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A memory defect in uremic encephalopathy
Journal o/the neurological Sciences, 1975, 26:245-249 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
245
A Memory Defect in Uremic Encephalopathy KENNETH M. HEILMAN, ROBBIE S. MOYER, FERNANDO MELENDEZ, HARVEY D. SCHWARTZ AND BAYARD D. MILLER Department o/ Neurology and Department o/ Clinical Psychology, University o/ Florida, College o/ Medicine and Veterans Administration Hospital, Gainesville, Fla. 32610 (U.S.A.) (Received 6 March, 1975)
INTRODUCTION
Hughlings Jackson (1958) hypothesized that central nervous system disease caused a dissolution of function. Dissolution was defined as the exact reverse of evolution. Phylogenetically newer structures were thought to be more fragile than the older structures because the newer structures were thought to be more complex. When French, Verzeano and Magoun (1953) studied the effects of anesthetics they found that the reticular activating system, a phylogenetically older system, was most sensitive. Whereas disorders of language and symbolic behavior are usually associated with cortical dysfunction, disorders of memory (acquisition) are usually associated with dysfunction in phylogenetically lower systems. Metabolic encephalopathy is frequently associated with neurological abnormalities (Schreiner 1959; Tyler 1968; Tyler 1970); however, no study has been carried out which assesses psychological function in these patients in order to determine if metabolic (uremic) encephalopathy disrupts cortical function and produces defects in language or affects phylogenetically lower systems and affects memory. The purpose of this investigation therefore was to study a population of uremic patients who were awake and normally oriented in time and place in order to ascertain if there are defects in neuropsychological functions and, if so, which functionz are affected and to what extent. MATERIALS AND METHODS
Subjects were patients who had been uremic for at least two months. The diagnosis of uremia was established by blood measurements such as a creatinine greater than Address for reprints: Dr. K. Heilman at the Department of Neurology, University of Florida, College of Medicine, Box 240, Gainesville, Fla. 32610, U.S.A.
246
r:. M. HEILMAN, R. S. MOYER, F. MELENDEZ, H. D. SCHWARTZ, B. D. MILLER
1.5 mg/100 ml or a blood urea nitrogen (BUN) of renal origin greater than 20 mg/100 ml (Harrison, Adam and Bennet 1966). Because we did not want our measurements to be confounded by variables unrelated to metabolic encephalopathy such as hereditary or acquired structural neurological disturbances, we tested only high school graduates (or those with high school equivalents) and patients without known structural neurological disease. In addition, we only tested patients who were awake and oriented for time, place, and person. Controls were drawn from the same population, the only difference being that controls were not uremic. The neuropsychological battery included the following tests: (1) tests of memory--logical memory portion of Wechsler Memory Scale (WMS) (immediate and 45 min delayed), digit retention of Wechsler Adult Intelligence Scale (WAIS), facial recognition (Milner 1968); (2) tests of intellectual function taken from the verbal portion of the WAIS: vocabulary, similarities, and mathematics; (3) evaluation of cortical function included tests for: aphasia, agraphia, alexia, right-left confusion, finger agnosia. Tests for cortical function were given in a manner similar to that described by Goodglass and Kaplan (1972); and (4) tests for trailmaking--Trailmaking (Reitan), Parts A and B (Reitan 1958). RESULTS
In a period of 11 months 36 patients were tested including 24 experimental subjects (uremies) and 12 controls. When the experimental and control groups were compared for sex, race, and age there was no significant difference. The greatest differ-
TABLE 1 COMPARISON BETWEEN EXPERIMENTAL AND CONTROL GROUPS ON NEUROPSYCHOLOGICAL BA'I~ERY
Mean +- Standard Deviation Variable
t- Value normal subjects
Age (years) BUN (rag/100 ml) Creatinine (mg/100 ml) Memory (immediate) Memory (delayed) Facial recognition Digits Mathematics Vocabulary Similarities Trailmaking A Trailmaking B
43.5 -+17.1 12.2 --+ 2.76 0.90--- 0.19 11.12-+ 2.72 8.6 -+ 3.10 8.83 + 2.12 11.75-+ 1.76 11.17-+ 3.38 11.33+ 2.93 11.75-+ 2.67 44.5 -+14.8 92.8 -----25.6
a significantly different (P <0.001). b significantly different (P <0.01). e significantly different (P <0.05). NS : not significantly different (P <0.05).
experimental subjects 50.6 -+16.4 84.0 -----34.8 10.9 -+ 7.0 7 . 6 0+- 3.72 5.29-+ 3.32 8.08-+ 1.98 10.04-+ 2.18 8 . 9 6+- 3.84 10.00-+ 3.36 9.54-+ 2.78 58.4 -+20.4 196.3 -+126.0
--0.47 +7.09a +3.74b --2.90b --2.90b --1.05 --2.35e --1.70 --1.17 --2.28e +2.08e --2.79b
(NS)
(NS) (NS) (NS)
MEMORY DEFECT IN UREMIC ENCEPHALOPATHY
247
ences between the experimental and control groups were in tests for immediate and delayed memory and Trailmaking, Part B (P ~0.01). Other significant differences between groups were found on tests for digit retention, Trailmaking, Part A (P ~0.05) and similarities. No uremic was aphasic, alexie, agraphic, had right-left confusion or finger agnosia. There was no significant difference in the mathematical and vocabulary portion of the WAIS and in the facial recognition task (See Table 1). DISCUSSION
Although it has been hypothesized that uremic encephalopathy would cause generalized intellectual abnormalities (Tyler 1968) or might interfere with cortical function, our data suggest that certain functions such as verbal memory are more sensitive to uremia than are other functions. Not only are the uremics' mean immediate memory scores significantly abnormal when compared to controls, but these scores are also lower than the expected score which can be predicted from the vocabulary subtest. Although there is also a significant difference between groups in the delayed memory portion of the test, when one looks at the loss from the immediate to the delayed condition there is no significant difference and this suggests that the delayed portion is absnormal because the immediate portion is abnormal. The uremics' psychological defects were similar to those seen with anesthesia (Parkhouse, Henrie, Duncan and Rome 1960) and the dissolution of cortical function as predicted by the Jacksonian hypothesis was not seen. The pathophysiology of this short term verbal memory disorder (immediate verbal memory) is not readily apparent. It may, however, be related to an attentional disturbance. Meldman (1970) has defined attention as having two main components; arousal and selection. Since Moruzzi and Magoun's work (1949) it has been well known that stimulation of the reticular system causes behavioral as well as electroencephalographic (EEG) evidence of arousal. Anesthetics have the opposite effect on the reticular system and these changes are reflected in behavioral changes and in the EEG. Several authors have made behavioral observations on uremics and feel that these patients have defects in attention (Schreiner 1959; Tyler 1968). Most patients with blood urea nitrogen levels of 60 mg/100 ml or greater have EEG abnormalities (Tyler 1968), the most frequent abnormality being slowing. In addition, in the uremic defective arousal mechanisms are suggested by the altered EEG reaction to afferent stimuli (Kiloh 1972). Broadbent (1970) has suggested that forgetting of well-learned material is caused by subsequent learning whereas forgetting in short term memory (immediate memory) is different. He suggests that rehearsal is dependent upon attention and "whatever distracts attention and prevents rehearsal may produce an insufficiency in short term memory". Perhaps uremics have a decrease in the immediate memory and digit span because they have poor attention, are distractable, and do poorly in tasks that require rehearsal. Rehearsal is also probably important for doing the Trailmaking Test, especially in Part B, where the patient must remember both the prior number and the prior letter in order to know where to make the next step on his trail.
248
K. M. HEILMAN, R. S. MOYER, F. MELENDEZ, H. D. S C H W A R T Z , B. D. MILLER
Uremics did not demonstrate a significant defect in facial recognition (memory') and it is o.f interest to note that when the effects of anesthetics on the memory functions of man were studied a similar phenomena was noted (Adam 1973). The authors who performed this study on the effects of anesthetics also found that nonverbal acoustic memory was less impaired than verbal memory but more impaired than non-verbal visual memory. They noted that verbal memory capacity develops later than either visual or acoustic memory and although they agreed that the Jacksonian concepts did not adequately describe the physiological sequence of action of anesthetics on the reticular system, they felt that Jackson's dissolution hypothesis did explain why the visual m e m o r y was spared when verbal memory was impaired. Another hypothesis, however, is that verbal material better lends itself to rehearsal than non-verbal material and therefore is more vulnerable to distraction. ACKNOWLEDGEMENT
The authors would like to thank John I. Thornby and Ronald Goebel for their help with statistical analysis. SUMMARY
It has been demonstrated that anesthesia primarily affects the reticular activating system and psychological studies on patients undergoing anesthesia demonstrated a verbal m e m o r y defect. This study was performed in order to determine whether metabolic (uremic) encephalopathy follows the Jacksonian dissolution hypothesis and disrupts cortical function or whether it acts like an anesthetic, causes dysfunction in phytogenetically older systems and thereby produces a memory defect. Twenty-four uremic subjects were tested for m e m o r y function, language function, and intellectual function, and compared to 12 control subjects. The greatest difference between the groups was in immediate m e m o r y function suggesting that uremia probably acts in a manner similar to anesthesia (by causing dysfunction in the reticular activating system). It is postulated that p o o r arousal interferes with rehearsal mad rehearsal is probably an important component of immediate memory. REFERENCES
ADAM, N. (1973) Effects of general anesthetics on memory function in man, J. comp. Physiol. Psychol., 3: 294-305. BROADBENT, D. E. (1970) Recent analyses of short memory. In: K. H. PUSNAM AND D. E. BROADaENT(Eds.), Biology of Memory, Academic Press, New York, N.Y., pp. 15-19. FRENCH, J. D., M. VERZEANOAND H. W. MAGOUN(1953) A neural basis of the anesthetic state, Arch. Neurol. Psychiat. (Chic.), 69: 510-529. GOOI~LASS, H. AND E. I~PLAN (1972) The Assessment o/Aphasia and Related Disorders, Lea and Febiger, Philadelphia, Pa. HARRISON, T. R., R. P. ADAM AND I. L. BENNET (1966) Principles o~ Internal Medicine, McGraw-Hill, New York, N.Y., p. 1811. JACKSON, J. H. (1958) Evolution and dissolution of the nervous system. In: J. TAYLOR(Ed.), Writings o/John Hughlings lackson, Vol. 2, Basic Books, Inc., New York, N.Y., pp. 45-75.
MEMORY DEFECT IN UREMIC ENCEPHALOPATHY
249
KILOH, L. G., A. J. McCOMAS AND J. W. OSSELTON (1972) Clinical Electroencephalogry, Appleton-Century-Crofts, New York, N.Y. MELDMAN, M. J. (1970) Diseases o/ Attention and Perception, Pergamon Press, Oxford. MILNER, B. (1968) Visual recognition and recall after right temporal lobe excision in man, Neuropsychologia, 6: 191-210. MORUZZI, G. AND H. W. MAGOUN (1949) Brain stem reticular formation and activation of the LEG, Electroceph. clin. Neurophysiol., 1: 455-473. PARKHOUSE, J., J. R. HENRIE, G. M. DUNCAN AND H. P. ROME (1960) Nitrous oxide analgesia in relation to mental performance, J. Pharmacol. exp. Ther., 128: 44-54. REITAN, R. M. (1958) Validity of the trailmaking test as an indicator of organic brain damage, Percept. Motor Skills, 8: 271-276. SCHREINER, G. E. (1959) Mental and personality changes in the uremic syndrome, Med. Ann. Distr. Columbia, 28: 3, 6-323. TYLER, H. R. (1968) Neurological disorders in renal failure, Amer. J. Med., 44: 734-748. TYLER, H. R. (1970) Neurological disorders seen in the uremic patient, Arch. int. Med., 126: 781-786.
245
A Memory Defect in Uremic Encephalopathy KENNETH M. HEILMAN, ROBBIE S. MOYER, FERNANDO MELENDEZ, HARVEY D. SCHWARTZ AND BAYARD D. MILLER Department o/ Neurology and Department o/ Clinical Psychology, University o/ Florida, College o/ Medicine and Veterans Administration Hospital, Gainesville, Fla. 32610 (U.S.A.) (Received 6 March, 1975)
INTRODUCTION
Hughlings Jackson (1958) hypothesized that central nervous system disease caused a dissolution of function. Dissolution was defined as the exact reverse of evolution. Phylogenetically newer structures were thought to be more fragile than the older structures because the newer structures were thought to be more complex. When French, Verzeano and Magoun (1953) studied the effects of anesthetics they found that the reticular activating system, a phylogenetically older system, was most sensitive. Whereas disorders of language and symbolic behavior are usually associated with cortical dysfunction, disorders of memory (acquisition) are usually associated with dysfunction in phylogenetically lower systems. Metabolic encephalopathy is frequently associated with neurological abnormalities (Schreiner 1959; Tyler 1968; Tyler 1970); however, no study has been carried out which assesses psychological function in these patients in order to determine if metabolic (uremic) encephalopathy disrupts cortical function and produces defects in language or affects phylogenetically lower systems and affects memory. The purpose of this investigation therefore was to study a population of uremic patients who were awake and normally oriented in time and place in order to ascertain if there are defects in neuropsychological functions and, if so, which functionz are affected and to what extent. MATERIALS AND METHODS
Subjects were patients who had been uremic for at least two months. The diagnosis of uremia was established by blood measurements such as a creatinine greater than Address for reprints: Dr. K. Heilman at the Department of Neurology, University of Florida, College of Medicine, Box 240, Gainesville, Fla. 32610, U.S.A.
246
r:. M. HEILMAN, R. S. MOYER, F. MELENDEZ, H. D. SCHWARTZ, B. D. MILLER
1.5 mg/100 ml or a blood urea nitrogen (BUN) of renal origin greater than 20 mg/100 ml (Harrison, Adam and Bennet 1966). Because we did not want our measurements to be confounded by variables unrelated to metabolic encephalopathy such as hereditary or acquired structural neurological disturbances, we tested only high school graduates (or those with high school equivalents) and patients without known structural neurological disease. In addition, we only tested patients who were awake and oriented for time, place, and person. Controls were drawn from the same population, the only difference being that controls were not uremic. The neuropsychological battery included the following tests: (1) tests of memory--logical memory portion of Wechsler Memory Scale (WMS) (immediate and 45 min delayed), digit retention of Wechsler Adult Intelligence Scale (WAIS), facial recognition (Milner 1968); (2) tests of intellectual function taken from the verbal portion of the WAIS: vocabulary, similarities, and mathematics; (3) evaluation of cortical function included tests for: aphasia, agraphia, alexia, right-left confusion, finger agnosia. Tests for cortical function were given in a manner similar to that described by Goodglass and Kaplan (1972); and (4) tests for trailmaking--Trailmaking (Reitan), Parts A and B (Reitan 1958). RESULTS
In a period of 11 months 36 patients were tested including 24 experimental subjects (uremies) and 12 controls. When the experimental and control groups were compared for sex, race, and age there was no significant difference. The greatest differ-
TABLE 1 COMPARISON BETWEEN EXPERIMENTAL AND CONTROL GROUPS ON NEUROPSYCHOLOGICAL BA'I~ERY
Mean +- Standard Deviation Variable
t- Value normal subjects
Age (years) BUN (rag/100 ml) Creatinine (mg/100 ml) Memory (immediate) Memory (delayed) Facial recognition Digits Mathematics Vocabulary Similarities Trailmaking A Trailmaking B
43.5 -+17.1 12.2 --+ 2.76 0.90--- 0.19 11.12-+ 2.72 8.6 -+ 3.10 8.83 + 2.12 11.75-+ 1.76 11.17-+ 3.38 11.33+ 2.93 11.75-+ 2.67 44.5 -+14.8 92.8 -----25.6
a significantly different (P <0.001). b significantly different (P <0.01). e significantly different (P <0.05). NS : not significantly different (P <0.05).
experimental subjects 50.6 -+16.4 84.0 -----34.8 10.9 -+ 7.0 7 . 6 0+- 3.72 5.29-+ 3.32 8.08-+ 1.98 10.04-+ 2.18 8 . 9 6+- 3.84 10.00-+ 3.36 9.54-+ 2.78 58.4 -+20.4 196.3 -+126.0
--0.47 +7.09a +3.74b --2.90b --2.90b --1.05 --2.35e --1.70 --1.17 --2.28e +2.08e --2.79b
(NS)
(NS) (NS) (NS)
MEMORY DEFECT IN UREMIC ENCEPHALOPATHY
247
ences between the experimental and control groups were in tests for immediate and delayed memory and Trailmaking, Part B (P ~0.01). Other significant differences between groups were found on tests for digit retention, Trailmaking, Part A (P ~0.05) and similarities. No uremic was aphasic, alexie, agraphic, had right-left confusion or finger agnosia. There was no significant difference in the mathematical and vocabulary portion of the WAIS and in the facial recognition task (See Table 1). DISCUSSION
Although it has been hypothesized that uremic encephalopathy would cause generalized intellectual abnormalities (Tyler 1968) or might interfere with cortical function, our data suggest that certain functions such as verbal memory are more sensitive to uremia than are other functions. Not only are the uremics' mean immediate memory scores significantly abnormal when compared to controls, but these scores are also lower than the expected score which can be predicted from the vocabulary subtest. Although there is also a significant difference between groups in the delayed memory portion of the test, when one looks at the loss from the immediate to the delayed condition there is no significant difference and this suggests that the delayed portion is absnormal because the immediate portion is abnormal. The uremics' psychological defects were similar to those seen with anesthesia (Parkhouse, Henrie, Duncan and Rome 1960) and the dissolution of cortical function as predicted by the Jacksonian hypothesis was not seen. The pathophysiology of this short term verbal memory disorder (immediate verbal memory) is not readily apparent. It may, however, be related to an attentional disturbance. Meldman (1970) has defined attention as having two main components; arousal and selection. Since Moruzzi and Magoun's work (1949) it has been well known that stimulation of the reticular system causes behavioral as well as electroencephalographic (EEG) evidence of arousal. Anesthetics have the opposite effect on the reticular system and these changes are reflected in behavioral changes and in the EEG. Several authors have made behavioral observations on uremics and feel that these patients have defects in attention (Schreiner 1959; Tyler 1968). Most patients with blood urea nitrogen levels of 60 mg/100 ml or greater have EEG abnormalities (Tyler 1968), the most frequent abnormality being slowing. In addition, in the uremic defective arousal mechanisms are suggested by the altered EEG reaction to afferent stimuli (Kiloh 1972). Broadbent (1970) has suggested that forgetting of well-learned material is caused by subsequent learning whereas forgetting in short term memory (immediate memory) is different. He suggests that rehearsal is dependent upon attention and "whatever distracts attention and prevents rehearsal may produce an insufficiency in short term memory". Perhaps uremics have a decrease in the immediate memory and digit span because they have poor attention, are distractable, and do poorly in tasks that require rehearsal. Rehearsal is also probably important for doing the Trailmaking Test, especially in Part B, where the patient must remember both the prior number and the prior letter in order to know where to make the next step on his trail.
248
K. M. HEILMAN, R. S. MOYER, F. MELENDEZ, H. D. S C H W A R T Z , B. D. MILLER
Uremics did not demonstrate a significant defect in facial recognition (memory') and it is o.f interest to note that when the effects of anesthetics on the memory functions of man were studied a similar phenomena was noted (Adam 1973). The authors who performed this study on the effects of anesthetics also found that nonverbal acoustic memory was less impaired than verbal memory but more impaired than non-verbal visual memory. They noted that verbal memory capacity develops later than either visual or acoustic memory and although they agreed that the Jacksonian concepts did not adequately describe the physiological sequence of action of anesthetics on the reticular system, they felt that Jackson's dissolution hypothesis did explain why the visual m e m o r y was spared when verbal memory was impaired. Another hypothesis, however, is that verbal material better lends itself to rehearsal than non-verbal material and therefore is more vulnerable to distraction. ACKNOWLEDGEMENT
The authors would like to thank John I. Thornby and Ronald Goebel for their help with statistical analysis. SUMMARY
It has been demonstrated that anesthesia primarily affects the reticular activating system and psychological studies on patients undergoing anesthesia demonstrated a verbal m e m o r y defect. This study was performed in order to determine whether metabolic (uremic) encephalopathy follows the Jacksonian dissolution hypothesis and disrupts cortical function or whether it acts like an anesthetic, causes dysfunction in phytogenetically older systems and thereby produces a memory defect. Twenty-four uremic subjects were tested for m e m o r y function, language function, and intellectual function, and compared to 12 control subjects. The greatest difference between the groups was in immediate m e m o r y function suggesting that uremia probably acts in a manner similar to anesthesia (by causing dysfunction in the reticular activating system). It is postulated that p o o r arousal interferes with rehearsal mad rehearsal is probably an important component of immediate memory. REFERENCES
ADAM, N. (1973) Effects of general anesthetics on memory function in man, J. comp. Physiol. Psychol., 3: 294-305. BROADBENT, D. E. (1970) Recent analyses of short memory. In: K. H. PUSNAM AND D. E. BROADaENT(Eds.), Biology of Memory, Academic Press, New York, N.Y., pp. 15-19. FRENCH, J. D., M. VERZEANOAND H. W. MAGOUN(1953) A neural basis of the anesthetic state, Arch. Neurol. Psychiat. (Chic.), 69: 510-529. GOOI~LASS, H. AND E. I~PLAN (1972) The Assessment o/Aphasia and Related Disorders, Lea and Febiger, Philadelphia, Pa. HARRISON, T. R., R. P. ADAM AND I. L. BENNET (1966) Principles o~ Internal Medicine, McGraw-Hill, New York, N.Y., p. 1811. JACKSON, J. H. (1958) Evolution and dissolution of the nervous system. In: J. TAYLOR(Ed.), Writings o/John Hughlings lackson, Vol. 2, Basic Books, Inc., New York, N.Y., pp. 45-75.
MEMORY DEFECT IN UREMIC ENCEPHALOPATHY
249
KILOH, L. G., A. J. McCOMAS AND J. W. OSSELTON (1972) Clinical Electroencephalogry, Appleton-Century-Crofts, New York, N.Y. MELDMAN, M. J. (1970) Diseases o/ Attention and Perception, Pergamon Press, Oxford. MILNER, B. (1968) Visual recognition and recall after right temporal lobe excision in man, Neuropsychologia, 6: 191-210. MORUZZI, G. AND H. W. MAGOUN (1949) Brain stem reticular formation and activation of the LEG, Electroceph. clin. Neurophysiol., 1: 455-473. PARKHOUSE, J., J. R. HENRIE, G. M. DUNCAN AND H. P. ROME (1960) Nitrous oxide analgesia in relation to mental performance, J. Pharmacol. exp. Ther., 128: 44-54. REITAN, R. M. (1958) Validity of the trailmaking test as an indicator of organic brain damage, Percept. Motor Skills, 8: 271-276. SCHREINER, G. E. (1959) Mental and personality changes in the uremic syndrome, Med. Ann. Distr. Columbia, 28: 3, 6-323. TYLER, H. R. (1968) Neurological disorders in renal failure, Amer. J. Med., 44: 734-748. TYLER, H. R. (1970) Neurological disorders seen in the uremic patient, Arch. int. Med., 126: 781-786.