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Journal of the Neurological Sciences, 103 (1991) $39-$42 1991 Elsevier Science Publishers B.V. 0022-510X/91/$03.

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JNS 03591

Treatment of postconcussional symptoms with CDP-choline


H.S. L e v i n
Dil'ision of Neurosurgery, The Unirersity of Texas Medical Branch at Gah'eston, Gah'eston, Texas (U.S.A.)

Summary
To evaluate the efficacy of cytidine diphosphoryl choline (CDP-choline) in treating postconcussional symptoms for one month after mild to moderate closed head injury (CHI), we completed a preliminary double blind placebo-controlled study. Fourteen young men admitted to the neurosurgery service after sustaining mild to moderate CHI were randomized to oral CDP-choline (l g) and placebo control groups which were matched for age, education and severity of impaired consciousness. Baseline (prior to discharge) and one month examinations consisted of a structured postconcussional symptom interview and neuropsychological tests. Results (Wilcoxon test) showed that CDP-choline produced a greater reduction of postconcussional symptoms than placebo ( P < 0.005). Analysis of the neuropsychologicai findings revealed a significantly greater improvement in recognition memory for designs in the CDP-choline treated patients ( P < 0.02) whereas other changes in test performance did not differ for the two groups. Pending replication in a larger series of patients, our findings suggest that CDP-choline may be effective in treating sequelae of mild to moderate CHI.

Introduction
The patients who are admitted to hospital with mild to moderate head injury account for the vast majority of cases seen in the neurosurgery service and represent at least a 90-95% of the survivors of head injury. However, in the United States, there was a National survey of sampling individuals who had sustained a head injury and one of the interesting findings was that a surprising percentage of patients who were restricted to bedrest or milder restriction of activity after a relatively mild head injury were never even hospitalized (Table 1). These patients are routinely overlooked; they are not even considered in most epidemiologicai studies of head injury. And yet, they constitute a large number of individuals who are quite distressed and disabled at least for a short period of time, and for
TABLE 1 PERCENTAGE HOSPITALIZED AMONG PEOPLE WITH MORBIDITY FROM ACUTE HEAD INJURY BY DURATION AND TYPE OF DISABILITY Type of disability Bed disability Restricted activity Duration of disability < 3 days 3-7 days 23 (17-30) 17 (9-24) 51 (34-66) 38 (24-52)

> 7 days 67 (46-89) 53 (41-64)

whom there is really very little treatment available currently. When we consider mild to moderate head injury, it is useful to divide the total insult into several components. We must consider the effect of trauma which may be relatively nonspecific, such as the stress of the trauma, hospitalization, frequent depressions, a reduction in mobility, and the effects of medication. Generally, increase in anxiety is a main concern, and we should be aware of individuals who are prone to high levels of anxiety, particulary in the form of somatic concerns, and this may predispose them to a much longer period of distress following a mild head injury, as compared to other individuals. In the assessment of post-concussional symptoms, we cannot overemphasize the importance of a structured interview. Administering neuropsychological tests which 1 will describe, without also using a structured interview of post-concussional complaints will tend to overlook a great deal of information. One of the interesting findings in recent studies of mild to moderate head injuries is that many patients continue to complain of subjective symptoms, even though their performance on what we consider to be more objective tests has improved to a relatively normal level. This is taken from a study that we completed at three centers in Galveston, the Bronx, N.Y., and San Diego. This study included consecutive admissions of patients who had a score of 13-15 on the Glasgow Coma Scale. An inter-

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TABLE 2 RANK O R D E R OF TOP 10 POSTCONCUSSIONAL COMPLAINTS AT BASELINE (n -- 155) Complaint Total series (n = 155) Rank Headaches Fatigue Dizziness Sleep Memory Depression Anxiety Appetite Thinking Concentration 1 2 3 4 5 6 7 8 9.5 9.5 % 71 56 50 44 39 36 33 31 30 30 Galveston (n = 62) Rank 1 2 3 4 9 7 6 5 9 12 % 69 61 55 50 29 34 39 42 29 24 Bronx (n = 51) Rank 1 3.5 2 6 3.5 5 12 14 13 8.5 % 67 41 43 37 41 39 22 18 20 26 San Diego (n = 42) Rank 1 2 3 4.5 9.5 7.5 6 11 4.5 7.5 % 79 64 52 43 33 36 38 31 43 36

view was done prior to the patient's discharge from the hospital. Table 2 presents the results from 155 patients. They included 3 samples from 3 different geographic regions of the United States and the rank order of the most common complaints of the patients on the structured interview was consistent, at least for the most common complaints of headache, fatigue and dizziness. When we consider the methodologic issues in undertaking the clinical trials for patients with mild to moderate head injury, an important consideration is the outcome measures. If we use a global measure such as the Glasgow Outcome Scale, this is probably going to be less informative than specific measures of functioning. On the other hand, to compare large series of patients, it is certainly useful to be able to categorize their outcome, particulary at specific points in time, such as 1 and 3 months after a mild to moderate head injury. We also have to consider the effects of repeatedly examining the patient. There are known practice effects on some of the tests. The brevity of the examination is also important in order to obtain the compliance of patients in returning for follow-up visits. All these considerations are the background for the preliminary trial of CDP-choline that I will describe. There have been a couple of case reports in the literature using preparations which were precursors of CDP-choline and suggesting that this approach might be useful in facilitating recovery from mild to moderate head injury. However, none of these studies had placebo control, nor any attempt was done to use double-blind method. For this reason, we decided to conduct the present trial on the effects of CDP-choline in patients with head injury.

to moderate head injury. They were recruited at bedside once they had come out of posttraumatic amnesia, which we evaluated daily. The patients, after agreeing to participate, underwent a baseline assessment and were randomized to either 1 gr. of oral CDP-choline, or a placebo, which was an identical capsule. Then they were given an appointment for a 1-month follow-up examination. The selection criteria were: first, the patients were hospitalized; second, they had a mild to moderate head injury, although in most cases these were mildly injured patients, and they had no deterioration from the initial criteria consistent with a mild to moderate head injury. Their age was from 16 to 70 years. We excluded patients with previous head injuries, drug or alcohol abuse, psychiatric disease or severe systemic disease. In this preliminary study, we were able to enroll 7 patients in each group: they were young adults, may be they had a high school education, and, for the most part, they were individuals who sustained mild head injury (Table 3). The procedures that we used in the baseline assessment and the 1-month follow-up included tests of memory, fluency and attention. We also administered a structured interview to ask about postconcussional symptoms. The memory assessment included: 1) a verbal recall test with 12 words and 12 trials; after each trial, the researcher reminds the patient of the words he missed in the previous trial; 2) a spatial memory test for memorizing the location of marbles which were preTABLE 3 PATIENTS' FEATURES Median values.

Material and methods


CDP-choline (n = 7) Placebo (n = 7) 20 12 15

The study that we have completed was a randomized trial on the effects of CDP-choline in patients that were admitted at the neurosurgery service with a mild

Age (yrs) Education (years) GCS score

25 12 15

$41 sented in array to the patient; the procedure was analogous to that used in the verbal recall test; and 3) a recognition memory test in which designs were presented and some designs were repeated, whereas most designs were presented only once. The patient simply had to say yes or nod his head when he had seen the same design repeated. Fluency tests measure what we call fluency or divergent thinking. Verbal fluency was finding as many words as possible beginning with a specific letter, and it is performed under a time limit. Design fluency was creating unique designs, again under a time limit. We evaluated attention using two measures. One of them is the Continuous Performance Test, that is administered by a computer. This is a non-verbal test; when the patient saw the silhouette of an airplane, he would push a key on the computer. When the patient had a specified number of correct responses consecutively, the computer would increase the speed of presentation of the stimuli. If the patient made an error, either by not pushing the key when the airplane was on, or by pushing the key when a non-target, i.e. distractor, was on, the computer would slow down the rate of presentation. The computer continuously tracked the performance of the patient. The measure is the shortest average interval that the patient can drive the computer. This very sensitive measure of attention is quite vulnerable to the early effects of even a mild head injury. The other measure of attention in information processing is the Paced Auditory Serial Addition Test (PASAT). The patient hears a tape-recorded series of numbers and is asked to add each number to the immediately preceding number. Initially, the tape-recorded numbers are presented at a very slow rate, and in a normal individual, the performances are at a very high level. However, when the interval between the numbers is greatly reduced, the accuracy of the serial addition is reduced.

Results and Discussion

Table 4 shows the mean results of every test. We found that patients in both groups tended to improve on most tests. Non-parametric comparison of the results (Wilcoxon test) at baseline, follow-up as well as the percent change, revealed 2 findings that were significant. There was a tendency towards more improvement in the recognition memory in the CDP-choline group than in the placebo group. The CDP-choline group improved by over 100% versus 29% in the placebo patients ( P < 0.02). Gn the other hand, at follow-up there was a higher performance in the test of creating designs in the placebo group, in terms of their absolute score; however, when we calculated the percent change, this trend was not significantly different from the percent change with CDP-choline. These results have to be considered very preliminary, because we have made many comparisons and the groups are small. The most interesting trend that we have so far is perhaps in the post-concussional symptoms. Fig. 1 is based on the structured interview that we administered. We asked about headaches, dizziness, tinnitus, blurring of vision or any kind of visual complaint, and insomnia; we also asked about gastrointestinal distress as a potential side-effect of the medication. When we compare the CDP-choline and the placebo-treated groups, at baseline, they are fairly similar. However at follow-up there is a trend among the patients on the placebo group to complain more of headaches, dizziness and tinnitus. The only symptom in which we see a slight reversal of this trend is in

TABLE 4 N E U R O P S Y C H O L O G I C A L FINDINGS A T BASELINE (BL) A N D FOLLOW-UP (FU) CDP-choline BL Memory Recall of words Recall of locations Recall of designs Fluency Verbal (words) Designs-free Designs-fixed Attention CPT (msec) PASAT (correct/time) * P < 0.05. 76 67 25 22 18 14 1527 0.315 FU ! 11 94 38 41 16 11 * 1225 0.344 % Change 147 40 104 * 8 - 9 0 - 9 25 Placebo BL 117 95 40 35 13 13 1444 0.398 FU % Change

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gastrointestinal distress, and maybe this is due to CDP-choline. When we used the non-parametric test, we had more patients in the placebo group who complained of being dizzy one month after injury, as compared to the CDP-choline group (P < 0.005). None of them complained of dizziness. Although these results are very preliminary, we think it would be worthwhile to study more patients. At least there appears to be some encouragement that perhaps the subjective symptoms following a mild head injury may be helped by CDP-choline. On the other hand, it does not appear that we can demonstrate this by the cognitive tests that were used in this trial. However, we should point out that the results might be a little bit different if the treatment was introduced even earlier.

The patients did not begin this treatment until their posttraumatic amnesia had been resolved and until they underwent the baseline or psychological testing. By that time, they were very close to being discharged from the hospital. So it is possible, perhaps, beginning the treatment much earlier would have different results. Again, we have to be very cautious interpreting the results at his time. On the other hand, it appears that CDP-choline is well tolerated, although the patients who were treated did complain more of gastrointestinal distress at one month than the non-treated patients. We think it may be informative to extend the study to a larger trial.