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Effect of intravenous urea on the EEG of brain tumor patients
E F F E C T O F I N T R A V E N O U S U R E A O N T H E EEG OF BRAIN TUMOR PATIENTS1, 2 DANIEL SILVERMAN, M. D., SHAHPOOR PARANDIAN, M . D . AND HENRY SHENKIN, M.D.
with the technical assistance of MARIA MELLIES
Department of Neurosurgery, Episcopal Hospital, Philadelphia, Pa. (U.S.A.)
(Received for publication: December 20, 1960) The impetus for this investigation was the observation that the slow wave focus in the serial E E G study of brain tumor patients may occasionally diminish or disappear temporarily (Churchill and Gonzales 1956; Daly and Thomas 1958) and that one cause of this phenomenon is a reduction in local edema surrounding a tumor (Silverman 1960). The re-introduction of intravenous urea (Javid and Settlage 1956) to reduce cerebral edema and intracranial pressure seemed to present a unique opportunity to study the effects of such reduction of edema and pressure on the E E G of brain tumor patients, i.e., to reproduce experimentally what might occur under certain clinical conditions. The major portion of this paper will deal with this aspect of our investigations ; a few observations on the effect of intravenous urea in other brain diseases will be mentioned. METHOD
Only patients with verified brain tumors were included in the main part of this study; thus far six patients have been tested with intravenous urea. E E G ' s done according to the technique recommended by the International Federation were performed before urea administration and the montage which best delineated the abnormality was selected. Ninety grams of urea were dissolved in 210 cc of 10 per cent invert sugar according to the method of Javid (1958) and * This research was supported in part by a grant from the Baxter Laboratories, Inc., Martin Grove, I11.; the company also supplied the intravenous urea, available as "Urevert". Presented at the 14th Annual Meeting of the American Electroencephalographic Society on June 11, 1960 in Hyannis, Mass.
given intravenously at approximately 60 drops/ min. The full amount usually was injected and this procedure took from 70 80 min. E E G ' s were usually continued during the urea administration and for 1 3 h afterwards. On a number of patients the cerebrospinal fluid pressure was measured before and immediately after completion of the urea administration and the urinary output recorded. A catheter was always inserted in the urinary bladder. RESULTS
The effect of intravenous urea on the E E G of patients with brain tumors thus far has been remarkably constant. In all cases a reduction in the amount of generalized delta and especially local delta and theta activity was observed; the E E G patterns distinctly moved in the direction of normalcy and in one case, for a brief period, did appear normal. This effect began 20-30 min after the intravenous injection was started, reached its zenith 70-100 rain after the beginning of the procedure and gradually diminished by the end of the observation period of approximately 3 h. Concomitantly, with the above effect on the slow activity there was a slight increase in the fast (beta) components of the records. These phenomena are illustrated in the following cases: Case 1. A 44 year old man with aphasia, confusion, right hemiparesis and papilledema was later found to have a left frontal glioblastoma. Fig. 1A shows an obvious left frontal slow wave focus; the cerebrospinal fluid pressure was 500 m m water. A full dosage of urevert was administered and the pressure fell to 100 m m water. The urinary output was 1000 cc. The m a x i m u m effect on the E E G was noted at 90 587
P. SILVERMAN e t al.
588
min (Fig. 1B) and showed a diminution o f delta activity and some increase o f fast activity. Case 2. A 48 year old w o m a n with headaches, personality change for 6 months, weak-
The initial cerebrospinal fluid pressure was 500 m m water; the pressure fell by the end o f the full urevert administration to 100 m m water and the urinary output was 1000 cc. The m a x i m u m E E G Right Temporal Meningicma
L e f t Fronfal Glioblastoma F1
F3-A I
T3 C3-A 1
T5
P3-AI
O1 O1-A 1 FG F4-A 2
T4
C4-A 2
P4-A2
02 02-A 2
~ - ~ TL 50m!~ or{e .~ec Before U r e a
1232
~
,
,
~
.
~
~
90 minutes a f t e r
Fig.
~
t o Cz
1248
Before Urea
sec'~ 50m~ Jan,30,1960
A
Jan.19,1960 A
~
Infusion started
B
1
Left frontal lobe glioblastorna. A. Before intravenous urea infusion, B. 90 rain after infusion started. ness on the left, a left Babinski and papilledema, on operation performed at a later date was found to have a right temporal meningioma. E E G showed a right temporal delta focus (Fig. 2A).
85 minutes after Infusion started B
Fig. 2 Right temporal lobe rneningioma. A. Before intravenous urea infusion. B. 85 min after infusion started. effect was noted at 85 min and again consisted o f a diminution o f delta activity and a slight increase of beta activity (Fig. 2B). Case 3. A 47 year old woman, who had had a
INTRAVENOUS UREA AND BRAIN TUMOR PATIENTS
breast removed for carcinoma, complained of headache and diplopia for a week. Examination revealed bilateral papilledema, more on the right, and X-rays showed a metastatic lung Right Temporal Metastatic Carcinoma
Fs-F4 F4-F3
F3-F 7 T4-C 4
C4-C 3 C3-T 3
TB "P4 ~ P3-T~
one
1217 Before Urea
95 minutes a f t e r
50 mp
sec
Jan.7,1960
A
Infusion started
B
Fig. 3 Right temporal lobe metastatic carcinoma. A. Before intravenous urea infusion. B. 95 rain after infusion started.
lesion. Cerebrospinal fluid (xanthochromic) pressure was 400 m m water; after the administration of the urevert the pressure fell to 50 m m water (it still was xanthochromic) and her urinary output was 1500 cc. The preinjection E E G (Fig. 3A) showed a theta-delta focus in the right temporal area; the maximum urevert effect was
589
achieved at 90 min and showed (Fig. 3B) almost total disappearance of the abnormality. We have had occasion to try intravenous urea in other pathologic conditions; we shall only mention these in passing, since our experience is too limited to permit definite conclusions. One patient, a 45 year old male semi-comatose 10 days after removal of a large right temporoparietal brain abscess, had a marked depression of electrical activity on the right, together with some slowing; intravenous urea had no effect upon this record. A 69 year old man, who had a cerebral thrombosis 9 days prior to the test resulting in a right hemiplegia, disorientation and confusion, showed diffuse delta and theta activity in his EEG, more pronounced in the left temporal region; the maximal effect of urevert, a reversion to essentially normal patterning, was seen in 90 rain with a return to the pre-injection pattern by 180 min. Another cerebrovascular accident, a 60 year old diabetic who had a right hemiparesis with intermittent Jacksonian seizures for 6 days prior to study, showed no change in his EEG by the end of 50 min of urevert infusion at which point the procedure was terminated because of continuing Jacksonian seizures. A 16 year old boy, unconscious six days from a severe cerebral contusion, showed diffuse delta and theta activity in his EEG which diminished considerably after 20 rain of the urevert injection. A 56 year old man, with signs suggestive of a left cerebral lesion which turned out to be a subdural hygroma, had a left temporal delta-theta focus; this temporarily disappeared a few minutes after the urevert administration was completed. Two patients with a primary diagnosis of convulsive seizures of undetermined etiology were given intravenous urea; one had focal temporal random spike and sharp wave discharges and the other focal temporal spike-waves. In both instances there appeared to be a slight diminution in the abnormal activity, but we could not be certain whether this was fortuitous or due to the urea. DISCUSSION
The effect of intravenous urea on the cerebrospinal fluid pressure has been well documented; Javid (1958) reported that the greatest pressure drop with dosages comparable with those we employed is reached between 1-2 h after
590
D, SILVERMANet al.
the beginning of the intravenous infusion. The cerebrospinal fluid pressure remains relatively low for about 3 h and then rises, but may not return completely to the pre-injection level for as long as 10-12 h. Our experiments showed a good correlation between the maximal E E G effect and the anticipated time for maximal reduction of cerebrospinal fluid pressure. However, it is well known that increased intracranial pressure itself does not cause E E G abnormality so that the reduction in pressure cannot be the crucial factor. In view of the marked diuresis and the direct observation by Javid (1958) of brain shrinkage during the administration of urea, we feel that the conclusion is inescapable that the diminution in EEG abnormality described is due to the temporary reduction of edema surrounding a tumor. This should, of course, be no surprise, since it has long been recognized that the focal delta waves in brain tumor patients arise out of malfunctioning neuronal networks surrounding the tumor and not out of the tumor itself. It is a confirmation of our supposition that one major explanation for the rare, but important, instances of a diminished delta focus in brain tumor patients is a temporary reduction of cerebral edema. This could occur under the following circumstances: 1. removal of cerebrospinal fluid or other temporary factors that acutely could reduce intracranial edema and pressure (such as the use of diuretics); 2. lumor shrinkage due to X-Ray, cytotoxic agents and corticosteroid or other hormone administration; 3. involution following hemorrhage or infarction within or surrounding a tumor; and 4. disappearance of local tissue reaction about a metastatic neoplasm (allergic phenomenon?). We can surmise that this effect of intravenous urea on the EEG will be observable also in other types of diseases in which there is edema surrounding a brain lesion. For example, it can be expected to be observed in acute cerebrovascular thrombosis, cerebral contusion and subdural hygroma; indeed we have seen this effect demonstrated in such patients already. We expect to extend our knowledge of intravenous urea effects on many pathologic conditions; however it is probably contraindicated in acute cerebral hemorrhage. That this technique will be of help
in differential E E G diagnosis is not too likely, but it may prove to be of some value in special situations. We hope to pursue this phase of the problem further. One diagnostic possibility, analogous to the utilization of hypertonic solutions earlier (Waiter 1939: Williams 1939; Baudouin e t al. 1946), has been mentioned by Javid (1958). In a diffusely slowed record where there is not a clear focus, intravenous urea may bring out a specific localization. Since beginning this work we have not had a tumor case in which the focus was not clear in order to test this hypothesis, but it certainly is conceivable that this suggestion is correct. SUMMARY AND CONCLUSIONS
Intravenous urea administered by the slow drip method resulted in a diminution of the slow wave focus in the EEG of brain tumor patients. The maximal effect was observed approximately at the time of the greatest drop in cerebrospinal fluid pressure./t is concluded that the phenomenon is due to the reduction of cerebral edema surrounding a tumor and that any clinical change or therapeutic measure that has a similar effect will concomitantly cause the EEG of brain tumor patients to tend to normalize. REFERENCES BAUDOUIN, A., PUECH, P., FISCHGOLD, H. et LERIQUEKOECHLIN, A. k'dlectroencephalographie dans les tumeurs cdrhbrales. In Electroencdphalographie clinique. Exp. Sc. Franq;., Paris, 1946, pp. 57 75. CHURCHILL, J. A. and GONZALES, S. Worth of serial electroencephalograms, Heno' Ford Hosp. Bull.. 1956, 4:186 193. DALY, D. D. and THOMAS,J. C. Sequential alterations in the electroencephalograms of patients with brain tumors. Electroenceph. cl#~. Neurophysiol., 1958, 10: 395M04. JAVID, M. Urea--new use of an old agent; reduction of intracranial and intraocular pressure. Surg. Clin. N. Amer., 1958, 38: 907-928. JAVID, M. and SETTLAGE, P. Effect of urea on cerebrospihal fluid pressure in human subjects J. Amer. ,ted. Ass., 1956, 160:943 949. SmVERMAr%D. Serial electroencephalography in brain tumors and cerebrovascular accident,;. A.M.A. Arch. Neurol., 1960, 2 : 122-129. WALTER, W. GREY. The technique and application of electroencephalography. J. Neurol. Ps ychiat., 1939, /: 359-385. WILLIAMS,D. Cortical potentials with high intracranial pressure. Brain, 1939, 62: 321-334.
Reference: SILVERMAN,D., PARANDIAN,S., SHENK1N,H. and MELLIES,M. Effect of intravenous urea on the EEG of brain tumor patients. Eleetroenceph. olin. Neurophysiol., 1961, 13: 587-590.
with the technical assistance of MARIA MELLIES
Department of Neurosurgery, Episcopal Hospital, Philadelphia, Pa. (U.S.A.)
(Received for publication: December 20, 1960) The impetus for this investigation was the observation that the slow wave focus in the serial E E G study of brain tumor patients may occasionally diminish or disappear temporarily (Churchill and Gonzales 1956; Daly and Thomas 1958) and that one cause of this phenomenon is a reduction in local edema surrounding a tumor (Silverman 1960). The re-introduction of intravenous urea (Javid and Settlage 1956) to reduce cerebral edema and intracranial pressure seemed to present a unique opportunity to study the effects of such reduction of edema and pressure on the E E G of brain tumor patients, i.e., to reproduce experimentally what might occur under certain clinical conditions. The major portion of this paper will deal with this aspect of our investigations ; a few observations on the effect of intravenous urea in other brain diseases will be mentioned. METHOD
Only patients with verified brain tumors were included in the main part of this study; thus far six patients have been tested with intravenous urea. E E G ' s done according to the technique recommended by the International Federation were performed before urea administration and the montage which best delineated the abnormality was selected. Ninety grams of urea were dissolved in 210 cc of 10 per cent invert sugar according to the method of Javid (1958) and * This research was supported in part by a grant from the Baxter Laboratories, Inc., Martin Grove, I11.; the company also supplied the intravenous urea, available as "Urevert". Presented at the 14th Annual Meeting of the American Electroencephalographic Society on June 11, 1960 in Hyannis, Mass.
given intravenously at approximately 60 drops/ min. The full amount usually was injected and this procedure took from 70 80 min. E E G ' s were usually continued during the urea administration and for 1 3 h afterwards. On a number of patients the cerebrospinal fluid pressure was measured before and immediately after completion of the urea administration and the urinary output recorded. A catheter was always inserted in the urinary bladder. RESULTS
The effect of intravenous urea on the E E G of patients with brain tumors thus far has been remarkably constant. In all cases a reduction in the amount of generalized delta and especially local delta and theta activity was observed; the E E G patterns distinctly moved in the direction of normalcy and in one case, for a brief period, did appear normal. This effect began 20-30 min after the intravenous injection was started, reached its zenith 70-100 rain after the beginning of the procedure and gradually diminished by the end of the observation period of approximately 3 h. Concomitantly, with the above effect on the slow activity there was a slight increase in the fast (beta) components of the records. These phenomena are illustrated in the following cases: Case 1. A 44 year old man with aphasia, confusion, right hemiparesis and papilledema was later found to have a left frontal glioblastoma. Fig. 1A shows an obvious left frontal slow wave focus; the cerebrospinal fluid pressure was 500 m m water. A full dosage of urevert was administered and the pressure fell to 100 m m water. The urinary output was 1000 cc. The m a x i m u m effect on the E E G was noted at 90 587
P. SILVERMAN e t al.
588
min (Fig. 1B) and showed a diminution o f delta activity and some increase o f fast activity. Case 2. A 48 year old w o m a n with headaches, personality change for 6 months, weak-
The initial cerebrospinal fluid pressure was 500 m m water; the pressure fell by the end o f the full urevert administration to 100 m m water and the urinary output was 1000 cc. The m a x i m u m E E G Right Temporal Meningicma
L e f t Fronfal Glioblastoma F1
F3-A I
T3 C3-A 1
T5
P3-AI
O1 O1-A 1 FG F4-A 2
T4
C4-A 2
P4-A2
02 02-A 2
~ - ~ TL 50m!~ or{e .~ec Before U r e a
1232
~
,
,
~
.
~
~
90 minutes a f t e r
Fig.
~
t o Cz
1248
Before Urea
sec'~ 50m~ Jan,30,1960
A
Jan.19,1960 A
~
Infusion started
B
1
Left frontal lobe glioblastorna. A. Before intravenous urea infusion, B. 90 rain after infusion started. ness on the left, a left Babinski and papilledema, on operation performed at a later date was found to have a right temporal meningioma. E E G showed a right temporal delta focus (Fig. 2A).
85 minutes after Infusion started B
Fig. 2 Right temporal lobe rneningioma. A. Before intravenous urea infusion. B. 85 min after infusion started. effect was noted at 85 min and again consisted o f a diminution o f delta activity and a slight increase of beta activity (Fig. 2B). Case 3. A 47 year old woman, who had had a
INTRAVENOUS UREA AND BRAIN TUMOR PATIENTS
breast removed for carcinoma, complained of headache and diplopia for a week. Examination revealed bilateral papilledema, more on the right, and X-rays showed a metastatic lung Right Temporal Metastatic Carcinoma
Fs-F4 F4-F3
F3-F 7 T4-C 4
C4-C 3 C3-T 3
TB "P4 ~ P3-T~
one
1217 Before Urea
95 minutes a f t e r
50 mp
sec
Jan.7,1960
A
Infusion started
B
Fig. 3 Right temporal lobe metastatic carcinoma. A. Before intravenous urea infusion. B. 95 rain after infusion started.
lesion. Cerebrospinal fluid (xanthochromic) pressure was 400 m m water; after the administration of the urevert the pressure fell to 50 m m water (it still was xanthochromic) and her urinary output was 1500 cc. The preinjection E E G (Fig. 3A) showed a theta-delta focus in the right temporal area; the maximum urevert effect was
589
achieved at 90 min and showed (Fig. 3B) almost total disappearance of the abnormality. We have had occasion to try intravenous urea in other pathologic conditions; we shall only mention these in passing, since our experience is too limited to permit definite conclusions. One patient, a 45 year old male semi-comatose 10 days after removal of a large right temporoparietal brain abscess, had a marked depression of electrical activity on the right, together with some slowing; intravenous urea had no effect upon this record. A 69 year old man, who had a cerebral thrombosis 9 days prior to the test resulting in a right hemiplegia, disorientation and confusion, showed diffuse delta and theta activity in his EEG, more pronounced in the left temporal region; the maximal effect of urevert, a reversion to essentially normal patterning, was seen in 90 rain with a return to the pre-injection pattern by 180 min. Another cerebrovascular accident, a 60 year old diabetic who had a right hemiparesis with intermittent Jacksonian seizures for 6 days prior to study, showed no change in his EEG by the end of 50 min of urevert infusion at which point the procedure was terminated because of continuing Jacksonian seizures. A 16 year old boy, unconscious six days from a severe cerebral contusion, showed diffuse delta and theta activity in his EEG which diminished considerably after 20 rain of the urevert injection. A 56 year old man, with signs suggestive of a left cerebral lesion which turned out to be a subdural hygroma, had a left temporal delta-theta focus; this temporarily disappeared a few minutes after the urevert administration was completed. Two patients with a primary diagnosis of convulsive seizures of undetermined etiology were given intravenous urea; one had focal temporal random spike and sharp wave discharges and the other focal temporal spike-waves. In both instances there appeared to be a slight diminution in the abnormal activity, but we could not be certain whether this was fortuitous or due to the urea. DISCUSSION
The effect of intravenous urea on the cerebrospinal fluid pressure has been well documented; Javid (1958) reported that the greatest pressure drop with dosages comparable with those we employed is reached between 1-2 h after
590
D, SILVERMANet al.
the beginning of the intravenous infusion. The cerebrospinal fluid pressure remains relatively low for about 3 h and then rises, but may not return completely to the pre-injection level for as long as 10-12 h. Our experiments showed a good correlation between the maximal E E G effect and the anticipated time for maximal reduction of cerebrospinal fluid pressure. However, it is well known that increased intracranial pressure itself does not cause E E G abnormality so that the reduction in pressure cannot be the crucial factor. In view of the marked diuresis and the direct observation by Javid (1958) of brain shrinkage during the administration of urea, we feel that the conclusion is inescapable that the diminution in EEG abnormality described is due to the temporary reduction of edema surrounding a tumor. This should, of course, be no surprise, since it has long been recognized that the focal delta waves in brain tumor patients arise out of malfunctioning neuronal networks surrounding the tumor and not out of the tumor itself. It is a confirmation of our supposition that one major explanation for the rare, but important, instances of a diminished delta focus in brain tumor patients is a temporary reduction of cerebral edema. This could occur under the following circumstances: 1. removal of cerebrospinal fluid or other temporary factors that acutely could reduce intracranial edema and pressure (such as the use of diuretics); 2. lumor shrinkage due to X-Ray, cytotoxic agents and corticosteroid or other hormone administration; 3. involution following hemorrhage or infarction within or surrounding a tumor; and 4. disappearance of local tissue reaction about a metastatic neoplasm (allergic phenomenon?). We can surmise that this effect of intravenous urea on the EEG will be observable also in other types of diseases in which there is edema surrounding a brain lesion. For example, it can be expected to be observed in acute cerebrovascular thrombosis, cerebral contusion and subdural hygroma; indeed we have seen this effect demonstrated in such patients already. We expect to extend our knowledge of intravenous urea effects on many pathologic conditions; however it is probably contraindicated in acute cerebral hemorrhage. That this technique will be of help
in differential E E G diagnosis is not too likely, but it may prove to be of some value in special situations. We hope to pursue this phase of the problem further. One diagnostic possibility, analogous to the utilization of hypertonic solutions earlier (Waiter 1939: Williams 1939; Baudouin e t al. 1946), has been mentioned by Javid (1958). In a diffusely slowed record where there is not a clear focus, intravenous urea may bring out a specific localization. Since beginning this work we have not had a tumor case in which the focus was not clear in order to test this hypothesis, but it certainly is conceivable that this suggestion is correct. SUMMARY AND CONCLUSIONS
Intravenous urea administered by the slow drip method resulted in a diminution of the slow wave focus in the EEG of brain tumor patients. The maximal effect was observed approximately at the time of the greatest drop in cerebrospinal fluid pressure./t is concluded that the phenomenon is due to the reduction of cerebral edema surrounding a tumor and that any clinical change or therapeutic measure that has a similar effect will concomitantly cause the EEG of brain tumor patients to tend to normalize. REFERENCES BAUDOUIN, A., PUECH, P., FISCHGOLD, H. et LERIQUEKOECHLIN, A. k'dlectroencephalographie dans les tumeurs cdrhbrales. In Electroencdphalographie clinique. Exp. Sc. Franq;., Paris, 1946, pp. 57 75. CHURCHILL, J. A. and GONZALES, S. Worth of serial electroencephalograms, Heno' Ford Hosp. Bull.. 1956, 4:186 193. DALY, D. D. and THOMAS,J. C. Sequential alterations in the electroencephalograms of patients with brain tumors. Electroenceph. cl#~. Neurophysiol., 1958, 10: 395M04. JAVID, M. Urea--new use of an old agent; reduction of intracranial and intraocular pressure. Surg. Clin. N. Amer., 1958, 38: 907-928. JAVID, M. and SETTLAGE, P. Effect of urea on cerebrospihal fluid pressure in human subjects J. Amer. ,ted. Ass., 1956, 160:943 949. SmVERMAr%D. Serial electroencephalography in brain tumors and cerebrovascular accident,;. A.M.A. Arch. Neurol., 1960, 2 : 122-129. WALTER, W. GREY. The technique and application of electroencephalography. J. Neurol. Ps ychiat., 1939, /: 359-385. WILLIAMS,D. Cortical potentials with high intracranial pressure. Brain, 1939, 62: 321-334.
Reference: SILVERMAN,D., PARANDIAN,S., SHENK1N,H. and MELLIES,M. Effect of intravenous urea on the EEG of brain tumor patients. Eleetroenceph. olin. Neurophysiol., 1961, 13: 587-590.