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Show Journal of Neuro- Ophthalmology 25( 2): 70- 78, 1995. © 1995 Raven Press, Ltd., New York Visual Evoked Potentials During Hyperthermia Robert F. Saul, M. D., Ghazala Hay at, M. D., and John B. Selhorst, M. D. Abstract: Objectives: We sought to evaluate the effect of hyperthermia ( HT) on central conduction pathways by alterations in pattern visual evoked potentials ( PVEPs) in normal and demyelinated optic nerves. Materials and Methods: We studied PVEP peak latency and amplitudes in 10 normal subjects and six patients with demyelinating optic neuropathy before and during HT. Results: In normal subjects, a mean rise in temperature of 2.5° C resulted in a decrease in the second positive peak ( P2) latency of 6.1 ms ( p < 0.0001) and a slight decline in P2 amplitude of 1.16 | xV ( p < 0.009). These results were compared to those obtained from six patients with multiple sclerosis. These patients had a history of monocular optic neuritis; two patients had had bilateral optic neuritis, and one patient had not had involvement of the optic nerve. Average temperature elevations during PVEPs were 1.60° C. PVEPs among these patients showed decrease in mean P2 latencies, except in patients with multiple sclerosis, who showed an increase in latency with 60 min check size in the left eyes. There was a consistent decline in P2 amplitudes. Loss of amplitude was greater among the six optic nerves of those patients having transient, mild losses in visual acuity during HT. Reductions in P2 amplitude were best explained by partial or complete conduction block. Conclusions: These changes in conduction time and amplitude during HT provide a neurophysiologic correlation to the well- known sensitivity of demyelinated optic nerves to elevated temperatures. They are also relevant to the monitoring of central pathways in the operative or intensive care setting. The demonstrated reversible loss of amplitudes also gives promise to therapeutic manipulation of impaired pathways by impeding the loss of current from denuded nerve fibers. Key Words: Visual evoked potentials- Hyperthermia- Peak latency- Amplitudes- Demyelinating optic The reversible effect of hyperthermia ( HT) on the human nervous system was first described with the use of typhoid fever vaccine ( 1) and radiant heat ( 2) to treat multiple sclerosis ( MS). Subsequently, this effect was commonly employed in diagnostic studies of patients suspected of having MS ( 3- 5). Clinically silent neurological signs appeared with elevations in body temperatures and often substantiated the presence of multiple focal deficits. In experimentally demyelinated nerves, this phenomenon of HT is attributed to a reversible alteration in neural conduction ( 6,7). A beneficial effect after hypothermia has also been observed and suggests a therapeutic potential for improving neural conduction ( 8,9). The pattern visual evoked potential ( PVEP) has a highly consistent latency, especially for the P2 ( 10). The latency delays associated with MS are among the most notable and clinically useful ( 11). The P2 amplitude is less predictable because of variation in electrode placement, field potentials, and visual acuity but is affected by a variety of optic nerve diseases, including MS. This investigation was undertaken to determine the alterations in central conduction pathways caused by HT in normal subjects and in patients with MS. Those patients who had a history of obscured vision during increases in body temperature were preferentially selected. Comparisons were made between the symptomatic and asymptomatic eyes of the patients to ascertain if any augmented diagnostic yield of PVEPs, as previously speculated ( 12), was possible with induction of HT. From the Departments of Neurology and Ophthalmology ( R. F. S.), Geisinger Medical Center, Danville, Pennsylvania; and Department of Neurology ( G. H., J. B. S.), Saint Louis University Health Sciences Center, St. Louis, Missouri, U. S. A. Address correspondence and reprint requests to Dr. G. Hayat, Department of Neurology, Saint Louis University Health Sciences Center, 3635 Vista at Grand, St. Louis, MO 63110, U. S. A. METHODS Subjects The study was approved for normal subjects and consenting patients by a Committee on the Conduct of Human Research at the Medical College of 70 VEP AND HYPERTHERMIA 71 Virginia. First, healthy volunteers, eight men and two women, were studied. Their ages ranged from 19 to 43 years. None had a history of retinal or optic nerve disorder. Corrected visual acuity measured 20/ 20 in all but one subject ( 20/ 30). Ophthalmoscopy of the retina and optic nerve was normal in these controls. To evaluate conduction changes in potentially abnormal optic nerves, six patients with a definite diagnosis of MS ( 13) were studied ( Table 1). The six patients, two women and four men, ranged in age from 21 to 55 years. Ophthalmoscopy in each of these patients revealed normal retinal and choroidal appearance, so abnormalities in visual function were attributed to the optic nerve. Five patients had a previous history of retrobulbar optic neuritis, which was bilateral in two of them. Visual acuity recovered to 20/ 25 or better in six of the affected optic nerves and was 20/ 100 in the seventh. A history of blurry vision on exposure to heat was given by four of the patients with demy-elinating disease. One patient with MS had never experienced dysfunction of the optic nerves. Thus, among the six patients, there were seven previously symptomatic optic nerves and five asymptomatic optic nerves. Temperature Changes Body temperature was raised by immersion in a hydrotherapy bath. Oral thermometers were used to gauge body temperature throughout the procedure. In the controls, basal temperatures averaged 36.7° C ( 36.2- 37.1° C). Elevated temperatures were induced by raising the bath water to 43.3° C. The average high temperature was 39.1° C ( 38.4- 39.9° C). Temperatures were lowered by draining the bath or cooling the water. Visual acuity and neurological signs were serially monitored throughout the procedure. PVEPs were obtained at the beginning and termination of the entire procedure, as well as serially and at the highest oral temperature. The average pre- HT temperature among the six patients was 36.9° C ( 36.3- 37.3° C). By warming the bath water, a mean temperature of 38.6° C ( 38.2- 39.4° C) was achieved in 15- 30 min. PVEPs were obtained with the initial appearance of blurry vision, development of new neurological signs, or complaints of excess fatigue. The procedure was then discontinued. Consequently, the mean temperature increases among patients were lower than those of the normal subjects. All the effects of HT promptly reversed with recooling. Visual Evoked Potentials PVEPs were elicited with monocular presentation of a black- and- white checkerboard projected onto a transparent screen. Presentations were at random intervals that averaged two per second. Pattern reversal was accomplished by a mirror galvanometer that required 5 ms fully to reverse the projected checkerboard. The pattern subtended a circular 10° field at 1 m, the distance from which the patient was seated while fixating on the center of the stimulus. Check sizes of 15, 30, and 60 min of arc were employed to evaluate their independent sensitivities. The luminance of the 15- min white checks was 282 ft- lamberts and measured 32 ft- lamberts for the black 15- min checks. Evoked potentials were recorded from a single electrode placed on the midline 2 cm above the inion, the approximate region of the occipital poles, and ref- TABLE 1. Historical data and visual acuities in patients Patients 1 2 3 4 5 6 Cause and duration of disorder MS 6 months MS 7 years MS 10 years MS 2 months MS 4 years MS 2 years Duration of optic neuropathy 6 months 4 years 9 years 1 month 4 years None H istory of heat-in duced visual loss LE + + _ + - - RE + - + - - - Poorest visual Pi acuity ' eviously asymptomatic (*) symptomatic ( + ) LE 20/ 25 + HM + 20/ 400 20/ 70 + 20/ 20* 20/ 20* RE 20/ 25 ' 20/ 20* 20/ 800 + 20/ 20* CF + 20/ 20* Temp CO 37.0 37.2 36.3 37.3 37.3 36.7 Pre- HT LE 20/ 20 20/ 20- 20/ 25" 20/ 25 "• 20/ 20" 20/ 20 RE 20/ 20 20/ 20 20/ 100- 20/ 20 20/ 20 20/ 20 Temp CO 39.4 38.7 38.2 38.2 38.9 38.2 Hyperthermia LE 20/ 30 20/ 60 20/ 25 20/ 80 20/ 20 20/ 20 RE 20/ 40 20/ 20 CF 20/ 20 20/ 20 20/ 20 MS, multiple sclerosis; HT, hyperthermia; LE, left eye; RE, right eye; HM, hand motion; CF, count fingers. / Neuro- Ophthcilmol, Vol. 15, No. 2, 1995 72 R. F. SAUL ET AL. erenced to Cz. A ground lead was attached to the right ear lobe. Electrode resistance was maintained at < 2,000 ohms and monitored throughout the study. The amplifiers were set at a high- frequency response of 100 cps and a low- frequency response of 1 cps. An epoch of 225 ms was sampled from the scalp electrode. The cerebral evoked potentials after 128 stimuli were averaged and displayed so that upward along the ordinate indicated occipital positivity. A calibrated signal of 5 | xV amplitude and 100 ms latency was obtained in each channel used during the procedure. Statistical Analysis The changes in P2 latencies and amplitudes for 15-, 30-, and 60- min check sizes in the pre- HT and hyperthermia state were analyzed by paired t statistical method. Analysis was done in a manner that multiple eyes from one patient were never analyzed in the same analysis. This was done to prevent violation of the rule of independence of cross- observation. Nonparametric Wilcoxon signal rank test was also carried out to stabilize the variance, as conduction block in one patient created very high standard deviation. RESULTS The results of the PVEPs were divided into three groups. Group I was composed of the PVEPs obtained after stimulating the 20 eyes of 10 healthy volunteers. The right and left eyes were analyzed separately. Group II included the PVEPs from four patients with definite MS, three asymptomatic right and two asymptomatic left optic nerves. One patient had bilaterally asymptomatic eyes. Group III consisted of the PVEPs from the five patients with definite MS, three with right and four with left symptomatic optic nerves. In two patients, both eyes were symptomatic. The mean P2 latencies and amplitudes for the three different check sizes of PVEPs among Groups I, II, and III are found in Table 2. Included is a comparative statistical analysis of the pre- HT and the effect of HT. Group I In the normal subjects, there was a consistent effect of HT on the 15-, 30-, or 60- min PVEPs. With increased oral temperature ( 2.4° C), a consistent decrease in P2 latencies was found compared to the pre- HT P2 conduction times except in controls, in whom an increase in P2 latency was noted for 60- and 30- min check sizes, respectively, on the right side ( Fig. 1A and B). The decrease in conduction was maximum for check sizes 15 and 30 min when compared separately for right and left eyes. For check size 15 min, mean difference of 6.1 ms ( p < 0.0001) for right eyes and 6.7 ms ( p < 0.0001) for left eyes was found. A slight reduction in P2 am- TABLE 2. Outcome measures Situation Sample Group 1: Normals Right eye 15' 30' 60' Left eye 15' 30' 60' Group II: M. S. Right eye 15' 30' 60' Left eye 15' 30' 60' Group III: M. S. Right eye 15' 30' 60' Left eye 15' 30' 60' 10 10 Normal V. A. 3 2 Pre Mean 101.80 98.30 99.35 101.90 97.15 99.20 105.33 100.66 100.33 102.50 98.50 100.00 Abnormal V. A. 3 4 132.33 138.33 135.66 131.50 128.75 123.50 - HT SD 5.30 2.94 3.43 6.89 5.44 3.36 15.27 12.66 12.09 3.53 2.12 0.00 15.37 11.54 13.65 16.60 16.99 16.21 Laten HT Mean 95.70 93.55 93.40 95.20 91.80 91.75 102.33 96.00 97.33 98.00 99.00 92.50 89.33 138.00 132.00 101.50 93.00 130.75 cy SD 4.78 4.00 5.64 6.00 5.24 2.07 13.31 11.53 14.74 1.41 4.24 3.53 78.00 18.24 11.26 67.94 64.67 30.20 Paired ( statistics 5.46 ( p < 4.51 ( p < .0001) 0.001) 3.30 ( p < 0.009 7.36 ( p < 0.0001) 5.18 ( p < 0.001) 7.36 ( p < 2.60 NS 2.51 NS 1.96 NS 1.29 NS -. 11 NS 3.00 NS .80 NS .08 NS 2.08 NS .77 NS 1.02 NS -. 74 NS 0.0001) Pre- HT Mean 7.07 7.18 7.46 8.62 7.66 7.68 10.46 10.10 9.63 8.85 8.90 9.40 5.36 5.80 6.60 4.82 5.35 6.67 SD 2.47 1.83 1.59 2.28 2.01 1.89 3.45 3.05 1.84 4.87 1.55 1.27 3.84 4.24 2.60 1.67 1.79 1.94 Amplitude HT Mean 7.11 5.61 6.27 8.32 6.77 6.52 8.06 7.26 6.60 7.65 7.35 6.90 4.1 5.13 4.70 1.90 2.45 5.30 SD 3.54 2.09 2.18 3.21 2.04 1.85 3.05 2.15 0.78 4.03 1.76 1.27 4.95 2.90 2.62 1.44 2.56 1.45 Paired ( statistics -. 04 NS 3.02 ( p < 0.015) 1.87 NS .33 NS 1.71 NS 3.30 ( p < 0.009) 10.39 ( p < 0.009) 2.43 NS 4.91 NS 2.00 NS 10.33 NS - 1.38 NS .81 NS 1.72 NS 2.66 NS 2.94 NS LOONS HT, hyperthermia; NS, not significant. / Neuro- Ophthalmol, Vol. 15, No. 2, 1995 VEP AND HYPERTHERMIA 73 i i i i i i i i i i i i i i i i i i i i 36 39 38 39 .4 .1 .7 .1 LEFT EYES FIG. 1. A: P2 latency for check sizes ( 15, 30, and 60 min) is shown prehyperthermia ( HT) and during HT for right eyes in 10 controls. At mean increase of 2.4° C, the mean decrease in latency was 6.1 ms ( p < 0.0001) for check size 15 min. B: P2 latency for check sizes ( 15, 30, and 60 min) is shown prehyperthermia ( HT) and during HT for left eyes. At mean increase of 2.4° C, the mean decrease in latency was 7.4 ms ( p < 0.0001). plitudes during HT occurred ( p < 0.009); more particularly, the amplitude reduction was negligible for the 15- min PVEP but readily apparent for the 30- min PVEP and 60- min PVEP. An example in one normal subject depicting the effect of HT on PVEPs with three different check sizes is shown in Fig. 2. Group II In the five asymptomatic optic nerves ( three right, two left) in four MS patients, the pre- HT and HT latencies and amplitudes for each check were not significantly different. With the mild increase in temperature ( 1.6° C), P2 latencies decreased in all patients except the left eyes when tested with 30- min check size. The mean decrease in P2 latency was 7.5 ms for the left eyes when tested with check size 60 min. However, this decline was not statistically meaningful in the small sample size. This decline was consistent for the 15-, 30-, and 60- min checks but again statistically not significant because of small sample size. A mean reduction in P2 amplitude during HT of 2.4 | xV ( p < 0.009) occurred when compared to pre- HT in right eyes. RIGHT EYE FIG. 2. The increase in conduction and decrease in P2 latency in each eye of a control with an increase in body temperature of 2.2° C for check sizes ( 15, 30, and 60 min). : L 0 50mi Pre- HT ( 36,4° C) HT ( 38.6° C) / Neuw- Ophthalmol, Vol. 15, No. 2, 1995 74: R. F. SAUL ET AL. Group III Among the seven previously symptomatic optic nerves ( three right and four left), five MS patients had well- compensated visual function, and one retained a moderate loss of vision in the left eye ( Table 1). The pre- HT P2 latencies for each check were prolonged (> 2.5 SD) in six optic nerves and were within normal limits in one optic nerve. The pre- HT P2 amplitudes in Group III averaged 2.4 ( xV less than the initial mean P2 amplitudes for Group I ( Fig. 3A and B). The trend in all patients was a decrease in conduction time. Nonetheless, the mean change in P2 latencies and amplitudes was statistically not significant because of small sample size. With elevated temperature, loss of a discernible P2 amplitude occurred for the 15- and the 30- min PVEPs of the left optic nerve and for the 15- min PVEP of the right optic nerve of patient 1 ( Fig. 4). Because of the loss of a recognizable P2, latency analysis of PVEPs during temperature elevations created very high standard deviation. Nonpara-metric Wilcoxon signed rank test was also carried out to stabilize the variance. No statistical difference was noted by this method either, because of small sample size. Among the total 18 interpretable PVEPs obtained during HT from the previously symptomatic optic nerves, the P2 latency increased in eleven and decreased in seven. Conduction in P2 decreased in three 15- min PVEPs, four 30- min PVEPs, and four 60- min PVEPs. Conversely, P2 conduction increased in two 15- min PVEPs, two 30- min PVEPs, and two 60- min PVEPs. In only one patient, the change in P2 latency during HT consistently increased for all three of the different check sizes for the left eye. In another patient, P2 latency decreased for all check sizes on the right side. Overall, an average decrease of 3 ms was found in the discernible P2 latencies during HT but was not significant. In one patient, both optic nerves exhibiting a loss of discernible P2 amplitude, only a mild loss in visual acuity occurred ( Table 1). A reduction in P2 amplitude, sometimes marked ( Fig. 5), was found in the three other patients experiencing mild decreases in visual acuity during HT. Visual loss did not occur in two patients with previously symptomatic optic nerves, even though the initial PVEPs showed significant P2 conduction delays. The change in P2 latency and amplitude during HT for each of these two optic nerves resembled the milder effects of increased temperature found in the PVEPs of Group I and II. The P2 amplitude declined consistently and was significant for check size 30 min ( left eyes) ( p < 0.061). DISCUSSION With PVEPs, intrasession and intersession variations in the latency of P2 are negligible ( 14,15). However, differences in the amplitude of the pattern- shift P2 are well known to occur from trial to trial. Variations in stimulus parameters ( pattern size, configuration, rate, field of presentation, color, and luminance), recording factors ( filter settings, electrode resistance, electrode placement), and physiologic parameters ( refraction, eye movement, concentration, and fixation; 16,17) may account for the intersession differences in amplitude. Uren et al. ( 16) suggested that results can be RIGHT EYES FIG. 3. A: Mean P2 amplitude changes prehyperthermla ( HT) and HT in right eyes for three groups. Decline in amplitudes was highly consistent. B: Mean P2 amplitude changes prehyperthermla ( HT) and HT in left eyes for three groups. Decline in amplitude was highly consistent. / Neuro- Ophthalmol, Vol. 25, No. 2, 1995 VEP AND HYPERTHERMIA 75 LEFT EYE RIGHT EYE 20/ 20 20/ 20 FIG. 4. Bilateral P2 conduction block was found with presentation of 15- min checks to either eye and in the left eye with 30- min checks in patient 1, who had multiple sclerosis. The decline in vision was nonetheless mild as the temperature rose to 2.2° C. 20/ 30 20/ 40 20/ 20 5/. V L Post- HT( 37° C) I5' VEP 20/ 20 P, Norm » 15' 101 ma ( SD 7 ) 10.0/ » V ( SD 4.6 ) 30' 98ma( SD5) 8.0^ V( SD3.7> 60' IOOma( S04) 8.5^ V( S03.6) affected only if subjects focus away from the checkerboard stimulus on the corner of the screen. Most of these factors were minimized in this study because our subjects were studied in a single session of 1 to 2 h. During this time, their interest was held constant, and focusing was maintained on the center of the screen. The only major variable was the induced HT. Furthermore, the stability and reliability of the testing procedure was evident by the lack of a statistical difference between pre- HT and post- HT P2 latencies and amplitudes for the three separate size PVEPs. The highly consistent, shorter P2 latencies in Group I clearly suggest an accelerating effect of HT on conduction within central visual pathways. This hyperthermic effect is comparable to animal studies in which increased conduction is attributed to a more rapid generation of nodal current in myelinated mammalian nerves ( 6,7) and influx of sodium ions in amphibian nodes ( 18). An explanation for the small, but consistent, fall in P2 amplitude for Group I is also suggested by experimental work. With increases in temperature, the duration of the action potential shortens, possibly because / Neuro- Ophthalmol, Vol. 25, No. 2, 1995 76 R. F. SAULETAL. 20/ 25 20/ 20 HT ( 3 8 2" C) 20/ 80 20/ 20 FIG. 5. Vision declined from 20/ 25 to 20/ 80 as temperature increased 0.9° C in patient 4, who had multiple sclerosis and previous optic neuritis of the left eye. Left P2 conduction block during hyperthermia is evident in 15- min pattern visual evoked potentials. 20/ 25 20/ 20 P2 Normj 15 I0I mi ( SD7) JO1 98 ms ( SD 5) 60' 100mt ( SO 4) 10.0/ iV ( S D 4 . 6) 8 0 M V ( SD 3 . 7 ) 8 5^ V ( SD 3 . 6) of increasing outward nodal currents that have also been demonstrated in amphibian nodes ( 18). The more rapid repolarization would blunt the peak height of single responses and possibly the composite response of the cortex forming the PVEP. In clinically asymptomatic optic nerves of Group II, the increase in temperature and changes in latency were less than but similar to those of Group I. There was also a trend toward a slightly greater loss in P2 amplitude. These minor changes are either due to the degree of HT, which was 1.8° C in Group I and 0.9° C in Group II, or due to partial conduction block. The rise in body temperature provoked both increases and decreases in the P2 conduction among the impaired optic nerves of Group III. This was true for 15- min P2s obtained during increasing temperatures and P2s of each pattern size recorded at peak increases in body temperature. These variations in P2 latency during HT among the demy-elinated optic nerves are not altogether unexpected. The optic nerve has > 1 million nerve fibers, each presumably with varying degrees of demyelina- / Neum- Ophthalmol, Vol. 15, No. 2, 1995 VEP AND HYPERTHERMIA 77 tion. Investigations in demyelinated mammalian peripheral nerves ( 6,19) and modeling of demyelinated axons ( 7,20) show increase in conduction time with increases in temperature as in normal myelinated fibers. Saltatory conduction continues in many demyelinated fibers ( 21), so fibers in demyelinated optic nerves are expected to behave during HT as normal fibers do. The decrease in P2 conduction time found in seven of 18 discernible PVEPs of Group III is surprising because of the lack of an experimental corroboration. Interestingly, this decrease in conduction time was found in the PVEPs of patients experiencing mild loss in visual acuity during hyperthermia. Conduction delays in demyelinated fibers are attributed to the shunting of a current through denuded internodal segments, lengthening the time for propagation of the action potential at the next node of Ranvier ( 22). Perhaps in some demyelinated axons, the increasing kinetic action among molecules with increases in temperature augments this shunting, further slowing saltatory conduction. Reduction in P2 amplitude during hyperthermia was the most remarkable finding in Group III. Complete loss of P2 amplitude occurred in three optic nerves and coincided with loss of vision. The reduction in P2 amplitude was most marked in the six optic nerves losing the capability for vision during HT. Loss of amplitude has previously been demonstrated with increases in temperature of injured peripheral nerves of amphibians ( 6,22) and mammals ( 6) and in single- fiber studies of normal and demyelinated mammalian nerves ( 7,20). Declines in P2 amplitude, perhaps due to conduction block in a subpopulation of fibers contributing to the PVEP, also accounted for a loss in visual acuity in three optic nerves. Alternatively, temporal dispersion due to both an increase and decrease in conducting fibers resulted in the decline in P2 amplitude and visual acuity. The findings in Group III support Davis and Jacobson's ( 6) earlier proposition that loss of visual acuity during HT in patients with demyelinated optic nerves is primarily due to conduction block and not to changes in conduction velocity. Conduction block occurs when the safety factor for axonal conduction ( the ratio of action current to threshold current) is reduced to < 1.0. Perhaps the shortening of the interval for inward and outward nodal currents with increasing temperature in addition to the pathologic shunting of intra- axonal current along demyelinated inter-nodes results in this critical loss of current. In the laboratory ( 6,7,19,20), the temperature required to achieve a decline in P2 amplitudes is typically lower in damaged or demyelinated nerves than in normal nerves. These findings are used to explain the well- known sensitivity of patients with MS to heat, which is sometimes as exquisite as 0.25° C ( 23) or 0.2° C ( 24). The lower temperatures that induced visual loss and conduction block or modest declines in P2 amplitudes in the patients in this study are consistent with these observations. There are several previous studies of the effect of HT on PVEP. Matthews et al. ( 25) found no appreciable change in latency to 28 PVEPs with a mean increase in oral temperatures of 1° C in six normal subjects. Significant decrease in amplitude ( 1.4 1- iV) ( p < 0.1) was found in normals similar to our Group I. In 27 optic nerves of patients with probable or definite MS, a similarly consistent reduction in amplitude was reported ( 1.7 ( xV). Bajada et al. ( 26) reported no visual loss during HT in five controls ( 0.7- 1.5° C) and five MS patients ( 0.3- 1.1° C. Only one had a history of optic neuritis. Changes in latency were not statistically significant. Amplitude of the P2 peak decreased 4- 26% in eight optic nerves of the control group. In the MS group, HT caused P2 latency to decrease in five optic nerves and increase in two optic nerves. The work of Regan and associates ( 27) on the effect of HT on visual function in normal and MS patients revealed that psychovisual recognition tests were more sensitive to thermal variations than to VEPs. After immersing the lower limbs in warm water ( 44° C) in four controls and two patients with definite MS, no change in latency of the PVEP was detected. In two other patients with an increase in P2 latency, " darkening" of vision occurred in one patient. Kazis et al. ( 28) studied the effect of fever on PVEP and somatosensory evoked potentials in 19 patients with MS and 17 controls. Seventeen patients had abnormal PVEP. PVEP peak latency was shortened by 1.4 ms when they had various degrees of fever. The amplitudes were smaller by 50% during fever as compared to normal temperature. The higher temperatures employed and the selection of patients with a history of a sensitivity to heat in this study explain the consistent effect of HT on latency and amplitude in Group I and the findings of conduction block, greater loss in P2 amplitude, and visual loss in Group III. Among the five optic nerves losing vision during HT, only the one with the poorest baseline visual acuity exhibited a pre- HT afferent pupillary defect. With HT, an afferent pupillary defect appeared in only one additional eye, despite the decline in visual acuity and P2 amplitude among three other optic nerves. The disparity between change in the PVEP and pupillary deafferentation to light demonstrates that one is a measure of finely graded / Neuro- Ophthalmol, Vol. 15, No. 2, 1995 78 R. F. SAUL ET AL. contrasts, whereas the other is sensitive to light-responsive pathways. In one patient ( 1, Table 1; Fig. 4), a prompt return in visual acuity occurred shortly after the peak increase in body temperature, but P2 conduction block persisted for 15 min. This patient subsequently reported slightly better visual acuity at the end of the procedure than at its beginning. Michael and Davis ( 29) similarly observed transiently improved visual acuity after HT in three eyes of two patients. The explanation for this post- HT effect is not known. The normal decrease in latency and the decline in amplitude as the first manifestations of neural impairment during HT are useful observations for intensive care and intraoperative monitorings of central nervous system pathways. The reversible conduction block also shows that extrinsic factors such as HT may appreciably influence conduction along damaged neural pathways. 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