348 Treatment of Postconcussional Symptoms With CDP-Choline

7/30/2019 348 Treatment of Postconcussional Symptoms With CDP-Choline

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Journal of the N eurological Sciences, 103 (1991) $39-$ 42 1991 Elsevier Science Publishers B.V. 0022 -510X /91/$0 3.50JNS 03591

$39

Treatm ent o f postconcuss ional symptoms with CD P-chol ineH . S . L e v i n

Dil'ision of Neurosurgery, The U nirersity of Texas Medical Bra nch at Ga h'eston, Gah'eston, Texas (U.S.A.)

SummaryT o e v a l u a t e t h e e f fi c a c y o f c y t id i n e d i p h o s p h o r y l c h o l i n e ( C D P - c h o l i n e ) i n t r e a ti n g p o s t c o n c u s s i o n a l s y m p t o m s f o r o n e m o n t ha f t e r m i l d to m o d e r a t e c l o se d h e a d i n j u r y ( C H I ) , w e c o m p l e t e d a p r e l i m i n a r y d o u b l e b l i n d p l a c e b o - c o n t r o ll e d s t u d y. F o u r t e e ny o u n g m e n a d m i t t e d t o t h e n e u r o s u r g e r y s e rv i c e a f t e r su s t a i n in g m i l d to m o d e r a t e C H I w e r e r a n d o m i z e d t o o r a l C D P - c h o l i n e ( lg ) a n d p l a c e b o c o n t r o l g r o u p s w h i c h w e r e m a t c h e d f o r a g e , e d u c a t i o n a n d s e v e r it y o f i m p a i r e d c o n s c i o u s n e s s . B a s e l i n e ( p r i o r t od i s c h ar g e ) a n d o n e m o n t h e x a m i n a t i o n s c o n s is t e d o f a s t r u c t u r e d p o s t c o nc u s s io n a l s y m p t o m i n t e rv i e w a n d n e u r o p sy c h o l o g ic a lt e s ts . R e s u l t s ( W i l c o x o n te s t ) s h o w e d t h a t C D P - c h o l i n e p r o d u c e d a g r e a t e r r e d u c t i o n o f p o s t c o n c u s s i o n a l s y m p t o m s t h a n p l a c e b o( P < 0 .0 0 5 ). A n a l y s i s o f t h e n e u r o p s y c h o l o g i c a i f i n d i n g s r e v e a l e d a s i g n i f i c a n t l y g r e a t e r i m p r o v e m e n t i n r e c o g n i t i o n m e m o r y fo rd e s i g n s i n t h e C D P - c h o l i n e t r e a t e d p a t i e n t s ( P < 0 .0 2 ) w h e r e a s o t h e r c h a n g e s i n t es t p e r f o r m a n c e d i d n o t d i f f e r fo r t h e t w og r o u p s . P e n d i n g r e p l i c a t i o n i n a l a r g e r s e r i e s o f p a t i e n t s , o u r f i n d i n g s s u g g e s t t h a t C D P - c h o l i n e m a y b e e f f e c t i v e in t r e a t in gs e q u e l a e o f m i l d t o m o d e r a t e C H I .

Introduction

T h e p a t i e n t s w h o a r e a d m i t t e d t o h o s p i t a l w i t h m i l dt o m o d e r a t e h e a d i n j u r y a c c o u n t f o r t h e v a s t m a j o r i t yo f cas es s een in the neu ros u rge ry s e rv ice and r ep res en ta t l eas t a 90 -95% o f the s u rv ivo r s o f head in ju ry .H o w e v e r , i n t h e U n i t e d S t a t e s , t h e r e w a s a N a t i o n a ls u r v e y o f s a m p l i n g i n d i v i d u a l s w h o h a d s u s t a i n e d ah e a d i n ju r y a n d o n e o f t h e i n t e r e s t i n g f i n d in g s w a s t h a ta s u r p r is i n g p e r c e n t a g e o f p a t i e n t s w h o w e r e r e s tr i c te dto bed res t o r mi lde r r e s t r i c t ion o f ac t iv i ty a f t e r a r e l a -t ive ly mi ld he ad in ju ry w ere n eve r ev en hos p i t a l i zed(Tab le 1 ). Th es e pa t i en t s a r e rou t ine ly ove r looked ;t h e y a r e n o t e v e n c o n s i d e r e d i n m o s t e p i d e m i o l o g i c a is tud ies o f head in ju ry . A nd ye t , t hey cons t i tu t e a l a rgen u m b e r o f i n d i v i d u a l s w h o a r e q u i t e d i s t r e s s e d a n dd i s ab led a t l eas t f o r a s ho r t pe r iod o f t ime , and fo rT A B L E 1P E R C E N T A G E H O S P I T A L I Z E D A M O N G P E O P L E W I T HM O R B I D I T Y F R O M A C U T E H E A D I N J U R Y B Y D U R A T I O NAND TYP E O F DI S ABILI TYType of Du ration of disabilitydisability < 3 days 3-7 days > 7 daysBed disability 23 51 67(17-30) (34-66) (46-89)Restricted activity 17 38 53(9-24) (24-52) (41-64)

w hom the re i s r ea l ly ve ry l i t t l e t r ea tmen t ava i l ab lecu r r en t ly .

W h e n w e c o n s i d e r m i l d t o m o d e r a t e h e a d i n j u r y , i ti s u s e fu l to d iv ide the to ta l in s u l t i n to s eve ra l compo-n e n t s . W e m u s t c o n s i d e r t h e e f f e c t o f t r a u m a w h i c hmay be r e l a t ive ly nons pec i f i c , s uch a s the s t r e s s o f thet r auma , hos p i t a l i za t ion , f r equen t dep res s ions , a r educ -t ion in mob i l i ty , and the e f f ec t s o f med ica t ion . G ener -a l ly , inc r eas e in anx ie ty i s a ma in conce rn , and w es h o u l d b e a w a r e o f i n d i v i d u a ls w h o a r e p r o n e t o h i ghleve l s o f anx ie ty , pa r t i cu la ry in the fo rm o f s omat icc o n c e r n s , a n d t h i s m a y p r e d i s p o s e t h e m t o a m u c hlonger pe r iod o f d i s t r e s s fo l low ing a mi ld head in ju ry ,a s c o m p a r e d t o o t h e r i n d i v i d u a l s .In the a s s es s men t o f pos t - concus s iona l s ymptoms ,w e c a n n o t o v e r e m p h a s i z e t h e i m p o r t a n c e o f a s t r u c -tu r ed in te rv iew . A dmin i s t e r ing neu rops ycho log ica l t e s t sw h ich 1 w i l l des c r ibe , w i thou t a l s o u s ing a s t ruc tu redin te rv iew o f pos t - concus s iona l compla in t s w i l l t end too v e r l o o k a g r e a t d e a l o f i n f o r m a t i o n . O n e o f t h e i n t e r -e s t ing f ind ings in r ecen t s tud ies o f mi ld to modera teh e a d i n j u r i e s i s t h a t m a n y p a t i e n t s c o n t i n u e t o c o m -p la in o f s ub jec t ive s ymptoms , even though the i r pe r fo r -m a n c e o n w h a t w e c o n s i d e r t o b e m o r e o b j e c t i v e t e s t shas improved to a r e l a t ive ly no rmal l eve l . Th i s i s t akenf r o m a s t u d y t h a t w e c o m p l e t e d a t t h r e e c e n t e r s i nG a lves ton , the Bronx , N .Y . , and S an D iego . Th i s s tudyi n c l u d e d c o n s e c u ti v e a d m i s si o n s o f p a t ie n t s w h o h a d as c o re o f 1 3 - 1 5 o n t h e G l a s g o w C o m a S c a l e . A n i n te r -


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$40T A B L E 2R A N K O R D E R O F T O P 10 P O S T C O N C U S S I O N A L C O M P L A I N T S A T B A S E L I N E ( n -- 1 55 )C o m p l a i n t T o t a l s e r i e s ( n = 1 5 5) G a l v e s t o n ( n = 6 2 ) B r o n x ( n = 5 1 ) S a n D i e g o ( n = 4 2 )

R a n k % R a n k % R a n k % R a n k %H e a d a c h e s 1 7 1 1 6 9 1 6 7 1 7 9Fat igu e 2 56 2 61 3 .5 41 2 64Dizz iness 3 50 3 55 2 43 3 52Sleep 4 44 4 50 6 37 4 .5 43Me mo ry 5 39 9 29 3 .5 41 9 .5 33De press ion 6 36 7 34 5 39 7 .5 36Anxie ty 7 33 6 39 12 22 6 38Ap pet i t e 8 31 5 42 14 18 11 31Think ing 9 .5 30 9 29 13 20 4 .5 43Co nce nt ra t i on 9 .5 30 12 24 8 .5 26 7 .5 36

v iew was done p r io r t o t he p a t i en t ' s d i scha rge f rom thehospi ta l . Table 2 presents the resul t s from 155 pat ients .They inc luded 3 samples f rom 3 d i f fe ren t geograph icreg ions o f t he Un i t ed S t a t e s and the rank o rde r o f t hemos t common compla in t s o f t he pa t i en t s on the s t ruc -tu red in t e rv iew was cons is t en t, a t l eas t fo r t he m os tcomm on com pla in t s o f headache , fa t i gue and d i zz iness .When we cons ide r t he me thodo log ic i s sues i n un -dertaking the c l in ical t r ia l s for pat ients wi th mi ld tomodera t e head in ju ry , an impor t an t cons ide ra t ion i sthe ou tcome m easu res . I f we use a g loba l measu re suchas t he Glasgow Outcome Sca l e , t h i s i s p robab ly go ingto be l e ss i n fo rma t ive t han spec i f i c measu res o f func -t i on ing . On the o the r hand , t o compare l a rge se r i e s o fpat ients , i t i s certa in ly useful to be able to ca tegorizethei r outcome, part iculary a t speci f ic poin ts in t ime,such a s 1 and 3 m on ths a f t e r a m i ld t o mo dera t e headinjury . We also have to consider the effects of repeat -ed ly examin ing the pa t i en t . The re a re known p rac t i cee f fect s on some o f t he t e st s . The b rev i ty o f t he exami -na t ion i s a l so impor t an t i n o rde r t o ob t a in t he compl i -ance of pat ients in re turning for fo l low-up v is i t s .A l l t hese cons ide ra t ions a re t he background fo r t hep re l im ina ry tr i a l o f CD P-cho l ine t ha t I w i l l desc r ibe .There have been a coup le o f case repo r t s i n t hel i t e ra tu re u s ing p repa ra t ions wh ich were p recu rso rs o fCDP-cho l ine and sugges t ing tha t t h i s app roach migh tbe useful in faci l i ta t ing recovery from mild to moderatehead in ju ry . However , none o f t hese s tud i es hadp lacebo con t ro l , no r any a t t empt was done to u sedoub le -b l ind me thod . Fo r t h i s reason , we dec ided toconduc t t he p r esen t t r i a l on the e f fec t s o f CDP-cho l inein pa t i en t s w i th head in ju ry .

Mater ial and m ethods

T h e s t u d y t h a t w e h a v e c o m p l e t e d w a s a r a n d o m -ized t r i a l on the e f fec ts o f CDP-c ho l ine i n pa t i en t s t ha twere admi t t ed a t t he neu rosu rge ry se rv i ce wi th a mi ld

t o m o d e r a t e h e a d i nj u ry . T h e y w e r e r e c r u i t e d a t b e d -s i d e on c e t h e y h a d c o m e o u t o f p o s t t r a u m a t i c a m n e s i a ,wh ich we eva lua t ed da i ly . The pa t i en t s , a f t e r ag ree ingt o p a r t i c i p a t e , u n d e r w e n t a b a s e l i n e a s s e s s m e n t a n dw e r e r a n d o m i z e d t o e i t h e r 1 g r. o f o r a l C D P - c h o l i n e ,o r a p l acebo , wh ich was an iden t i ca l capsu le . T hen theywere g iven an appo in tmen t fo r a 1 -mon th fo l low-upexamina t ion .The se l ec t ion c r i t e r i a were : f i r s t , t he pa t i en t s werehosp i t a l i zed ; second , t hey had a mi ld t o modera t e headin ju ry , a l t hough in m os t cases t hese we re m i ld ly i n ju redpa t i en t s , and they had no de t e r io ra t i on f rom the i n i t i a lc r i t e r i a cons i s t en t w i th a mi ld to m ode ra t e hea d in ju ry.The i r age was f rom 16 to 70 yea rs . We exc ludedpa t i en t s w i th p rev ious head in ju r i e s , d rug o r a l coho labuse , p sych ia tr i c d i sease o r seve re sys t emic d i sease .In t h i s p re l im ina ry s tudy , we were ab l e t o en ro l l 7pa t i en t s i n each g roup : t hey were young adu l t s , may bethey had a h igh schoo l educa t ion , and , fo r t he mos tpa r t , t hey were i nd iv idua l s who sus t a ined mi ld headin ju ry (Tab le 3 ) . The p rocedures t ha t we used in t hebase l ine a ssessmen t and the 1 -mon th fo l low-up in -c luded t e s t s o f mem ory , f l uency and a t t en t ion . W e a l soadm in i s t e red a s t ruc tu re d in t e rv i ew to a sk abo u t pos t -concuss iona l symptoms .

The memory assessmen t i nc luded : 1 ) a ve rba l reca l lt e s t w i th 12 words and 12 t r i a l s ; a f t e r each t r i a l , t her e s e a r c h e r r e m i n d s t h e p a t i e n t o f t h e w o r d s h e m i s s e din t he p rev ious t r i a l ; 2 ) a spa t i a l memory t e s t fo rm e m o r i z i n g t h e l o c a t i o n o f m a r b l e s w h i c h w e r e p r e -

T A B L E 3P A T I E N TS ' F E A T U R E SM e d i a n v a l ue s .

C D P - c h o l i n e ( n = 7 ) P l a c e b o ( n = 7 )Ag e (yrs) 25 20E d u c a t i o n ( y e a r s ) 1 2 1 2G C S s c o r e 1 5 1 5


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s e n t e d i n a r r a y t o t h e p a t i e n t ; t h e p r o c e d u r e w a sana logous to tha t u s ed in the ve rba l r eca l l t e s t ; and 3 )a r e c o g n i t i o n m e m o r y t e s t i n w h i c h d e s i g n s w e r e p r e -s e n t e d a n d s o m e d e s i g n s w e r e r e p e a t e d , w h e r e a s m o s td e s i g ns w e r e p r e s e n t e d o n l y o n c e . T h e p a t i e n t s i m p l yh a d t o s a y y e s o r n o d h i s h e a d w h e n h e h a d s e e n t h es a m e d e s i g n r e p e a t e d .F l u e n c y t e s t s m e a s u r e w h a t w e c a l l f lu e n c y o r d i v e r-g e n t t h i n k i n g . V e r b a l f l u e n c y w a s f i n d i n g a s m a n yw ords a s pos s ib le beg in n ing w i th a s pec if i c l e t te r , an di t i s p e r f o r m e d u n d e r a t i m e l im i t . D e s i g n f l u en c y w a sc r e a t i n g u n i q u e d e s i g n s , a g a i n u n d e r a t i m e l i m i t .W e e v a l u a t e d a t t e n t i o n u s i n g t w o m e a s u r e s . O n e o ft h e m i s t h e C o n t i n u o u s P e r f o r m a n c e T e s t , t h a t i s a d -min i s t e r ed by a compu te r . Th i s i s a non -ve rba l t e s t ;w h e n t h e p a t i e n t s a w t h e s i l h o u e t t e o f a n a i r p l a n e , h ew o u l d p u s h a k e y o n t h e c o m p u t e r . W h e n t h e p a t i e n th a d a s p e c if i e d n u m b e r o f c o r r e c t r e s p o n s e s c o n s e c u -t i v e l y , t h e c o m p u t e r w o u l d i n c r e a s e t h e s p e e d o f p r e -s e n t a t i o n o f t h e s t i m u li . I f t h e p a t i e n t m a d e a n e r r o r ,e i t h e r b y n o t p u s h i n g t h e k e y w h e n t h e a i r p l a n e w a so n , o r b y p u s h i n g t h e k e y w h e n a n o n - t a r g e t , i . e .d i s t r a c t o r , w a s o n , t h e c o m p u t e r w o u l d s l o w d o w n t h er a t e o f p r e s e n t a t i o n . T h e c o m p u t e r c o n t i n u o u s l yt r a c k e d t h e p e r f o r m a n c e o f t h e p a t i e n t . T h e m e a s u r e i st h e s h o r t e s t a v e r a g e i n t e r v a l t h a t t h e p a t i e n t c a n d r i v et h e c o m p u t e r . T h i s v e r y s e n s i t i v e m e a s u r e o f a t t e n t i o ni s qu i t e v u lne rab le to the ea r ly e f f ec t s o f even a mi ldhead in ju ry .

T h e o t h e r m e a s u r e o f a t te n t i o n i n i n f o r m a t i o n p r o -c e s s i n g i s t h e P a c e d A u d i t o r y S e r i a l A d d i t i o n T e s t( P A S A T ) . T h e p a t i e n t h e a r s a t a p e - r e c o r d e d s e r ie s o fn u m b e r s a n d i s a s k e d t o a d d e a c h n u m b e r t o t h ei m m e d i a t e l y p r e c e d i n g n u m b e r . I n i t i a l l y , t h e t a p e - r e -c o r d e d n u m b e r s a r e p r e s e n t e d a t a v e ry sl ow ra t e , a n din a no rmal ind iv idua l , t he pe r fo rmances a r e a t a ve ryh i g h l e v e l . H o w e v e r , w h e n t h e i n t e r v a l b e t w e e n t h e

$41number s i s g r ea t ly r educed , the accu racy o f the s e r i a la d d i t i o n i s r e d u c e d .

R e s u l t s a n d D i s c u s s i o n

Tab le 4 s how s the mean r e s u l t s o f eve ry t e s t . Wef o u n d t h a t p a t i e n t s i n b o t h g r o u p s t e n d e d t o i m p r o v eo n m o s t te s ts . N o n - p a r a m e t r i c c o m p a r i s o n o f th e r e -s u l t s (Wi lcoxon t e s t ) a t bas e l ine , f o l low -up as w e l l a sthe pe rcen t change , r evea led 2 f ind ings tha t w ere s ig -n i f i c a n t . T h e r e w a s a t e n d e n c y t o w a r d s m o r e i m p r o v e -m e n t i n t h e r e c o g n i t i o n m e m o r y i n t h e C D P - c h o l i n eg r o u p t h a n i n t h e p l a c e b o g r o u p . T h e C D P - c h o l i n eg r o u p i m p r o v e d b y o v e r 1 0 0 % v e r s u s 2 9 % i n t h ep l a c e b o p a t i e n t s ( P < 0 .0 2 ). G n t h e o t h e r h a n d , a tf o l lo w - u p t h e r e w a s a h i g h e r p e r f o r m a n c e i n th e t e s t o fc r ea t ing des igns in the p lacebo g roup , in t e rms o f the i ra b s o l u t e s c o r e ; h o w e v e r , w h e n w e c a l c u l a t e d t h e p e r -cen t change , th i s t r end w as no t s ign i f i can t ly d i f f e r en tf r o m t h e p e r c e n t c h a n g e w i t h C D P - c h o l i n e .T h e s e r e s u l t s h a v e t o b e c o n s i d e r e d v e r y p r e l i m i -n a r y , b e c a u s e w e h a v e m a d e m a n y c o m p a r i s o n s a n dt h e g r o u p s a r e s m a l l .T h e m o s t i n t e r e s t i n g t r e n d t h a t w e h a v e s o f a r i spe rh aps in the p os t - concus s iona l s ymptom s . F ig . 1 i sb a s e d o n t h e s t r u c t u r e d i n te r v ie w t h a t w e a d m i n i s-t e r ed . We as ked abou t headaches , d i zz ines s , t i nn i tu s ,b lu r r ing o f v is ion o r an y k ind o f v i sua l compla in t , andins omnia ; w e a l s o a s ked abou t gas t ro in te s t ina l d i s t r e s sas a po ten t i a l s ide -e f f ec t o f the med ica t ion .W h e n w e c o m p a r e t h e C D P - c h o l i n e a n d t h ep lace bo - t r ea ted g roup s , a t bas e l ine , they a r e f a ir ly s im-i l a r . H ow ever a t f o l low -up the re i s a t r end among thep a t i e n t s o n t h e p l a c e b o g r o u p t o c o m p l a i n m o r e o fh e a d a c h e s , d i z z i n es s a n d t i nn i t us . T h e o n l y s ym p t o m i nw h ich w e s ee a s l igh t r eve r s a l o f th i s t r end i s in

T A B L E 4N E U R O P S Y C H O L O G I C A L F I N D I N G S A T B A S E L I N E ( BL ) A N D F O L L O W - U P (F U )

C D P - c h o l i n e P l a c e b oB L F U % C h a n g e B L F U % C h a n g e

M e m o r yReca l l o f wo rds 76 ! 11 147 117 106 8R e c a l l o f l o c a t i o n s 6 7 9 4 4 0 9 5 9 5 - 1Reca l l o f des i gns 25 38 104 * 40 45 29 *

F l u e n c yV e r b a l ( w o r d s ) 2 2 4 1 8 3 5 3 7 1 3Des igns - f ree 18 16 - 9 13 20 25De sign s-fi xed 14 11 * 0 13 19 * 77

A t t e n t i o nC P T ( m s e c ) 1 5 2 7 1 2 2 5 - 9 1 4 4 4P A S A T ( c o r r e c t / t i m e ) 0 .3 1 5 0 .3 4 4 2 5 0 . 39 8

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gas t ro in te s t ina l d i s t r e s s , and maybe th i s i s due toC D P - c h o l i n e . W h e n w e u s e d t h e n o n - p a r a m e t r i c t e s t ,w e h a d m o r e p a t i e n t s i n t h e p l a c e b o g r o u p w h o c o m -p la ined o f be ing d izzy one mon th a f t e r in ju ry , a s com-pared to the CD P -cho l ine g roup (P < 0 .005 ) . N one o fthem compla ined o f d izz ines s .A l thoug h thes e r e s u l t s a r e ve ry p re l imina ry , w e th inki t w ou ld be w or thw h i le to s tudy more pa t i en t s . A t l eas tt h e r e a p p e a r s t o b e s o m e e n c o u r a g e m e n t t h a t p e r h a p sthe s ub jec t ive s ymptoms fo l low ing a mi ld head in ju rymay be he lped by CD P -cho l ine . O n the o th e r hand , i tdoes no t appea r tha t w e can demons t r a t e th i s by thecogni t ive tes ts that were used in th is t r ia l . However , wes hou ld po in t ou t tha t the r e s u l t s migh t be a l i t t l e b i td i f f e r en t if t he t r ea tme n t w as in t roduce d even ea r l i e r.

T h e p a t i e n t s d i d n o t b e g i n t h i s t r e a t m e n t u n t i l t h e i rp o s t t r a u m a t i c a m n e s i a h a d b e e n r e s o l v e d a n d u n t i lthey underw en t the bas e l ine o r p s ycho log ica l t e s t ing .By tha t t ime , they w ere ve ry c lo s e to be ing d i s cha rgedf rom the hos p i t a l . S o i t i s pos s ib le , pe rhaps , beg inn ingt h e t r e a t m e n t m u c h e a r l i e r w o u l d h a v e d i f f e r e n t r e -s u l t s . A ga in , w e have to be ve ry cau t ious in te rp re t ingthe r e s u l t s a t h i s t ime .

O n t h e o t h e r h a n d , i t a p p e a r s t h a t C D P - c h o l i n e i sw e l l t o l e r a t e d , a l t h o u g h t h e p a t i e n t s w h o w e r e t r e a t e dd id compla in more o f gas t ro in te s t ina l d i s t r e s s a t onem o n t h t h a n t h e n o n - t r e a t e d p a t i e n t s .

We th ink i t may be in fo rma t ive to ex tend the s tudyto a l a rge r t r i a l .

Documents

348 Treatment of Postconcussional Symptoms With CDP-Choline