E L E C T R O - O C U L O G R A P H I C STUDY O F C A L O R I C V E S T I B U L A R R E A C TIONS IN P A T I E N T S W I T H S E V E R E H E A D INJURIES. T. W. van Weerden, Th. C. A. M. van Woerkom, W. Mees and J. M. Minderhoud*. I. E l e c t r o - o c u l o g r a p h y as a m e t h o d to p r e d i c t o u t c o m e .
SUMMARY In this study electro-oculographic recordings were made after caloric vestibular stimulation (C.O.G.) in 42 patients with severe head-injuries. The curves with eyes open and the changes when eyes were closed were evaluated and scored. A correlation was found between the C.O.G. and the state of consciousness but only the degree of improvement of the C.O.G. showed a good correlation with the clinical improvement. The presence of a paradoxical response in patients with a prolonged coma was found to predict possibilities of further improvement. It was proposed that in the patients with a paradoxical response a rather diffuse biochemical dysfunction of the brain-stem was present, which could be influenced by treatment. In the second part of this study the results of the trials with a treatment with L-Dopa and physostigmine are given. It was found that patients in a vegetative state or in a state of prolonged coma could be stimulated width the therapy only when the paradoxical response had been present. L-Dopa and physostigmine respectively improved the m o t o r pattern and the contact activities.
INTRODUCTION
Studies of vestibulo-ocular responses in patients with altered consciousness may be helpful in establishing the degree of distributed consciousness (NATHANSON, BERGMAN and ANDERSON, 1957; NATHANSON and BERGMAN, 1958; BLEGVAD 1962). This method may also provide important information about the localisation of lesions of the brainstem (RODRIGUEZBARRIOS, BOTTINELLI and MEDOC,1966; VAERNET, 1 9 5 7 ; PLUM a n d POSNER, 1 9 6 6 ) . MINGRINO, MOLINARI, ANDRIOLO a n d FRU-
GONI (1965) and POULSEN and ZILSTORFF (1972) investigated vestibulo-ocular reactions induced by caloric stimulation in patients with a brain-injury. POULSEN and ZILSTORFF (1972) concluded that a prediction of the outcome could be made with the aid of this procedure which they performed in the first three days after the injury. MACCARIO, BACKMAN and KEREIN (1972) described the so-called paradoxical caloric reaction (P.C.R.) in which after closing of the eyes a decrease instead of an increase of the caloric vestibular reaction had been observed in patients with altered state of consciousness. This study was performed in our clinic as part of a more extensive investigation * D e p a r t m e n t of Neurology, University Hospital, Groningen, The Netherlands. Clin. Neurol. Neurosurg. 1975-1
42 concerning the prediction of outcome of severe head injured patients. In a considerable part of the patients a caloric oculogram (C.O.G.) was repeatedly recorded and especially the changes in the C.O.G. in the course of time were studied. It will be shown that the degree of improvement in the course of time enabled us to make an estimate of the prognosis of the patient.
Materials and methods In 42 patients, aged 4 to 62 years, admitted to our department because of a braininjury, oculographic examination after caloric vestibular stimulation was performed. Patients with lesions of the middle ear, as well as patients receiving sedatives were excluded from the investigation. The patients were classified according to their clinical state of consciousness at the moment the C.O.G. was made. The following classification was used: State 1 : clear, verbal contact can be achieved immediately; some desorientation and confusion may be present. State 2 : somnolent; contact can only be achieved after painful stimulation. If the patient is left alone he usually falls asleep. State 3 : subcoma, no contact can be achieved; only painful stimulation can lighten the level of consciousness (localising motor activity can often be elicited). State 4a: vegetative state, in which the patient has his eyes open most of the time and may seemingly be looking around without real fixation. Only weak abnormal activity or no motoractivity at all can be obtained by painful stimulation. State 4b: coma, even strong painful stimulation does not raise the level of deeply disturbed consciousness (only abnormal motor activity can be obtained). We also classified our patients according to the duration of coma or persistent vegatative state (state 4a and 4b). Four groups were used: a. in state 4 less than 5 days (20 patients) b. in state 4 more than 4 and less than 20 days (7 patients) c. in state 4 more than 19 and less than 70 days (12 patients) d. in state 4 more than 69 days (3 patients). For comparison 10 normal subjects, without any neurological, audiological or vestibular disturbances, aged 20 to 45 years, were included.
OculographicaI registration The horizontal component of the eye movement was recorded by two electrodes fixed lateral to the eyes. The recording was performed by using one channel of an
43 Offner 8-channel E.E.G. apparatus type T, adapted A.C. registration with long time constant. The registration was performed invariably with A.C. amplifying with a time constant of 10 seconds and a paper velocity of 15 mm p. sec.
Caloric stimulation During the caloric stimulation and the registration the patient was resting on his back with his head in 30 ° flexion. By means of otoscopy the auditory canal was inspected whether it was normal and clean and then 40 cc clean water of 20 ° C was injected into the auditory canal. The stimulation usually lasted 20 seconds. Then registrations were made with eyes open (e.o.) and with eyes closed (e.c.). The person was asked to open or close the eyes if he was able to do it himself. If not the examiner performed this manually avoiding hindrance to the eyemovements. If no nystagmus was observed with eyes closed, then at least once, during consecutive 30 seconds, recordings were made with closed eyes in a period of maximal intensity (50 to 100 seconds after the beginning of the stimulation). In several patients the influence of pain stimuli and in case of alert patients the influence of performing simple arithmetic during the registration was recorded.
Scoring C.O.G. The picture of the nystagmogram with eyes open and the changes when the eyes were closed were evaluated and scored. The changes after closing of the eyes were evaluated separately according to the intensity (velocity of the slow phase) and changes in form of the curve. As far as the form of the nystagmogram is concerned special attention was paid to the quick phase. Abnormal rounded off curves could be found because of retarded acceleration and deceleration. Also the steepness (speed) of the quick phase got special attention. The picture with eyes open was scored on a six-point scale as follows: 0. normally shaped nystagmus (or no nystagmus but a good nystagmus after closing of the eyes). 1. normal and some abnormally shaped nystagmus beats. 2. mostly abnormal nystagmus beats. 3. dominating of slow phases combined with a few, usually considerably abnormal quick phases. 4. slow deviation only. 5. no response. The changes of the C.O.G. after closing of the eyes was scored on a fourpoint scale: 0. normal: improvement of the nystagmus. 1. questionable or no decrease of intensity with or without dubious to slight increase of abnormally shaped recordings.
44 2. paradoxical response: decrease of intensity and/or obvious increase of abnormal shapes. 3. pronounced paradoxical response: considerable decrease of intensity combined with obvious increase of abnormal shapes. This score was combined with the C.O.G. score with eyes open to a general C.O.G. score (Table I).
C.O.G. score with o9 c O (/)
0
open
eyes
2
3
4
5
2
5
7
8
9
3
5
m
._o X O "O
0
0
O (D G)
2
3
4
6
3
4
5
6
O
TABLE I General C.O.G. score made by combination of the C.O.G. score with eyes open and the score of C.O.G. changes after closing of the eyes (total score of the paradoxical response).
In this general score the abnormalities of the C.O.G. with eyes open were considered as the most important factor. Especially in the normal or nearly normal C.O.G. scoring with eyes open, slight differences in the scoring were inserted because of the paradoxical responses. In case the scoring of the C.O.G. with eyes open was more than 2, closing of the eyes could not worsen the curve.
RESULTS
Normal persons
All 10 normal persons showed a vivid nystagmus after caloric vestibular stimula-
45 tion with closed eyes. After opening of the eyes the intensity of the nystagmus decreased considerably in all cases or disappeared entirely (fig. l a and b). If present the nystagmus with eyes open showed a normal shape and appeared to be of low
a
ec
eo
ec
b
eo
ec
eo ec Fig. 1. C.O.G. in three normal subjects, eo: eyes open; ec: eyes closed. a and b: recording of horizontal movements; c: recordings of horizontal and vertical movements in a normal person who showed a shortlasting inhibition of the nystagmus after closing
of the eyes.
intensity. With eyes closed also normal sharp curves were recorded. Only a few deviating nystagmus beats were observed in three subjects when the nystagmus had a low intensity at the end of the response. In one case the nystagmus disappeared in the C.O.G. immediately after closing of the eyes but reappeared after a few seconds with a higher intensity than previously had been present with open eyes. The quick phase of the first reappearing nystagmus beats were often rather slow. Such 'inhibitions' of the nystagmus directly after closing of the eyes and the reappearing a few seconds later were also observed in some of the patients. The occurrence of this phenomenon was regularly observed in certain individuals, whereas it was never seen in other subjects. In the relevant normal person, showing this phenomenon the vertical component of the eye movements was also registered with D. C. amplifying. The reappearing of the horizontal vestibular nystagmus after closing of the eyes appeared to have no relation with the vertical change of position of the eye (fig. lc). These shortlasting inhibitions after closing of the eyes were always interpreted as a normal variety.
46 PATIENTS
Most patients showed an abnormal C.O.G. (Fig. 2). As far as their response with eyes open is concerned, the abnormalities may be classified according to their degree as follows: no response at all; only slow deviation of the eyes and abnormal nystagmus. a
b ec
c •. ,
~
ec
4~ ~
eo
\ l..~L/l'\._..l"~ fl"q J~--~v'~.eo
e x........., ,,,r-.,..r~r'x~.,.r,r'x,. ~ ~
,.-~--------.-'-"/~'--.,.,-~ . . . . .
ec
1'
f
"\,,.r,,-r'-'-~
t ~...~_~.]~ a,
ec
t'
Fig. 2. C.O.G. in six different patients, co: eyes open; ec: eyes closed. ~ : pain stimulus.
No response at all was only seen in a few deep comatose patients in the first days after the injury. The abnormal nystagmus was more irregular than in normal persons. There was a considerable changing of frequencies and amplitudes. The most spectacular, however, were the changes of quick phases, which were slower than normally and might even be slower than the slow phases. At the same time the acceleration and particularly the deceleration of the quick phase elapsed slower most of the time, which lead to the forming of rounded off shapes. These abnormal shapes occurred more frequently when the intensity of the nystagmus had decreased. Next to the mentioned abnormalities of the quick phase of the nystagmus we sometimes observed disturbances of the slow phase, disturbances in the se-
47 quences of the slow and quick phase, dysmetric quick phases or an uninhibited very rough nystagmus. These disturbances proved to be very personal. They only occurred in some patients during certain periods and seemed to indicate local lesions of the brain stem. We intend to discuss these phenomena in another paper in the near future. After closing the eyes a deterioration of the nystagmus was often observed. This so-called paradoxical caloric response, showed itself as a decreased intensity (decreasing velocity of the slow phase) and/or in more abnormalities of the shape (slower quick phases, more rounded off shapes). We also often observed the nystagmus turning more irregular and adapting a lower frequency. If the C.O.G. with open eyes was already abnormal (score 3, 4 and 5) no further deterioration could be registered after closing of the eyes. Not all patients, however, showed a deterioration of the C.O.G, after closing of the eyes, even if already a fairly normal nystagmus was present with open eyes. This was also the case in some comatose patients in which the curve usually remained the same. An increase of the intensity of the nystagmus, as was normally observed after closing of the eyes, was only seen in clinically alert patients. In some clinically alert patients a paradoxical response could be observed even when a normal picture was present with eyes open. This paradoxical response often concerned only the shape of the curve. Occasionally also the intensity of the reponse decreased. In these cases usually an obvious improvement could be observed during the performance of simple arithmetic by the patients. However, in some cases the abnormalities of the shape failed to disappear. In patients showing a paradoxical response or an obvious abnormal nystagmus with open eyes an improvement of the nystagmus could often be obtained by means of a pain stimulus e.g. by pinching the upper-arm (Fig. 2e, and f). The duration of this improvement varies from a few seconds to a few decades of seconds. Patients with severely disturbed consciousness often showed an improvement which lasted shorter than in those patients with a less disturbed state of consciousness. In these recordings, spontaneous fluctuations of the arousal level can be presumed. However, repeated examinations in these patients within a short period of time, practically always showed analogous pictures with the same scoring. Therefore it was presumed that spontaneous fluctuations of the arousal level did not influence the results. C.O.G. and disturbed consciousness
The C.O.G.'s were scored according to the method described previously and this score was related with the clinical state of consciousness (fig. 3). It appears that the C.O.G. has a positive relation to the degree of unconsciousness in the first 19 days after the brain injury (fig. 3a). From the recordings made after the 19th day this appears not to be so evident. In the patients with a long duration of the
48 cog.
cQg.
8
8
z
z
6
6
5
s
4
4 1
7,
2
~
% "" Z
Fig. 3. Relation C.O.G. and clinical condition. A: recording in the first nineteen post-traumatic days in patients who were in state 4 (comatose) less than 20 days. B: recording after nineteen post-traumatic days in patients who were in state 4 (coma or vegetative days. state) fOr mOre than twenty
L~ Z
c.l.: clear (state 1);
77 Z
%
Z Z
% ~½
% ~"" ~,
2
'
~
0
' .....
el
~
o
s
vs
sc
c
"
' ~" cl
s
~
~5
consciousness s: soporous
(state 2); v.s.: vegetative
~ " "~" ' ~zs sc
state (state 4a); s.c.: subcomatose (state 3); c: comatose (state 4b).
e
coma (more than 19 days; fig. 3b) we only observed a marked improvement of the C.O.G. when the patients had achieved a clear consciousness. The C.O.G. also appears to improve in the course of time independently of the clinical state of consciousness. Fig. 4 shows this spontaneous improvement of the C.O.G. in the course of time in comatose patients. The average C.O.G. scores continuously decrease in the course of time until a fairly constant level is reached after about 40 days.
COG 8
7
°0
--0"--
• state IV < 5 d ostate IV/> 5 - < 2 0 d estate IV I> 20d
o
6 5
~Q---
4
3 2 1
5
10
15
20
30
40
50
60
70
>
days after t r a u m a
Fig. 4. Relation between the C.O.G. and the time after the injury in comatose patients (state 4).
49 The average values for the separate groups were on the same level in the first days after the trauma. Therefore a single C.O.G. especially when made in the first days after the trauma cannot predict the duration of unconsciousness.
The changes of the C.O.G. in the course of time for individual patients In 20 patients two or more C.O.G.'s were made. If we plot this C.O.G. score against the time it nearly always appears that a practically straight line can be drawn. By producing this line to the zero line, the point of intersection (p) was determined. That is the day at which the C.O.G. theoretically may be expected to be normal (fig. 5A). This point of intersection, representing a measure for the degree of improvement, shows a clear correlation with the total duration of coma and 'vegetative state' (state 4a and b; fig. 5B). In 3 patients with a period of unconsciousness of more than 70 days hardly any improvement in the C.O.G. could be observed. A point of intersection could not be determined in these cases. days o f s t a t e IV
3 oatients
80
p > 200
70 e,
60
e
",
•
g
50 I0
20
p
40 30 oo
20
•e
oo
10
o
o| i
10
• i
I
I
I
i
i
20
30
40
~
60
70
i
80
I
i
90
I00
p
Fig. 5. Relation between the improvement of the C.O.G. and the duration of coma or vegetative state (state 4) in twenty patients. A: way of scoring p. B: relation between p. and duration of state 4. See text.
The paradoxical response in patients with longlasting periods of unconsciousness Patients unconscious for more than three weeks can gradually get into a clinical condition of a vegetative state. Also the C.O.G. inclines to be stabilized (scoring between 3 and 5; fig. 4). However, some of these patients were found to regain consciousness afterwards. Looking at the paradoxical response alone, a difference was found between the patients who regained consciousness afterwards (before the 70th day) and those who persisted in a comatose or vegetative state (fig. 6). Both groups have the same mean score of the paradoxical response before the 20th day (while being in coma). However, the first group still has a pronounced paradoxical response afterwards, while the second group does not show this difference between eyes open and closed. So the presence of a paradoxical response during prolonged coma can predict the possibility of improvement.
50 p.F.
_
77 IJ
_
lJ lJ lJ lJ II lJ i
i
ii 71 lJ
I -
7/ //
77 I/ i
/
II II II ii i i
0
// // // // // // // // /./i
II
II
C
V.S.
cl
Fig. 6. Paradoxical responses (p. r.) in patients comatose for more than 19 days. Hatched: those who stayed in state 4 (coma or p.v.s.) for more than 70 days; open: those who regained clear consciousness before the 70th posttraumatic day.
DISCUSSION
Changes of the calorically induced vestibulo-ocular response (C.V.O.R.) in states of changed consciousness have been described by several authors. Along with an increasing degree of disturbed consciousness the following reactions have been observed successively: nystagmus, only a slow deviation of the eyes; slow dissociated eye movements in which the adducted eye usually remained behind; and finally, no response at all (NATHANSON et al., 1957; BLEGVAD, 1962; MINGRINO et al., 1965; RODRIOUEZBAgRIOS et al., 1966; POULSEN and ZILSTORFF, 1972). Changes in the form of the nystagmus caused by decreasing velocity and slowing off of the acceleration and deceleration of the quick phase of the nystagmus are observed in animals and in man in a state of drowsiness (GOTO, TOKUMARU and COHEN, 1968; SUZUKI, 1969; MELVILLE JONES and SU6IE, 1972). So the changes in the C.V.O.R. found in our patients are in accordance with the data found by oth-
51 ers in man and animals with disturbances of consciousness or a decreased level of arousal. A general scale of the C.O.G., in which the scoring of the shape and the intensity of the nystagmus with open eyes as well as the changes occurring when the eyes were closed, were included, was found to be useful. It appears from our investigation that in head-injured patients the degree of improvement of the C.O.G. provides a possibility to predict the duration of unconsciousness. It can supply information in addition to other criteria, as for example the state of consciousness. POULSEN and ZmSTORFF (1972) found an obvious relation between a C.O.G. made in the first three days after the injury and the ultimate prognosis of the patient. They did not make a difference between the various degrees of unconsciousness in their patients. While a correlation between the state of unconsciousness and the C.O.G. in the first 2 weeks was found and also a rough correlatoin of the depth of initial unconsciousness and the duration of unconsciousness was found by us before (MINOERHOUDet al. 1974) their results are comprehensible. These authors found in the group of patients they examined, four cases not at all responding to caloric stimulation, to have a very bad prognosis. In fact all four died. In some of our patients we also found no response in the first few days after the injury. Out of these patients several regained consciousness after some time and recovered. In our study special attention was paid to the changes of the vestibular response when eyes are closed. In normal persons a so-called inhibition of the nystagmus was sometimes observed by other authors during C.O.G. examination with closed eyes. This inhibition started some time after closing of the eyes, while in the first short period the nystagmus increased normally. The effect of the inhibition is usually described as an irregular course of the nystagmus with a decreased intensity. Most of the time it is of short duration and it can be opposed by asking the patient to perform arithmetic (GILLINGHAM,1968). With our procedure we did not see this kind of inhibition, which is probably due to the activating influences of regular opening and closing of the eyes. An other kind of inhibition was observed in some of our patients and in one of the normal controls. In these cases we observed a short-lived inhibition of the nystagmus directly after closing of the eyes. Also RASHBASS and RUSSELL(1961) reported about this phenomenon. It seems to be an individual phenomenon, i.e. that it has always been observed in certain individuals, whereas it was never seen in others. TJERNSTROM (1973) found an inhibiting influence on the vestibular nystagmus, when the eyeballs were turned upwards. We controlled this in one normal person, but in this case no influence of the vertical eyemovements on the nystagmus were found. For the evaluation of the C.O.G. it is important to be aware of this kind of inhibition. Recording has to be sustained for a sufficiently long period, in case the nystagmus happens to disappear directly after closing the eyes. This is important because it is necessary to differentiate these, probably normal, short-lived inhibitions from the inhibitions only observed in patients. Especially in patients with a prolonged coma the question arises whether they
52 will stay in a coma or persistent vegetative state or regain consciousness within a reasonable time. Although the degree of improvement of the C.O.G. can provide this information, especially the paradoxical response can give answers to this question. Twelve of these patients in which a paradoxical response was found regained consciousness and three of these patients without a paradoxical response did not regain consciousness for a much longer time or not at all. From investigations performed by DONSING and SCHAFER (1957a and b) and POMPEIANO (1972) in the rabbit and in the cat, it seems likely that the activity of the vesitbular nystagmus is highly determined by the activity of the pontine reticular formation. DUNSING and SCH~FER (1957b) showed reciprocal influence of the vestibular neurons and pontine reticular formation, which proves that the vestibular neurons have a stimulating influence on the reticular formation, which on their turn stimulate vestibular neurons. The activating influence of pain stimuli and cortical influences on the reticular formation have been described repeatedly (see survey by ROSSI, 1965, and PLUM and POSNER, 1966). The activating influence of light stimuli especially on the mesencephalic reticular formation in rats has been found (GROVES, 1973). By means of stimulating experiments, YULES, KREBS and GAULT showed in 1966 that the mesencephalic reticular formation in the cat had an obvious influence on the vestibular nystagmus. The improvement of the vestibular nystagmus in our patients after pain stimuli and opening of the eyes (light stimuli), as well as the occurrence of the least abnormal nystagmus at the highest point of the C.V.O.R. may therefore be explained by an increased level of arousal resulting in activation of the pontine reticular formation. The paradoxical response can partly be explained in this way. Moreover there seems to be an absence of the normal optokinetic inhibition of the vestibular nystagmus. In all our normal persons optokinetic suppression of the nystagmus was found after opening of the eyes. In patients it was only observed after regaining a clinically alert state of consciousness. RASHBASSand RUSSELL (1961) were able to suppress these optokinetic influences without changing the vestibular nystagmus recorded with closed eyes in humans by administering amylobarbitone sodium. We observed optokinetic inhibition in some clinically alert patients, whereas a shortlived abnormal nystagmus could be seen directly after closing of the eyes, which indicated a non-optimal level of arousal. The optokinetic suppression and the vestibulo-ocular reaction itself therefore seem to be partly separate systems which can be disturbed independently. These optokinetic influences in human subjects will probably be of cortical origin (JUNG and KORNHUBER, 1946). This corresponds with our finding: we only observed this phenomenon in clinically alert patients. So the paradoxical caloric response may be explained by failing of the normal optokinetic suppression with eyes open and a lowered vestibular arousal system. The latter can be stimulated by light stimuli (opening of the eyes), as well as by pain stimuli resulting in an improvement of the C.V.O.R. HACISKA (1973) claims
53 that this activating effect is caused by an attempt to fixate, which seems to be improbable because this paradoxical response has also been observed in comatose patients. According to ROSSI (1965) and PLUM and POSNER (1966) the disturbances of consciousness can be related to disturbances in the so-called A.R.A.S. system, situated in the median part of the reticular formation rostrally of the pons. The relationship between C.O.G. and consciousness found in this study can be explained by the fact that both depend on the state of tonical activation of the reticular formation. On the other hand, in several patients an obvious discrepancy existed between the C.O.G. and the state of consciousness. Especially in a period several days after the injury the C.O.G. had improved spontaneously without change of the state of consciousness. This can be explained by the fact that consciousness is mainly influenced by the rostral part of the reticular formation and the vestibulo-ocular response mainly by the pontine part. In most of our patients the results can correspond with a general inhibition of the reticular formation, indicating a diffuse disturbance of the arousal system. In comatose patients the outcome seemed to depend on the presence of the paradoxical response. It can be presumed that in the comatose patients with a paradoxical response only a diffuse disturbance of the arousal system was present. Light stimuli influencing especially in the rostral part of the reticular formation still could influence also the pontine and vestibular areas pointing to the fact that anatomical connections are present. In patients without a paradoxical response more localised, anatomical lesions could be present, preventing light stimuli to activate pontine areas. The proposal that only diffuse disturbances of the arousal system should cause the clinical state of consciousness and the C.O.G. seems to be in agreement wit~ the findings of MITCHELL and HUME ADAMS (1973). They seldom observed local lesions in the brainstem of patients who had died after an injury, when no raised intracranial pressure or herniation had been present. The results on the C.O.G. in head-injured patients resemble those found by NATHANSON et al. (1957) in patients with a barbiturate poisoning. It can be proposed that the diffuse disturbances of the brainstem in head-injured patients are not only caused by diffuse loss of cells but also biochemical disturbances. Therefore it is presumable that this dysfunction can be influenced by treatment.
H. Influence of neurotransmitting agents on the electro-oculogram and the clinical state.
INTRODUCTION
Biochemical investigations in our patients have shown decreased levels of homovanillic acid in the cerebrospinal fluid, especially in patients with prolonged dis-
54 turbances of consciousness (LAKKE, KORF, VAN PRAAG, MINDERHOUD and SCHUT, 1973; VECHT, VAN WOERKOM and MINDERHOUD, 1974). L-Dopa appeared to have an arousal effect in cats with brainstem lesions (KADZIELAWA and WIDY-WYSKIEWlCZ, 1969). Also arousal effects in humans were found by HORVATH and MEARES 1974). Therefore some patients, who had been unconscious for more than three weeks were treated with L-Dopa. Also the effect of an other agent, physostigmine, was examined. The result of this treatment with respect to the changes in the clinical state of the patients and the alterations of the C.O.G. will be discussed.
MATERIALS AND METHODS
Eight patients were included in this series. The classification of the clinical state of consciousness and the way of scoring of the C.O.G. were the same as described in Part I. All the patients were in a vegetative state (V.S.) for at least one week. No changes in the clinical condition were observed for at least the last week before treatment was started. Treatment was done by Madopar (L-Dopa combined with decarboxylase inhibitor). The dose was raised to 1000 mg. daily in four or five days. One or two weeks later all these patients were also given 1 mgr. physostigmine salicylate intravenously and some of them were treated afterwards with three doses of 1 rag. physostigmine i.m. daily. A C.O.G. was made in each patient before and during the L-Dopa therapy and before and 20 min. after the administration of physostigmine salicylate intravenously. Special attention was paid to the paradoxical response in the C.O.G. One patient was given neostigmine bromide 2 mg. intravenously (before the physostigmine salicylate) and in two patients 0.5 mg. atropine sulfate intramuscular was used some days before installation of physostigmine was started. RESULTS L-DOPA
In five patients an improvement of the clinical condition could be observed, especially with respect to their motor pattern. Where akinesis or just flexor movements were present before, localising and voluntary movements started. This improvement already could be observed at the end of the first week of treatment. In one patient this treatment was discontinued two weeks later, which caused a decrease of volontary movements. When treatment was started again voluntary movements soon reappeared. In four patients the treatment was continued for at least six weeks. In three of them the treatment was discontinued shortly after the sixth week, without worsening influences on the motor pattern. A correlation was found between the presence of a paradoxical response before this treatment was started and the positive results (fig. 7). In three patients who did not demonstrate a paradoxical response no improvement of the clinical state
55 C.OG 8
7 6
!!
5 4
3 2-
+ +
14-
30
,i0
50
~0
7'0
80
Fig. 7. Changes of the C.O.G. caused by LDOPA treatment in patients in coma or vegetative state +: patients with a paradoxical response; -: patients without a paradoxical response; o: patients improving ~;0£]ays after trauma by therapy; a: patients not improving.
or of the C.O.G. could be obtained. No correlation was found in this group of patients between the general score of the C.O.G. before treatment and the influences on the clinical condition.
Physostigmine therapy The previously mentioned eight patients were also given 1 mg. physostigmine intravenously, one or two weeks after L-Dopa therapy had been adjusted. In the three patients who did not respond to treatment with L-Dopa, no clinical improvement could be observed. A spectacular improvement could be observed in two of the remaining five patients. These two patients who had previously been in a state of total mutism, started talking about five minutes after intravenous injection of physostigmine salicylate, and were able to answer simple questions. A third patient appeared to be able to express himself in writing one hour after the injection and st~irted to talk the next day. In the remaining patients the results were less clear; speech did not return, but it seemed that these patients were able to perform simple tasks. Later on both patients proved to be severely aphasic. The C.O.G. was made directly before and 10 to 20 minutes after the administering of physostigmine. The C.O.G. often improved clearly (fig. 8b), also in the group of patients who did not improve clinically. One patient who showed an improvement with physostogmine later on, was treated with Neostigmine bromide 2 mg. intravenously. Though cholinergic sideeffects were obvious, no improvement could be observed in the C.O.G. (fig. 8a and c). Two patients were given 0.5 mg atropine sulfate i.m.; it appeared that this re-
56 a
eo
ec
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SUMMARY In this study electro-oculographic recordings were made after caloric vestibular stimulation (C.O.G.) in 42 patients with severe head-injuries. The curves with eyes open and the changes when eyes were closed were evaluated and scored. A correlation was found between the C.O.G. and the state of consciousness but only the degree of improvement of the C.O.G. showed a good correlation with the clinical improvement. The presence of a paradoxical response in patients with a prolonged coma was found to predict possibilities of further improvement. It was proposed that in the patients with a paradoxical response a rather diffuse biochemical dysfunction of the brain-stem was present, which could be influenced by treatment. In the second part of this study the results of the trials with a treatment with L-Dopa and physostigmine are given. It was found that patients in a vegetative state or in a state of prolonged coma could be stimulated width the therapy only when the paradoxical response had been present. L-Dopa and physostigmine respectively improved the m o t o r pattern and the contact activities.
INTRODUCTION
Studies of vestibulo-ocular responses in patients with altered consciousness may be helpful in establishing the degree of distributed consciousness (NATHANSON, BERGMAN and ANDERSON, 1957; NATHANSON and BERGMAN, 1958; BLEGVAD 1962). This method may also provide important information about the localisation of lesions of the brainstem (RODRIGUEZBARRIOS, BOTTINELLI and MEDOC,1966; VAERNET, 1 9 5 7 ; PLUM a n d POSNER, 1 9 6 6 ) . MINGRINO, MOLINARI, ANDRIOLO a n d FRU-
GONI (1965) and POULSEN and ZILSTORFF (1972) investigated vestibulo-ocular reactions induced by caloric stimulation in patients with a brain-injury. POULSEN and ZILSTORFF (1972) concluded that a prediction of the outcome could be made with the aid of this procedure which they performed in the first three days after the injury. MACCARIO, BACKMAN and KEREIN (1972) described the so-called paradoxical caloric reaction (P.C.R.) in which after closing of the eyes a decrease instead of an increase of the caloric vestibular reaction had been observed in patients with altered state of consciousness. This study was performed in our clinic as part of a more extensive investigation * D e p a r t m e n t of Neurology, University Hospital, Groningen, The Netherlands. Clin. Neurol. Neurosurg. 1975-1
42 concerning the prediction of outcome of severe head injured patients. In a considerable part of the patients a caloric oculogram (C.O.G.) was repeatedly recorded and especially the changes in the C.O.G. in the course of time were studied. It will be shown that the degree of improvement in the course of time enabled us to make an estimate of the prognosis of the patient.
Materials and methods In 42 patients, aged 4 to 62 years, admitted to our department because of a braininjury, oculographic examination after caloric vestibular stimulation was performed. Patients with lesions of the middle ear, as well as patients receiving sedatives were excluded from the investigation. The patients were classified according to their clinical state of consciousness at the moment the C.O.G. was made. The following classification was used: State 1 : clear, verbal contact can be achieved immediately; some desorientation and confusion may be present. State 2 : somnolent; contact can only be achieved after painful stimulation. If the patient is left alone he usually falls asleep. State 3 : subcoma, no contact can be achieved; only painful stimulation can lighten the level of consciousness (localising motor activity can often be elicited). State 4a: vegetative state, in which the patient has his eyes open most of the time and may seemingly be looking around without real fixation. Only weak abnormal activity or no motoractivity at all can be obtained by painful stimulation. State 4b: coma, even strong painful stimulation does not raise the level of deeply disturbed consciousness (only abnormal motor activity can be obtained). We also classified our patients according to the duration of coma or persistent vegatative state (state 4a and 4b). Four groups were used: a. in state 4 less than 5 days (20 patients) b. in state 4 more than 4 and less than 20 days (7 patients) c. in state 4 more than 19 and less than 70 days (12 patients) d. in state 4 more than 69 days (3 patients). For comparison 10 normal subjects, without any neurological, audiological or vestibular disturbances, aged 20 to 45 years, were included.
OculographicaI registration The horizontal component of the eye movement was recorded by two electrodes fixed lateral to the eyes. The recording was performed by using one channel of an
43 Offner 8-channel E.E.G. apparatus type T, adapted A.C. registration with long time constant. The registration was performed invariably with A.C. amplifying with a time constant of 10 seconds and a paper velocity of 15 mm p. sec.
Caloric stimulation During the caloric stimulation and the registration the patient was resting on his back with his head in 30 ° flexion. By means of otoscopy the auditory canal was inspected whether it was normal and clean and then 40 cc clean water of 20 ° C was injected into the auditory canal. The stimulation usually lasted 20 seconds. Then registrations were made with eyes open (e.o.) and with eyes closed (e.c.). The person was asked to open or close the eyes if he was able to do it himself. If not the examiner performed this manually avoiding hindrance to the eyemovements. If no nystagmus was observed with eyes closed, then at least once, during consecutive 30 seconds, recordings were made with closed eyes in a period of maximal intensity (50 to 100 seconds after the beginning of the stimulation). In several patients the influence of pain stimuli and in case of alert patients the influence of performing simple arithmetic during the registration was recorded.
Scoring C.O.G. The picture of the nystagmogram with eyes open and the changes when the eyes were closed were evaluated and scored. The changes after closing of the eyes were evaluated separately according to the intensity (velocity of the slow phase) and changes in form of the curve. As far as the form of the nystagmogram is concerned special attention was paid to the quick phase. Abnormal rounded off curves could be found because of retarded acceleration and deceleration. Also the steepness (speed) of the quick phase got special attention. The picture with eyes open was scored on a six-point scale as follows: 0. normally shaped nystagmus (or no nystagmus but a good nystagmus after closing of the eyes). 1. normal and some abnormally shaped nystagmus beats. 2. mostly abnormal nystagmus beats. 3. dominating of slow phases combined with a few, usually considerably abnormal quick phases. 4. slow deviation only. 5. no response. The changes of the C.O.G. after closing of the eyes was scored on a fourpoint scale: 0. normal: improvement of the nystagmus. 1. questionable or no decrease of intensity with or without dubious to slight increase of abnormally shaped recordings.
44 2. paradoxical response: decrease of intensity and/or obvious increase of abnormal shapes. 3. pronounced paradoxical response: considerable decrease of intensity combined with obvious increase of abnormal shapes. This score was combined with the C.O.G. score with eyes open to a general C.O.G. score (Table I).
C.O.G. score with o9 c O (/)
0
open
eyes
2
3
4
5
2
5
7
8
9
3
5
m
._o X O "O
0
0
O (D G)
2
3
4
6
3
4
5
6
O
TABLE I General C.O.G. score made by combination of the C.O.G. score with eyes open and the score of C.O.G. changes after closing of the eyes (total score of the paradoxical response).
In this general score the abnormalities of the C.O.G. with eyes open were considered as the most important factor. Especially in the normal or nearly normal C.O.G. scoring with eyes open, slight differences in the scoring were inserted because of the paradoxical responses. In case the scoring of the C.O.G. with eyes open was more than 2, closing of the eyes could not worsen the curve.
RESULTS
Normal persons
All 10 normal persons showed a vivid nystagmus after caloric vestibular stimula-
45 tion with closed eyes. After opening of the eyes the intensity of the nystagmus decreased considerably in all cases or disappeared entirely (fig. l a and b). If present the nystagmus with eyes open showed a normal shape and appeared to be of low
a
ec
eo
ec
b
eo
ec
eo ec Fig. 1. C.O.G. in three normal subjects, eo: eyes open; ec: eyes closed. a and b: recording of horizontal movements; c: recordings of horizontal and vertical movements in a normal person who showed a shortlasting inhibition of the nystagmus after closing
of the eyes.
intensity. With eyes closed also normal sharp curves were recorded. Only a few deviating nystagmus beats were observed in three subjects when the nystagmus had a low intensity at the end of the response. In one case the nystagmus disappeared in the C.O.G. immediately after closing of the eyes but reappeared after a few seconds with a higher intensity than previously had been present with open eyes. The quick phase of the first reappearing nystagmus beats were often rather slow. Such 'inhibitions' of the nystagmus directly after closing of the eyes and the reappearing a few seconds later were also observed in some of the patients. The occurrence of this phenomenon was regularly observed in certain individuals, whereas it was never seen in other subjects. In the relevant normal person, showing this phenomenon the vertical component of the eye movements was also registered with D. C. amplifying. The reappearing of the horizontal vestibular nystagmus after closing of the eyes appeared to have no relation with the vertical change of position of the eye (fig. lc). These shortlasting inhibitions after closing of the eyes were always interpreted as a normal variety.
46 PATIENTS
Most patients showed an abnormal C.O.G. (Fig. 2). As far as their response with eyes open is concerned, the abnormalities may be classified according to their degree as follows: no response at all; only slow deviation of the eyes and abnormal nystagmus. a
b ec
c •. ,
~
ec
4~ ~
eo
\ l..~L/l'\._..l"~ fl"q J~--~v'~.eo
e x........., ,,,r-.,..r~r'x~.,.r,r'x,. ~ ~
,.-~--------.-'-"/~'--.,.,-~ . . . . .
ec
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f
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t ~...~_~.]~ a,
ec
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Fig. 2. C.O.G. in six different patients, co: eyes open; ec: eyes closed. ~ : pain stimulus.
No response at all was only seen in a few deep comatose patients in the first days after the injury. The abnormal nystagmus was more irregular than in normal persons. There was a considerable changing of frequencies and amplitudes. The most spectacular, however, were the changes of quick phases, which were slower than normally and might even be slower than the slow phases. At the same time the acceleration and particularly the deceleration of the quick phase elapsed slower most of the time, which lead to the forming of rounded off shapes. These abnormal shapes occurred more frequently when the intensity of the nystagmus had decreased. Next to the mentioned abnormalities of the quick phase of the nystagmus we sometimes observed disturbances of the slow phase, disturbances in the se-
47 quences of the slow and quick phase, dysmetric quick phases or an uninhibited very rough nystagmus. These disturbances proved to be very personal. They only occurred in some patients during certain periods and seemed to indicate local lesions of the brain stem. We intend to discuss these phenomena in another paper in the near future. After closing the eyes a deterioration of the nystagmus was often observed. This so-called paradoxical caloric response, showed itself as a decreased intensity (decreasing velocity of the slow phase) and/or in more abnormalities of the shape (slower quick phases, more rounded off shapes). We also often observed the nystagmus turning more irregular and adapting a lower frequency. If the C.O.G. with open eyes was already abnormal (score 3, 4 and 5) no further deterioration could be registered after closing of the eyes. Not all patients, however, showed a deterioration of the C.O.G, after closing of the eyes, even if already a fairly normal nystagmus was present with open eyes. This was also the case in some comatose patients in which the curve usually remained the same. An increase of the intensity of the nystagmus, as was normally observed after closing of the eyes, was only seen in clinically alert patients. In some clinically alert patients a paradoxical response could be observed even when a normal picture was present with eyes open. This paradoxical response often concerned only the shape of the curve. Occasionally also the intensity of the reponse decreased. In these cases usually an obvious improvement could be observed during the performance of simple arithmetic by the patients. However, in some cases the abnormalities of the shape failed to disappear. In patients showing a paradoxical response or an obvious abnormal nystagmus with open eyes an improvement of the nystagmus could often be obtained by means of a pain stimulus e.g. by pinching the upper-arm (Fig. 2e, and f). The duration of this improvement varies from a few seconds to a few decades of seconds. Patients with severely disturbed consciousness often showed an improvement which lasted shorter than in those patients with a less disturbed state of consciousness. In these recordings, spontaneous fluctuations of the arousal level can be presumed. However, repeated examinations in these patients within a short period of time, practically always showed analogous pictures with the same scoring. Therefore it was presumed that spontaneous fluctuations of the arousal level did not influence the results. C.O.G. and disturbed consciousness
The C.O.G.'s were scored according to the method described previously and this score was related with the clinical state of consciousness (fig. 3). It appears that the C.O.G. has a positive relation to the degree of unconsciousness in the first 19 days after the brain injury (fig. 3a). From the recordings made after the 19th day this appears not to be so evident. In the patients with a long duration of the
48 cog.
cQg.
8
8
z
z
6
6
5
s
4
4 1
7,
2
~
% "" Z
Fig. 3. Relation C.O.G. and clinical condition. A: recording in the first nineteen post-traumatic days in patients who were in state 4 (comatose) less than 20 days. B: recording after nineteen post-traumatic days in patients who were in state 4 (coma or vegetative days. state) fOr mOre than twenty
L~ Z
c.l.: clear (state 1);
77 Z
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~ " "~" ' ~zs sc
state (state 4a); s.c.: subcomatose (state 3); c: comatose (state 4b).
e
coma (more than 19 days; fig. 3b) we only observed a marked improvement of the C.O.G. when the patients had achieved a clear consciousness. The C.O.G. also appears to improve in the course of time independently of the clinical state of consciousness. Fig. 4 shows this spontaneous improvement of the C.O.G. in the course of time in comatose patients. The average C.O.G. scores continuously decrease in the course of time until a fairly constant level is reached after about 40 days.
COG 8
7
°0
--0"--
• state IV < 5 d ostate IV/> 5 - < 2 0 d estate IV I> 20d
o
6 5
~Q---
4
3 2 1
5
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15
20
30
40
50
60
70
>
days after t r a u m a
Fig. 4. Relation between the C.O.G. and the time after the injury in comatose patients (state 4).
49 The average values for the separate groups were on the same level in the first days after the trauma. Therefore a single C.O.G. especially when made in the first days after the trauma cannot predict the duration of unconsciousness.
The changes of the C.O.G. in the course of time for individual patients In 20 patients two or more C.O.G.'s were made. If we plot this C.O.G. score against the time it nearly always appears that a practically straight line can be drawn. By producing this line to the zero line, the point of intersection (p) was determined. That is the day at which the C.O.G. theoretically may be expected to be normal (fig. 5A). This point of intersection, representing a measure for the degree of improvement, shows a clear correlation with the total duration of coma and 'vegetative state' (state 4a and b; fig. 5B). In 3 patients with a period of unconsciousness of more than 70 days hardly any improvement in the C.O.G. could be observed. A point of intersection could not be determined in these cases. days o f s t a t e IV
3 oatients
80
p > 200
70 e,
60
e
",
•
g
50 I0
20
p
40 30 oo
20
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oo
10
o
o| i
10
• i
I
I
I
i
i
20
30
40
~
60
70
i
80
I
i
90
I00
p
Fig. 5. Relation between the improvement of the C.O.G. and the duration of coma or vegetative state (state 4) in twenty patients. A: way of scoring p. B: relation between p. and duration of state 4. See text.
The paradoxical response in patients with longlasting periods of unconsciousness Patients unconscious for more than three weeks can gradually get into a clinical condition of a vegetative state. Also the C.O.G. inclines to be stabilized (scoring between 3 and 5; fig. 4). However, some of these patients were found to regain consciousness afterwards. Looking at the paradoxical response alone, a difference was found between the patients who regained consciousness afterwards (before the 70th day) and those who persisted in a comatose or vegetative state (fig. 6). Both groups have the same mean score of the paradoxical response before the 20th day (while being in coma). However, the first group still has a pronounced paradoxical response afterwards, while the second group does not show this difference between eyes open and closed. So the presence of a paradoxical response during prolonged coma can predict the possibility of improvement.
50 p.F.
_
77 IJ
_
lJ lJ lJ lJ II lJ i
i
ii 71 lJ
I -
7/ //
77 I/ i
/
II II II ii i i
0
// // // // // // // // /./i
II
II
C
V.S.
cl
Fig. 6. Paradoxical responses (p. r.) in patients comatose for more than 19 days. Hatched: those who stayed in state 4 (coma or p.v.s.) for more than 70 days; open: those who regained clear consciousness before the 70th posttraumatic day.
DISCUSSION
Changes of the calorically induced vestibulo-ocular response (C.V.O.R.) in states of changed consciousness have been described by several authors. Along with an increasing degree of disturbed consciousness the following reactions have been observed successively: nystagmus, only a slow deviation of the eyes; slow dissociated eye movements in which the adducted eye usually remained behind; and finally, no response at all (NATHANSON et al., 1957; BLEGVAD, 1962; MINGRINO et al., 1965; RODRIOUEZBAgRIOS et al., 1966; POULSEN and ZILSTORFF, 1972). Changes in the form of the nystagmus caused by decreasing velocity and slowing off of the acceleration and deceleration of the quick phase of the nystagmus are observed in animals and in man in a state of drowsiness (GOTO, TOKUMARU and COHEN, 1968; SUZUKI, 1969; MELVILLE JONES and SU6IE, 1972). So the changes in the C.V.O.R. found in our patients are in accordance with the data found by oth-
51 ers in man and animals with disturbances of consciousness or a decreased level of arousal. A general scale of the C.O.G., in which the scoring of the shape and the intensity of the nystagmus with open eyes as well as the changes occurring when the eyes were closed, were included, was found to be useful. It appears from our investigation that in head-injured patients the degree of improvement of the C.O.G. provides a possibility to predict the duration of unconsciousness. It can supply information in addition to other criteria, as for example the state of consciousness. POULSEN and ZmSTORFF (1972) found an obvious relation between a C.O.G. made in the first three days after the injury and the ultimate prognosis of the patient. They did not make a difference between the various degrees of unconsciousness in their patients. While a correlation between the state of unconsciousness and the C.O.G. in the first 2 weeks was found and also a rough correlatoin of the depth of initial unconsciousness and the duration of unconsciousness was found by us before (MINOERHOUDet al. 1974) their results are comprehensible. These authors found in the group of patients they examined, four cases not at all responding to caloric stimulation, to have a very bad prognosis. In fact all four died. In some of our patients we also found no response in the first few days after the injury. Out of these patients several regained consciousness after some time and recovered. In our study special attention was paid to the changes of the vestibular response when eyes are closed. In normal persons a so-called inhibition of the nystagmus was sometimes observed by other authors during C.O.G. examination with closed eyes. This inhibition started some time after closing of the eyes, while in the first short period the nystagmus increased normally. The effect of the inhibition is usually described as an irregular course of the nystagmus with a decreased intensity. Most of the time it is of short duration and it can be opposed by asking the patient to perform arithmetic (GILLINGHAM,1968). With our procedure we did not see this kind of inhibition, which is probably due to the activating influences of regular opening and closing of the eyes. An other kind of inhibition was observed in some of our patients and in one of the normal controls. In these cases we observed a short-lived inhibition of the nystagmus directly after closing of the eyes. Also RASHBASS and RUSSELL(1961) reported about this phenomenon. It seems to be an individual phenomenon, i.e. that it has always been observed in certain individuals, whereas it was never seen in others. TJERNSTROM (1973) found an inhibiting influence on the vestibular nystagmus, when the eyeballs were turned upwards. We controlled this in one normal person, but in this case no influence of the vertical eyemovements on the nystagmus were found. For the evaluation of the C.O.G. it is important to be aware of this kind of inhibition. Recording has to be sustained for a sufficiently long period, in case the nystagmus happens to disappear directly after closing the eyes. This is important because it is necessary to differentiate these, probably normal, short-lived inhibitions from the inhibitions only observed in patients. Especially in patients with a prolonged coma the question arises whether they
52 will stay in a coma or persistent vegetative state or regain consciousness within a reasonable time. Although the degree of improvement of the C.O.G. can provide this information, especially the paradoxical response can give answers to this question. Twelve of these patients in which a paradoxical response was found regained consciousness and three of these patients without a paradoxical response did not regain consciousness for a much longer time or not at all. From investigations performed by DONSING and SCHAFER (1957a and b) and POMPEIANO (1972) in the rabbit and in the cat, it seems likely that the activity of the vesitbular nystagmus is highly determined by the activity of the pontine reticular formation. DUNSING and SCH~FER (1957b) showed reciprocal influence of the vestibular neurons and pontine reticular formation, which proves that the vestibular neurons have a stimulating influence on the reticular formation, which on their turn stimulate vestibular neurons. The activating influence of pain stimuli and cortical influences on the reticular formation have been described repeatedly (see survey by ROSSI, 1965, and PLUM and POSNER, 1966). The activating influence of light stimuli especially on the mesencephalic reticular formation in rats has been found (GROVES, 1973). By means of stimulating experiments, YULES, KREBS and GAULT showed in 1966 that the mesencephalic reticular formation in the cat had an obvious influence on the vestibular nystagmus. The improvement of the vestibular nystagmus in our patients after pain stimuli and opening of the eyes (light stimuli), as well as the occurrence of the least abnormal nystagmus at the highest point of the C.V.O.R. may therefore be explained by an increased level of arousal resulting in activation of the pontine reticular formation. The paradoxical response can partly be explained in this way. Moreover there seems to be an absence of the normal optokinetic inhibition of the vestibular nystagmus. In all our normal persons optokinetic suppression of the nystagmus was found after opening of the eyes. In patients it was only observed after regaining a clinically alert state of consciousness. RASHBASSand RUSSELL (1961) were able to suppress these optokinetic influences without changing the vestibular nystagmus recorded with closed eyes in humans by administering amylobarbitone sodium. We observed optokinetic inhibition in some clinically alert patients, whereas a shortlived abnormal nystagmus could be seen directly after closing of the eyes, which indicated a non-optimal level of arousal. The optokinetic suppression and the vestibulo-ocular reaction itself therefore seem to be partly separate systems which can be disturbed independently. These optokinetic influences in human subjects will probably be of cortical origin (JUNG and KORNHUBER, 1946). This corresponds with our finding: we only observed this phenomenon in clinically alert patients. So the paradoxical caloric response may be explained by failing of the normal optokinetic suppression with eyes open and a lowered vestibular arousal system. The latter can be stimulated by light stimuli (opening of the eyes), as well as by pain stimuli resulting in an improvement of the C.V.O.R. HACISKA (1973) claims
53 that this activating effect is caused by an attempt to fixate, which seems to be improbable because this paradoxical response has also been observed in comatose patients. According to ROSSI (1965) and PLUM and POSNER (1966) the disturbances of consciousness can be related to disturbances in the so-called A.R.A.S. system, situated in the median part of the reticular formation rostrally of the pons. The relationship between C.O.G. and consciousness found in this study can be explained by the fact that both depend on the state of tonical activation of the reticular formation. On the other hand, in several patients an obvious discrepancy existed between the C.O.G. and the state of consciousness. Especially in a period several days after the injury the C.O.G. had improved spontaneously without change of the state of consciousness. This can be explained by the fact that consciousness is mainly influenced by the rostral part of the reticular formation and the vestibulo-ocular response mainly by the pontine part. In most of our patients the results can correspond with a general inhibition of the reticular formation, indicating a diffuse disturbance of the arousal system. In comatose patients the outcome seemed to depend on the presence of the paradoxical response. It can be presumed that in the comatose patients with a paradoxical response only a diffuse disturbance of the arousal system was present. Light stimuli influencing especially in the rostral part of the reticular formation still could influence also the pontine and vestibular areas pointing to the fact that anatomical connections are present. In patients without a paradoxical response more localised, anatomical lesions could be present, preventing light stimuli to activate pontine areas. The proposal that only diffuse disturbances of the arousal system should cause the clinical state of consciousness and the C.O.G. seems to be in agreement wit~ the findings of MITCHELL and HUME ADAMS (1973). They seldom observed local lesions in the brainstem of patients who had died after an injury, when no raised intracranial pressure or herniation had been present. The results on the C.O.G. in head-injured patients resemble those found by NATHANSON et al. (1957) in patients with a barbiturate poisoning. It can be proposed that the diffuse disturbances of the brainstem in head-injured patients are not only caused by diffuse loss of cells but also biochemical disturbances. Therefore it is presumable that this dysfunction can be influenced by treatment.
H. Influence of neurotransmitting agents on the electro-oculogram and the clinical state.
INTRODUCTION
Biochemical investigations in our patients have shown decreased levels of homovanillic acid in the cerebrospinal fluid, especially in patients with prolonged dis-
54 turbances of consciousness (LAKKE, KORF, VAN PRAAG, MINDERHOUD and SCHUT, 1973; VECHT, VAN WOERKOM and MINDERHOUD, 1974). L-Dopa appeared to have an arousal effect in cats with brainstem lesions (KADZIELAWA and WIDY-WYSKIEWlCZ, 1969). Also arousal effects in humans were found by HORVATH and MEARES 1974). Therefore some patients, who had been unconscious for more than three weeks were treated with L-Dopa. Also the effect of an other agent, physostigmine, was examined. The result of this treatment with respect to the changes in the clinical state of the patients and the alterations of the C.O.G. will be discussed.
MATERIALS AND METHODS
Eight patients were included in this series. The classification of the clinical state of consciousness and the way of scoring of the C.O.G. were the same as described in Part I. All the patients were in a vegetative state (V.S.) for at least one week. No changes in the clinical condition were observed for at least the last week before treatment was started. Treatment was done by Madopar (L-Dopa combined with decarboxylase inhibitor). The dose was raised to 1000 mg. daily in four or five days. One or two weeks later all these patients were also given 1 mgr. physostigmine salicylate intravenously and some of them were treated afterwards with three doses of 1 rag. physostigmine i.m. daily. A C.O.G. was made in each patient before and during the L-Dopa therapy and before and 20 min. after the administration of physostigmine salicylate intravenously. Special attention was paid to the paradoxical response in the C.O.G. One patient was given neostigmine bromide 2 mg. intravenously (before the physostigmine salicylate) and in two patients 0.5 mg. atropine sulfate intramuscular was used some days before installation of physostigmine was started. RESULTS L-DOPA
In five patients an improvement of the clinical condition could be observed, especially with respect to their motor pattern. Where akinesis or just flexor movements were present before, localising and voluntary movements started. This improvement already could be observed at the end of the first week of treatment. In one patient this treatment was discontinued two weeks later, which caused a decrease of volontary movements. When treatment was started again voluntary movements soon reappeared. In four patients the treatment was continued for at least six weeks. In three of them the treatment was discontinued shortly after the sixth week, without worsening influences on the motor pattern. A correlation was found between the presence of a paradoxical response before this treatment was started and the positive results (fig. 7). In three patients who did not demonstrate a paradoxical response no improvement of the clinical state
55 C.OG 8
7 6
!!
5 4
3 2-
+ +
14-
30
,i0
50
~0
7'0
80
Fig. 7. Changes of the C.O.G. caused by LDOPA treatment in patients in coma or vegetative state +: patients with a paradoxical response; -: patients without a paradoxical response; o: patients improving ~;0£]ays after trauma by therapy; a: patients not improving.
or of the C.O.G. could be obtained. No correlation was found in this group of patients between the general score of the C.O.G. before treatment and the influences on the clinical condition.
Physostigmine therapy The previously mentioned eight patients were also given 1 mg. physostigmine intravenously, one or two weeks after L-Dopa therapy had been adjusted. In the three patients who did not respond to treatment with L-Dopa, no clinical improvement could be observed. A spectacular improvement could be observed in two of the remaining five patients. These two patients who had previously been in a state of total mutism, started talking about five minutes after intravenous injection of physostigmine salicylate, and were able to answer simple questions. A third patient appeared to be able to express himself in writing one hour after the injection and st~irted to talk the next day. In the remaining patients the results were less clear; speech did not return, but it seemed that these patients were able to perform simple tasks. Later on both patients proved to be severely aphasic. The C.O.G. was made directly before and 10 to 20 minutes after the administering of physostigmine. The C.O.G. often improved clearly (fig. 8b), also in the group of patients who did not improve clinically. One patient who showed an improvement with physostogmine later on, was treated with Neostigmine bromide 2 mg. intravenously. Though cholinergic sideeffects were obvious, no improvement could be observed in the C.O.G. (fig. 8a and c). Two patients were given 0.5 mg atropine sulfate i.m.; it appeared that this re-
56 a
eo
ec
b ",.',"~. "t\\,.,,.,,,C~/,,
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