=Acta . . N6urochlrurglca
Acta Neurochir (Wien) (1992) 115:106-111
9 Springer-Verlag 1992 Printed in Austria
Increased Serum Creatine Kinase BB and Neuron Specific Enolase Following Head Injury Indicates Brain Damage I. M. Skogseid 1, H. K. Nordby 1, P. Urdal z, E. Paus 4 and F. Lilleaas 3 ~Departments of Neurosurgery, 2Clinical Chemistry, 3Neuroradiology, UllevgdHospital and 4Central Laboratory, The Norwegian Radium Hospital, Oslo, Norway
Summary The aim of this study was to examine whether an increase in the serum concentrations of the two brain enzymes creatine kinase BB (CK-BB) and neuron specific enolase (NSE) can be demonstrated in pattens with acute head injury and whether such an increasereflects release from damaged brain tissue. In 60 patients who had suffered minor to severe head injury, serial blood samples were drawn during the first hours after impact, and CK-BB and NSE were measured by radio-immuno-assay. Computed tomography (CT) was also performed shortly after admission to hospital, and was repeated 1-3 days later in selected patients. Increased serum concentrations of both CK-BB and NSE were found in 88% of the patients with moderate to severe head injury (group 1, n = 18) and in 23% of the patients with minor head injury (group2, n = 42), whereas CT showed contusion in only 41% and 2% of the group 1 and 2 patients, respectively.The followingfindings suggest that the enzymes had been released from brain tissue: 1) The maximum concentrations of CK-BB and NSE correlated with the severity of injury as assessed clinicallyand with the volume of contusion as estimated from CT (r = 0.79 with CK-BB, r = 0.72 with NSE). 2) The maximum concentrations of CK-BB and NSE were closely correlated (r = 0.87). 3) The ratio between CK-BB and NSE was approximately the same in a subgroup of 10 patients with multiple trauma as in the group as a whole (median 2.2 versus 2.0). Measurements of the serum concentrations of CK-BB and NSE in patients with acute head trauma, therefore, appears to provide information about the presence and, to some degree, extent of the resulting brain injury. Further studies are required to reveal the value of such measurements in the management of patients with acute head trauma.
Keywords: Creatine kinase BB; neuron specific enolase; computed tomography; traumatic damage.
Introduction F o l l o w i n g head i n j u r y the r o u t i n e use of c o m p u t e d t o m o g r a p h y (CT) has greatly facilitated the detection of operable i n t r a c r a n i a l lesions. I n the diagnosis of
m o r e diffuse b r a i n damage, however, the C T scanner seems to be less sensitive 1~. Thus, there is a need for m o r e sensitive m e t h o d s to reveal the presence a n d extent of diffuse b r a i n damage, which is one of the m o s t i m p o r t a n t factors d e t e r m i n i n g the o u t c o m e after head injury. I n searching for more sensitive m e t h o d s to diagnose p e r m a n e n t b r a i n damage, biochemical markers in the cerebrospinal fluid (CSF) a n d b l o o d have been studied. A m o n g these, creatine kinase BB (CK-BB) appears to be p r o m i s i n g 1-6' 12, 13, 16, 17. W h e n m e a s u r e d in C S F C K - B B has proved to be a sensitive m a r k e r of acute b r a i n d a m a g e 1' 2, 5- 6, 9, 12- 14, 1 7 - 1 8 . Reports from measurements of C K - B B in b l o o d have been less encouraging, as m o s t 2' 4, 6, 9, ~9 b u t n o t all 16, 18 investigators have f o u n d n o r m a l c o n c e n t r a t i o n s of C K - B B in a significant p r o p o r t i o n of patients with severe head injury. Such findings m i g h t in part be due to methodological problems. I n a previous series o f patients with severe head i n j u r y we m e a s u r e d C K - B B using a specially developed r a d i o - i m m u n o - a s s a y21 a n d f o u n d increased c o n c e n t r a t i o n s in all b l o o d samples d r a w n within 6 hours o f t r a u m a 13. I n the present study we also included patients with m i n o r head injuries. I n a d d i t i o n to C K - B B we measured the c o n c e n t r a t i o n of n e u r o n specific enolase (NSE) which is present in a lower c o n c e n t r a t i o n t h a n C K - B B in b r a i n tissue, b u t is more b r a i n specific (22, u n p u b l i s h e d data). Increased c o n c e n t r a t i o n s of b o t h enzymes in b l o o d following acute head injury, therefore, w o u l d strongly suggest b r a i n p a r e n c h y m a l damage. N S E in C S F has previously been shown to be a sensitive m a r k e r of m a n y types of neurological injury 1,7, b u t to o u r knowledge, has not been studied in serum of patients with head injuries.
I. M. Skogseid et al. Increased Serum Creatine Kinase BB and Neuron Specific Enolase
Materials and Methods
107
Table 1. Epidemiological Data of Group land 2
Patients Sixty patients who had suffered head injury of varying severity within twelve hours of admission to hospital were included. Severity of injury was assessed clinically on the basis of Glasgow Coma Scale scores (GCS) 2~ obtained during the first six hours after admission, and the registration of focal neurological deficits. According to this evaluation the patients were divided into two diagnostic groups: Group 1 included 18 patients: 11 severely injured patients with a GCS of 3 - 8, and 7 moderately injured patients who either had a GCS of 9 - 12 or had a higher GCS but showed a focal neurological deficit. Group 2 included 42 patients who had suffered a minor head injury and had a GCS of 13 - 15. Table 1 summarizes the epidemiological data of the two groups, Male patients predominate and median age is 38 years (range 14 - 77 years). A traffic accident was the major cause of injury in group 1, whereas a fall was an equally prevalent cause of injury in group 2. Assault was the cause of injury in 15% of the patients. A blood alcohol concentrations of 2 g/1 or more was present in 30% of the patients, whereas another 20% had concentrations up to 2 g/1. Ten patients (17%) suffered in addition from major trauma in other regions of the body, such as lung contusion, serious fractures and rupture of abdominal organs of large vessels. These injuries were mainly seen in cases of more severe head injury.
Sex male female Age 59 Mechanism of trauma traffic accident falls human assault non-violent blows unknown Blood conc. of alcohol 0 0.1 - 1.9 g/1 > 1.9 g/1
Group 1 (n = 18)
Group 2 (n = 42)
16 (89%) 2 (11%)
35 (83%) 7 (17%)
9 (50%) 8 (44%) 1 (6%)
13 (31%) 21 (50%) 8(19%)
1I (61%)
16 (38%)
5 (28%) 2(11%)
14 (33%) 7 (17%) 3 (7%) 2 (5%)
6 (50%) 3 (25%) 3 (25%)
16 (49%) 6 (18%) 11 (33%)
Measurements of CK-BB and NSE The first blood sample for determination of CK-BB and NSE was drawn as soon as possible after admission to hospital Emedian (M) = 1 hour post injury in group 1, M = 2.5 hours post injury in group 2]. Further samples were drawn at intervals of 2 - 6 hours resulting in 1 to 7 samples per patient (M = 5 in group 1, M = 2 in group 2). The blood samples were kept at + 4 ~ until serum was separated. Serum was stored at - 70 ~ until analysis. Concentrations of NSE and CK-BB were measured using radio-immuno-assays as described previouslylS. 21 NSE concentrations of 10 ~tg/1 or above and CK-BB concentrations of 6 gg/1 or above were defined as being increased 15,
2I.
One patient with minor head injury had "macro CK-BB" in his blood, making determination of CK-BB in this patient impossible with our method. In one patient with moderate head injury NSE could not be determined because plasma had been obtained instead of serum.
brain parenchyma of normai density. Their volumes were estimated by multiplying the area observed on each slice with the slice thickness and adding the volumes thus obtained from consecutive CT slices. The percentage of damaged brain tissues shown by CT was calculated on the basis of an estimate of the total brain volume of the individual patient.
Results Serum Concentrations o f C K - B B and N S E Figure 1 shows how the serum concentrations CK-BB
of
a n d N S E v a r i e d w i t h t i m e a f t e r i n j u r y in in-
d i v i d u a l p a t i e n t s o f g r o u p s 1 a n d 2. I n all s u r v i v i n g patients CK-BB
w a s a t its h i g h e s t level i n t h e f i r s t
s a m p l e a n d fell r a p i d l y t o n o r m a l levels w i t h i n 6 -
12
h o u r s . I n c o n t r a s t , t h e h i g h e s t levels o f N S E w e r e s o m e -
CT Examinations
times found in the second or third sample and the
Computed tomography of the head was performed in all patients except one in whom massive brain damage resulted death three hours after admission to hospital. Two different CT scanners were used; CT GE Max and CT GE 9800 Quick. Group 1 patients were examined within 4 hours of trauma in 90% of cases (median 3 h, range 1 - 18 h), whereas group2 patients were examined within 24hours of trauma in 83% of cases (median 16h range 1 - 3 6 h ) . A second CT examination was performed in 11 patients in group 1 who had a persistently reduced level of consciousness and/or needed respiratory care. These repeated CT examinations were performed within 48 hours of trauma in 90% of cases (median 28 h, range 1 0 - 58 h). Primary parenchymal brain contusions were defined as areas of reduced or mixed density ("salt and pepper appearance") within
e l e v a t e d levels p e r s i s t e d f o r m a n y h o u r s a f t e r i n j u r y . In two patients who died of massive cerebral contusions w i t h r e s u l t i n g t r a n s t e n t o r i a l h e r n i a t i o n , h i g h levels o f both enzymes persisted or even increased until death e n s u e d ( F i g . 1, o p e n circles). F r o m t h e d a t a o f Fig. 1 w e c o n s i d e r e d t h a t s a m p l e s for determination
of CK-BB
should
preferably
be
d r a w n w i t h i n six h o u r s p o s t i n j u r y a n d f o r N S E w i t h i n 24 h o u r s . I n six o f t h e g r o u p 2 p a t i e n t s t h e first b l o o d s a m p l e w a s d r a w n b e t w e e n 6 a n d 24 h o u r s p o s t i n j u r y . H e n c e (cf. M e t h o d s a n d M a t e r i a l s ) , o f t h e 60 p a t i e n t s
108
I . M . Skogseid et al. Increased Serum Creatine Kinase BB and Neuron Specific Enolase GROUP 1 140
140
u, 120
~120
m 100
m 100
I
GROUP 2
160
160
co
80
a9
o
o
60
60
'\
40
4o o)
r
20
20 3
6
9
12
15
18
21
i
i
3
6
9
9
12
,
15
18
21
TIME AFTER INJURY (hoursl
TIME AFTER INJURY (hours)
160
160 B
140
I40
12o
120
I00
100
:I uJ
~_ 80 =m s0 n-"
uJ 40 9
/_o-
Acta Neurochir (Wien) (1992) 115:106-111
9 Springer-Verlag 1992 Printed in Austria
Increased Serum Creatine Kinase BB and Neuron Specific Enolase Following Head Injury Indicates Brain Damage I. M. Skogseid 1, H. K. Nordby 1, P. Urdal z, E. Paus 4 and F. Lilleaas 3 ~Departments of Neurosurgery, 2Clinical Chemistry, 3Neuroradiology, UllevgdHospital and 4Central Laboratory, The Norwegian Radium Hospital, Oslo, Norway
Summary The aim of this study was to examine whether an increase in the serum concentrations of the two brain enzymes creatine kinase BB (CK-BB) and neuron specific enolase (NSE) can be demonstrated in pattens with acute head injury and whether such an increasereflects release from damaged brain tissue. In 60 patients who had suffered minor to severe head injury, serial blood samples were drawn during the first hours after impact, and CK-BB and NSE were measured by radio-immuno-assay. Computed tomography (CT) was also performed shortly after admission to hospital, and was repeated 1-3 days later in selected patients. Increased serum concentrations of both CK-BB and NSE were found in 88% of the patients with moderate to severe head injury (group 1, n = 18) and in 23% of the patients with minor head injury (group2, n = 42), whereas CT showed contusion in only 41% and 2% of the group 1 and 2 patients, respectively.The followingfindings suggest that the enzymes had been released from brain tissue: 1) The maximum concentrations of CK-BB and NSE correlated with the severity of injury as assessed clinicallyand with the volume of contusion as estimated from CT (r = 0.79 with CK-BB, r = 0.72 with NSE). 2) The maximum concentrations of CK-BB and NSE were closely correlated (r = 0.87). 3) The ratio between CK-BB and NSE was approximately the same in a subgroup of 10 patients with multiple trauma as in the group as a whole (median 2.2 versus 2.0). Measurements of the serum concentrations of CK-BB and NSE in patients with acute head trauma, therefore, appears to provide information about the presence and, to some degree, extent of the resulting brain injury. Further studies are required to reveal the value of such measurements in the management of patients with acute head trauma.
Keywords: Creatine kinase BB; neuron specific enolase; computed tomography; traumatic damage.
Introduction F o l l o w i n g head i n j u r y the r o u t i n e use of c o m p u t e d t o m o g r a p h y (CT) has greatly facilitated the detection of operable i n t r a c r a n i a l lesions. I n the diagnosis of
m o r e diffuse b r a i n damage, however, the C T scanner seems to be less sensitive 1~. Thus, there is a need for m o r e sensitive m e t h o d s to reveal the presence a n d extent of diffuse b r a i n damage, which is one of the m o s t i m p o r t a n t factors d e t e r m i n i n g the o u t c o m e after head injury. I n searching for more sensitive m e t h o d s to diagnose p e r m a n e n t b r a i n damage, biochemical markers in the cerebrospinal fluid (CSF) a n d b l o o d have been studied. A m o n g these, creatine kinase BB (CK-BB) appears to be p r o m i s i n g 1-6' 12, 13, 16, 17. W h e n m e a s u r e d in C S F C K - B B has proved to be a sensitive m a r k e r of acute b r a i n d a m a g e 1' 2, 5- 6, 9, 12- 14, 1 7 - 1 8 . Reports from measurements of C K - B B in b l o o d have been less encouraging, as m o s t 2' 4, 6, 9, ~9 b u t n o t all 16, 18 investigators have f o u n d n o r m a l c o n c e n t r a t i o n s of C K - B B in a significant p r o p o r t i o n of patients with severe head injury. Such findings m i g h t in part be due to methodological problems. I n a previous series o f patients with severe head i n j u r y we m e a s u r e d C K - B B using a specially developed r a d i o - i m m u n o - a s s a y21 a n d f o u n d increased c o n c e n t r a t i o n s in all b l o o d samples d r a w n within 6 hours o f t r a u m a 13. I n the present study we also included patients with m i n o r head injuries. I n a d d i t i o n to C K - B B we measured the c o n c e n t r a t i o n of n e u r o n specific enolase (NSE) which is present in a lower c o n c e n t r a t i o n t h a n C K - B B in b r a i n tissue, b u t is more b r a i n specific (22, u n p u b l i s h e d data). Increased c o n c e n t r a t i o n s of b o t h enzymes in b l o o d following acute head injury, therefore, w o u l d strongly suggest b r a i n p a r e n c h y m a l damage. N S E in C S F has previously been shown to be a sensitive m a r k e r of m a n y types of neurological injury 1,7, b u t to o u r knowledge, has not been studied in serum of patients with head injuries.
I. M. Skogseid et al. Increased Serum Creatine Kinase BB and Neuron Specific Enolase
Materials and Methods
107
Table 1. Epidemiological Data of Group land 2
Patients Sixty patients who had suffered head injury of varying severity within twelve hours of admission to hospital were included. Severity of injury was assessed clinically on the basis of Glasgow Coma Scale scores (GCS) 2~ obtained during the first six hours after admission, and the registration of focal neurological deficits. According to this evaluation the patients were divided into two diagnostic groups: Group 1 included 18 patients: 11 severely injured patients with a GCS of 3 - 8, and 7 moderately injured patients who either had a GCS of 9 - 12 or had a higher GCS but showed a focal neurological deficit. Group 2 included 42 patients who had suffered a minor head injury and had a GCS of 13 - 15. Table 1 summarizes the epidemiological data of the two groups, Male patients predominate and median age is 38 years (range 14 - 77 years). A traffic accident was the major cause of injury in group 1, whereas a fall was an equally prevalent cause of injury in group 2. Assault was the cause of injury in 15% of the patients. A blood alcohol concentrations of 2 g/1 or more was present in 30% of the patients, whereas another 20% had concentrations up to 2 g/1. Ten patients (17%) suffered in addition from major trauma in other regions of the body, such as lung contusion, serious fractures and rupture of abdominal organs of large vessels. These injuries were mainly seen in cases of more severe head injury.
Sex male female Age 59 Mechanism of trauma traffic accident falls human assault non-violent blows unknown Blood conc. of alcohol 0 0.1 - 1.9 g/1 > 1.9 g/1
Group 1 (n = 18)
Group 2 (n = 42)
16 (89%) 2 (11%)
35 (83%) 7 (17%)
9 (50%) 8 (44%) 1 (6%)
13 (31%) 21 (50%) 8(19%)
1I (61%)
16 (38%)
5 (28%) 2(11%)
14 (33%) 7 (17%) 3 (7%) 2 (5%)
6 (50%) 3 (25%) 3 (25%)
16 (49%) 6 (18%) 11 (33%)
Measurements of CK-BB and NSE The first blood sample for determination of CK-BB and NSE was drawn as soon as possible after admission to hospital Emedian (M) = 1 hour post injury in group 1, M = 2.5 hours post injury in group 2]. Further samples were drawn at intervals of 2 - 6 hours resulting in 1 to 7 samples per patient (M = 5 in group 1, M = 2 in group 2). The blood samples were kept at + 4 ~ until serum was separated. Serum was stored at - 70 ~ until analysis. Concentrations of NSE and CK-BB were measured using radio-immuno-assays as described previouslylS. 21 NSE concentrations of 10 ~tg/1 or above and CK-BB concentrations of 6 gg/1 or above were defined as being increased 15,
2I.
One patient with minor head injury had "macro CK-BB" in his blood, making determination of CK-BB in this patient impossible with our method. In one patient with moderate head injury NSE could not be determined because plasma had been obtained instead of serum.
brain parenchyma of normai density. Their volumes were estimated by multiplying the area observed on each slice with the slice thickness and adding the volumes thus obtained from consecutive CT slices. The percentage of damaged brain tissues shown by CT was calculated on the basis of an estimate of the total brain volume of the individual patient.
Results Serum Concentrations o f C K - B B and N S E Figure 1 shows how the serum concentrations CK-BB
of
a n d N S E v a r i e d w i t h t i m e a f t e r i n j u r y in in-
d i v i d u a l p a t i e n t s o f g r o u p s 1 a n d 2. I n all s u r v i v i n g patients CK-BB
w a s a t its h i g h e s t level i n t h e f i r s t
s a m p l e a n d fell r a p i d l y t o n o r m a l levels w i t h i n 6 -
12
h o u r s . I n c o n t r a s t , t h e h i g h e s t levels o f N S E w e r e s o m e -
CT Examinations
times found in the second or third sample and the
Computed tomography of the head was performed in all patients except one in whom massive brain damage resulted death three hours after admission to hospital. Two different CT scanners were used; CT GE Max and CT GE 9800 Quick. Group 1 patients were examined within 4 hours of trauma in 90% of cases (median 3 h, range 1 - 18 h), whereas group2 patients were examined within 24hours of trauma in 83% of cases (median 16h range 1 - 3 6 h ) . A second CT examination was performed in 11 patients in group 1 who had a persistently reduced level of consciousness and/or needed respiratory care. These repeated CT examinations were performed within 48 hours of trauma in 90% of cases (median 28 h, range 1 0 - 58 h). Primary parenchymal brain contusions were defined as areas of reduced or mixed density ("salt and pepper appearance") within
e l e v a t e d levels p e r s i s t e d f o r m a n y h o u r s a f t e r i n j u r y . In two patients who died of massive cerebral contusions w i t h r e s u l t i n g t r a n s t e n t o r i a l h e r n i a t i o n , h i g h levels o f both enzymes persisted or even increased until death e n s u e d ( F i g . 1, o p e n circles). F r o m t h e d a t a o f Fig. 1 w e c o n s i d e r e d t h a t s a m p l e s for determination
of CK-BB
should
preferably
be
d r a w n w i t h i n six h o u r s p o s t i n j u r y a n d f o r N S E w i t h i n 24 h o u r s . I n six o f t h e g r o u p 2 p a t i e n t s t h e first b l o o d s a m p l e w a s d r a w n b e t w e e n 6 a n d 24 h o u r s p o s t i n j u r y . H e n c e (cf. M e t h o d s a n d M a t e r i a l s ) , o f t h e 60 p a t i e n t s
108
I . M . Skogseid et al. Increased Serum Creatine Kinase BB and Neuron Specific Enolase GROUP 1 140
140
u, 120
~120
m 100
m 100
I
GROUP 2
160
160
co
80
a9
o
o
60
60
'\
40
4o o)
r
20
20 3
6
9
12
15
18
21
i
i
3
6
9
9
12
,
15
18
21
TIME AFTER INJURY (hoursl
TIME AFTER INJURY (hours)
160
160 B
140
I40
12o
120
I00
100
:I uJ
~_ 80 =m s0 n-"
uJ 40 9
/_o-
