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Slowed Saccades in the Acquired Immunodeficiency Syndrome
Slowed Saccades in the Acquired Immunodeficiency Syndrome Ngoc Nguyen, M.D., Steve Rimmer, M.D., and Barrett Katz, M.D.
We recorded eye movements using infrared oculography in ten patients with the acquired immunodeficiency syndrome (AIDS) and ten control subjects of similar age. Peak saccadic velocity for the AIDS group was significantly lower than that of the control group for both adducting and abducting saccades (P < .001). Saccadic duration for the AIDS group was significantly greater than that of the controls for both adducting and abducting saccades (P < .02 for adduction and P < .01 for abduction). There was no difference in saccadic latencies between the two groups. We add slowed saccades to the ocular motility manifestations of AIDS. Our study indicated that analysis of ocular motility may be of value in providing early detection of neurologic dysfunction, and may also be an important quantitative measure of the responsiveness of patients to different types of potential therapies. RECENT EVIDENCE suggests early central nervous system human immunodeficiency virus (HIV) infection may directly affect ocular motility. Tervo and associates' described two patients with disturbed eye movements who had progressive convergence insufficiency, disturbed optokinetic nystagmus, and abnormalities of both fast and slow eye movements. Rehman and Mehler- described "reverse ocular dipping" in a patient with HIV infection (slow upward deviation of the eyes followed by a rapid return to midposition). Teschke" found slowed saccadic eye movements to be one of four early neurologic signs of central nervous
Accepted for publication Jan. 30, 1989. From the Departments of Ophthalmology (Drs. Nguyen, Rimmer, and Katz) and Neurosciences (Dr. Katz), University of California, San Diego, School of Medicine, La Jolla, California. Reprint requests to Barrett Katz, M.D., UCSD Eye Center, M-018, La Jolla, CA 92093.
356
system HIV infection. Currie and colleagues! demonstrated both saccadic and pursuit dysfunction in a group of patients with the acquired immunodeficiency syndrome (AIDS); in patients with the AIDS dementia complex, the severity of ocular motility dysfunction correlated with the severity of dementia. We undertook our study to quantitate the ocular motility disturbance in AIDS patients without clinical signs of AIDS dementia complex.
Material and Methods We studied ten men aged 28 to 52 years (mean ± S.D., 36.1 ± 6.8 years) and ten male control subjects of similar age (range, 24 to 58 years; mean ± S.D., 36.0 ± 11.9 years) (P = .982). All patients met the criteria of the Centers for Disease Control for a diagnosis of AIDS.5 None of the patients had any clinical evidence of AIDS dementia complex, and all were ambulatory. No patient or control subject had previous neurologic dysfunction or ocular disease. No patient or control received any medication known to affect ocular motility. All patients (Table 1) underwent detailed neurologic assessment, including the minimental status examination." Best-corrected visual acuity was 20/40 or better in all subjects. Pupillary responses were normal, without evidence of an afferent pupillary defect. Saccades and pursuits were judged to be clinically normal and ductions were full. No patient had cranial nerve palsy, nystagmus, or other adventitious eye movements. We·recorded saccadic eye movements in the horizontal meridian using infrared corneoscleral limbus reflection oculography, as previously described." The eye-movement recording apparatus detects the reflections of infrared lightemitting diodes from each eye. Briefly, a mirror transparent for visible light yet refractive for infrared light projects the light reflected from
©AMERICAN JOURNAL OF OPHTHALMOLOGY
107:356-360,
APRIL,
1989
Slowed Saccades in AIDS
Vol. 107, No.4
357
TABLE 1 CLINICAL CHARACTERISTICS OF THE PATIENT GROUP SCORE ON MINI-MENTAL STATE EXAMINATION'
PATIENT NO., AGE (YRS)
R.E.
L.E.
1,40 2,35
20/20 20/40
20120 20/20
None None
30 28
3,41
20/40
20120
None
30
4,36
20/20
20120
None
27
5,32
20/20
20120
30
6, 38 7,33
20/20 20/30
20120 20140
8,51
20/20
20120
Mild intention tremor None Glabellar reflex, snout reflex Snout reflex
9,42 10,61
20/30 20/30
20130 20140
None None
30 30
VISUALACUITY
NEUROLOGIC ABNORMALITIES
SYSTEMIC MEDICATION
Tetracycline Zidovudine, pyrimethamine/sulfadoxine Isoniazid, rifampin, pyrazinamide, pyridoxine Ampicillin, gentamicin, thiamine, cimetidine, folate, MgS04 Pentamidine, sucralfate
30 29
Zidovudine Amphotericin B, KCI, MgS04 Protriptyline, prochlorperazine, cimetidine None Pentamidine, sucralfate
30
'The mini-mental state examination is scored as the number of questions answered correctly out of a possible total of 30.
each iris plane onto a linear array of 1,024 photo diodes. A videographic signal is generated from the output of the photo diodes, and the margin of the pupil's space is determined electronically. The locations of the appropriate diodes are read by a microprocessor, and the data are analyzed by computer. The system has a linear range of 40 degrees, a spatial resolution of greater than 0.1 degree, and a temporal resolution of 8 msec. It allows for the simultaneous recording of each eye. The target stimulus was generated by a helium neon laser mounted on the recording apparatus. The laser beam was reflected by a mirror galvanometer and projected onto a white screen in front of the subject. The target subtended approximately 0.06 degree of visual angle. Saccades were elicited by moving the target in predictable square wave trajectories (amplitudes of ±5, ±10, ±15, ±20, ±30 degrees; frequency, 0.25 Hz), as well as in unpredictable fashion with respect to direction, amplitude, and frequency. We measured at least 150 abducting and adducting sacca des for each patient and control. Data for abducting and adducting saccades were analyzed separately. Saccadic latencies were measured for all amplitudes. Main-
sequence diagrams (duration vs amplitude, and peak velocity vs amplitude) were constructed from scatter plots of each subject using simple linear regression (y = a + bx) and logarithmic regression analysis (y = a + b In x), where y is either the duration for the linear regression or the maximum velocity for the logarithmic regression, a is the y intercept, b is the slope, and x is the amplitude. Both duration-amplitude relationships and peak velocity-amplitude relationships were compared by calculating the area under the curve for each subject's main-sequence diagram and comparing mean values between groups. The data for each group were pooled to construct group main sequence diagrams for each variable. Results
Peak velocity-Peak saccadic velocity (area under the peak velocity-amplitude curve) for the AIDS group was significantly lower than that of the control group, for both adducting and abducting sacca des (P <.001; Table 2). The Figure shows the relationship between saccadic
358
Latency-Latencies of saccades of all amplitudes for both the AIDS and control groups were normal for our laboratory. Mean ± S.D. saccadic latency for the AIDS group was 240 ± 35 msec. Mean saccadic latency for the control group was 236 ± 31 msec. There was no statistically significant difference between the two groups (P > .5).
TABLE 2 AMPLITUDE-PEAK VELOCITY MAIN SEQUENCE DIAGRAM COMPARISON BETWEEN AIDS PATIENTS AND CONTROLS (OEG 2/SEC)*
Abducting Mean S.D. Adducting Mean S.D.
AIDS PATIENTS
CONTROLS
PVALUE'
10,068 806
11,543 602
<.001
10,368 1,006
12,163 801
<.001
Discussion We detected specific eye movement abnormalities in patients with AIDS even before the declaration of any frank neurologic dysfunction, confirming the observations of Currie and colleagues.' Our AIDS patients demonstrated slowed saccadic peak velocities and long saccadic durations compared to normal controls, even though their ocular motility appeared to be clinically normal. Currie and associates" calculated a saccadic error score for each subject by comparing the number of saccadic errors made (hypornetric, corrective, anticipatory, and wrong-way saccades) with the number of normal saccades made. They found eye movement abnormalities in seven of seven patients with AIDS dementia complex and in six of seven AIDS patients without dementia. These abnormalities included impairment of saccadic accuracy, saccadic distractability, fixation instability, sac-
*Values represent areas underthe curve. 'Student's t-test.
peak velocity and amplitude for patients and controls, with logarithmic regression fit to each population's data. Coefficients of variance were 0.96 (adduction) and 0.96 (abduction) for the AIDS group, and 0.93 (adduction) and 0.96 (abduction) for the control group. Duration-Saccadic duration for the AIDS group (area under the duration-amplitude curve) was significantly greater than that of the controls for both adducting and abducting saccades (P < .02 for adduction and P < .01 for abduction; Table 3). Coefficients of variance were 0.83 (adduction) and 0.86 (abduction) for the AIDS group, and 0.77 (adduction) and 0.80 (abduction) for the control group.
oQ)
en
<,
April, 1989
AMERICAN JOURNAL OF OPHTHALMOLOGY
600
Controls
Controls
500
AIDS
AIDS
Ol
--..... Q)
"'0
400
>o
300
Q)
200
0
> ~
CO Q)
a...
100 00
10
20
30 Amplitude
40 0
10
20
30
40
(degrees)
Figure (Nguyen, Rimmer, and Katz). Main sequence diagram relating saccadic peak velocity and amplitude for AIDS patients and controls, for adducting (left) and abducting (right) saccades.
Slowed Saccades in AIDS
Vol. 107, No.4
TABLE 3 AMPLITUDE-DURATION MAIN SEQUENCE DIAGRAM COMPARISON BETWEEN AIDS PATIENTS AND CONTROLS (DEG . MSEC)*
Abducting Mean
S.D. Adducting Mean
S.D.
AIDS PATIENTS
CONTROLS
P VALUE t
1,443 136
1,302 68
<.01
1,351 161
1,198 87
<.02
'Values represent areas underthe curve. 'Student's t-test.
cadic intrusions in normal gain pursuit, and catch-up sacca des in low gain pursuit. We used a different quantitative method to analyze the data and were able to demonstrate additional eye movement abnormalities. We constructed main-sequence diagrams that incorporate a large number of saccades and found AIDS patients to have decreased peak saccadic velocity and prolonged saccadic duration. Our methodology provides easily quantifiable and reproducible results. The neuroanatomic substrate causing slowed saccades in HIV infection is yet to be determined. Commands for horizontal saccades are probably programmed within the pontine paramedian reticular formation. Voluntary saccadic eye movement commands are thought to be mediated by parallel pathways from the contralateral frontal eye field and the superior colliculi, which converge within the brainstem. Horizontal saccadic velocity has been shown to correlate with firing frequency of the mediumlead burst neurons in the pontine paramedian reticular formation." The frequency of burstcell spikes and the recruitment of burst cells are under the modulation of cerebral input. Since the neuropathologic changes in HIV infection are found predominantly in the white matter and subcortical structures (most commonly the basal ganglia, brainstem, and pons), with relative sparing of cortical involvement.P'" the slowed saccades in AIDS patients may reflect a defect in burst neurons of the pontine paramedian reticular formation rather than a defect in cerebral input from the frontal lobe. Saccadic velocities may be slowed by drowsiness, inattention, or drugs. 16 Our AIDS patient population was relatively healthy. No clinical
359
signs of fatigue or impaired concentration were noted, as confirmed by the mental status examination (Table 1). Currie and colleagues' found poor correlation between eye movement abnormalities and the general state of health in their AIDS patients. They recognized severe eye movement abnormalities in healthy but demented patients, and therefore suggested that the eye movement abnormalities in AIDS patients cannot simply be attributed to acute or chronic debilitating AIDS-related illness. None of our patients were taking drugs recognized to affect eye movements. Our patients had no evidence of central nervous system opportunistic infection or neoplasm to confound our results. While neurologic abnormalities are observed in approximately 40% of adult AIDS patients,":" neuropathologic changes are reported in 70% to 80% of cases,":" suggesting the prevalence of neurologic dysfunction to be even higher. The noncytopathic nature of early histologic changes in AIDS dementia complex and the expectation of more effective antiviral agents highlight the importance of early diagnosis of HIV infection in the central nervous system. We therefore agree with Currie and associates' that the analysis of ocular motility is not only of value in providing early detection of neurologic dysfunction, but may be an important quantitative measure of the responsiveness of patients to different types of potential therapies.
References 1. Tervo, T., Elovaara, I., Karli, H., Valle, S.-L., Suni, J., Lahdevirta, J., and Iivanainen, M.: Abnormal ocular motility as early sign of CNS involvement in HIV infection. Lancet 2:512, 1986_ 2. Rehman, F., and Mehler, M. F.: Reverse ocular dipping. Neurology 38:506, 1988. 3. Teschke, R. 5.: A tetrad of neurologic signs sensitive to early human immunodeficiency virus brain disease. Arch. Neurol. 44:693, 1987. 4. Currie, J., Benson, E., Ramsden, B., Perdices, M., and Cooper, D.: Eye movement abnormalities as a predictor of the acquired immunodeficiency syndrome dementia complex. Arch. Neurol. 45:949, 1988. 5. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. M.M.W.R 36:15, 1987. 6. Folstein, M. F., Folstein, S. E., and McHugh, P. R: Mini-mental state. A practical method for
360
AMERICAN JOURNAL OF OPHTHALMOLOGY
grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12:189, 1975. 7. Katz, B., Mueller, K., and Helmle, H.: Binocular eye movement recording with CCD arrays. Neuro. Ophthalmol. 7:81, 1987. 8. Van Gisbergen, J. A. M., Robinson, D. A., and Gielen, 5.: A quantitative analysis of generation of saccadic eye movements by burst neurons. J. Neurophysiol. 45:417, 1981. 9. Navia, B. A., Cho, E. 5., Petito, C. K., and Price, R. W.: The AIDS dementia complex. II. Neuropathology. Ann. Neurol. 19:525, 1986. 10. Booss, J., and Harris, S. A.: Neurology of AIDS virus infection. A clinical classification. Yale J. BioI. Med. 60:537, 1987. 11. Elder, G. A., and Sever, J. L.: AIDS and neurological disorders. An overview. Ann. Neurol. 23(suppl.):S4, 1988. 12. Schwenk, J., Cruz-Sanchez, F., Gosztonyi, G., and Cervos-Navarro, J.: Spongiform encephalopathy in a patient with acquired immune deficiency syndrome (AIDS). Acta Neuropathol. 74:389, 1987. 13. Pumarola-Sune, T., Navia, B. A., CordonCardo, c.. Cho, E. 5., and Price, R. W.: HIV antigen in the brains of patients with the AIDS dementia complex. Ann. Neurol. 21:490, 1987. 14. Rottenberg, D. A., Moeller, J. R., Strother, S. C.; Sid tis, J. J., Navia, B. A., Dhawan, V., Ginos, J. Z., and Price, R. W.: The metabolic pathology of the AIDS dementia complex. Ann. Neurol. 22:700, 1987. 15. Rostad, S. W., Sumi, S. M., Shaw, C. M., Olson, K., and McDougall, J. K.: Human immunode-
April, 1989
ficiency virus (HIV) infection in brains with AIDSrelated leukoencephalopathy. AIDS Res. Hum. Retroviruses 3:363, 1987. 16. JUrgens, R., Becker, W., and Kornhuber, H. H.: Natural and drug-induced variations of velocity and duration of human saccadic eye movements. Evidence for a control of the neural pulse generator by local feedback. BioI. Cybern. 39:87, 1981. 17. Snider, W. D., Simpson, D. M., Nielsen,S., Gold, J. W. M., Metroka, C. E., and Posner, J. B.: Neurological complications of acquired immune deficiency syndrome. Analysis of 50 patients. Ann. Neurol. 14:403, 1983. 18. Levy, R. M., Bredesen, D. E., and Rosenblum, M. L.: Neurological manifestations of the acquired immunodeficency syndrome (AIDS). Experience at UCSF and a review of the literature. J. Neurosurg. 62:475, 1985. 19. Moskowitz, L. B., Hensley, G. T., Chan, J. c.. Gregorios, J., and Conley, F. K.: The neuropathology of the acquired immunodeficiency syndrome. Arch. Pathol. Lab. Med. 108:867, 1984. 20. Petito, C. K., Navia, B. A., Cho, E. 5., Jordan, B. D., George, D. c., and Price, R. W.: Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 312:874, 1985. 21. Petito, C. K., Cho, E. 5., Lemann, W., Navia, B. A., and Price, R. W.: Neuropathology of acquired immunodeficiency syndrome (AIDS). An autopsy review. J. Neuropathol. Exp. Neurol. 45:635, 1986.
We recorded eye movements using infrared oculography in ten patients with the acquired immunodeficiency syndrome (AIDS) and ten control subjects of similar age. Peak saccadic velocity for the AIDS group was significantly lower than that of the control group for both adducting and abducting saccades (P < .001). Saccadic duration for the AIDS group was significantly greater than that of the controls for both adducting and abducting saccades (P < .02 for adduction and P < .01 for abduction). There was no difference in saccadic latencies between the two groups. We add slowed saccades to the ocular motility manifestations of AIDS. Our study indicated that analysis of ocular motility may be of value in providing early detection of neurologic dysfunction, and may also be an important quantitative measure of the responsiveness of patients to different types of potential therapies. RECENT EVIDENCE suggests early central nervous system human immunodeficiency virus (HIV) infection may directly affect ocular motility. Tervo and associates' described two patients with disturbed eye movements who had progressive convergence insufficiency, disturbed optokinetic nystagmus, and abnormalities of both fast and slow eye movements. Rehman and Mehler- described "reverse ocular dipping" in a patient with HIV infection (slow upward deviation of the eyes followed by a rapid return to midposition). Teschke" found slowed saccadic eye movements to be one of four early neurologic signs of central nervous
Accepted for publication Jan. 30, 1989. From the Departments of Ophthalmology (Drs. Nguyen, Rimmer, and Katz) and Neurosciences (Dr. Katz), University of California, San Diego, School of Medicine, La Jolla, California. Reprint requests to Barrett Katz, M.D., UCSD Eye Center, M-018, La Jolla, CA 92093.
356
system HIV infection. Currie and colleagues! demonstrated both saccadic and pursuit dysfunction in a group of patients with the acquired immunodeficiency syndrome (AIDS); in patients with the AIDS dementia complex, the severity of ocular motility dysfunction correlated with the severity of dementia. We undertook our study to quantitate the ocular motility disturbance in AIDS patients without clinical signs of AIDS dementia complex.
Material and Methods We studied ten men aged 28 to 52 years (mean ± S.D., 36.1 ± 6.8 years) and ten male control subjects of similar age (range, 24 to 58 years; mean ± S.D., 36.0 ± 11.9 years) (P = .982). All patients met the criteria of the Centers for Disease Control for a diagnosis of AIDS.5 None of the patients had any clinical evidence of AIDS dementia complex, and all were ambulatory. No patient or control subject had previous neurologic dysfunction or ocular disease. No patient or control received any medication known to affect ocular motility. All patients (Table 1) underwent detailed neurologic assessment, including the minimental status examination." Best-corrected visual acuity was 20/40 or better in all subjects. Pupillary responses were normal, without evidence of an afferent pupillary defect. Saccades and pursuits were judged to be clinically normal and ductions were full. No patient had cranial nerve palsy, nystagmus, or other adventitious eye movements. We·recorded saccadic eye movements in the horizontal meridian using infrared corneoscleral limbus reflection oculography, as previously described." The eye-movement recording apparatus detects the reflections of infrared lightemitting diodes from each eye. Briefly, a mirror transparent for visible light yet refractive for infrared light projects the light reflected from
©AMERICAN JOURNAL OF OPHTHALMOLOGY
107:356-360,
APRIL,
1989
Slowed Saccades in AIDS
Vol. 107, No.4
357
TABLE 1 CLINICAL CHARACTERISTICS OF THE PATIENT GROUP SCORE ON MINI-MENTAL STATE EXAMINATION'
PATIENT NO., AGE (YRS)
R.E.
L.E.
1,40 2,35
20/20 20/40
20120 20/20
None None
30 28
3,41
20/40
20120
None
30
4,36
20/20
20120
None
27
5,32
20/20
20120
30
6, 38 7,33
20/20 20/30
20120 20140
8,51
20/20
20120
Mild intention tremor None Glabellar reflex, snout reflex Snout reflex
9,42 10,61
20/30 20/30
20130 20140
None None
30 30
VISUALACUITY
NEUROLOGIC ABNORMALITIES
SYSTEMIC MEDICATION
Tetracycline Zidovudine, pyrimethamine/sulfadoxine Isoniazid, rifampin, pyrazinamide, pyridoxine Ampicillin, gentamicin, thiamine, cimetidine, folate, MgS04 Pentamidine, sucralfate
30 29
Zidovudine Amphotericin B, KCI, MgS04 Protriptyline, prochlorperazine, cimetidine None Pentamidine, sucralfate
30
'The mini-mental state examination is scored as the number of questions answered correctly out of a possible total of 30.
each iris plane onto a linear array of 1,024 photo diodes. A videographic signal is generated from the output of the photo diodes, and the margin of the pupil's space is determined electronically. The locations of the appropriate diodes are read by a microprocessor, and the data are analyzed by computer. The system has a linear range of 40 degrees, a spatial resolution of greater than 0.1 degree, and a temporal resolution of 8 msec. It allows for the simultaneous recording of each eye. The target stimulus was generated by a helium neon laser mounted on the recording apparatus. The laser beam was reflected by a mirror galvanometer and projected onto a white screen in front of the subject. The target subtended approximately 0.06 degree of visual angle. Saccades were elicited by moving the target in predictable square wave trajectories (amplitudes of ±5, ±10, ±15, ±20, ±30 degrees; frequency, 0.25 Hz), as well as in unpredictable fashion with respect to direction, amplitude, and frequency. We measured at least 150 abducting and adducting sacca des for each patient and control. Data for abducting and adducting saccades were analyzed separately. Saccadic latencies were measured for all amplitudes. Main-
sequence diagrams (duration vs amplitude, and peak velocity vs amplitude) were constructed from scatter plots of each subject using simple linear regression (y = a + bx) and logarithmic regression analysis (y = a + b In x), where y is either the duration for the linear regression or the maximum velocity for the logarithmic regression, a is the y intercept, b is the slope, and x is the amplitude. Both duration-amplitude relationships and peak velocity-amplitude relationships were compared by calculating the area under the curve for each subject's main-sequence diagram and comparing mean values between groups. The data for each group were pooled to construct group main sequence diagrams for each variable. Results
Peak velocity-Peak saccadic velocity (area under the peak velocity-amplitude curve) for the AIDS group was significantly lower than that of the control group, for both adducting and abducting sacca des (P <.001; Table 2). The Figure shows the relationship between saccadic
358
Latency-Latencies of saccades of all amplitudes for both the AIDS and control groups were normal for our laboratory. Mean ± S.D. saccadic latency for the AIDS group was 240 ± 35 msec. Mean saccadic latency for the control group was 236 ± 31 msec. There was no statistically significant difference between the two groups (P > .5).
TABLE 2 AMPLITUDE-PEAK VELOCITY MAIN SEQUENCE DIAGRAM COMPARISON BETWEEN AIDS PATIENTS AND CONTROLS (OEG 2/SEC)*
Abducting Mean S.D. Adducting Mean S.D.
AIDS PATIENTS
CONTROLS
PVALUE'
10,068 806
11,543 602
<.001
10,368 1,006
12,163 801
<.001
Discussion We detected specific eye movement abnormalities in patients with AIDS even before the declaration of any frank neurologic dysfunction, confirming the observations of Currie and colleagues.' Our AIDS patients demonstrated slowed saccadic peak velocities and long saccadic durations compared to normal controls, even though their ocular motility appeared to be clinically normal. Currie and associates" calculated a saccadic error score for each subject by comparing the number of saccadic errors made (hypornetric, corrective, anticipatory, and wrong-way saccades) with the number of normal saccades made. They found eye movement abnormalities in seven of seven patients with AIDS dementia complex and in six of seven AIDS patients without dementia. These abnormalities included impairment of saccadic accuracy, saccadic distractability, fixation instability, sac-
*Values represent areas underthe curve. 'Student's t-test.
peak velocity and amplitude for patients and controls, with logarithmic regression fit to each population's data. Coefficients of variance were 0.96 (adduction) and 0.96 (abduction) for the AIDS group, and 0.93 (adduction) and 0.96 (abduction) for the control group. Duration-Saccadic duration for the AIDS group (area under the duration-amplitude curve) was significantly greater than that of the controls for both adducting and abducting saccades (P < .02 for adduction and P < .01 for abduction; Table 3). Coefficients of variance were 0.83 (adduction) and 0.86 (abduction) for the AIDS group, and 0.77 (adduction) and 0.80 (abduction) for the control group.
oQ)
en
<,
April, 1989
AMERICAN JOURNAL OF OPHTHALMOLOGY
600
Controls
Controls
500
AIDS
AIDS
Ol
--..... Q)
"'0
400
>o
300
Q)
200
0
> ~
CO Q)
a...
100 00
10
20
30 Amplitude
40 0
10
20
30
40
(degrees)
Figure (Nguyen, Rimmer, and Katz). Main sequence diagram relating saccadic peak velocity and amplitude for AIDS patients and controls, for adducting (left) and abducting (right) saccades.
Slowed Saccades in AIDS
Vol. 107, No.4
TABLE 3 AMPLITUDE-DURATION MAIN SEQUENCE DIAGRAM COMPARISON BETWEEN AIDS PATIENTS AND CONTROLS (DEG . MSEC)*
Abducting Mean
S.D. Adducting Mean
S.D.
AIDS PATIENTS
CONTROLS
P VALUE t
1,443 136
1,302 68
<.01
1,351 161
1,198 87
<.02
'Values represent areas underthe curve. 'Student's t-test.
cadic intrusions in normal gain pursuit, and catch-up sacca des in low gain pursuit. We used a different quantitative method to analyze the data and were able to demonstrate additional eye movement abnormalities. We constructed main-sequence diagrams that incorporate a large number of saccades and found AIDS patients to have decreased peak saccadic velocity and prolonged saccadic duration. Our methodology provides easily quantifiable and reproducible results. The neuroanatomic substrate causing slowed saccades in HIV infection is yet to be determined. Commands for horizontal saccades are probably programmed within the pontine paramedian reticular formation. Voluntary saccadic eye movement commands are thought to be mediated by parallel pathways from the contralateral frontal eye field and the superior colliculi, which converge within the brainstem. Horizontal saccadic velocity has been shown to correlate with firing frequency of the mediumlead burst neurons in the pontine paramedian reticular formation." The frequency of burstcell spikes and the recruitment of burst cells are under the modulation of cerebral input. Since the neuropathologic changes in HIV infection are found predominantly in the white matter and subcortical structures (most commonly the basal ganglia, brainstem, and pons), with relative sparing of cortical involvement.P'" the slowed saccades in AIDS patients may reflect a defect in burst neurons of the pontine paramedian reticular formation rather than a defect in cerebral input from the frontal lobe. Saccadic velocities may be slowed by drowsiness, inattention, or drugs. 16 Our AIDS patient population was relatively healthy. No clinical
359
signs of fatigue or impaired concentration were noted, as confirmed by the mental status examination (Table 1). Currie and colleagues' found poor correlation between eye movement abnormalities and the general state of health in their AIDS patients. They recognized severe eye movement abnormalities in healthy but demented patients, and therefore suggested that the eye movement abnormalities in AIDS patients cannot simply be attributed to acute or chronic debilitating AIDS-related illness. None of our patients were taking drugs recognized to affect eye movements. Our patients had no evidence of central nervous system opportunistic infection or neoplasm to confound our results. While neurologic abnormalities are observed in approximately 40% of adult AIDS patients,":" neuropathologic changes are reported in 70% to 80% of cases,":" suggesting the prevalence of neurologic dysfunction to be even higher. The noncytopathic nature of early histologic changes in AIDS dementia complex and the expectation of more effective antiviral agents highlight the importance of early diagnosis of HIV infection in the central nervous system. We therefore agree with Currie and associates' that the analysis of ocular motility is not only of value in providing early detection of neurologic dysfunction, but may be an important quantitative measure of the responsiveness of patients to different types of potential therapies.
References 1. Tervo, T., Elovaara, I., Karli, H., Valle, S.-L., Suni, J., Lahdevirta, J., and Iivanainen, M.: Abnormal ocular motility as early sign of CNS involvement in HIV infection. Lancet 2:512, 1986_ 2. Rehman, F., and Mehler, M. F.: Reverse ocular dipping. Neurology 38:506, 1988. 3. Teschke, R. 5.: A tetrad of neurologic signs sensitive to early human immunodeficiency virus brain disease. Arch. Neurol. 44:693, 1987. 4. Currie, J., Benson, E., Ramsden, B., Perdices, M., and Cooper, D.: Eye movement abnormalities as a predictor of the acquired immunodeficiency syndrome dementia complex. Arch. Neurol. 45:949, 1988. 5. Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. M.M.W.R 36:15, 1987. 6. Folstein, M. F., Folstein, S. E., and McHugh, P. R: Mini-mental state. A practical method for
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