01992 VOL. 23 NO. 4
CLINICAL ELECTROENCEPHALOGRAPHY
Differences in Pattern Visual Evoked Potential (PVEP) Between Hernodialysis and Peritoneal Dialysis Patients R. L. Storch, S. Storch, R. London and W. T. Pordy
Key Words Aluminum Hemodialysis N70-P100 Dissociation Peritoneal Dialysis Visual Evoked Potential
INTRODUCTION The visual evoked potential recorded over the occipital scalp in response to a pattern stimulus (PVEP), is a noninvasive and reliable method of detecting central and peripheral nerve system abnormalities.' A high percentage of uremic patients (dialysis and nondialysis) was reported to have VEP abnormalities. Peritoneal dialysis (PD) patients were found to have lower rates of peripheral neuropathy than patients undergoing hemodialysis (HD).2-4The peripheral neuropathy is thought to be caused by high levels of middle molecules. Middle molecules are substances with a molecular weight of 3001500, which are better cleared by the peritoneal membrane than by the artificial membrane of hemod ialys is,536 However, q u ite su rp r is i ng Iy , PD patients were reported to have longer VEP latencies as compared to H D patients and to controls.? Recently a correlation was found between cumulative oral aluminum (Al) intake and the VEP latency of dialysis patients.' Although the nature of the VEP changes found in dialysis patients is still unclear, since the two modes of dialysis, the PD and HD, differ in their efficacy to eliminatevarious substances, different patterns of toxicity are to be expected. The present study was undertaken to further quantitate the PVEP response in H D and PD patients as compared to normal subjects. As a secondary aim, we have searched for a correlation between the biochemical effects of renal replacement therapy ( b l o o d urea n i t r o g e n (BUN), creatinine (Cr), aluminum (Al) and parathyroid hormone (PTH) and the parameters of the PVEP measured.
METHODS Patients selection The PVEPwas recorded in 33 subjects: 11 HD and 11 PD patients and 11 controls. Regarding the difference between peritoneal and hemodialysis, in peritoneal dialysis fluid is introduced into the peritoneal cavity. and the human peritoneal membrane is being used as thedialyzing membrane. Since the peritoneal membrane differs from the artificial dialyzer of hemodialysis in its permeability characteristics, it provides different clearance capability for the various solutes. The H D patients were undergoing dialysis therapy 4 hours/day, three times a week, for a duration of 6 months to 15 years. The age range was 20 to 66 years. The end stage renal disease (ESRD) in this group was secondary to hypertension (HTN, 8 pts) systemic lupus erythematosus (SLE, 2 pts) and hemolytic uremic syndrome (1 pt). The PD patients were undergoing c o n t i n u o u s ambulatory peritoneal dialysis (CAPD),for a duration of 14 months to 9 years. The age range of this group was 29 to 63 years. The ESRD of these patients was secondary to HTN (9 pts), SLE (1 pt), and Alport's syndrome (1 pt). The 11 controls were age and sex matched without any known renal, ophthalmologic or neurologic disease. An IRB informed consent was obtained from all patients. All subjects had a visual acuity of 20/30 or better without significant hypertensive retinopathy (Keith-Wagener I 1). Patients with diabetes mellitus, or any stigmata of visual or neu-
R L Storch M D is from the Department of Ophthalmology Rambam Medical Center and S Storch M D I S wtth the Department of Medicine at Carmel Medical Center Mtchal St 7 Haifa Israel R London M D and W T Pordy M D are from the Renal Division Department of Medicine Mount Sinai Medical Center N Y N Y Requests for reprints should be addressed to Rita L Storch M D Dept of Ophthalmology Rambam Medical Center Haifa 31096 Israel
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Chemical analysis The serum levels of BUN, Cr, Aluminum, and PTH were drawn before the PVEP test. Serum aluminum was measured with flamelessatomic absorption spectrophotometry as described by Fuchset aI.’The serum PTH level was obtained by the radioimmunoassay method.” Statistical analysis The data were analyzed by the one way ANOVA analysis of variance and the Fisher’s LSD multiple comparison test, Number Cruncher Statistical System.“
0 PI00
- i
l o o rnsec
Figure 1. PVEP of normal subject showing the waves N70. P100 and N145. OD, right eye; OS, left eye; P100-N145 slope(s) was calculated as shown in the lower 0s
tracing (s = x/y).
rologic abnormalities were excluded from the study.
PVEP recording The PVEP was recorded monocularly using gold-cup electrodes placed at Z5 (active site), and 263 (reference). The “Z” represents the midline and the number refers t o the percentage of the inion-nasion distance. A ground electrode was placed on the midforehead. Electrode impedance was always below 5 Kohms. The signals were filtered between 0.3 and 100 Hz, amplified by50 K and wereaveraged on-line with NeuroScope Siegen averager. At least 150 responses per trial were COIL lected. To ensure reliability all responses were replicated. The latencies and amplitudes of the major positive (P100) and the latencies of the negative waves (N70 and N145) were measured. The P100-Nl45 slope, which is the slope between the lowest point on the P100 wave and the highest point on the N145 wave, was calculated as shown in Figure 1. The visual stimulus consisted of vertical sinusoidal gratings generated on a Joyce Electronics display unit with a mean luminance of 100 cd/m2. The contrast, defined as the difference over the sum of the l u m i n a n c e of t w o adjacent light-dark bars: (Lmax-Lmin/Lmax+Lmin), was 45%. The spatial frequencyof the pattern (number of pairsof light-dark bars per degree of visual angle) was 2.3 cpd. The pattern was counterphase modulated at 1.5 Hz ( 3 dark-light reversals per second). The viewing distance was 72 c m and the visual angle subtended was 18 degrees.
RESULTS PD patients showed a significant delay in the latency of P100 as compared to controls (P < 0.05). No significant change in the amplitude of PlOO was observed. The latency of N70 did not differ significantly from controls, implying a dissociation between the latency of N70 and P100 in PD patients (Table 1, Figure 2A, B, C). The N145 wave showed a significant (P 50 mcg/l) have all shown prolonged P100 latencies and decreased P100-Nl45 slope (Figure 3). This finding could suggest a possible correlation between serum aluminum and the delay in the PVEP in PD patients, however it needs further evaluation in a larger number of patients. DISCUSSION A summary of the main findings of previous VEP studies d o n e i n uremic and dialysis patien tS7,8.1 2-22 I. S shown in Table 3. Since most of these studies paid no attention to the negativecomponents N7Oand N145and to the P100 morphology, a comparison to our results is difficult. Thedelayed PlOO latencyfound in the PD
170
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Table 1 Comparison of PVEP Parameters PVEP Wave
HD
PD
CTRL
P < 0.05
N70 I (ms) PlOO a (uv) P100 I (ms) N145 I (ms) N145 s
76.2 f 6.0 *4.6 f 2.31 113.4 i 18.8 155.7 f 22.5 1.3 f 0.63
77.5 i 5.95 6.7 i 3.36 '116.8 i 16.4 "169.3 k 28.5 *1.0 i 0.43
73.9 i 4.7 7.3 k 1.96 103.9 4.23 142.0 f 6.6 1.8 k 0.77
NS vs CTRL *SG vs CTRL *SG vs CTRL 'SG vs CTRL *SG vs CTRL
*
I , latency; a, amplitude; s, slope; HD, hemodialysis; PD, peritoneal dialysis; CTRL, controls; SG = p < 0.05; NS, nonsignificant.
P I 0 0 LATENCY
UTENCl
P I 0 0 AMPLITUDE
RMPUTUDE
13
12
(ms) 11
10
9
HD
C7RL
P3
LATENCY
CTRL
HD
A
PD
s
P100-Nl45 SLOPE
N70 LATENCY '-1
CTRL
0
PO
2
4
6
8
12
D
Figure 2. A, means of PlOO latency, B, means of P100 amplitude, C . means of N70 latency D. means of P100-N145 slope HD, hemodialysis, PD, peritoneal dialysis, CTRL. controls
171
CLINICAL ELECTROENCEPHALOGRAPHY
(c
1992 VOL 23 NO 4
Table 2
Age (Y) Dialysis (y) BUN (mgo/o) Creatinine (mg%) Aluminum (mcg/l) PTH (pg/ml)
HD
PD
P < 0.05
47.7 f 12.4 5.53 -+ 5.55 73.2 i 17.5 10.6 3.87 25.8 f 18.5 44.5 f 3 2 . 0
40.5 t 9.9 4.05 t 2.66 67.2 i 11.0 13.1 31 2.73 53.1 t 4 2 . 2 68.3 t 43.6
NS NS NS NS NS NS
*
CORRELATION OF ALUMINUM AND PI00 IN P D PATIENTS
200
7
(R2 = 0.93)
180 160 -
138
140 120 100
-
80 -
60
-
0
120.5
114
125 LATENCY
Figure 3. The correlation between the three highest serum aluminum levels and P100 latency in PD patients.
patients in our study gives some support to the findings of Hugheset al,’which havesuggested that the main toxic effect of peritoneal dialysis could be o n the visual system. Their finding of delayed VEP latency in PD as compared t o HD patients is quite surprising considering the fact PD patients were reported to have a lower rate of peripheral neuropathy due to a more efficient removal of middle molecules substances than HD patient~.~.~T h e o previous nly study compar-
ing VEP changes between HD and PD patients was done using flash VEP,’ while the present study was carried out with sinusoidal pattern reversal (PVEP). The PVEP is more steady inter- and intrasubject than the flash VEP.23,24 The PVEP is determined by such parameters as the pattern’s contrast, orientation, and mode of presentation (e.g., pattern reversal, onset/offset), thus it gives more strict representation of the cortical
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Table 3 Visual Evoked Potential in Uremia: Summary of the Literature Author
Year
1954 Klingler" 1969 H y manZ2 1978 Hame113 1978 ~ewis'~ 1980 Hughes' L o w i t z ~ c h ' ~ 1981 Rossini" 1981 Ku ba" 1983 Cohen17 1983 ~a~ser'' 1984 Russellz0 1984 Brown 1987
''
Altman'
1989
No. of Patients
F-VEP
? ? *129 for 4y 8 6 H D vs 6 PD 3 43 88 22 34 14 18
+ + + + +
27
++
P-VEP
+
t AMP f LAT t LAT ns AMP r LAT t AMP t LAT PD > H D befD vs aftD ns t LAT f LAT 1 AMP f LAT t LAT 1 AMP 12-8cpd t LAT f AMP
+
*N70-P100 Dissociation t LAT (+) to 'AL
+ +
vs
++
+
+ +
+
*CSF
vs
Main Finding P2/P100
BUN
+ -
+ -
+ -
-
-
AMP, amplitude; LAT, latency; I,increased; I , decreased; ns, nonsignificant; D, dialysis; (+), direct correlation; CSF, contrast sensitivity function.
nervous function. Cells in the striate cortex that respond maximally with respect to a particular parameter are grouped t ~ g e t h e r , ' thus ~ the PVEP gives more strict representation of the cortical nervous function than the flash VEP. Therefore, by using the appropriate pattern stimulus one could probe the cortex in ways that are close to its own organization and disclose pathologies specific t o various dise a s e ~ . ' ~The ' ~ ~PVEP recorded with patternreversal stimulation of a whole visual field is a c o m p o u n d c o r t i c a l response composed of three distinct components: the negative early N70 wave, the major positive P100 wave, and the negative N145 wave.27728 The different VEP patterns found in this study in the two dialysis groups suggest that the mode of dialysis could alter the nervous system function of uremic patients. The dissociation found in this study in the PD group between the latency of the N70 and the PlOO supports a previous study by Brown et al." It implies a CNS pathology in these patients, since the N70 is considered the earliest cortical component of the VEP.28,29 This early negative peak of the PVEP, which occursaround 70-80 msec, has been measured only in afew ~ t u d i e s ' ~ - ~ ~ s iitnwas c e considered an "unreliable peak." However, it has been shown recently that the N70 could be a useful marker of visual pathways dysfunction when one uses the appropriate stimulation. The N70
is a postsynaptic cortical component of the PVEP with properties that are distinct from the P100. N70 shows clear spatial tuning, while P100 does not. The N70 is largest at medium spatial frequency, near the peak of human foveal contrast sensitivity, being most probably determined by foveal neuron^.^^-^' According to this information, we have obtained reliable N70 with a pattern of 2.3 cpd in most of the subjects. We did not measure the amplitude of the N70 in this study. The N70 was shown to be produced by two generators, one in each hemisphere with opposite orientation, therefore, with full-field recording its amplitude is small and variable due to electrical can~ellation.'~-'~ The second important finding of this study is the significant decrease in the P100-N145 slope in PD patients only (Figure 4A, B, C). This finding was present in some PD patients with normal P100 latencyand was absent in HD patients even with delayed P100 latency (Figure 4D), making it unlikely to be the result of a delayed PlOO alone. While the N145 has been studied and occasionally d e ~ c r i b e d , ~ 'it- ~has ~ not on the whole received much attention. The clinical significance of the N145 and its relationship to the P100 are still obscure owing to the complex structure of the visual system. According to Lesevre and Joseph,35 the N145 is a midline component with a different site of origin than the P100. Therefore, the findings of this study
CLINICAL ELECTROENCEPHALOGRAPHY
A
01992 VOL 23 NO. 4
C
1.1 p
B
25
D
Figure4. PVEP tracing A, normal subject; B and C, PD patients; D, HD patients; showing the different morphology of the PVEP in the two dialysis groups.
point toward a specific postsynaptic visual pathway abnormality in PD patients.
again a postsynaptic pathology. The EEG was altered relatively little until late in the course of the encephalopathy. Recently, Altman et ale In the present study there was no significant reported a direct correlation between cumulacorrelation between the age of the patient, the tive oral aluminum intake and the delayed flash time on dialysis, BUN, Cr, Al, PTH and the PVEP VEP in patients undergoing hemodialysis. The parameters measured. Some author^^^'^,'^ have pattern VEP was in the normal range. Whole found a direct correlation between the PVEP brain tissue aluminum concentration has been latencies and serum BUN. These results are in found to be increased in Alzheimer presenile contradiction to the studies that did not find VEP changes before and after d i a l y ~ i s . ~It~is. * ~ dementia,36 amyotrophic lateral sclerosis and parkinsonism associated with The reasonable to assume that the PVEP paramerole of these findings in the etiology of the ters will correlate with the chronic uremic state above diseases is still unknown. and not with acute changes as reflected by the The finding that the amplitude of the PlOO in serum BUN levels. the PD group in our study was not statistically Therefore. for an accurate evaluation of the significant from that of the controls could be correlation between uremia and PVEP parameexplained by the greatervariability of theampliters, clearance studies of creatinine, inulin, and tude as compared to the latency of the PVEP 812 (as representative of middle molecules) are r e s p o n ~ e . ~ ~ ~amplitude ~ T h i s variability also required. The three PD patients in our study diminishes the significance of the decrease in with the highest serum aluminum levels (>50 amplitude of the PlOO obtained in HD patients mcg/l) have all shown markedly increased as compared to controls. P100 latencies and decreased P100-N145 To conclude, by using the appropriate visual slope. This finding could suggest a possible stimulus we wereable in thisstudy todisclosea correlation between serum aluminum and the postsynaptic visual abnormality specific to PD altered PVEP morphology obtained in the PD patients. The relationship of the present PVEP group. Crapper et a136have followed the VEP findings to serum aluminum requires further during the course of aluminum induced eninvestigation. cephalopathy in rabbit, caused by direct injection of aluminum chloride to the cerebral cortex. SUMMARY According to their study, the later components The visual evoked potential was recorded in of the VEP declined progressively in amplitude peritoneal and hernodialysis patients as comduring the encephalopathy, while the earlier pared to normal controls. By using the approcomponents persisted unchanged, suggesting priate visual stimulus we were able to disclose 174
1992 VOL 23 NO 4
CLINICAL ELECTROENCEPHALOGRAPHY
ACKNOWLEDGMENTS We thank Dr. Ivan Bodis-Wollner for his critical reading of an earlier version of this manuscript a n d his invaluable suggestions. The research described herein was supported in part by Fight for Sight, Inc., New York City postdoctoral fellowship 88001, in memory of Mary E. and Alexander P. Hirsh.
specific VEP abnormalities for each of the two dialysis groups. The dissociation found between the latency of N70 and PlOO in peritoneal dialysis patients suggests a possible postsynaptic visual abnormality not described previously. T h e c o r r e l a t i o n between t h e h i g h serum aluminum and the P100 latency of peritoneal dialysis patients requires further investigation.
REFERENCES 1. Riemslag FCC. Introduction. In: Riemslag FCC (ed). Retinal and Occipital Pattern Evoked Potentials. Drukkerij Enschede: Amsterdam ; 1986:7-59.
ually evoked cortical potentials in renal failure: transient potentials. Electroencephalogr Clin Neurophysiol 1978; 44:606-608.
2. Tenckhoff HA, Curtis FK. Experience with maintenance peritoneal dialysis in the home. Am SOC Artif Intern Organs 1970; 16:90-96.
14. Lewis EG, Dustman RE, Beck EC. Visual and somatosensory evoked potential characteristics of patients undergoing hernodialysis and kidney transplantation. Electroencephalogr Clin Neurophysiol 1978; 44:223-231.
3. Buoncristiani U, Mazzotta G, Carobi C, Gallai V, Cozzari M, Di Paolo B. Control of uremic neuropathy by equilibrium peritoneal dialysis. Int J Artificial Organs 1984; 7:97-100.
15. Lowitzsch K, Gohring U. Hecking E, Kohler H. Refractory period sensory conduction velocity and visual evoked potentials before and after hemodialysis. J Neurol Neurosurg Psychiat 1981; 44:121-128.
4. Hamed LM, Winward KE, Glaser JS, Schatz NJ. Optic neuropathy in uremia. Am J Ophthalmol 1989; 108:30-35.
16. Rossini PM, Pirchio M, Treviso M, Gambi D, Di Paolo B, Albertazzi A. Checkerboard reversal pattern and flash VEPs in dialysed and nondialysed subjects. Electroencephalogr Clin Neurophysiol 1981; 52:435-444. 17. Cohen SN. Syndulko K. Rever B, Kraut J. Coburn J. Tourtellotte WW. Visual evoked potentials and long latency event-related potentials in chronic renal failure Neurology 1983; 33.1219-1222.
5. Bab AL, Popovich RP, Christopher TG, Scribner B H . T h e genesis of the square meter-hour hypothesis. Trans Am SOC Artif Intern Organs 1971; 17181-88. 6. Bab AL, Ahrnad S, Bergstrom J, Scribner BH. The middle molecule hypothesis in perspective. Am J Kidney Dis 1981; 1:46-52. 7. Hughes JR, Roxe DM, del Greco F, et al. Electrophysiological studies on uremic patients: comparison of peritoneal dialysis and hemodialysis. Clin Electroencephalogr 1980; 11:72-82. 8. Altman P, Dhanesha U, Harnon C, Cunningham J, Blair J, Marsh F.Disturbance of cerebral function by aluminum in hernodialysis patients without overt aluminum toxicity. Lancet 1989; 1:7-11.
18. Kuba M, Peregrin F, Vit F. Hanusova I, Erben-J Pattern reversal visual evoked potentials i n patients with chronic renal insufficiency. Electroencephalogr Clin Neurophysioll983; 56: 438-442 19. Walser H, Kriss A, Cunningham K, Halliday AM, Jones SJ. Taube D. A multimodal evoked potential assessment of uremia. In: Nodar RH. Barber C (eds). Evoked Potentials II. The Second International Evoked Potential Symposium. Boston: Butterworth; 1984; 80:643-649.
9. FuchsC, Brashe M, Pascen K, Nordbeck H,Quellhorst E. Aluminum-Besimmung im serum mit flammenloser atomabsorption. Clin Chim Acta 1979; 52:71-80. 10. Segre GV. Amino terminal radioimmunoassay for human parathyroid hormone. Frame B, Potts JT Jr (eds). Clinical Disorders of Bone and Mineral Metabolism. Amsterdam: Excerpta Medica 1983: 14PP. 11. Hintze JL. Number Cruncher Statistical System (4.21). 865 East 400 North, Kaysville, Utah 84037. 12. Brown JJ. Sufit RL, Sollinger HW. Visual evoked potential changes following renal transplantation. Electroencephalogr Clin Neurophysiol 1987; 66: 101-107. 13. Hamel B, Bourne JR, Ward, JW, Teschan PE. Vis-
20. Russell P, Sekuler R, Roxe D, Messersrnith R, Mulvanny P. Contrast sensitivity of hernodialysis patients. Met Ped SysOphthalmol 1984;7.201-205 21. Klinger M. EEG observations in uremia. Electroencephalogr Clin Neurophysiol 1954; 6519 22. H y m a n PR, K o o i K A . Visual evoked cortical responses in renal insufficiency. Univ Mich Med Centr J 1969; 35:177-179. 23. Fendick MG. Clinical use of the VECP. Reineck RD (ed). Ophthalmology Annual 1989. New York: Raven Press; 1989.169 pp. 24. Holiday AM, Barrett G, Blumhardt LD, Kriss A. In:
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responses elicited by the onset and offset of sinusoidal gratings: latency, waveform, and topographical characteristics. Invest Ophthalmol Visual Sci 1982; 22:675-680.
Lehmann D, Callaway E (eds). Human Evoked Potentials: Applications and Problems. New York: Plenum Press: 1979:135 pp. 25. Campbell FW, Robson JG. Application of Fourier analysis to thevisibilityof gratings. J Physiol (Lon) 1968; 197.551-556. 26 Bodis-Wollner I, Ghilardi MF. M y l i n L H . The importance of stimulus selection in VEP practice: the clinical relevance of visual physiology. In: Cracco RQ, Bodis-Wollner I (eds). Evoked Potentials: Frontiers of Clincal Neuroscience. New York: Alan R. Liss; 1986: 11 pp. 27 Halliday AM. The value of half-field stimulation in clinical visual evoked potential testing. In: Morocutti C, Rizzo PA (eds). Evoked Potentials. Neurophysiological and Clinical Aspects. Elsevier Science Pub1 BV; 1985: 293-313. 28. Bodis-Wollner I, Barris M, Mylin LH, Julesz B, Kropf LW. Binocular stimulation reveals cortical components of the human VEP. Electroencephalogr Clin Neurophysiol 1981; 52:298-385. 29. Bodis-Wollner I, Mylin L, Frkovic S. The topography of the N70 component of the visual evoked potential in humans. In: Maurer K (ed). Topographic Brain Mapping of EEG and Evoked Potentials. Berlin-Heidelberg: Springer-Verlag; 1989: 397 pp.
30 Ghilardi MF, Sartucci F, Brannan JB, et al. N70and PlOO can be independently affected in multiple sclerosis. Electroencephalogr Clin Neurophysiol 1991;80:1-7. 31. Parker DM. Salzen EA. Lishman JR Visual evoked
32. Previc FT. The neurophysiological significance of the N1 and P1 components of the visual evoked potential. Clin Vision Sci 1988; 3:195-202. 33. Jeffreys DA, Axford JG. Source locations of pattern specific components of human visual evoked potential. I component of striate cortical origin; II component of extrastriate cortical origin. Exp Brain Res 1970: 16:l-40. 34. Brecelj J, Prevec TS. Study of foveal and peripheral visual responses evoked by patternreversal stimulation. In: Nodar RH, Barberv C (eds), Evoked Potentials 11. The Second International Evoked Potential Symposium. Boston: Butterworth; 1984; 31:280-286. 35. Lesevre N , Joseph JP. Modifications of the pattern-evoked potential (PEP) in relation to the stimulated part of the visual field clues for the most probable origin of each component. Electroencephalogr Clin Neurophysiol 1979; 47:183-203. 36. Crapper DR, Quittkat S, Krishnan SS, et al. Intranuclear aluminum content in Alzheimer's disease, dialysis encephalopathy and experimental alumin u m encephalopathy, Acta Neuropath (Berl) 1986; 50:19-24. 37. Per1DP, Gajdusek DC, Garruto RM. lntraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinson dementia of Guam. Science 1982; 217:1053-1055.
176
CLINICAL ELECTROENCEPHALOGRAPHY
Differences in Pattern Visual Evoked Potential (PVEP) Between Hernodialysis and Peritoneal Dialysis Patients R. L. Storch, S. Storch, R. London and W. T. Pordy
Key Words Aluminum Hemodialysis N70-P100 Dissociation Peritoneal Dialysis Visual Evoked Potential
INTRODUCTION The visual evoked potential recorded over the occipital scalp in response to a pattern stimulus (PVEP), is a noninvasive and reliable method of detecting central and peripheral nerve system abnormalities.' A high percentage of uremic patients (dialysis and nondialysis) was reported to have VEP abnormalities. Peritoneal dialysis (PD) patients were found to have lower rates of peripheral neuropathy than patients undergoing hemodialysis (HD).2-4The peripheral neuropathy is thought to be caused by high levels of middle molecules. Middle molecules are substances with a molecular weight of 3001500, which are better cleared by the peritoneal membrane than by the artificial membrane of hemod ialys is,536 However, q u ite su rp r is i ng Iy , PD patients were reported to have longer VEP latencies as compared to H D patients and to controls.? Recently a correlation was found between cumulative oral aluminum (Al) intake and the VEP latency of dialysis patients.' Although the nature of the VEP changes found in dialysis patients is still unclear, since the two modes of dialysis, the PD and HD, differ in their efficacy to eliminatevarious substances, different patterns of toxicity are to be expected. The present study was undertaken to further quantitate the PVEP response in H D and PD patients as compared to normal subjects. As a secondary aim, we have searched for a correlation between the biochemical effects of renal replacement therapy ( b l o o d urea n i t r o g e n (BUN), creatinine (Cr), aluminum (Al) and parathyroid hormone (PTH) and the parameters of the PVEP measured.
METHODS Patients selection The PVEPwas recorded in 33 subjects: 11 HD and 11 PD patients and 11 controls. Regarding the difference between peritoneal and hemodialysis, in peritoneal dialysis fluid is introduced into the peritoneal cavity. and the human peritoneal membrane is being used as thedialyzing membrane. Since the peritoneal membrane differs from the artificial dialyzer of hemodialysis in its permeability characteristics, it provides different clearance capability for the various solutes. The H D patients were undergoing dialysis therapy 4 hours/day, three times a week, for a duration of 6 months to 15 years. The age range was 20 to 66 years. The end stage renal disease (ESRD) in this group was secondary to hypertension (HTN, 8 pts) systemic lupus erythematosus (SLE, 2 pts) and hemolytic uremic syndrome (1 pt). The PD patients were undergoing c o n t i n u o u s ambulatory peritoneal dialysis (CAPD),for a duration of 14 months to 9 years. The age range of this group was 29 to 63 years. The ESRD of these patients was secondary to HTN (9 pts), SLE (1 pt), and Alport's syndrome (1 pt). The 11 controls were age and sex matched without any known renal, ophthalmologic or neurologic disease. An IRB informed consent was obtained from all patients. All subjects had a visual acuity of 20/30 or better without significant hypertensive retinopathy (Keith-Wagener I 1). Patients with diabetes mellitus, or any stigmata of visual or neu-
R L Storch M D is from the Department of Ophthalmology Rambam Medical Center and S Storch M D I S wtth the Department of Medicine at Carmel Medical Center Mtchal St 7 Haifa Israel R London M D and W T Pordy M D are from the Renal Division Department of Medicine Mount Sinai Medical Center N Y N Y Requests for reprints should be addressed to Rita L Storch M D Dept of Ophthalmology Rambam Medical Center Haifa 31096 Israel
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CLINICAL ELECTROENCEPHALOGRAPHY
01992 VOL. 23 NO. 4
Chemical analysis The serum levels of BUN, Cr, Aluminum, and PTH were drawn before the PVEP test. Serum aluminum was measured with flamelessatomic absorption spectrophotometry as described by Fuchset aI.’The serum PTH level was obtained by the radioimmunoassay method.” Statistical analysis The data were analyzed by the one way ANOVA analysis of variance and the Fisher’s LSD multiple comparison test, Number Cruncher Statistical System.“
0 PI00
- i
l o o rnsec
Figure 1. PVEP of normal subject showing the waves N70. P100 and N145. OD, right eye; OS, left eye; P100-N145 slope(s) was calculated as shown in the lower 0s
tracing (s = x/y).
rologic abnormalities were excluded from the study.
PVEP recording The PVEP was recorded monocularly using gold-cup electrodes placed at Z5 (active site), and 263 (reference). The “Z” represents the midline and the number refers t o the percentage of the inion-nasion distance. A ground electrode was placed on the midforehead. Electrode impedance was always below 5 Kohms. The signals were filtered between 0.3 and 100 Hz, amplified by50 K and wereaveraged on-line with NeuroScope Siegen averager. At least 150 responses per trial were COIL lected. To ensure reliability all responses were replicated. The latencies and amplitudes of the major positive (P100) and the latencies of the negative waves (N70 and N145) were measured. The P100-Nl45 slope, which is the slope between the lowest point on the P100 wave and the highest point on the N145 wave, was calculated as shown in Figure 1. The visual stimulus consisted of vertical sinusoidal gratings generated on a Joyce Electronics display unit with a mean luminance of 100 cd/m2. The contrast, defined as the difference over the sum of the l u m i n a n c e of t w o adjacent light-dark bars: (Lmax-Lmin/Lmax+Lmin), was 45%. The spatial frequencyof the pattern (number of pairsof light-dark bars per degree of visual angle) was 2.3 cpd. The pattern was counterphase modulated at 1.5 Hz ( 3 dark-light reversals per second). The viewing distance was 72 c m and the visual angle subtended was 18 degrees.
RESULTS PD patients showed a significant delay in the latency of P100 as compared to controls (P < 0.05). No significant change in the amplitude of PlOO was observed. The latency of N70 did not differ significantly from controls, implying a dissociation between the latency of N70 and P100 in PD patients (Table 1, Figure 2A, B, C). The N145 wave showed a significant (P 50 mcg/l) have all shown prolonged P100 latencies and decreased P100-Nl45 slope (Figure 3). This finding could suggest a possible correlation between serum aluminum and the delay in the PVEP in PD patients, however it needs further evaluation in a larger number of patients. DISCUSSION A summary of the main findings of previous VEP studies d o n e i n uremic and dialysis patien tS7,8.1 2-22 I. S shown in Table 3. Since most of these studies paid no attention to the negativecomponents N7Oand N145and to the P100 morphology, a comparison to our results is difficult. Thedelayed PlOO latencyfound in the PD
170
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CLINICAL ELECTROENCEPHALOGRAPHY
Table 1 Comparison of PVEP Parameters PVEP Wave
HD
PD
CTRL
P < 0.05
N70 I (ms) PlOO a (uv) P100 I (ms) N145 I (ms) N145 s
76.2 f 6.0 *4.6 f 2.31 113.4 i 18.8 155.7 f 22.5 1.3 f 0.63
77.5 i 5.95 6.7 i 3.36 '116.8 i 16.4 "169.3 k 28.5 *1.0 i 0.43
73.9 i 4.7 7.3 k 1.96 103.9 4.23 142.0 f 6.6 1.8 k 0.77
NS vs CTRL *SG vs CTRL *SG vs CTRL 'SG vs CTRL *SG vs CTRL
*
I , latency; a, amplitude; s, slope; HD, hemodialysis; PD, peritoneal dialysis; CTRL, controls; SG = p < 0.05; NS, nonsignificant.
P I 0 0 LATENCY
UTENCl
P I 0 0 AMPLITUDE
RMPUTUDE
13
12
(ms) 11
10
9
HD
C7RL
P3
LATENCY
CTRL
HD
A
PD
s
P100-Nl45 SLOPE
N70 LATENCY '-1
CTRL
0
PO
2
4
6
8
12
D
Figure 2. A, means of PlOO latency, B, means of P100 amplitude, C . means of N70 latency D. means of P100-N145 slope HD, hemodialysis, PD, peritoneal dialysis, CTRL. controls
171
CLINICAL ELECTROENCEPHALOGRAPHY
(c
1992 VOL 23 NO 4
Table 2
Age (Y) Dialysis (y) BUN (mgo/o) Creatinine (mg%) Aluminum (mcg/l) PTH (pg/ml)
HD
PD
P < 0.05
47.7 f 12.4 5.53 -+ 5.55 73.2 i 17.5 10.6 3.87 25.8 f 18.5 44.5 f 3 2 . 0
40.5 t 9.9 4.05 t 2.66 67.2 i 11.0 13.1 31 2.73 53.1 t 4 2 . 2 68.3 t 43.6
NS NS NS NS NS NS
*
CORRELATION OF ALUMINUM AND PI00 IN P D PATIENTS
200
7
(R2 = 0.93)
180 160 -
138
140 120 100
-
80 -
60
-
0
120.5
114
125 LATENCY
Figure 3. The correlation between the three highest serum aluminum levels and P100 latency in PD patients.
patients in our study gives some support to the findings of Hugheset al,’which havesuggested that the main toxic effect of peritoneal dialysis could be o n the visual system. Their finding of delayed VEP latency in PD as compared t o HD patients is quite surprising considering the fact PD patients were reported to have a lower rate of peripheral neuropathy due to a more efficient removal of middle molecules substances than HD patient~.~.~T h e o previous nly study compar-
ing VEP changes between HD and PD patients was done using flash VEP,’ while the present study was carried out with sinusoidal pattern reversal (PVEP). The PVEP is more steady inter- and intrasubject than the flash VEP.23,24 The PVEP is determined by such parameters as the pattern’s contrast, orientation, and mode of presentation (e.g., pattern reversal, onset/offset), thus it gives more strict representation of the cortical
172
CLINICAL ELECTROENCEPHALOGRAPHY
'1992 VOL 23 NO 4
Table 3 Visual Evoked Potential in Uremia: Summary of the Literature Author
Year
1954 Klingler" 1969 H y manZ2 1978 Hame113 1978 ~ewis'~ 1980 Hughes' L o w i t z ~ c h ' ~ 1981 Rossini" 1981 Ku ba" 1983 Cohen17 1983 ~a~ser'' 1984 Russellz0 1984 Brown 1987
''
Altman'
1989
No. of Patients
F-VEP
? ? *129 for 4y 8 6 H D vs 6 PD 3 43 88 22 34 14 18
+ + + + +
27
++
P-VEP
+
t AMP f LAT t LAT ns AMP r LAT t AMP t LAT PD > H D befD vs aftD ns t LAT f LAT 1 AMP f LAT t LAT 1 AMP 12-8cpd t LAT f AMP
+
*N70-P100 Dissociation t LAT (+) to 'AL
+ +
vs
++
+
+ +
+
*CSF
vs
Main Finding P2/P100
BUN
+ -
+ -
+ -
-
-
AMP, amplitude; LAT, latency; I,increased; I , decreased; ns, nonsignificant; D, dialysis; (+), direct correlation; CSF, contrast sensitivity function.
nervous function. Cells in the striate cortex that respond maximally with respect to a particular parameter are grouped t ~ g e t h e r , ' thus ~ the PVEP gives more strict representation of the cortical nervous function than the flash VEP. Therefore, by using the appropriate pattern stimulus one could probe the cortex in ways that are close to its own organization and disclose pathologies specific t o various dise a s e ~ . ' ~The ' ~ ~PVEP recorded with patternreversal stimulation of a whole visual field is a c o m p o u n d c o r t i c a l response composed of three distinct components: the negative early N70 wave, the major positive P100 wave, and the negative N145 wave.27728 The different VEP patterns found in this study in the two dialysis groups suggest that the mode of dialysis could alter the nervous system function of uremic patients. The dissociation found in this study in the PD group between the latency of the N70 and the PlOO supports a previous study by Brown et al." It implies a CNS pathology in these patients, since the N70 is considered the earliest cortical component of the VEP.28,29 This early negative peak of the PVEP, which occursaround 70-80 msec, has been measured only in afew ~ t u d i e s ' ~ - ~ ~ s iitnwas c e considered an "unreliable peak." However, it has been shown recently that the N70 could be a useful marker of visual pathways dysfunction when one uses the appropriate stimulation. The N70
is a postsynaptic cortical component of the PVEP with properties that are distinct from the P100. N70 shows clear spatial tuning, while P100 does not. The N70 is largest at medium spatial frequency, near the peak of human foveal contrast sensitivity, being most probably determined by foveal neuron^.^^-^' According to this information, we have obtained reliable N70 with a pattern of 2.3 cpd in most of the subjects. We did not measure the amplitude of the N70 in this study. The N70 was shown to be produced by two generators, one in each hemisphere with opposite orientation, therefore, with full-field recording its amplitude is small and variable due to electrical can~ellation.'~-'~ The second important finding of this study is the significant decrease in the P100-N145 slope in PD patients only (Figure 4A, B, C). This finding was present in some PD patients with normal P100 latencyand was absent in HD patients even with delayed P100 latency (Figure 4D), making it unlikely to be the result of a delayed PlOO alone. While the N145 has been studied and occasionally d e ~ c r i b e d , ~ 'it- ~has ~ not on the whole received much attention. The clinical significance of the N145 and its relationship to the P100 are still obscure owing to the complex structure of the visual system. According to Lesevre and Joseph,35 the N145 is a midline component with a different site of origin than the P100. Therefore, the findings of this study
CLINICAL ELECTROENCEPHALOGRAPHY
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01992 VOL 23 NO. 4
C
1.1 p
B
25
D
Figure4. PVEP tracing A, normal subject; B and C, PD patients; D, HD patients; showing the different morphology of the PVEP in the two dialysis groups.
point toward a specific postsynaptic visual pathway abnormality in PD patients.
again a postsynaptic pathology. The EEG was altered relatively little until late in the course of the encephalopathy. Recently, Altman et ale In the present study there was no significant reported a direct correlation between cumulacorrelation between the age of the patient, the tive oral aluminum intake and the delayed flash time on dialysis, BUN, Cr, Al, PTH and the PVEP VEP in patients undergoing hemodialysis. The parameters measured. Some author^^^'^,'^ have pattern VEP was in the normal range. Whole found a direct correlation between the PVEP brain tissue aluminum concentration has been latencies and serum BUN. These results are in found to be increased in Alzheimer presenile contradiction to the studies that did not find VEP changes before and after d i a l y ~ i s . ~It~is. * ~ dementia,36 amyotrophic lateral sclerosis and parkinsonism associated with The reasonable to assume that the PVEP paramerole of these findings in the etiology of the ters will correlate with the chronic uremic state above diseases is still unknown. and not with acute changes as reflected by the The finding that the amplitude of the PlOO in serum BUN levels. the PD group in our study was not statistically Therefore. for an accurate evaluation of the significant from that of the controls could be correlation between uremia and PVEP parameexplained by the greatervariability of theampliters, clearance studies of creatinine, inulin, and tude as compared to the latency of the PVEP 812 (as representative of middle molecules) are r e s p o n ~ e . ~ ~ ~amplitude ~ T h i s variability also required. The three PD patients in our study diminishes the significance of the decrease in with the highest serum aluminum levels (>50 amplitude of the PlOO obtained in HD patients mcg/l) have all shown markedly increased as compared to controls. P100 latencies and decreased P100-N145 To conclude, by using the appropriate visual slope. This finding could suggest a possible stimulus we wereable in thisstudy todisclosea correlation between serum aluminum and the postsynaptic visual abnormality specific to PD altered PVEP morphology obtained in the PD patients. The relationship of the present PVEP group. Crapper et a136have followed the VEP findings to serum aluminum requires further during the course of aluminum induced eninvestigation. cephalopathy in rabbit, caused by direct injection of aluminum chloride to the cerebral cortex. SUMMARY According to their study, the later components The visual evoked potential was recorded in of the VEP declined progressively in amplitude peritoneal and hernodialysis patients as comduring the encephalopathy, while the earlier pared to normal controls. By using the approcomponents persisted unchanged, suggesting priate visual stimulus we were able to disclose 174
1992 VOL 23 NO 4
CLINICAL ELECTROENCEPHALOGRAPHY
ACKNOWLEDGMENTS We thank Dr. Ivan Bodis-Wollner for his critical reading of an earlier version of this manuscript a n d his invaluable suggestions. The research described herein was supported in part by Fight for Sight, Inc., New York City postdoctoral fellowship 88001, in memory of Mary E. and Alexander P. Hirsh.
specific VEP abnormalities for each of the two dialysis groups. The dissociation found between the latency of N70 and PlOO in peritoneal dialysis patients suggests a possible postsynaptic visual abnormality not described previously. T h e c o r r e l a t i o n between t h e h i g h serum aluminum and the P100 latency of peritoneal dialysis patients requires further investigation.
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