factors.5 In early stages, such impairment would be more functional than structural. Our results suggest that electrophysiologic tests are the most sensitive indicators of subclinical impairment of cerebral function in asymptomatic HIV-seropositive homosexual men — a finding that agrees with an emerging consensus based on preliminary cross-sectional17 18 19 20 , 22 , 23 , 35 , 36 and time-sequence studies.21 , 23 Apparent discrepancies in results may be explained by the small size of many studies, the lack of adequate controls, the heterogeneity of the patients studied, and the lack of uniform criteria for the interpretation of results. These problems were largely eliminated in our study.
A word of caution may be necessary. It is not clear whether patients with subclinical electrophysiologic abnormalities are at increased risk of AIDS dementia complex. Indeed, there was no apparent correlation between electrophysiologic measures and the results of the neuropsychological examination. The prognostic importance of our findings can be ascertained only by a large prospective study with a follow-up of several years. However, it would now be difficult to justify such a study of the natural history of AIDS dementia complex, because antiviral therapy delays the progression to AIDS in asymptomatic seropositive men.41 Electrophysiologic indexes could nevertheless help determine the effects of antiviral drugs on the nervous system. Parisi et al. have reported a case in which there was amelioration of the EEG after treatment.42 A study is now in progress in our institution to follow the evolution of early electrophysiologic abnormalities in patients treated with zidovudine.
Supported by grants from the Reuter Foundation and the Schweizerische Stiftung für klinische Aidsforschung.
We are indebted to Drs. Kinloch, Martin, and Wintsch and to Mrs. Kohli for assistance with patient referral; to Mrs. Girod and Mrs. Dunand for outstanding assistance in the preparation of the manuscript; to Drs. Ochsner and Balavoine and to Professor Cruchaud for helpful advice and support; to Dr. Schinas for performing the MRI scans; and to Professor Saurat for the serologic testing for syphilis.
Source Information
From the Departments of Internal Medicine (I.J.K., F.A.W.), Neurology (A.B., A.K., R.D., E.M., P.B., A.N., M.R.M., P.M., F.Q., G.G.), Ear, Nose, and Throat (R.H., D.V.), Ophthalmology (A.B.S., F.P.), and Radiology (J.S.), and the Divisions of Infectious Diseases (V.G., L.P., B.H.) and Statistics and Computer Sciences (B.M.), Geneva University Hospital, Geneva. Address reprint requests to Dr. Hirschel at the Division of Infectious Diseases, Hôpital Cantonal Universitaire, CH-1211 Geneva, Switzerland.
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