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A preliminary note of the effect of hexafluorodiethyl ether (Indoklon) on the electroencephalogram of the epileptic
A PRELIMINARY NOTE OF THE EFFECT OF HEXAFLUORODIETHYL ETHER (INDOKLON) ON THE ELECTROENCEPHALOGRAM OF THE EPILEPTIC 1 ALBERT A. KURLAND, M . D . , ENRIQUE DELAMONICA, M . D . AND CURTIS MARSHALL, M . D .
Research Department, Spring Grove State Hospital, Baltimore, Md. and Division of Neurologic Surgery, The Johns Hopkins Hospital, Baltimore, Md. (U.S.A.) (Received for publication: April 10, 1961)
prior to their being tested with Indoklon are indicated in Table I. The EEG's were obtained with an Offner 8channel type T. Eighteen electrodes were placed and common reference and bipolar montages were obtained. The testing procedure with Indoklon consisted of administering 1 cc of a 5 per cent solution (Kurland et al. 1960) intravenously within a time interval of 5-10 sec into the median cubital vein at the time of completion of the resting baseline EEG record. This procedure was repeated at intervals of 2-4 weeks on each patient with 20 out of 26 patients being tested at least 3 times as indicaled in the table.
INTRODUCTION In a series of studies carried out by Esquibel et al. (1957), Krantz et al. (1958, 1959), and Kurland et al. (1960) with hexafluorodiethyl ether (henceforth referred to as Indoklon) as a convulsant in psychiatric treatment it became of interest to carry out further observations relative to its effect on the EEG of the epileptic. This interest arose from the experiences gleaned in the use of this compound as a convulsant and was predicated by: 1. the drug's ability to be given by inhalation and its excretion by the respiratory system (subsequently a technique was developed for administering the drug intravenously with the same end results); 2. the rapidity of its actions, namely, the onset of a convulsion within 30-50 sec following its administration; 3. the relatively wide range between the average convulsant dose of 5 cc necessary to reliably induce a therapeutic seizure and the smaller amounts which could induce subclinical seizure patterns in the EEG.
RESULTS
PATIENT MATERIAL AND METHOD A group of 26 male and female patients residing in the epileptic colony of the Springfield State Hospital was selected for this study. The basis of the selection was their ability to come to the EEG laboratory since they were ambulatory and had ground privileges. These patients were all receiving some type of anti-convulsant medication such as Phenobarbital (100 mg), Dilantin (100 mg), Mesantoin (100 rag), Mysoline (16 mg) and Diamox (250 mg). Some of the patients were also receiving tranquilizers such as Trilafon (4 rag), Compazine (50 rag) and Thorazine (100 mg). This maintenance medication was not altered during the study. The medications were all given on a T.I.D. basis except Diamox which was administered B.I.D. The diagnostic categories and the routine EEG's 1 This study was made possible by research grant No. My-2844 from the National Advisory Mental Health Council, National Institutes of Health, U.S. Public Health Service, and administered by Friends of Psychiatric Research, Inc., Spring Grove State Hospital, Baltimore, Maryland.
Most of the patients experienced some very transient discomfort accompanying the injections. This was described as a burning pain radiating up the arm. In those patients in whom a subclinical seizure was precipitated a subjective feeling of movement was experienced in the lower extremities. Out of a total of 71 records obtained, 52 displayed abnormalities as tabulated during the resting pre-lndoklon phase. Of these 52 records, 24 showed changes following the administration of Indoklon. Of nineteen resting normal pre-lndoklon records only two displayed a change. The types of abnormalities produced were: (a) paroxysms of generalized 3~/sec spike-dome (Fig. 1) (patients 1, 4, 6, 12 and 18); (b) multiple focal spikes (patient 18); (e) accentuation of the spontaneous abnormalities by an increase in voltage of generalized theta range activity and increase in the number of spike discharges (patients 2, 4, 7, 10~ 13, 19 and 20). Wherever activation occurred this appeared within 3 min after the injection had been given. A group of patients with abnormal resting records (patients 4, 10, 13 and 19) consistently exhibited significant actiw~tions whereas a second group of patients (5, 17, 25) with persistent abnormal records constantly exhibited refractoriness to attempted activation. These two groups of patients were compared from the standpoint of etiology, clinical pattern of seizures, treatment, age, sex, present neurological and physical examinations and no differences were found. This would seem to imply that different mechanisms were being affected.
781
782
A. A. KURLAND, E. DELAMONICA AND C. MARSHALL TABLE I A c o m p a r a t i v e t a b u l a t i o n o f the I n d o k l o n activations 1st Testing
2nd Testing
3rd Testing
Diagnosis
°~ C h r o n i c brain s y n d r o m e associated with convulsive disorder (grand real seizures)
C E F
Ab(l) Ab(2) N Ab(l) Ab(l) Ab(l) Ab(5) N
~ -~-+ + --
Ab Ab N Ab Ab Ab Ab N
Ab(1) Ab(2) Ab(1) Ab(7) Ab(1) Ab(1)
C B E B E B, F B
? Ab(3) Ab(1) Ab(1) Ab(l) N Ab(3)
__ + -+ ----
? Ab N Ab Ab N Ab
N Ab(l) Ab(1) Ab(1)
---k +
I 2 3 4 5 6 7 8
34 48 33 56 34 35 50 30
A, A, A, A, A, A, A, A,
B, B, B, B, B B, C, B,
C h r o n i c brain s y n d r o m e associated 9 with convulsive disorder (grand m a l 10 seizures) a n d psychotic reaction ll 12 13 14 15
53 35 48 53 20 29 43
B, A, C, A, A, A, A,
Mental defective with convulsive 16 disorder (grand m a l seizures) 17 18 19
38 50 51 32
A,C,D,G A, E A, B C, H
Miscellaneous: G r a n d m a l seiz. with mental deficiency a n d left hemiparesis Organic brain syn. with g r a n d m a l seiz. a n d m e n t a l deficiency G r a n d mal seizures Psych. with g r a n d m a l seiz. CBS psych, react, g r a n d m a l seiz. a n d m e n t a l deficiency Psych. with syphilitic m e n i n g o encephalitis Schizophrenic react.
C C D C, E
---_ ---
Ab Ab Ab Ab Ab Ab
Ab(5) N
--
Ab N
Ab(l)
--
Ab
?
N
Ab(l)
--
Ab
9 Ab(3) N Ab(1) Ab(7) Ab(I) Ab(1)
-÷ --~ +* ---
? Ab N Ab Ab Ab Ab
Ab(l) Ab(3) Ab(3) Ab(I) Ab(7) Ab(l) Ab(4)
--
Ab Ab Ab Ab Ab Ab Ab
N Ab Ab Ab
N Ab(4) Ab(5) Ab(l)
--~ f
N Ab Ab Ab
N Ab(4) Ab(5) Ab(6)
-f t
N Ab Ab Ah
N
t ? ] !*
20
31 A, B
Ab(4)
-k
Ab
Ab(4)
--
Ab
21 22 23
39 A 31 A, B 48 A, E
Ab(2) N Ab(4)
----
Ab N Ab
Ab(1) N Ab(2)
----? --?
Ab N Ab
Ab(5) N Ab(2)
I~~
Ab N Ab
24
21 A, B, C
N
--
N
N
÷
N
N
-t ?
N
25 26
31 E 55 C, F
Ab(2) N
---
Ab N
Ab(2) N
---
Ab N
Ab(2)
--
Ab
D r u g s : A Phenobarbital, B - - D i l a n t i n , C D i a m o x , D - - M e s a n t o i n , E - - M y s o l i n e , F .Trilafon, G Compazine, H - - T h o r a z i n e . Abnormality: (1) Generalized slow activity (theta range). (6) Bursts of diffuse low voltage theta range activity a n d 14 a n d (2) Slow activity lateralized with t e m p o r a l s h a r p waves. 6 pattern. (3) T e m p o r a l s h a r p waves (without slow). (7) Generalized slow activity a n d spikes without consistent (4) Slow activity lateralized to o n e hemisphere. localization. (5) Spike focus. * Convulsive clinical seizure. ? A questionable p r e - l n d o k l o n record or questionable activation was counted as negative.
783
INDOKLON ACTIVATION Out of a total of 71 testings there was only one patient (13) who developed a clinical seizure, although there were 21 subclinical seizures brought about by the Indoklon administration. One patient (19) presented a very interesting finding: initially the patient's EEG was abnormal with a suggestion of a "14 and 6" pattern.
FPI- rl
A
EEG pathology when present without creating new abnormalities. The help of Dr. Robert E. Gardner, Superintendent of the Springfield State Hospital and Dr. Irene Hitchman, Clinical Director, is gratefully acknowledged in making
/3
T1-T3
'
T3-O1
02-T4
1"4- r2
F2-FP2
FP2-
FPI
V
,I
A
J~V h
--
Fig. 1 Patient 4, HK. Burst of diffuse spike dome pattern which was not present in the resting record. Subsequent testing with Indoklon activated the "14 and 6" pattern by increasing the voltage and percentage time visible. CONCLUSIONS In a small number of epileptics being maintained on anticonvulsant drugs, hexafluorodiethyl ether produced EEG activation predominantly in those with resting abnormal records of various categories as opposed to those with normal resting records. This compound demonstrated a capacity to produce EEG abnormalities within 3 rain where this occurred. The consistency of presence or absence of activation over repeated trials with certain cases appears worthy of follow up. Within this pilot study [ndoklon appears to clarify the underlying
available the patients of the Springfield Epileptic Colony for this study. The hexafluorodiethyl ether used in this clinical study was supplied as Indoklon by the Trubek Laboratories, Inc., of East Rutherford, New Jersey, through the courtesy of the Medical Research Foundation of Philadelphia, Inc., and the Ohio Clinical and Surgical Equipment Company. REFERENCES ESQUIBEL, A.,
KRANTZJR., J.C.,
TRUITT,E . G .
and
KURLAND,A. A. The use of hexafluorodiethyl ether (1ndoklon) as Psychiat., 1957, KRANTZ JR., J.C., A. S.C. and
an inhalant convulsant. Amer. J. 114: 461. ESQUIBEL,A., TRUITT, E.B., LING, KURLAND, A . A . Hexafluorodiethyl
784
A . A . KURLAND, E. DELAMONICA AND C. MARSHALL
ether (Indoklon)--an inhalant convulsant (its use in psychiatric treatment). J. Amer. med. Ass., 1958, 116: 1555-1562. KRANTZ JR., J. C., MANCHEY,L. L., TRUITT, E. B., LING, A. S.C. and KURLAND,A . A . The availability of hexafluorodiethyl ether by intravenous injection as a
convulsant in psychiatric treatment. J. herr. ment. Dis., 1959, 192: 92-94. KURLAND, A . A . , CUERVO,R. and KRANTZJR., J. C. The intravenous use of hexafluorodiethyl ether as a convulsant in psychiatric treatment. J. Ne,ropsychiat.. 1960, 1: 260-265.
Reference: KURLAND,A. A., DELAMONICA,E. and MARSHALL,C. A preliminary note of the effect of hexafluorodiethyl ether (Indoklon) on the electroencephalogram of the epileptic. Electroenceph. clin. Neurophysiol., 1961, 13:781-784.
Research Department, Spring Grove State Hospital, Baltimore, Md. and Division of Neurologic Surgery, The Johns Hopkins Hospital, Baltimore, Md. (U.S.A.) (Received for publication: April 10, 1961)
prior to their being tested with Indoklon are indicated in Table I. The EEG's were obtained with an Offner 8channel type T. Eighteen electrodes were placed and common reference and bipolar montages were obtained. The testing procedure with Indoklon consisted of administering 1 cc of a 5 per cent solution (Kurland et al. 1960) intravenously within a time interval of 5-10 sec into the median cubital vein at the time of completion of the resting baseline EEG record. This procedure was repeated at intervals of 2-4 weeks on each patient with 20 out of 26 patients being tested at least 3 times as indicaled in the table.
INTRODUCTION In a series of studies carried out by Esquibel et al. (1957), Krantz et al. (1958, 1959), and Kurland et al. (1960) with hexafluorodiethyl ether (henceforth referred to as Indoklon) as a convulsant in psychiatric treatment it became of interest to carry out further observations relative to its effect on the EEG of the epileptic. This interest arose from the experiences gleaned in the use of this compound as a convulsant and was predicated by: 1. the drug's ability to be given by inhalation and its excretion by the respiratory system (subsequently a technique was developed for administering the drug intravenously with the same end results); 2. the rapidity of its actions, namely, the onset of a convulsion within 30-50 sec following its administration; 3. the relatively wide range between the average convulsant dose of 5 cc necessary to reliably induce a therapeutic seizure and the smaller amounts which could induce subclinical seizure patterns in the EEG.
RESULTS
PATIENT MATERIAL AND METHOD A group of 26 male and female patients residing in the epileptic colony of the Springfield State Hospital was selected for this study. The basis of the selection was their ability to come to the EEG laboratory since they were ambulatory and had ground privileges. These patients were all receiving some type of anti-convulsant medication such as Phenobarbital (100 mg), Dilantin (100 mg), Mesantoin (100 rag), Mysoline (16 mg) and Diamox (250 mg). Some of the patients were also receiving tranquilizers such as Trilafon (4 rag), Compazine (50 rag) and Thorazine (100 mg). This maintenance medication was not altered during the study. The medications were all given on a T.I.D. basis except Diamox which was administered B.I.D. The diagnostic categories and the routine EEG's 1 This study was made possible by research grant No. My-2844 from the National Advisory Mental Health Council, National Institutes of Health, U.S. Public Health Service, and administered by Friends of Psychiatric Research, Inc., Spring Grove State Hospital, Baltimore, Maryland.
Most of the patients experienced some very transient discomfort accompanying the injections. This was described as a burning pain radiating up the arm. In those patients in whom a subclinical seizure was precipitated a subjective feeling of movement was experienced in the lower extremities. Out of a total of 71 records obtained, 52 displayed abnormalities as tabulated during the resting pre-lndoklon phase. Of these 52 records, 24 showed changes following the administration of Indoklon. Of nineteen resting normal pre-lndoklon records only two displayed a change. The types of abnormalities produced were: (a) paroxysms of generalized 3~/sec spike-dome (Fig. 1) (patients 1, 4, 6, 12 and 18); (b) multiple focal spikes (patient 18); (e) accentuation of the spontaneous abnormalities by an increase in voltage of generalized theta range activity and increase in the number of spike discharges (patients 2, 4, 7, 10~ 13, 19 and 20). Wherever activation occurred this appeared within 3 min after the injection had been given. A group of patients with abnormal resting records (patients 4, 10, 13 and 19) consistently exhibited significant actiw~tions whereas a second group of patients (5, 17, 25) with persistent abnormal records constantly exhibited refractoriness to attempted activation. These two groups of patients were compared from the standpoint of etiology, clinical pattern of seizures, treatment, age, sex, present neurological and physical examinations and no differences were found. This would seem to imply that different mechanisms were being affected.
781
782
A. A. KURLAND, E. DELAMONICA AND C. MARSHALL TABLE I A c o m p a r a t i v e t a b u l a t i o n o f the I n d o k l o n activations 1st Testing
2nd Testing
3rd Testing
Diagnosis
°~ C h r o n i c brain s y n d r o m e associated with convulsive disorder (grand real seizures)
C E F
Ab(l) Ab(2) N Ab(l) Ab(l) Ab(l) Ab(5) N
~ -~-+ + --
Ab Ab N Ab Ab Ab Ab N
Ab(1) Ab(2) Ab(1) Ab(7) Ab(1) Ab(1)
C B E B E B, F B
? Ab(3) Ab(1) Ab(1) Ab(l) N Ab(3)
__ + -+ ----
? Ab N Ab Ab N Ab
N Ab(l) Ab(1) Ab(1)
---k +
I 2 3 4 5 6 7 8
34 48 33 56 34 35 50 30
A, A, A, A, A, A, A, A,
B, B, B, B, B B, C, B,
C h r o n i c brain s y n d r o m e associated 9 with convulsive disorder (grand m a l 10 seizures) a n d psychotic reaction ll 12 13 14 15
53 35 48 53 20 29 43
B, A, C, A, A, A, A,
Mental defective with convulsive 16 disorder (grand m a l seizures) 17 18 19
38 50 51 32
A,C,D,G A, E A, B C, H
Miscellaneous: G r a n d m a l seiz. with mental deficiency a n d left hemiparesis Organic brain syn. with g r a n d m a l seiz. a n d m e n t a l deficiency G r a n d mal seizures Psych. with g r a n d m a l seiz. CBS psych, react, g r a n d m a l seiz. a n d m e n t a l deficiency Psych. with syphilitic m e n i n g o encephalitis Schizophrenic react.
C C D C, E
---_ ---
Ab Ab Ab Ab Ab Ab
Ab(5) N
--
Ab N
Ab(l)
--
Ab
?
N
Ab(l)
--
Ab
9 Ab(3) N Ab(1) Ab(7) Ab(I) Ab(1)
-÷ --~ +* ---
? Ab N Ab Ab Ab Ab
Ab(l) Ab(3) Ab(3) Ab(I) Ab(7) Ab(l) Ab(4)
--
Ab Ab Ab Ab Ab Ab Ab
N Ab Ab Ab
N Ab(4) Ab(5) Ab(l)
--~ f
N Ab Ab Ab
N Ab(4) Ab(5) Ab(6)
-f t
N Ab Ab Ah
N
t ? ] !*
20
31 A, B
Ab(4)
-k
Ab
Ab(4)
--
Ab
21 22 23
39 A 31 A, B 48 A, E
Ab(2) N Ab(4)
----
Ab N Ab
Ab(1) N Ab(2)
----? --?
Ab N Ab
Ab(5) N Ab(2)
I~~
Ab N Ab
24
21 A, B, C
N
--
N
N
÷
N
N
-t ?
N
25 26
31 E 55 C, F
Ab(2) N
---
Ab N
Ab(2) N
---
Ab N
Ab(2)
--
Ab
D r u g s : A Phenobarbital, B - - D i l a n t i n , C D i a m o x , D - - M e s a n t o i n , E - - M y s o l i n e , F .Trilafon, G Compazine, H - - T h o r a z i n e . Abnormality: (1) Generalized slow activity (theta range). (6) Bursts of diffuse low voltage theta range activity a n d 14 a n d (2) Slow activity lateralized with t e m p o r a l s h a r p waves. 6 pattern. (3) T e m p o r a l s h a r p waves (without slow). (7) Generalized slow activity a n d spikes without consistent (4) Slow activity lateralized to o n e hemisphere. localization. (5) Spike focus. * Convulsive clinical seizure. ? A questionable p r e - l n d o k l o n record or questionable activation was counted as negative.
783
INDOKLON ACTIVATION Out of a total of 71 testings there was only one patient (13) who developed a clinical seizure, although there were 21 subclinical seizures brought about by the Indoklon administration. One patient (19) presented a very interesting finding: initially the patient's EEG was abnormal with a suggestion of a "14 and 6" pattern.
FPI- rl
A
EEG pathology when present without creating new abnormalities. The help of Dr. Robert E. Gardner, Superintendent of the Springfield State Hospital and Dr. Irene Hitchman, Clinical Director, is gratefully acknowledged in making
/3
T1-T3
'
T3-O1
02-T4
1"4- r2
F2-FP2
FP2-
FPI
V
,I
A
J~V h
--
Fig. 1 Patient 4, HK. Burst of diffuse spike dome pattern which was not present in the resting record. Subsequent testing with Indoklon activated the "14 and 6" pattern by increasing the voltage and percentage time visible. CONCLUSIONS In a small number of epileptics being maintained on anticonvulsant drugs, hexafluorodiethyl ether produced EEG activation predominantly in those with resting abnormal records of various categories as opposed to those with normal resting records. This compound demonstrated a capacity to produce EEG abnormalities within 3 rain where this occurred. The consistency of presence or absence of activation over repeated trials with certain cases appears worthy of follow up. Within this pilot study [ndoklon appears to clarify the underlying
available the patients of the Springfield Epileptic Colony for this study. The hexafluorodiethyl ether used in this clinical study was supplied as Indoklon by the Trubek Laboratories, Inc., of East Rutherford, New Jersey, through the courtesy of the Medical Research Foundation of Philadelphia, Inc., and the Ohio Clinical and Surgical Equipment Company. REFERENCES ESQUIBEL, A.,
KRANTZJR., J.C.,
TRUITT,E . G .
and
KURLAND,A. A. The use of hexafluorodiethyl ether (1ndoklon) as Psychiat., 1957, KRANTZ JR., J.C., A. S.C. and
an inhalant convulsant. Amer. J. 114: 461. ESQUIBEL,A., TRUITT, E.B., LING, KURLAND, A . A . Hexafluorodiethyl
784
A . A . KURLAND, E. DELAMONICA AND C. MARSHALL
ether (Indoklon)--an inhalant convulsant (its use in psychiatric treatment). J. Amer. med. Ass., 1958, 116: 1555-1562. KRANTZ JR., J. C., MANCHEY,L. L., TRUITT, E. B., LING, A. S.C. and KURLAND,A . A . The availability of hexafluorodiethyl ether by intravenous injection as a
convulsant in psychiatric treatment. J. herr. ment. Dis., 1959, 192: 92-94. KURLAND, A . A . , CUERVO,R. and KRANTZJR., J. C. The intravenous use of hexafluorodiethyl ether as a convulsant in psychiatric treatment. J. Ne,ropsychiat.. 1960, 1: 260-265.
Reference: KURLAND,A. A., DELAMONICA,E. and MARSHALL,C. A preliminary note of the effect of hexafluorodiethyl ether (Indoklon) on the electroencephalogram of the epileptic. Electroenceph. clin. Neurophysiol., 1961, 13:781-784.