on the nature of brain stem disorders in severe head injured patients

Acta Neuroehirm'gica 34, 11--21 (1976) �9 by Springer-Verlag 1976

Department of l~eurology, University Hospital, Groningen, The iKetherlands

On the Nature of Brain Stem Disorders in Severe Head Injured Patients

I. Changes in Cerebra l N e u r o t r a n s m i t t e r Me tabo l i sm

By

Ch. J. Vecht, Th. C. A. M. van Woerkom, A.W. Teelken, and J. M. Minderhoud

With 5 Figures

Summary

In head injured patients changes were found in the CSF levels of metabo- ]ires of the dopaminergie and the serotonergic neurotransmission (HVA and 5-1KIAA). After the fifth~ day following trauma a significant derease of the HVA levels in the lumbar CSF after probeneeid treatment was found. The intensity of this decrease was found to be related to the severity of the trauma (period of unconsciousness), but not to the state of consciousness.

Also the probenecid-induced 5-HIAA levels in conscious patients were decreased after the fifth post-traumatic day. In unconscious patients, however, an increased turnover of serotonin was found to be also related to the period of unconsciousness, particularly in the period of 5-20 days after trauma. Between 21 and 60 days after trauma the 5-I-IIAA concentrations in unconscious patients decreased remarkably, but they were still significantly higher than in the conscious patients. It can be concluded that during unconsciousness serotonergie neurons have a high rate of turnover, but that both neurotransmitter systems are damaged by the direct or indirect consequences of the injury.

Introduction

Changes in cerebral ilenrotrunsmitter metabolism have been described in a growing number of neurological disorders, including head injury.

The concentrations in the cerebrospinM fluid (CSF) of homovanillie acid (HVA), the main metabolite of the putative neurotransmitter dopamine, and of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of the putative neurotransmitter serotonin reflect the metabolism of their parent amines (Guldberg et al. 1966, Neff et al. 1967, ~Terdinius,

12 Ch. J. Vecht et al. :

1966, Moir et at. 1970, Garelis et al. 1974). Under the influence of the drug probenecid, which impairs the active t ranspor t of these acid metaboli tes from bra in and CSF to the blood, the concentrat ions of t t V A and 5 - t I IAA indicate the rate of tu rnover of dopamine and serotonin in the bra in (01sson and Roos 1968, Bowers 1970, Kerr and Van Praag 1971, Sampath and Neff 1974).

Decreased levels of HVA have been reported in pat ients with post- t r aumat ic akinetic tourism and in other bra in in jured pat ients (Lakke et al. 1973, Johansson and l~oos 1974). We also found low concentra- t ions of HVA in the lumbar CSF after head injury, t.he reduct ion of HVA concentrat ions correlated with the severity of in ju ry (Vecht et at . ,

1975 a). Wi th regard to the cerebral serotonin metabolism, we found normal concentrat ions of 5 -HIAA during the period of unconsciousness; however, after the pat ients had regained consciousness the 5 -HIAA levels decreased remarkably. Other authors found increased concentra- t ions of serotonin in bra in and CSF in brain t r auma in an imal experi- ments as well as in man (Sachs 1957, Osterholm et al. 1969).

At present, having studied brain in jured pat ients during a longer follow-up period, we have gained an insight into the f luctuat ions of HVA and 5-HIAA during the post - t raumat ic course.

Patients and Methods

Forty two patients (13 64 years old), of whom seven were females, were studied; each had sustained a closed head injury. Six patients were conscious on admission to the hospital. The average duration of unconsciousness was 27.2 days (median 8.5 days). Four patients died between seven weeks and half a year after injury. Patients with spinal injury were excluded from the study.

All patients were admitted to the intensive care unit, and were treated, if necessary, with glucose/saline infusions, oxygen, mannitol or urea infusions, tracheal intubat ion or traeheostomy, and physiotherapy. Most received antibiotics and steroids. No patient received L-dopa.

The state of consciousness of the patients was assessed by a clinical coma scale developed by Teasdale and Jennet t (1974), in which the degree of coma is determined by the rate of (a) eye opening (4 grades), (b) motor respon- siveness (6 grades), and (c) verbal response (5 grades) of the patient to verbal command and pain stimulus, i n this study a patient was labelled unconscious if he had a total coma score of 12 points or less, and was labelled conscious if he had 13, 14, or 15 points.

Five grams of probeneeid were administered to all patients over a four hours period, as described by Van Praag et al. (1973). Lumbar puncture followed eight hours after the first, administration. About 12 ml of CSF was removed and stored at - - 20 ~ Lumbar puncture was not performed in patients suspected of having increased intracranial pressure. In a number of patients the probenecid technique was repeatedly performed during the subsequent periods studied i.e. the first 5 days after injury, 6-20 days, 21-60 days, and more than 60 days after injury.

On the Na tu re of Bra in S tem Disorders in Severe H e a d In ju r ed Pa t ien ts 13

H V A , 5 -HIAA, and probeneeid de te rmina t ions were done as described by Vecht et al. (1975 b).

As i t m a y be supposed tha t b lood-brain barr ier lesions could influence HVA and 5-HIAA CSF-levels, we made calculations for at least two different periods: (a) the first five days after injury--the period of expected blood- brain barrier disturbances (K]atzo et al. 1958),--and (b) five days or more after injury. Theoretically, antibiotics (e.g. penicillin) and other drugs may influence probeneeid concentrations, and thus HVA and 5-HIAA CSF- levels. Therefore, patients punctured five or more days after injury were examined for biases: there were no significant differences (p > 0.i0; Fischer's exact probability test) between conscious and unconscious patients for the following items :

penici l l in or ampiei l l in; o ther ant ibiot ics ; steroids ; sedat ives (including ant i -eonvulsants) .

As xan thoch romia implies the presence of blood cell degrada t ion products in the CSF and thus the presence of 5 - H I A A from platelets, we inves t iga ted the effect of the presence or the absence of CSF xan thochromia in conscious and unconscious pa t ien ts : there was no significant difference in this respect (p > 0.10).

The control group consisted of 13 pa t ien ts (10 males, 3 females) be tween 18 and 52 years old. All these mobi le pat ients were suspected of lumbar disc protrusions, and did no t show other diseases of the nervous system. CSF was r emoved before myelography .

Stat is t ical me thods included the Mann-Whi tney U test, Spearman ' s rank correlat ion test, and linear regression (Bravais-Pearson).

Results

Fig. i shows that during post-traumatic course a steady decrease of I.IVA in the lumbar CSF occurs. During the first five days no changes between HVA levels of the brain injured and the control group are present. After that, decreased HVA concentrations occurred compared to the control patients. In addition, Fig. 1 demonstrates that the state of consciousness of the patients did not make any difference with respect to the level of the HVA concentrations. The duration of unconsciousness, which is a measure of the severity of brain injury (Carlsson et al. 1968, Heiskanen and Sipponen 1970), correlated significantly (r z -- 0.46; p ~ 0.05) with the HVA levels, as Fig. 2 shows.

Fig. 3 shows that during the first five days after injury, the 5-HIAA concentrations remained within the normal range. Between 6-20 days after trauma the 5-HIAA levels of the unconscious patients turned out to be significantly higher than those of the patients who had regained consciousness (p ~ 0.005). Moreover, during this period the unconscious patients showed significantly (p ~ 0.05) higher 5-HIAA concentrations than did the control group. Between 21-60 days after trauma the 5-HIAA concentrations of the unconscious patients decreased remark-

14 Ch. J. Vecht et a l . :

ng/rnl HVA

i!i;iii!tiiiiiiii iii i i i i i i i l i i i i i i i i; i i i i i i i i l iii iiiii!iiiiiiiiiiiii~ii~iiiiiii!~i i ~! i iii! i i ii ii! ii i ili i i

100

80

60

20

I / / i I / i i / / o-s 6-~o 2,-6o >_-s~ days

Fig. 1. EVA concentrations (mean • S.E.M.) in lumbar CSF of head injured patients during post-traumatic course. Open circles represent patients who were conscious at the moment of the lumbar puneture. Closed circles represent unconscious patients at the moment of the lumbar puncture.

Shaded area represents HVA values of control patients (mean • S.E.M.)

ably, but they were still significantly (p < 0.005) higher than those of the conscious patients. The same pa t te rn was also present more than 60 days after injury, though not significantly. Concerning all patients who were conscious at the moment of the lumbar puncture, a significant correlation (r = - - 0.52 ; p < 0.05) between the durat ion of unconsciousness and the 5 -HIAA concentrations in the lumbar CSF could be shown (Fig. 4).

Fig. 5 shows the mean values of conscious post - t raumat ic patients, who were arbitrari ly divided into patients who remained uneonseious during a relatively shorter ( ~< 6 days) and longer (/> 7 days) period. I n the longer period group both HVA and 5 -HIAA lumbar CSF coneentra- tions were significantly (p < 0.05) decreased compared to the control group. Table 1 represents the correlation coefficients between I-IVA, 5 - t t IAA and probeneeid before and after the fifth post - t raumat ic day. Before the fifth day no significant correlations are present. After the fifth day the conscious as well as the unconscious pat ients show significant correlation coefficients between probenecid and 5 - H I A A concentrations. However, in the joint group of conscious and unconscious patients no significant correlations are found. Probeneeid concentrations did no t differ significantly between the various groups.

On the Nature of Brain Stem Disorders in Severe Head Injured Patients 15

ng/ml HVA 0

7 0 -

6 0 -

5 0 -

4 0 -

3 0 -

2 0 -

1 0 -

O 0

0 r=-0.46 (p< .05)

0

O0 0

0 0 0 0

0 0 O o

0

/ / i i i [ [ / / i i i i

1 2 3 4 5 I0 20 30 40 50 60 days l g

duration of unconsciousness

Fig. 2. Relationship between height of HVA concentrations in lumbar CSF and duration of unconsciousness (in days) of head injured patients, who were punctured after regaining consciousness and after the fifth post- traumatic day (r = - -0 .46; p < 0.05; Spearman's rank correlation test)

Discussion

A few reports have been published about cerebral dopamine and serotonin metabolism following head injury in man (Sachs, 1957; Lakke et al., 1973 ; Johansson and Roos, 1974). In agreement with these studies, we found decreased HVA concentration in the lumbar CSF. Moreover, we found a significant inverse relationship between the height of the HVA levels and the duration of unconsciousness (Fig. 2). The duration of unconsciousness (as well as the duration of the post-traumatic amne- sia) gives a good indication of the severity of injury (Carlsson et al. 1968, Heiskanen and Sipponen 1970). The 5-HIAA lumbar CSF concentrations of conscious post-traumatic patients also showed a significant inverse correlation with the duration of days of unconsciousness (Fig. 4). Since both neurotransmitter metabolites were decreased following head injury and showed a relationship with the severity of injury (Fig. 5), it may be concluded that these findings are a feature of primary or secon- dary anatomical damage to the brain, which leads, among other things, to a reduced number of dopamine and serotonin producing neurones. If this is correct, we may expect that this not only occurs during the later

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120

100

80

60

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I1 - t t

........ .................... i ..................... i ............... .....

, // , // , // l 0_5 6_2o 21_6o ~>61 days

Fig. 3. 5-I-IIAA concentrations (mean • S.E.M.) in lumbar CSF of head injured patients during post-traumatic course. Open circles (o) represent patients who were conscious at the moment of the lumbar puncture. Closed circles (0) represent unconscious patients at the moment of the lumbar puncture. Shaded area represents 5-HIAA values of control patients (mean ~: S.E.M.). * ~ significant difference (p ~ 0.005) from corresponding conscious patients ; ** = significant difference from corresponding conscious

patients (p % 0.005) and control group (p ~ 0.05)

post- traumatic phase but also in the acute stage i. e. up to two or three weeks after injury. Nevertheless, during the first five days after injury, no abnormal metabolite concentrations were found. This may well be explained through the occurrence of blood-brain barrier disturbances during this early period. Klatzo et al. (1958) showed in animals that the five days after a local brain injury is about the time for blood-brain barrier defects. Our findings tha t during the first five days no correlations were present between HVA or 5-I-IIAA and probenecid concentrations, while after the fifth day significant correlations between these meVabolites and probenecid did occur (Tab. 1), may be explained by a disturbed blood-brain barrier function during the first five days after t rauma.

Acta Neurochirurgica, Vol. 34, Fast . 1--4 2

18 Ch. J. Veeht et al. :

ng/ml 5 -HIAA

70 O

60 O O o

50

40,

30

20

10

O

O

O

O O

O

O

r =-0.52 (p<O.O5)

O O

O

i i L , J / ~ / I i , i I i I

I 2 3 4 5 I0 20 30 40 50 60 70 days

duration of unconsciousness

Fig. 4. Relationship between the height of the 5-HIAA concentrations in lumbar CSF and duration of unconsciousness (in days) of head injured patients, who were punctured after regaining consciousness and after the fifth post-traumatic day (r -- ---0.52; p < 0.05; Spearm~n's rank correla-

tion test)

After the fifth day decreased HVA levels were present, whether the patients were conscious or not (Fig. 1).

The 5-HIAA levels of the conscious patients also showed a fall after the fifth day (Fig. 3). However, it turned out that the unconscious patients had significantly higher 5-HIAA levels compared to patients who were already conscious during the corresponding period after trauma, the latter having sustained less severe head injuries. In earlier studies, we did not have at our disposal a group of probenecid treated control patients (Vecht et al . 1975 a and b), but now it seems apparent that the unconscious patients showed remarkably and significantly higher 5-HIAA levels during 6-20 days after injury than did the control group (Fig. 3).

Korf and Van Praag (1971), and Sampath and Neff (1974), drew attention to the fact that measuring the probeneeid concentrations should be an integral part of the probenecid technique, since differences in concentrations could mask deficiencies in amine metabolism. There- fore, the correlation of probenecid and the metabolites helps to give a


ng/ml

60

30-

20 -

HVA ng/ml 5 - HIAA

T O

[]

t>7 days

co .<6 co days

.<6 days

97 days

Fig. 5. HVA and 5-HIAA concentrations (mean ~ S.E.M.) in lumbar CSF of conscious head injured patients, who remained unconscious during ~< 6 days and >~ 7 days, resp. * indicates significant difference (p < 0.05)

from control groups

better insight into the cerebral turnover of the parent amines than the HVA and 5-HIAA concentrations as such. It is important to recognize that between probenecid and 5-HIAA concentrations significant positive

correlations occurred in both the separate groups of conscious and unconscious patients (Tab. i). However, in the joint group of conscious and unconscious patients no significant correlation was found between

probenecid and 5-HIAA concentrations. It can thus be concluded that the serotonin-produeing neurones have

a higher rate of turnover during unconsciousness than after consciousness has been regained. In particular, during the acute period i.e. up to about

the 20th day, a remarkably increased cerebral serotonin turnover must

be present. As it was e0nsidered that HVA levels decreased whether the patients

were conscious or not, and that 5-HIAA levels were also low after the patients had recovered consciousness, it may be assumed that during unconsciousness a loss of serotonergic neurones was also present.

A high rate of turnover of the remaining serotonergie neurones, which have their cell bodies in the middle and upper part of the brainstem,

g*

20 Ch. J. Vecht et al. :

during the period of unconsciousness, points to a concurrent occurrence of anatomical damage and functional Mterations in the brainstem. The fact that a functional change of serotonergie activity may be related to unconsciousness is supported by other findings. During hepatic coma in pigs an increased cerebral turnover of serotonin has been deduced from the increased concentrations of tryptophan and serotonin in the brain, together with increased 5-HIAA CSF concentrations (Curzon et al. 1973). In man, increased 5-HIAA concentrations in lumbar CSF have also been found in hepatic coma (Knell et al. 1974). Munro et al. (1975) outlined a hypothesis in which they related unconseioumless to increased cerebral serotonin activity and tried to give an explanation for this raised activity by a changed aminoaeid uptake from the blood into the brain resulting in increased serotonin concentrations in the brain. During sleep it has also been shown that, apart from changes in noradre- nalin and acetylcholine metabolism, an increased serotonergic activity plays a major role (Jouvet 1972).

The relationship between unconsciousness and an increased cerebral serotonergic activity might thus be a general phenomenon, although the explanation still remains open.

Relerences

Bowers, M. B., CSF homovanillie acid: effects of probenecid and ~-methyl- tyrosine. Life Sci. 9 (1970), 691--694.

Carlsson, C.A., yon Essen, C., L6fgren, J., Factors affecting the clinical course of patients with severe head injuries. Part 2: significance of posttraumatie coma. J. Neurosurg. 29 (1968), 248--251.

Curzon, G., Kantamaneni, B. D., Wind, J., Bojas-Bueno, A., Murray-Lyon, I. M., Williams, R., Plasma and brain tryptophan changes in experimental acute hepatic failure. J. Neuroehem. 21 (1973), 137--145.

Garelis, E., Young, S. N., Lal, S., Sourkes~ T. L., Monoamine metabolites in lumbar CSF: The question of their origin in relation to eIinieat studios. Brain ires. 79 (1974), 1--8.

Guldberg, tt. C., Asheroft, G.W., Crawford, T. B. B., Concentrations of 5-hydroxy-indoleacetic acid aiad homovanillie acid in the cerebrospinal fluid of the dog before and during treatment with probenecid. Life Sci. 5 (1966), 1571--1575.

Heiskanen, O., Sipponen, P., Prognosis of severe brain injury. Aeta neurol. scand. 66 (1970), 343--348.

Jacobsen, S.A., Protracted unconsciousness due to closed head injury. Neurology 6 (1956), 281--287.

Johansson, B., tloos, B.E., 5-Hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid of patients with neurological diseaseS. Europ. Neurol. 11 (1974), 37--45.

Jouvet, M., The role of monoamines and aeetyleholine-containing neurons in the regulation of the sleep-waking cycle. In: Reviews of Physiology, Vol. 64, p. 166. Berlin-Heidelberg-New York: Springer. 1972.


Knell, A. J., Davidson, A. 1%., Williams, R., Kantamaneni , B.D. , Curzon, G., Dopamine and serotonin metabolism in hepatic encephMopathy. Brit. med. J. 1 (1974), 549--551.

Korf, J., van Praag, I-I. M., Amine metabolism in the human brain: further evaluation of the probeneeid test. Brain l~es. 35 (1971), 221--230.

Lakke, J. P. W. F., Xorf, J., van Praag, I-I. M., Minderhoud, J. M., Sehut, T., Clinical significance of probeneeid test. Lancet 1 (1973), 614--615.

Molt, A. T. B., Ashcroft, G. W., Crawford, T. B. B., Eceleston, D., Guldberg, I-I. C., Cerebral metabolites in cerebrospinal fluid as a biochemical approach to the brain. Brain 93 (1970), 357--368.

Munro, I-I. N., Fernstrom, J. D., Wurtman, 1~. J., Insulin, plasma aminoaeid imbalance and hepatic coma. Lancet 1 (1975), 722--724.

Neff, N. H., Tozer, T. N., Brodie, B. B., Application of steadystate kinetics to studies of the transfer of 5-hydroxyindoleaeetic acid from brain to plasma. J. Pharmacol. exp. Ther. 158 (1967), 214--218.

Olsson, ]~., l:Loos, B. E., Concentrations of 5-hydroxyindoleaeetie acid and homovanillie acid in the eerebrospinal fluid after treatment with probeneeid in patients with Parkinson's disease. Nature 219 (1968), 502--503.

Osterholm, J. L., Bell, E., Meyer, R., Pyenson, J., Experimental effects of free serotin on the brain and its relation to brain injury. J. Neurosurg. 31 (1969), 408--421.

Sachs, E., Acetylcholine and serotonin in the spinal fluid. J. Neurosurg. 14 (1957), 22--27.

Sampath, S. S., Neff, N. H., The elimination of 5-hydroxyindoleacetic acid from eerebrospinal fluid: characteristics of the acid transport system of the ehoroid plexus. J. Pharmacol. exp. Ther. 188 (1974), 410--414.

Teasdale, G., Jennett, B., Assessment of coma and impaired consciousness. Lancet 2 (1974), 81--84.

Van Praag, H. M., Korf, J., Sehut, T., Cerebral monoamines and depression. An investigation with the probenecid technique. Arch. gen. Psychiat. 28 (1973), 827--831.

Vecht, Ch. J., van Woerkom, Th. C. A. M., Teelken, A.W. , Minderhoud, J. M., HVA and 5-HIAA CSF levels and the state of consciousness after head-injury. Arch. Neurol. (1975 a) in press.

5-Hydroxyindoleacetie acid (5-I-IIAA) CSF levels in consciousness and unconsciousness after head injury. Life Sci. 16 (1975 b), 1179--1186.

W~rdinius, B., Effect of probenecid on the levels of monoamine metabolites in the rat brain. Acta Pharmacol. toxicol. 25 (1967), 18--23.

Authors' addresses: Ch. J. Veeht, Department of Neurology, Wilhelmina Gasthuis, Amsterdam, The Netherlands; Th. C.A.M. van Woerkom, Dr. A. W. Teelken, and Prof. Dr. J. M. Minderhoud, Department of Neurology, University Hospital, Oostorsingel 59, Groningen, The Netherlands.

on the nature of brain stem disorders in severe head injured patients

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