Studies on homocarnosine in cerebrospinal fluid in infancy and childhood. Part II. Homocarnosine levels in cerebrospinal fluid from children with epilepsy, febrile convulsion or meningitis

Studies on Homocarnosine in Cerebrospinal Fluid in Infancy and Childhood. Part II. Homocarnosine Levels in Cerebrospinal Fluid from Children with Epilepsy, Febrile Convulsion or Meningitis Hiroshi Takahashi, MD

To clarify the pathophysiological role of homocarnosine in the cerebrospinal fluid (CSF) in children, homocarnosine levels in CSF were determined in patients with epilepsy (32 cases), febrile convulsion (5 cases) and meningitis (42 cases) with a high speed amino acid autoanalyzer (Hitachi Co.). Mean homocarnosine levels in CSF of controlled epileptic children, uncontrolled epileptic children and febrile convulsion cases were 0.61 ± 0.25 p.mol/dl, 1.03 ± 0.37p.mol/dl and 1.09 ± 0.04 p.mol/dl, respectively. High homocarnosine levels in CSF of children with uncontrolled epilepsy or febrile convulsion may indicate the reduced turnover rate from homocarnosine to GABA. In patients with meningitis, the unconscious states were accompanied by significantly lower homocarnosine levels in CSF (0.39 ± 0.20 p.mol/dl) than those in the patients with clear conscious states (0.91 ± 0.31 p.mol/dl), however, in patients with clear conscious states homo carnosine levels in CSF were almost the same as those of normal children (0.89 ± 0.23 p.mol/dl). These data suggest that homocarnosine in CSF might be related to the convulsive tendency and consciousness. Takahashi H. Studies on homocarnosine in cerebrospinal fluid in infancy and childhood. Part II. Homocarnosine levels in cerebrospinal fluid from children with epilepsy, febrile convulsion or meningitis. Brain Dev 1981;3:263-70

Homocarnosine (gamma-aminobutyryl-L-histidine), a dipeptide of gamma-aminobutyric acid and histidine, was first isolated and identified from bovine brain by Pisano et al [1] in 1961 and it was reported by Abraham et al [2] and Kanazawa et al [3] that homo carnosine was From the Department of Pediatrics, Juntendo University School of Medicine, Tokyo.

Received for pUblication: December 4, 1980. Accepted for publication: February 23, 1981.

Key words: Homocarnosine, cerebrospinal fluid, GABA (gamma-aminobutyric acid), epilepsy, menin· gitis, febrile convulsion. Correspondence address: Dr. Hiroshi Takahashi, Department of Pediatrics, Juntendo University, 3-1-3, Hongo, Bunkyo-ku, Tokyo 113, Japan.

specific to the central nervous system as well as gamma-aminobutyric acid. In part I of this study [4], the author reported that the homocarnosine level in CSF changed with age and reflected the maturation of the brain. It has been reported that homocarnosine in the brain decreases in Huntington's chorea [5, 6] and increases in the malnutritional state with various neurological symptoms [7-9], phenylketonuria [10-12] and familial spastic diplegia (13-16]. These reports suggest that homocarnosine in CSF might play some pathophysiological roles in various diseases of the central nervous system in children. To clarify the pathophysiological roles of homocarnosine in CSF, the author determined homocarnosine in CSF of children with epilepsy, febrile convulsion and meningitis, and discussed the relationship between homocarnosine levels in CSF and neurological symptoms such as epileptic convulsion and consciousness disturbance.

Materials and Method The subjects tested were 37 cases with convulsive disorders and 42 cases with neuroinfections. Epileptic patients with grand mal or hemiconvulsion were divided into two groups: uncontrolled and controlled epileptic groups (Tables 1 and 2). CSF homocarnosine was identified and determined by the same method as mentioned in Part I of this study [4] .

epileptic children, febrile convulsion cases and normal children. Mean homo carnosine levels in CSF of the controlled and uncontrolled epileptic groups were 0.61 ± 0.25 Ilmol/dl and 1.03 ± 0.37 J1IlloIjdl, respectively. Significant differences of homocarnosine levels in CSF were found between the controlled epileptic group and the normal group (0.75 ± 0.24 Ilmol/dl) [4] (p < 0.1), between the uncontrolled and controlled epileptic groups (p < 0.01), and between the uncontrolled epileptic group and the normal group (p < 0.001), respectively. Table 4 and Fig 1 show the homocarnosine levels in CSF of the normal, controlled and uncontrolled epileptic groups divided into different age groups. The homocarnosine levels in CSF in febrile convulsion shown in Table 3 are 1.09 ± 0.04 Ilmol/dl, which is Significantly higher than those in controlled epilepsy (p < 0.001), but almost the same as those in uncontrolled epilepsy. In the cases of from 1 to 5 years, because the age distribution of the cases with febrile

Table I No of patients with convulsive

disorders

Uncon· trolled and Total Male Female controlled (ratio) No of patients

Age 14 daysGrand mal 15 yrs Hemicon- 1 mo9 yrs vulsion

Results 1. Epilepsy and Febrile Convulsion Table 3 shows homo carnosine levels in CSF of

25

18

7

15:10 (20*:10)

7

3

4

6:1

5

2

3

Febr~e con- 1-5 yrs

vulSlOn

*Twenty specimens were collected from 15 uncontrolled cases.

Table 2 No of patients with neuroinfections No of patients Agents (No)

Age Total

Male

Female

Bacterial meningitis

5 days-6 yrs

17

8

9

HemophilUS (4) E. coli (3) Pneumococcus (2)

Viral meningitis

3 mos-14 yrs

25

17

8

Mumps (3) Varicella (1)

42

25

17

Total

264 Brain & Development, Vol 3, No 3,1981

convulsion is limited to from 1 to 5 years old, the homocarnosine levels in CSF in febrile convulsion are significantly higher than those of controlled epileptic children (p < 0.05), but remarkably near to those in normal and uncontrolled epileptic children.

2. Meningitis There was no significant difference of homocarnosine levels in CSF between bacterial and viral meningitis in the acute phase. The mean levels of homocarnosine in CSF in bacterial and viral meningitis were 0.69 ± 0.38 Ilmol/dl (n = 17) and 0.81 ± 0.29 Ilmol/dl (n = 24), respectively. In the cases with meningitis complicated with convulsion, homocarnosine levels in CSF were 0.51 ± 0.29 Ilmol/dl (n = 13). On the other hand, in the cases with meningitis but without convulsion, homo carnosine levels in CSF were 0.78 ± 0.30 Ilmol/dl (n = 125). A significant difference of homocarnosine levels in CSF was found between the cases with and without convulsion (p < 0.005). The relationship between homo carnosine levels in CSF and the grade of consciousness of patients with meningitis is shown in Fig 2. Consciousness was divided into three grades: clear, somnolence and coma. The patients' ages checked were ranged from 1 month to 5 years of age, excluding newborn cases where the consciousness level was difficult to judge. There was no significant difference between CSF homocarnosine levels in meningitis cases with clear consciousness (0.91 ± 0.31 Ilmol/dl, n = 68) and those in the normal controls (0.89 ± 0.23 J.Lffiol/dl, n = 23). However, significant

differences of homo carnosine levels in CSF were found between the normal and coma groups (0.39 ± 0.20 J.Lffiol/dl, n = 13) (p < 0.001), between the clear and somnolence groups (0.67 ± 0.32 Ilmol/dl, n = 16) (p < 0.01), between the clear and the coma groups (p < 0.001), between the somnolence and the coma groups (p < 0.01), respectively. On the other hand, the correlation between homocarnosine levels in CSF and cell counts in CSF was not significant. The correlation between homo carnosine levels in CSF and protein content in CSF was significant (r = -0.41, p < 0.001). The correlation between homocarnosine levels in CSF and sugar content in CSF was also significant (r = 0.36, p < 0.001). Fig 3 shows the alteration of homocarnosine levels in CSF of the patients with meningitis at the acute phase and the convalescence. Some cases have relatively lower homocarnosine levels in CSF, but the other have relatively higher homo carnosine levels in CSF at the acute phase. There was no uniform pattern in the alteration of homo carnosine levels in CSF through the clinical course of meningitis.

Table 3 Homocarnosine levels in CSF of

controlled and uncontrolled epilepsies, and febrile convulsion (Ilmolfdl) Diseases

Mean

SD

No

Normal Epilepsy (controlled) Epilepsy (uncontrolled) Febrile convulsion

0.75 0.61 1.03 1.09

0.24 0.25 ± 0.37 ± 0.04

49

±

±

±

11

26 5

Table 4 Homocarnosine levels in CSF of normal, controlled and uncontrolled epileptic children (Ilmolfdl) Age

Preterrn 40-43 wks 44 wks-11 mos 1-5 yrs 6-8 yrs 9-12 yrs Total

Normal 0.53 0.60 0.85 0.93 0.84 0.61

±

0.09 0.05 0.19 ± 0.27 ± 0.18 ± 0.23

0.75

±

± ±

0.24

No

Controlled

8 6 (p < 0.05) 11 (p < 0.005) 12 6 6

0.78 ± 0.17 0.49 ± 0.14 0.66 ± 0.41 0.42

49 (p < 0.1)

0.61

±

0.25

No 0 3 4 (p < 0.05) 3 (p < 0.1) 1 0

11 (p < 0.01)

Uncontrolled 0.83 ± 0.15 1.04 ± 0.42 1.25 ± 0.37 1.09 ± 0.23 1.02 ± 0.54 1.03

±

0.37

No 0 6 9 5 2 4 26

Between the cases of normal children and uncontrolled epilepsy, the differences of homocarnosine levels in CSF were significant in the cases from 40 to 43 weeks of gestation (p < 0.05), and the cases from 1 to 5 years of age (p < 0.1). Takahashi: Homocarnosine in CSF 265

'6 "0

1.5

---E

'l

l1:' (/) U .f

1.0

II)

Q;

> ..!!

.,

c ·iii

g :;;

Fig 1 Mean homocarnosine levels in CSF from normal children, patients with controlled and uncontrolled epilepsy. c:==J: normal children, ~ : controlled epilepsy, ~ : uncontrolled epilepsy.

0.5

o

o o J:

E

40-43weeks

.,c

44weeks-llmonths 1-5 years

..............- ..

normal

II) II)

6-8 years

9-12 years

aU ages

O.89±O.23(n=23)

II)

:J 0

·0

-.,

clear

II)

c

... I · .. WI

,...

0

r-o-a---

O.91±O.31(n=68)

0

0

somnolence

O.67±O.32(n=16)

."

(B'"

.,.

O.39±O.20{n=13)

Homocarnosine levels in CSF(l'mol/dl)

2.0

I

I I

-----+--I

I

~

~

"0 E ::\. 1.5

lL' II)

I I

I I I I I

()

I

.s UI

"ii 1.0 > ~

CD

.50

UI

o C

~

o

0.5

E

o

:r

Acute phase

convalescence

Course of meningitis

266 Brain & Development, Vol 3, No 3,1981

Fig 2 Homocarnosine levels in CSF from normal children, and patients with viral and I bacterial meningitis divided into 3 groups according to the grade of consciousness.

Discussion The relationship between homocarnosine levels in CSF and convulsion with epilepsy, fever and meningitis, and the relationship between homocarnosine levels in CSF and the conscious state through the clinical course of meningitis can be discussed. 1) Homocarnosine and Convulsion The homocarnosine levels in CSF of uncontrolled epileptic children were statistically higher than those of normal children, in the cases of from 40 to 43 weeks of gestation (p < 0.05), and from 1 to 5 years of age (p < 0.1). However, the homo carnosine levels. in CSF of controlled epileptic children were lower than those of normal children in the cases of from 40 to 43 weeks of gestation (p < 0.05), and from 44 weeks of gestation to 11 months of age (p < 0.005). Gamma-aminobutyric acid (GABA), a component of homocarnosine, has been recognized as a neuroinhibitory transmitter [17-22], and as an anticonvulsive agent [23-26] . High homocarnosine levels in CSF of uncontrolled epileptic children may indicate a reduced conversion of homo carnosine to GABA, because homocarnosine may be considered to be a pool of GABA [10]. However, Perry et al [27] reported that the average levels of GAB A and homo carnosine in human cortical epileptogenic foci were significantly higher than those of non-epileptic cortex. Hayashi [23, 28] reported the anticonvulsive effect of homocarnosine administered directly to the brain. On the other hand, it has been said that chronic cerebellar stimulation inhibited a convulsion in intractable epileptics [29-32] and the high levels of homo carnosine and GABA in the cerebellum [2, 33,34] may act as inhibitor for convulsions. Therefore further study is needed to understand the mechanism of elevation of homo carnosine levels in CSF of uncontrolled epileptic children. According to the reports on the influence of anticonvulsants on the GABA level in the brain, anticonvulsants, such as phenobarbital, mephobarbital, primidone, phenytoin and mephenytoin [35], and sodium valproate [36-38] were demonstrated to increase the GABA level in the brain. MacDonald and Betbesda [39] and Ransom and Barker [40] found that GABA-

mediated post synaptic inhibition was enhanced in cultured mammalian neurons by phenobarbital. Julien and Halpern [41] reported that Purkinje cell discharge was increased and cortical epileptiform bursts were decreased by phenytoin. The epileptic patients (controlled and uncontrolled) in the present study have been managed with one or more anticonvulsants among the following drugs; phenobarbital, diphenylhydantoin, sodium valproate, primidone, diazepam, carbamazepine and clonazepam. 2) Homocarnosine and GABA Marshall and Yockey [42] found that homocarnosine content was decreased and GABA content was increased in brain by administration of hydrazine derivatives, whereas homocarnosine also decreased but GABA was not increased by administration of reserpine. Marshall [43] reported that the homo carnosine level in rat brain was lowered by administration of reserpine, chlorpromazine and nembutal, and these results suggest the direct effect of these drugs on the enzyme synthesizing homocarnosine in brain. Perry et al [44] revealed that GABA level was elevated and the homocarnosine level lowered by administration of sodium valproate in rat brain. These studies suggest that the increase of brain GABA may be caused by the inhibition of GABA-transaminase and succinic semialdehyde dehydrogenase [45] and some metabolic changes of homocarnosine by the administration of anticonvulsants. In other words, these anticonvulsants may influence homocarnosinase [46] and/or homocarnosine synthetase [47]. The homocarnosine levels in CSF of epileptic children controlled with anticonvulsants also decreased in the present study and this is remarkably similar to the data of Marshall et al [42-44]. 3) Homocarnosine and Consciousness The author noticed that comatous patients in the present study had significantly lower homocarnosine levels in CSF than normal patients. All unconscious cases of this study, however, are the patients with meningitis. It is possible to think that decreased homo carnosine levels in CSF may be consequence of inflammation. On the other hand, some cases had relatively lower homocarnosine levels in CSF at the acute Takahashi: Homocarnosine in CSF 267

phase, but the other had relatively higher homocarnosine levels in CSF at the acute phase (Fig 3). The homocarnosine·levels in CSF were not always parallel with the grade of inflammatory signs, such as increasing leucocyte count, protein and sugar content in CSF. Therefore, it is not precisely correct that low homocarnosine levels in CSF may be a consequence of meningeal inflammation. Consciousness seems to be concerned with GABA. It is well-known fact that consciousness is controlled by reticular formation and hypothalamus. Homocarnosine and GABA in human hypothalamus are relatively high in concentration [3, 33, 48] and GABA level is high in corpus striatum and midbrain in pig [49]. According to Jasper's report [50], in cat brain showing sleeping stage of electrocorticogram, the rate of release of GABA was higher than in animals showing aroused stage. Anden et al [51] reported that baclofen ({3-p-chlorophenyl'Y-aminobutyric acid), a derivative of GABA, induced drowsiness in Huntington's chorea patients. Since homo carnosine may be the pool of GABA as suggested in Part I of this paper [4], homocarnosine levels in CSF might be concerned with the state of consciousness. Conclusion To clarify the pathophysiological significance of homocarnosine in infancy and childhood, homocarnosine levels in CSF were determined in 32 cases with epilepsy, 5 cases with febrile convulsion, 17 cases with bacterial meningitis and 25 cases with viral meningitis using an amino acid auto analyzer (Hitachi Co.). 1. Mean homo carnosine levels in CSF of controlled and uncontrolled epileptic children were 0.61 ± 0.25 /lmol/dl (n = 11) and 1.03 ± 0.37 J1illol/dl (n = 26), respectively. Significant differences of homocarnosine levels in CSF were present between controlled and uncontrolled epileptic children (p < 0.01), between controlled epileptic children and normal children (p < 0.1), and between uncontrolled epileptic and normal children (0.75 ± 0.24 /lmol/ dl, n = 49) (p < 0.001). 2. Mean homocarnosine levels in CSF of febrile convulsion cases was 1.09 ± 0.04 J1illol/dl (n = 5), which were significantly higher than those of controlled epileptic children. However, no significant differences of homocarnosine 268 Brain & Development, Vol 3, No 3,1981

levels in CSF were detected between febrile convulsion cases and normal children, and between febrile convulsion cases and uncontrolled epileptic children, aged from 1 to 5 years of age. 3. Although there was no significant difference of homo carnosine levels in CSF between normal children (0.89 ± 0.23 /lmol/dl, n = 23) and meningitic children with clear consciousness (0.91 ± 0.31 J1illol/dl, n = 68), significant differences of homocarnosine levels in CSF were found between normal and somnolent cases (0.67 ± 0.32 J1illol/dl, n = 16, P < 0.01), between normal and comatous cases (0.39 ± 0.20 /lmol/dl, n = 13, p < 0.001), between clear and somnolent cases (p < 0.01), between clear and comatous cases (p < 0.001), and between somnolent and comatous cases (p < 0.01), respectively. 4. Elevation or high homo carnosine levels in CSF of epileptic children unable to be controlled may indicate a reduced conversion of homo carnosine to GABA in brain, because homocarnosine is considered to be a pool of GABA. 5. In the cases with meningitis, the poor conscious state was accompanied by low homocarnosine levels in CSF. The data obtained suggest that homocarnosine in CSF might be related to the convulsive tendency and consciousness. Acknowledgments The author would like to thank Prof. H. Kato and Associate Prof. C. Ohtsuka for their valuable advice and for reviewing tlJ.is paper, and also K. Murayama, Ph.D. and her coworkers for their technical assistance. References 1. Pisano JJ, Wilson JD, Cohen L, et al. Isolation of 'Y-aminobutyryl-histidine (homo carnosine) from brain. J BioI Chern 1961;236:499-502. 2. Abraham D, Pisano JJ, Udenfriend S. The distribution of homocarnosine in mammals. Arch Biochern Biophys 1962;99:210-3. 3. Kanazawa A, Sano I. A method of determination of homocarnosine and its distribution in mammalian tissues. J Neurochern 1967;14:211-4. 4. Takahashi H. Studies on homocarnosine in cerebrospinal fluid in infancy and childhood. Part I. Homocarnosine level in cerebrospinal fluid of normal infants and children. Brain Dev (Tokyo) 1981;3:255-61. . 5. Urquhart N, Perry TL, Hansen S, et al. GABA content and glutamic acid decarboxylase activity in brain of Huntington's chorea patients and con-

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TakahaShi: Homocarnosine in CSF 269

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