reactivity does not seem to occur as rapidly. and one would expect to be able to continue to measure immune reactivity at times when enzyme activity is reduced or even possibly absent. Thus, since this radioimmunoassay is more sensitive than standard elecuophotometric and fluoromemc measurements of enzyme activity, and since measurements of enzyme activity may in some circumstances be misleading, we do not agree with Drs Moore and Norris that “measurement of enzyme activity should take preeminence, especially in such heterogeneous systems as the biological fluids“; in fact, we believe that a radioimmunoassay measurement of the isoenzymes is both quantitative and more accurate. This same reasoning has been applied to the quantificarion of many hormones and other substances in biological fluids. Regarding the m o u n t of CK-B isoenzyme chat can be detected with this radioimmunoassay, we do state in the legend to Figure 1 on page 53 [l] that “as little as 0.2 ng of CK-BB isoenzyme CM be recognized using this technique.” The data for this statement are shown in Figure 1, where it is apparent that the addition of as little as 0.2 ng of unlabeled CK-BB isoenzyme results in a reduction in the amount of antibody bound to labeled CK-BB isoenzyme. This is tested in an assay volume of 0.6 ml. The assay is capable of detecting as little as 1 ng of CK-B per milliliter. We are not certain of the origin of the previously demonstrated increases in CK-MB and CK-MM activity in some patients with cerebrovascular accidents as described in the work of Dub0 et al [ 2 ] . It is known from previous experiments that release of CK-MB from the heart m a y occur with stimulation of certain portions of the brain. CK-MM could be released in any circumstance in which skeletal muxle doccurs, or even with seizures which might themselves be associated with cerebrovascular accidents. Thus,either explanation might account for increases in these isoenzymes in patients with neurological diseases. W e cannot categorically exclude the possibility that stimulation or irritation of certain portions of the brain in patients with cerebrovascular accidents might have resulted in some release of CK-MB from the heart, and that a portion of the CK-B activity detected in our study [I] might not have occurred as a consequence of this phenomenon. We believe it more likely, however, that actual release of CK-BB in patients with cerebrovascular accidents was primarily responsible for the increased serum CK-B levels that we measured. As newer quantitative radioimmunoassays become available that are tissue specific for various types of organ injury, additional examination of this problem would seem warranted.
References Bell RD, Roscnberg RN, Ting R, et al: Crearine kin= BB isoenzyme levels by radioimmunoassay in patients with neurological disease. Ann Neurol 3:52-59. 1978 Dub0 H, Park DC, Pennington RJT. et al: Senun crcaune kin= in cases of suoke. head injury and meningitis. h c e t 2:743-748, 1967
Willerson JT,Stone MJ, Ting R. et al: Radioimmunoauay of CPK-B iroenzyme in human sera:results in patients with uute rnyocardialinhrction. ProcNatl Acad SciUSA 74:1711-1715, 1977
Multide Sclerosis and DogsLA Closer Look Robert W. Haile, MPH, Constance Baraxh Sullivan, MPH, and Sander Greenland, MSPH Within the last year there have been a number of studies investigating the possibility of an association between multiple sclerosis (MS) and ownership of dogs [ l , 2,4]. In their most recent article, Cook et al[2] again report a significant association between MS and overall indoor dog ownership and ownership of a dog within five years prior to the onset of MS. The table presented by Cook et al is reproduced on page 578. A number of points should be made concerning the finding of a significant difference in indoor dog ownership within five years prior to the onset of MS.particularly since the authors attach importance to this result in their discussion. The result of a significant difference in this table may reflect, at least in pan. the fact that indoor dog ownership oueruN was significantly different, thereby increasing the probability of attaining significance with any given subgrouping of these same data by time. Given the significant difference in overall indoor dog ownership, it is appropriate to analyze indoor dog ownership within five years of the onset of MS conditionally upon ever having owned a dog. Also. although the cell frequencies are small, if dog ownership within five years of onset is etiologically more important than overall dog ownership (by virtue of a closer time interval around the presumed etiological event), then within the same data set one would expect this to be manifested by an even stronger association for this time interval. Such was not the case. In fact, the estimate of the relative risk for overall dog ownership, obtained from the table presented, is 6.0 (12/2), while the relative risk estimate for dog ownership within five years of onset is only 3.4 (17/5).Therefore, adding cases in which the only dog ownership was longer than five years prior to onset actually contributed to the strength of the observed association. This fact is also borne out, although to a lesser extent, by an examination of the p values. The p value for overall dog ownership is less than thep value for dog ownership within five years of the onset of MS.This occurs even though the smallest cell frequency is found in the table for overall dog ownership rather than in the table for dog ownership within five years of onset.. Finally, it is of interest to note that dog ownership within ten years of onset was not significantly associated with MS. Since it was five years prior to onset, this implies that the association was in the opposite direction for the interval ten to five years prior to onset. Further analysis to determine the most important time interval, if a n y , relative to the onset of MS is warranted. T h e smaller the smallest cell frequency in a fourfold cable, the less the power. Prom the N e u r o b c D k Epidemiologic Study. UCLA School of Public Health. Los Angeles. CA 90024.
Notes and Letters
577
Pet Ownrrship in MS Patimts and ControfJ P r i w to tbt First Symptom of MS (Critical Age)a
Reply
Control Yes N o Yes18 - 1
Dog ownership
40
No 1 2
11
17
28
MS
MS
0.006
Tom1 29 Indoor dog 5 yr before onset of MS Small indoor dog 5 yr before onset of MS
31 5
Total 34
Total Indoor dog ownership
p Value NS
MS Cat ownership
Total
We did not wish to imply that the five-year period of dog exposure prior to onset of MS was the only important period in a possible canine-MS link. Since both the five- and ten-year periods of house pet exposure were significant in a previous study [I], we also analyzed for dog exposure at these times in our study. It is likely that dog contact for much lonEer periods may also be important. W e agree with Haile, Sullivan, and Greenland that additional information in this regard may come from using regression analysis or lo&nc regression for matched pairs in future studies.
Rrfcnnres
16 26
Yes
Stuart D. Cook, MD, Benjamin H . Natelson, MD, Barry E. Levin, MD,Pamela S. Chavis, MD, and Peter C. Dowling, MD
o,oo8
1. Cook SD.Dowling PC:A possible association berween house pets and multiple sclerosis. h c e t 1980-982, 1977
MS No[ 5 Total 14
14 119 31
MS
From the Neurolow Service, Veterans Administration Hospiral. East Orange, NJ 07019.
0.021
Total 12
33
."Yes" and "No" d e r to pet ownership for each pair of MS patients and their matched controls (e.g. for dog ownership. 8 patients and none of their mntchcd controls owned d=; 2 pacients did not own dogs while their controls did). p values refer to differences kcrve.cn tbese pairs with discordant observations. NS = not significant. Source: Reproduced from Cook et d [2].
Since a conditional analysis of the type referred to would again result in small cell frequencies and low power, regression analysis might be useful in this situation. If the original data permit, separate variables for number of years of dog ownership within different time intervals prior to the onset of MS could be entered as independent variables in a regression analysis, thereby enabling comparisons of the resulting coefficients for each time interval of interest. O n e model that is appropriate for this type of analysis is logistic regression for matched pairs [3]. It might help clarify in which time interval MS is significantly associated with years of dog ownership. Such a clarification is directly relevant to any further evaluation of this reported association.
Refwences 1. Cook SD. Dowling, PC:A possible association between h o w pets and multiple sclerosis. Iancer 1:980-982,1977 2. Cook SD,Nacelson BH, Lvin BE,et al: Funher evidence of a
possible association between house d o g and multiple sclerosis. Ann N e w 1 3:141-143, 1978 3. Holford TR, White C. Kelsey JL.: Multivariate analysis for matched cnse-contml scudics. Am J Epidemiol 107:245-256, 1978 4. Poskanzer DC.Prenney IB.Sheridan JL: House pets and m d tiple sclerosis. lancet 1:1204,1977
578 Annals of Neurolow
Saccadic Initiation Time in Multiple Sclerosis Alfred L. Ochs, PhD, William P. Hoyt, MD, Lawrence Stark, MD. and Michael A. Parchman,
MD
We wish to call attention to an alternative method by which temporal delay can be documented in the visual system of patients with multiple sclerosis, namely, by measuring the time required to initiate saccadic r e h a t i o n of the eyes in response to a sudden change of target position. Prolongation of this saccadic latency can be measured directly from an electrooculographic record, which provides at the same time useful diagnostic indices of eye movement disorder in these patients. W e recorded eye movements with infra-red photocell 121 or electrooculographic techniques. Peripheral stimuli were within 15 degrees of the fovea Nonpredictable target shifts avoided short latency values introduced by anricipatory saccades [3]. Deletion of saccades, with latency 100 msec above the patient's average, eliminated long latency values due to inattention. Normal time for saccadic initiation was 170 msec f 20 SD. W e set the upper limit of latency at 210 msec (plus 2 SDs; 98% chance level). In our study, patients and subjects had normal visual acuity and were not taking medication. In 19 of 20 patients with clinical diagnoses of mulriplc Prom the Department of Neurology and Neurosurgery, University of California Medical Center, San Pnncixo, CA 94143. Accepted for publication June 2, 1978. Address reprint requests to Dr Hoyt, Neuro-Ophthalmology Unit. 782-M.Department of N e u r o l w and Neurosurgery, University of Cdifornis Medical Center, San Francisco, CA 94143.
Vol 4 No 6 December 1978
References Bell RD, Roscnberg RN, Ting R, et al: Crearine kin= BB isoenzyme levels by radioimmunoassay in patients with neurological disease. Ann Neurol 3:52-59. 1978 Dub0 H, Park DC, Pennington RJT. et al: Senun crcaune kin= in cases of suoke. head injury and meningitis. h c e t 2:743-748, 1967
Willerson JT,Stone MJ, Ting R. et al: Radioimmunoauay of CPK-B iroenzyme in human sera:results in patients with uute rnyocardialinhrction. ProcNatl Acad SciUSA 74:1711-1715, 1977
Multide Sclerosis and DogsLA Closer Look Robert W. Haile, MPH, Constance Baraxh Sullivan, MPH, and Sander Greenland, MSPH Within the last year there have been a number of studies investigating the possibility of an association between multiple sclerosis (MS) and ownership of dogs [ l , 2,4]. In their most recent article, Cook et al[2] again report a significant association between MS and overall indoor dog ownership and ownership of a dog within five years prior to the onset of MS. The table presented by Cook et al is reproduced on page 578. A number of points should be made concerning the finding of a significant difference in indoor dog ownership within five years prior to the onset of MS.particularly since the authors attach importance to this result in their discussion. The result of a significant difference in this table may reflect, at least in pan. the fact that indoor dog ownership oueruN was significantly different, thereby increasing the probability of attaining significance with any given subgrouping of these same data by time. Given the significant difference in overall indoor dog ownership, it is appropriate to analyze indoor dog ownership within five years of the onset of MS conditionally upon ever having owned a dog. Also. although the cell frequencies are small, if dog ownership within five years of onset is etiologically more important than overall dog ownership (by virtue of a closer time interval around the presumed etiological event), then within the same data set one would expect this to be manifested by an even stronger association for this time interval. Such was not the case. In fact, the estimate of the relative risk for overall dog ownership, obtained from the table presented, is 6.0 (12/2), while the relative risk estimate for dog ownership within five years of onset is only 3.4 (17/5).Therefore, adding cases in which the only dog ownership was longer than five years prior to onset actually contributed to the strength of the observed association. This fact is also borne out, although to a lesser extent, by an examination of the p values. The p value for overall dog ownership is less than thep value for dog ownership within five years of the onset of MS.This occurs even though the smallest cell frequency is found in the table for overall dog ownership rather than in the table for dog ownership within five years of onset.. Finally, it is of interest to note that dog ownership within ten years of onset was not significantly associated with MS. Since it was five years prior to onset, this implies that the association was in the opposite direction for the interval ten to five years prior to onset. Further analysis to determine the most important time interval, if a n y , relative to the onset of MS is warranted. T h e smaller the smallest cell frequency in a fourfold cable, the less the power. Prom the N e u r o b c D k Epidemiologic Study. UCLA School of Public Health. Los Angeles. CA 90024.
Notes and Letters
577
Pet Ownrrship in MS Patimts and ControfJ P r i w to tbt First Symptom of MS (Critical Age)a
Reply
Control Yes N o Yes18 - 1
Dog ownership
40
No 1 2
11
17
28
MS
MS
0.006
Tom1 29 Indoor dog 5 yr before onset of MS Small indoor dog 5 yr before onset of MS
31 5
Total 34
Total Indoor dog ownership
p Value NS
MS Cat ownership
Total
We did not wish to imply that the five-year period of dog exposure prior to onset of MS was the only important period in a possible canine-MS link. Since both the five- and ten-year periods of house pet exposure were significant in a previous study [I], we also analyzed for dog exposure at these times in our study. It is likely that dog contact for much lonEer periods may also be important. W e agree with Haile, Sullivan, and Greenland that additional information in this regard may come from using regression analysis or lo&nc regression for matched pairs in future studies.
Rrfcnnres
16 26
Yes
Stuart D. Cook, MD, Benjamin H . Natelson, MD, Barry E. Levin, MD,Pamela S. Chavis, MD, and Peter C. Dowling, MD
o,oo8
1. Cook SD.Dowling PC:A possible association berween house pets and multiple sclerosis. h c e t 1980-982, 1977
MS No[ 5 Total 14
14 119 31
MS
From the Neurolow Service, Veterans Administration Hospiral. East Orange, NJ 07019.
0.021
Total 12
33
."Yes" and "No" d e r to pet ownership for each pair of MS patients and their matched controls (e.g. for dog ownership. 8 patients and none of their mntchcd controls owned d=; 2 pacients did not own dogs while their controls did). p values refer to differences kcrve.cn tbese pairs with discordant observations. NS = not significant. Source: Reproduced from Cook et d [2].
Since a conditional analysis of the type referred to would again result in small cell frequencies and low power, regression analysis might be useful in this situation. If the original data permit, separate variables for number of years of dog ownership within different time intervals prior to the onset of MS could be entered as independent variables in a regression analysis, thereby enabling comparisons of the resulting coefficients for each time interval of interest. O n e model that is appropriate for this type of analysis is logistic regression for matched pairs [3]. It might help clarify in which time interval MS is significantly associated with years of dog ownership. Such a clarification is directly relevant to any further evaluation of this reported association.
Refwences 1. Cook SD. Dowling, PC:A possible association between h o w pets and multiple sclerosis. Iancer 1:980-982,1977 2. Cook SD,Nacelson BH, Lvin BE,et al: Funher evidence of a
possible association between house d o g and multiple sclerosis. Ann N e w 1 3:141-143, 1978 3. Holford TR, White C. Kelsey JL.: Multivariate analysis for matched cnse-contml scudics. Am J Epidemiol 107:245-256, 1978 4. Poskanzer DC.Prenney IB.Sheridan JL: House pets and m d tiple sclerosis. lancet 1:1204,1977
578 Annals of Neurolow
Saccadic Initiation Time in Multiple Sclerosis Alfred L. Ochs, PhD, William P. Hoyt, MD, Lawrence Stark, MD. and Michael A. Parchman,
MD
We wish to call attention to an alternative method by which temporal delay can be documented in the visual system of patients with multiple sclerosis, namely, by measuring the time required to initiate saccadic r e h a t i o n of the eyes in response to a sudden change of target position. Prolongation of this saccadic latency can be measured directly from an electrooculographic record, which provides at the same time useful diagnostic indices of eye movement disorder in these patients. W e recorded eye movements with infra-red photocell 121 or electrooculographic techniques. Peripheral stimuli were within 15 degrees of the fovea Nonpredictable target shifts avoided short latency values introduced by anricipatory saccades [3]. Deletion of saccades, with latency 100 msec above the patient's average, eliminated long latency values due to inattention. Normal time for saccadic initiation was 170 msec f 20 SD. W e set the upper limit of latency at 210 msec (plus 2 SDs; 98% chance level). In our study, patients and subjects had normal visual acuity and were not taking medication. In 19 of 20 patients with clinical diagnoses of mulriplc Prom the Department of Neurology and Neurosurgery, University of California Medical Center, San Pnncixo, CA 94143. Accepted for publication June 2, 1978. Address reprint requests to Dr Hoyt, Neuro-Ophthalmology Unit. 782-M.Department of N e u r o l w and Neurosurgery, University of Cdifornis Medical Center, San Francisco, CA 94143.
Vol 4 No 6 December 1978
