Journal o f the Neurological Sciences, 103 (1991) $43-$47 $43 © 1991 Elsevier Science Publishers B.V. 0022-510X/91/$03.50

JNS 03592

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 syn- thesis 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 neu- rological clinical symptoms and the state of conscious- ness 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 cyti- choline 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 pa- tients with deterioration of the level of consciousness which, in 32 cases, was of traumatic origin, in compari- son with another series of patients with similar charac- teristics 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 normal- ization of the state of consciousness in patients af- fected by cranio-encephalic traumata.

B P o 2

40

1 s e c

CDP c h o l i n e l O O m g

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

Carcassonne and LeTourneau [3] carried out a dou- ble-blind study with a series of 43 children with alter- ation of consciousness caused by traumas, having dis- carded 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 recupera-

tion of a normal state of consciousness.

Patients

- l H m

Coma level

Fig. 2. D is t r ibu t ion o f pat ients according to level o f coma.

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% good resu l t s

1P"

Pot ients

I IT TIT IE"

Level of coma

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

- CDP-choline accelerates the disappearance of neu- ropsychic disorders and the impairment of cerebral electrogenesis.

- CDP-choline confers a better quality on the evolu- tion of the patients. Espagno et al. [4] compared the effects of cyti-

choline 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 insuffi- cient, 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 de- velopment 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 CDP- choline, an earlier recovery of consciousness and a greater number of clinical and electroencephalographic

Patients

'i[ 'iI 15

OL 15 6 0 90

Days

~ Placebo ~ C D P - C h o l i n e

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

>90

1 ~ 15 60 90 >90

Days

/ P l a c e b o ~ C D P - C h o l i n e

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

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 acceler- ated (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] com- pared 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

1 6 0 90 >90

Days

Placebo r - - ICDP-Cho l ine

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

I m p r o v e m e n t E E . G ( % )

6 0

5 0

4 0

/CDP-Choline [ ] Mechlophenoxote

Fig. 7. Improvement of EEG after 10 days of treatment.

The analysis of the results showed a significant im- provement in the group of patients treated with CDP choline, especially in reference to the recovery of con- sciousness, the modification in the EEG and functional recuperation. The average duration of coma was 10 days in the cyticholine group, and in the mechlophe- noxate group, 20 days. At 10 days, the EEG graph had improved in 50% of the patients treated with CDP- choline and in 18% of those receiving mechlophenox- ate. In conclusion, cyticholine was shown to be supe- rior 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 acceler- ated 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

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the effects of a head injury and reported that in 75% of the group of patients receiving CDP-cboline the devel- opment 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 con- tinuing 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, cyti- choline 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 treat- ment period. The index of total or partial remission of the symptomatology was significant (P < 0.001), espe- cially 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 ef- fect, 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 improve- ment 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

F2

Answer to coil Quality of voice Spontaneous speech At tent ion Spontaneous movement Att i tude during examination Orientat ion (pers.) Orientation (spatial)

Orientat ion (temp.)

Volition Consciousness

Reflection

, : . . . . . :-:¥: . . . . . T-,|i . . . . . . . . i : - . ~ - - - j

. . . . :, : _ _ . . . . _ , . . . . . . . : . ]

............................ :-, ...... .... :i

..................... ,:. _~i

0 10 20 30 40 =1= improvement

r"-3 Control

I 50 60

Fig. 8. Rate of improvement of individual symptoms.

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FACTOR OF STRATIF ICATION

A g e

15 -59 yea rs D + I

c

6 0 - 9 6 years D [ , !

C ! 1

< 3 w e e k s D ! . I D u r a t i o n of

C . I, , ! Deterioration of

> 3 weeks O [ J Consciousness

c - - r - T q

Stable per iod < 3 weeks D I

of d e t e r i o r a t i o n C D

of consciousness >3 weeks [ 1 c

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

ate improvement.

years of age and with a period of stabilized deteriora- tion 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 neuro- surgical centres in the application of cyticholine for the treatment of cranio-encephalic traumas was summa- rized, 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 associ- ated 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

Unchanged

• 9

TABLE 1

HOMOGENEITY OF THE GROUPS

C o n t r o l CDP-choline

Sex Male Female

Age (years) Height (cm) Weight (kg) Time (min)

between accident and admission of transfer

28 32 11 7 34.4± 16.7 31.1 + 8.99

169.1± 9.1 170.4+ 3.4 71.7± 8.2 68.8+ 10.02

51.3±29.9 52.5±26.5 (grade 5-240) (grade 8-210)

32.8± 17.9 48.1 ±35.7 (grade 5-120) (grade 8-210)

P a t i e n t s 25

15

5 6 7

C.G.S.

r - - I C o n t r o l

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 2 0

Reduced

26 Reduced 15

CDP- C h o l i n e C a n t ro l

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).

TABLE 2

LESIONS AT TIME OF ADMISSION

CDP-choline Control

CET 39 39 DAI 9 9 Cerebral contusion 25 24 Skull fracture 8 * 17 * Cerebral edema 35 36 Associated lesions 20 25

* P < 0 .01 .

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 differ- ences (P < 0.005).

Regarding the therapeutic requirements, no signifi- cant 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 accor- dance with the Glasgow Outcome Scale; however, ow- ing 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

16

14

12

lO

OJ

Potients

I K m" EZ

G.O.S.

Con t ro l

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

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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 rehabili- tation 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 ther- apeutic 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 CDP- choline on head injury". Gendai no Rinsho, 1(2): 114-120, 1967.

2 J. De La Herrfin, C. Cortina, J. Salazar y F. Fernfindez: "Utili- zaci6n del citidindifosfato de colina en las lesiones enceffilicas graves". Actas Luso-Espafiolas de Neurologia, Psiquiatr[a y Cien- cias 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 Pirac- etam-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 pa- cientes 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 con- sciousness (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 cy- tidinediphosphocholine". Elsevier Science Publ. Co., New York, 1985; pp: 317-327.