Journal of the Neurological Sciences, 103 (1991) $43-$47

1991 Elsevier Science Publishers B.V. 0022-510X/91/$03.50 JNS 03592

$43

CDP-choline in the treatment of cranio-encephalic traumata

R. L o z a n o
Ferrer S.A., 94 Gran Via Carlos 111, E-08028 Barcelona (Spain)

It has been shown in numerous experimental studies that the administration of cyticholine (CDP-choline) gives rise to a significant regression of cerebral edema as well as an improvement in the graphs of the EEG, the alteration of consciousness and of survival. This effect is attributable to its facilitating action on the electroencephalographic reaction of waking, provoked by the stimulation of the ascending reticular activating system at brain stem level by means of its action on the protection of the neuronal membrane and on the synthesis of neurotransmitters. With these experimental premises numerous clinical studies were carried out in order to determine whether these effects are translated in the treatment of patients suffering from cranio-encephalic traumata. In 1967, Moriyama et ai. [1] published their study of the effects of CDP-choline in 25 patients with cranial trauma and depression of the consciousness level, showing its effectiveness with recuperation of the neurological clinical symptoms and the state of consciousness in 70% of cases and, on the other hand, the perfect tolerance of the product which produced no secondary effects. The same authors had shown in an experimental study how the administration of cyticholine increased the P O 2 in the brain of the dog (Fig. 1). De La Herrfin et al. [2] studied the effects of the administration of CDP-choline in a series of 50 patients with deterioration of the level of consciousness which, in 32 cases, was of traumatic origin, in comparison with another series of patients with similar characteristics who were receiving the customary treatment. Fig. 2 shows the characteristics of the coma in these traumatic patients and Fig. 3 the results obtained, in terms of depth of coma. 34% of the patients recovered consciousness within the first 48 hours. Within the first 5 days 66% of the patients had regained consciousness, and these results were better than those obtained with the control group. They showed with these results how CDP-choline reactivates and accelerates the normalization of the state of consciousness in patients affected by cranio-encephalic traumata.

BPo 2

40

1 sec

CDP choline

lOOmg

Fig. 1. Modification of cerebral PO 2 of a dog by administration of 100 mg CDP-choline.

Carcassonne and LeTourneau [3] carried out a double-blind study with a series of 43 children with alteration of consciousness caused by traumas, having discarded the severe cases and those requiring surgery. Having analysed the results obtained, these authors came to the following conclusions: - CDP-choline is perfectly tolerated, locally as well as generally. - CDP-choline significantly accelerates the recuperation of a normal state of consciousness.

Patients

H Coma level

Fig. 2. D i s t r i b u t i o n o f patients according to level o f coma.

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% good r e s u l t s 1P" Pot ients

15 Days

60

90

>90

IT

TIT

IE"

/Placebo

~CDP-Choline

Level of coma Fig. 3. Percent of good results in terms of initial level coma.

Fig. 5. Development of motor deficit. * P < 0.04; * * P < 0.05.

- CDP-choline accelerates the disappearance of neuropsychic disorders and the impairment of cerebral electrogenesis. - CDP-choline confers a better quality on the evolution of the patients. Espagno et al. [4] compared the effects of cyticholine versus placebo in a series of 46 patients who had suffered a cranial trauma. They carried out a double-blind study in which 22 patients were given 250 mg a day Of parenteral cyticholine for 20 days and 24 patients a placebo. The results obtained showed that CDP-cholinc significantly accelerated (P<0.05) the recuperation of consciousness in less severe comas, whereas in the more severe comas and with the dose administered, which is nowadays considered insufficient, cyticholine improved the prognosis so that 75.2% of the patients of the placebo group presented a slow ~Jcuperation (> 15 days) of consciousness and/or development towards exitus; on the other hand, in the group treated with the active product, recuperation of consciousness beyond the 15th day was registered in 31% of the cases and the incidence of prolonged coma and/or exitus was 12.5%. In conclusion, with CDPcholine, an earlier recovery of consciousness and a greater number of clinical and electroencephalographic

improvements were obtained, and it was, furthermore, perfectly well tolerated. Richer and Cohadon [5] carried out a double-blind study with a group of 60 coma patients of trauma etiology, divided into two homogenous groups, one of which was given the active drug (cyticholine) and the other a placebo. As regards the duration of the coma (Fig. 4), the number of patients who had regained consciousness after 60 days was significantly greater (P < 0.01) in the group treated with cyticholine. After 90 days, the improvement in the motor deficit was better (P < 0.04) in the group treated with cyticholinc (Fig. 5). It was also shown that in the active drug group the recovery of walking ability was significantly accelerated (Fig. 6). Consequently, the rehabilitation in the group treated with cyticholinc was greater (P < 0.06) at day 60. This demonstrated the restrictive effect of CDP-cholinc on the duration of a post-traumatic coma as well as its contribution to the recovery of deficits in connection with enccphalic lesions associated with these comas. On the other hand, the mortality was not changed by these treatments. In a double-blind trial, Lecuire and Duplay [6] compared the effects of endovcnous cyticholinc at a dose of 750 mga day with those of mcchlophcnoxate at an cndovenous dose of 3 g/day in a group of 25 patients.
Patients

'i[
15 OL

Patients

'iI
15 60

90

>90

60

90 Days

>90

Days ~ Placebo ~CDP-Choline Placebo

r--ICDP-Choline

Fig. 4. Duration of coma. * P < 0.01.

Fig. 6. Recove~ of walking ability. * P < 0.03, * * P < 0.001.

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Improvement 60 E E.G (%)

50

40

/CDP-Choline [ ]

Mechlophenoxote

Fig. 7. Improvementof EEG after 10 daysof treatment. The analysis of the results showed a significant improvement in the group of patients treated with CDP choline, especially in reference to the recovery of consciousness, the modification in the EEG and functional recuperation. The average duration of coma was 10 days in the cyticholine group, and in the mechlophenoxate group, 20 days. At 10 days, the EEG graph had improved in 50% of the patients treated with CDPcholine and in 18% of those receiving mechlophenoxate. In conclusion, cyticholine was shown to be superior to mechlophenoxate, its main characteristic being the acceleration of the recovery of consciousness, which is related to an improvement in the EEG graph (Fig. 7). The same authors carried out an open study with a series of 154 patients with cranio-encephalic traumata [7], in which they evaluated the effects of the treatment with CDP-choline; they reported that this drug accelerated the waking of the patients and the recovery of the deficit syndromes, as well as improving the quality of survival. Subsequently, Lecuire [8] carried out a double-blind study, comparing pyracetam (6 g/day) with cyticholine (750 mg/day) in a group of 40 patients suffering from

the effects of a head injury and reported that in 75% of the group of patients receiving CDP-cboline the development was favourable, compared to 33% in the group with pyracetam ( P < 0.01). De Bias et al. [9], in a controlled open study, with treatment from the first day with cyticholine, and continuing the medication over a period of 6 months found: (a) in patients with subreactivity I CDP-choline improved all symptoms studied, especially attention, concentration ( P < 0.05); (b) in grades II and Ill, cyticholine reduced the duration of the coma. Altogether, cyticholine improved the motor deficit, attention/ concentration, memory and some aspects of WAIS, as well as the electrophysiological tests carried out. Lozano et ai. [10] compiled a retrospective series of 180 patients with cranio-encephalic trauma who were treated as outpatients and reported some excellent results with the administration of cyticholine at doses of between 200 and 1000 mg a day for periods of no more than 60 days. The development of the clinical symptomatology was controlled during the whole treatment period. The index of total or partial remission of the symptomatology was significant ( P < 0.001), especially in the psychosocial area. These results are an indication of the usefulness of the product in the rehabilitation phase of cranio-encephalic traumatism. Only 3 patients (1.66%) presented any secondary effect, which, in any case, was of little magnitude. Ogashiwa et al. [11] carried out a clinical trial on 101 patients with impaired levels of consciousness of varied etiology (20% traumatic cause), showing the efficacy of cyticholine in raising the general improvement rate (GIR), which is closely associated with the Principle Component Analysis Score (PCA score). They found the CDP-choline was mclre effective with the items associated with the executive factor, F1, than with those associated with the verbal factor, F2 (Fig. 8), and the best results were obtained in patients under 60

F1

Answer to coil Quality of voice Spontaneous speech Attention Spontaneous movement Attitude during examination Orientation (pers.) Orientation (spatial) Orientation (temp.) Volition Consciousness Reflection

. . . . . :-:: . . . . . . . . . :, : _

T-,|i . . . . . . . . _...._, .....

.

i: - . ~ - - - j
.

:.]

............................

:-, . . . . . .

....

:i

.....................

,:. _ ~ i

F2

10

20

30

40
r"-3 Control

50

60

=1= i m p r o v e m e n t

Fig. 8. Rate of improvement of individual symptoms.

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FACTOR OF S T R A T I F I C A T I O N

TABLE 1
D+
c

15-59 years Age 60-96

HOMOGENEITY OF THE GROUPS

years

D C !

[
1 ! . I,,

,!

Control Sex Male Female Age (years) Height (cm) Weight (kg) Time (min) between accident and admission of transfer
28 11 34.4 16.7 169.1 9.1 71.7 8.2 51.329.9 (grade 5-240) 32.8 17.9 (grade 5-120)

CDP-choline
32 7 31.1 + 8.99 170.4+ 3.4 68.8+ 10.02 52.526.5 (grade 8-210) 48.1 35.7 (grade 8-210)

Duration

of of

<3 weeks

D C

. I !

Deterioration
Consciousness Stable period of d e t e r i o r a t i o n

>3

weeks

O
c
D C D c

[
--r-Tq
I

< 3 weeks

of consciousness

> 3 weeks

Fig. 9. Stratified comparison of improvement of GIR. D, CDPcholine; C, control, r-a, slight improvement; [], obvious and moderate improvement.

25

Patients

years of age and with a period of stabilized deterioration of consciousness of no more than 3 weeks (Fig. 9). They also underlined the excellent tolerance of the product. Recently, the experience of 3 national neurosurgical centres in the application of cyticholine for the treatment of cranio-encephalic traumas was summarized, and for this 39 patients treated with CDP-choline who met the following criteria, were selected: - Initial score of 5-7 on the Glasgow Coma Scale. - No open cranio-encephalic lesion, no intracranial pathology requiring immediate surgery, no associated systemic lesions clouding the prognosis. These 39 patients were compared with a series of 39 eases of similar characteristics who had not received cyticholine. Table 1 shows the analysis of homogeneity of the groups with respect to sex, age, height, weight and time elapsed before attendance, and Fig. 10 the distribution according to the GCS, and no significant differences were found between the groups. In all cases, an initial and final CT was carried out in order to evaluate the development of the cerebral

15

6 C.G.S. r--I

Control

Fig. 10. Homogeneity in GCS. No significant difference.

edema picture. Further parameters investigated were the duration of hospitalisation and degree of autonomy at the time of discharge. The cyticholine was administered during the first 2 weeks at a dosage of 3-6 g a day, by continuous endovenous perfusion. In Table 2 the lesions presented by patients at the time of admission are summarized, and it is noted that
Unchanged
20

Unchanged

Reduced
26

Reduced
CDP- C h o l i n e C ant rol

15

Fig. 11. (a) Development of tomographic picture of cerebral edema in patients treated with CbP-choline. (b) Development of tomographic picture of the cerebral edema in the control group ( P < 0.005).

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TABLE 2 LESIONS AT TIME OF ADMISSION CDP-choline CET DAI Cerebral contusion Skull fracture Cerebral edema Associated lesions
* P < 0.01.

Control 39 9 24 17 * 36 25

39 9 25 8* 35 20

there were only significant differences in the incidence of cranial fracture ( P < 0.01). After 14 days of treatment, the tomographic image of the brain edema developed as shown in Fig. 11, and it is noted that in the group of patients treated with CDP-choline, this development is more favourable than in the control group, showing highly significant differences (P < 0.005). Regarding the therapeutic requirements, no significant differences were observed between the groups, and the same applies to treatments received. The average stay in hospital was 28.7 +_ 21.6 days for the group having received cyticholine and 37.3 _+35.2 for the control group, showing statistically significant differences ( P < 0.001). Fig. 12 shows the end results, evaluated in accordance with the Glasgow Outcome Scale; however, owing to the small number of cases and the special characteristics of this type of patient, the differences do not reach statistical significance. However, a more favourable tendency in the group of patients treated with cyticholine may be observed. In conclusion, having reviewed the clinical studies published, we can say that in cases of cranio-encephalic
Potients
16 14 12

traumatism, CDP-choline: (1) reduces the duration of post-traumatic coma; (2) reduces the incidence and severity of psychic and motor sequelae; (3) reduces the duration of stay in hospital; (4) promotes the rehabilitation of the patient; (5) is very well tolerated with hardly any incidence of secondary effects. It may be stated in conclusion that it was shown that patients affected by cranio-encephalic traumata benefit from the inclusion of CDP-choline in the general therapeutic schedules, since it has a favourable effect on the development of cerebral edema and the recovery of consciousness, as well as the neurological disorders, resulting in a shorter period of hospitalisation and a better quality of survival.

References
1 M. Moriyama, T. Tsukumo y Y. Nakagawa: "'Effects of CDPcholine on head injury". Gendai no Rinsho, 1(2): 114-120, 1967. 2 J. De La Herrfin, C. Cortina, J. Salazar y F. Fernfindez: "Utilizaci6n del citidindifosfato de colina en las lesiones enceffilicas graves". Actas Luso-Espafiolas de Neurologia, Psiquiatr[a y Ciencias Afines, 6(2): 3-12, 1978. 3 M. Carcassonne y J.N. LeTourneau: "l~tude double insu du R6xort en neuro-traumatologie infantile". La Vie M6dicale, 12: 1007, 1979. 4 J. Espagno, M. Tremoulet, M. Gigaud y C. Espagno: "l~tude de l'action de la CDP-choline dans les troubles de la vigilance post-traumatique". La Vie M6dicale, 3: 195-196, 1979. 5 E. Richer y F. Cohadon: "Essai th6rapeutique d'un pr6curseur des phospholipides sur le traitement des comas traumatiques". Symposium International: Souffrance C6r~brale et Pr~curseurs des Phospholipides, Paris, 18 de Enero de 1980. 6 J. Lecuire y J. Duplay: "Sperimentazione in doppio cieco della citicolina versus meclofenossato in pazienti colpiti da trauma cranico". Giorn. Ital. di Richerche Cliniche e Terapeutiche, 3: 51-55, 1982. 7 J. Lecuire y J. Duplay: "Sperimentazione delia citicolina in un campione di 154 traumatizzati cranici". Gior. Ital. Rich. Clin. Terap., 3: 61-67, 1982. 8 J. Lecuire: "Traumatismes crfinienr Etude comparative Piracetam-CDP-choline". CR Ther. Pharmacol. Clin., 3(30): 3-7, 1985. 9 A. de Blas, J. Martinez-Cubells y C. Hernando: "Valoraci6n de la efectividad de la citicolina en el tratamiento de los traumatismos craneoencefiilicos". Med. Clin. (Bare.), 87 (Supl. I): 41-44, 1986. I0 R. Lozano, A. Balaguer y V. Fermlndez: "Estudio de 180 pacientes que sufrieron traumatismo craneoenceffilico tratados con CDP-colina". Archivo m6dico F.I.S.A. I I M. Ogashiwa, K. Sano, S. Manaka, K. Kitamura, M. Kagawa y K. Takeuchi: "Effectiveness of CDP-choline on disturbance of consciousness (DOC): '. An experimental study of concussive head injury in mice. 2. A controlled trial in patients with DOC", en V. Zappia, E.P. Kennedy, B.I Nilsson y P. Galletti eds.: "Novel biochemical, pharmacological and clinical aspects of cytidinediphosphocholine". Elsevier Science Publ. Co., New York, 1985; pp: 317-327.

lO

OJ

m"

EZ

G.O.S. Control

Fig. 12. Final results evaluated in accordance with the GOS. No significant differences.