TOTAL SLEEP DEPRIVATION A N D PARKINSON DISEASE
PAULO H. F. BERTOLUCCI * LUIZ A. F. ANDRADE * JOSÉ G. C. LIMA * E. A. CARLINI **
A m a j o r p r o b l e m in t h e l o n g - t e r m m a n a g e m e n t of P a r k i n s o n d i s e a s e ( P D )
is t h e p r o g r e s s i v e l o s s of e f f i c a c y of L - D o p a , a n e f f e c t a t t r i b u t e d , at l e a s t in
p a r t t o d i m i n i s h e d r e s p o n s i v e n e s s of d o p a m i n e r g i c r e c e p t o r s in b a s a l g a n g l i a1 4
.
T h e r e s t o r a t i o n of n o r m a l r e s p o n s i v e n e s s or t h e i n d u c t i o n of r e c e p t o r s h y p e r -s e n -s i t i v i t y w o u l d b e v a l u a b l e n o t o n l y in t h e m a n a g e m e n t of L - D o p a t h e r a p y
c o m p l i c a t i o n s , b u t a l s o a s a t r e a t m e n t of P D . It is k n o w n , s i n c e t h e w o r k of F e r g u s o n & D e m e n t ( 1 9 6 9 ) t h a t rapid e y e m o v e m e n t s l e e p d e p r i v a t i o n ( R E M S D )
e n h a n c e s t h e a g g r e s s i v e b e h a v i o r i n d u c e d b y a m p h e t a m i n e8
. T h i s effect, first a t t r i b u t e d t o e i t h e r n o r e p i n e p h r i n e or s e r o t o n i n , w a s l a t e r d e m o n s t r a t e d t o be
d o p a m i n e d e p e n d e n t , at l e a s t in p a r t . T h u s , it w a s s h o w n t h a t R E M S D e n h a n c e s a g g r e s s i v e b e h a v i o r i n d u c e d b y a p o m o r p h i n e , a p o w e r f u l a g o n i s t of
d o p a m i n e r g i c r e c e p t o r5 , 1 6
. F u r t h e r s t u d i e s d e m o n s t r a t e d t h e s a m e e f f e c t for
t h e s t e r e o t y p e d b e h a v i o r i n d u c e d b y a p o m o r p h i n e2 4
. A g g r e s s i v e b e h a v i o r w a s a l s o o b s e r v e d in n o m i f e n s i n e , p i r i b e d i l a n d b r o m o c r i p t i n e - t r e a t e d r a t s after
R E M S D6 , 2 2
a g a i n s u g g e s t i n g d o p a m i n e r g i c s y s t e m p a r t i c i p a t i o n . T h e s e e v i -d e n c e s t a k e n t o g e t h e r s u g g e s t t h a t a n e f f e c t of R E M S D c o u l -d b e t h e i n -d u c t i o n
of h y p e r r e s p o n s i v e n e s s t o d o p a m i n e r g i c a g e n t s . In t h i s r e s p e c t , it i s p e r t i n e n t t h a t in r a t s w i t h a n e x p e r i m e n t a l m o d e l of P D o b t a i n e d b y b i l a t e r a l l e s i o n of
n i g r o s t r i a t a l p a t h w a y , R E M S D i m p r o v e d a m b u l a t i o n a n d r e a r i n g 1. It i s w e l l k n o w n t h a t in P D t h e r e i s a d o p a m i n e r g i c d e f i c i e n c y in t h e n i g r o s t r i a t a l s y s t e m
( f o r a r e v i e w of t h e s u b j e c t s e e H o r n y k i e w i c z1 1
a n d R i n n e2 0
) . A l e s s a p p r e -c i a t e d p o i n t i s t h e r o l e of C N S d o p a m i n e r g i -c s y s t e m s in d e p r e s s i o n : a l t h o u g h
d a t a a r e o f t e n c o n f l i c t i n g , s e v e r a l i n v e s t i g a t o r s r e p o r t e d l o w e r e d l e v e l s of 5 h y d r o x y n d o l a c e t i c a c i d ( 5 H I A A ) , h o m o v a n i l i c a c i d ( H V A ) a n d 3 m e t h o x y
-- 4 -- h y d r o x y p h e n i l g l y c o l ( M H P G ) , r e s p e c t i v e l y m a j o r m e t a b o l i t e s of s e r o t o n i n , d o p a m i n e a n d n o r e p i n e r p h r i n e , in c e r e b r o s p i n a l fluid of d e p r e s s e d p a t i e n t s 2,7,18.
S i m i l a r t r e n d s w e r e o b s e r v e d w i t h t h e u r i n a r y e x c r e t i o n of c a t h e c o l a m i n e s a n d t h e i r m e t a b o l i t e s2 1
. S e v e r a l a n t i d e p r e s s a n t d r u g s , i n c l u d i n g n o m i f e n s i n e , e x h i b i t
a r a t h e r p o t e n t i n h i b i t i o n of d o p a m i n e u p t a k e in b r a i n9 , 1 9 . 2 9
. T h e r a p e u t i c t r i a l s of L - D o p a in d e p r e s s i v e p a t i e n t s w e r e b e n e f i t i a l , s p e c i a l l y in t h e c a s e s w i t h
r e t a r d e d b e h a v i o r a n d l o w m o t o r a c t i v i t y4 , 2 5
, a l t h o u g h t h i s r e s p o n s e w a s n o t
o b s e r v e d b y o t h e r r e s e a r c h e r s1 2
. In a n o t h e r line of i n v e s t i g a t i o n t h e r e h a s
b e e n a n i n c r e a s i n g n u m b e r of p a p e r s s h o w i n g t h a t t o t a l3 , 1 3 , 1 7
0r s e l e c t i v e
R E M S D2 6 - 2 8
b r i n g s a s i g n i f i c a n t , a l t h o u g h t r a n s i t o r y , i m p r o v e m e n t t o d e p r e s s e d p a t i e n t s .
T h e s e d a t a led u s t o s t u d y t h e e f f e c t s of o n e n i g h t of t o t a l S D o n p a t i e n t s w i t h P D .
MATERIAL A N D METHODS
Patients — Twelve parkinsonian patients were included in the experiment. Diagnosis of P D was based on the presence of at least three clinical signs: bradykinesia, rigidity and posture and gait disturbances. All the volunteers had a diagnosis of idiophatic PD, age ranging from 40 to 70 years, and a score for parkinsonian syndrome from 20 to 50% b y the N e w York University Parkinson's disease evaluation form (NYU form) (15). No patient had history of any other neurological disorder, previous exposition to manganese, neuroleptics and other drugs known to induce parkinsonian syndrome. All patients signed an informed consent, after being explained in details about the experimental protocol, care being taken in order to avoid describing the expected therapeutic effect, so that an undesired placebo effect w a s avoided.
Procedure — After admission to the protocol, the patients were maintained for at least two weeks with their medication unchanged. They were then admitted to a special ward at the Medical School Hospital, where they had contact only with the research staff. The admittance day w a s considered day 0. At 5:00 PM the patients were evaluated using the Hamilton R a t i n g Scale for Depression (HRSD) (-">) followed by t h e NYU form. The patients were instructed to g o to bed on that evening and to awake in the next morning at their usual time. The patients remained all day 1 in the Hospital and at 5:00 PM they w e r e again evaluated using both rating scales. At 9:00 PM the patients were removed to an isolated Clinical Research Unit to spend the night awaken. The Unit w a s composed b y a visiting room and a bathroom, w i t h a TV set, ambiental music and game sets (like chess and playing cards). Patients were instructed not to drink coffee or other stimulant beverages and not to smoke. The procedure w a s done with groups of 2 or 3 patients under close supervision of 2 members of our staff. A t morning of day 2 the patients returned to the special ward and at 10:00 AM were evaluated by the NYU form (except appendix 6). At 5:00 PM they w e r e evaluated again u s i n g both rating scales. After that they were, discharged, with instructions to return at 5:00 PM on day 8, 15 and 29 when both rating scales were again applied. The rating scales were applied by an independent researcher who w a s beforehand aware of the protocol conditions, that is, the experiment w a s not run blind, because of its own peculiarities. In fact, in the first phase of the clinical interview the patients spontaneously reported his previous sleep deprivation. On the other hand, video taped examinations would not be applicable taking into consideration all the items of the NYU form.
The H R S D w a s modified so that items 7 (work and activities), 9 (agitation), 13 (general somatic symptoms) w e r e excluded as to cope w i t h disability of the patients. Item 17 (insight) w a s also excluded as the P D patients have a clear insight of their own disease. Therefore t h e maximum score for the remaining 13 items w a s 40 points, instead of the original 53. The NYU form w a s applied according to the author's instructions (J5).
U s i n g the s a m e test, a comparison w a s done of t h e data obtained at day 0 (afternoon before deprivation) w i t h data collected at d a y s 2, 8, 15 and 29, s o that it w a s possible to a s s e s s t h e influence of sleep deprivation on the clinical picture of P D .
R E S U L T S
COMMENTS
S D r e v e a l e d t o b e a s i m p l e a n d w e l l t o l e r a t e d p r o c e d u r e b y all p a t i e n t s
i n v o l v e d in t h i s s t u d y .
I m p r o v e m e n t in d e p r e s s i o n in o u r p a t i e n t s d i d n o t d i f f e r g r e a t l y f r o m t h e
r e s u l t s o b t a i n e d in n o n - P D d e p r e s s i v e p a t i e n t s r e p o r t e d e l s e w h e r e , e i t h e r w i t h
t o t a l 3,13,17 or s e l e c t i v e R E M S D 26-28. B e n e f i t s , like in o u r p a t i e n t s w e r e
s h o r t - l i v e d a n d t e n t a t i v e e x p l a n a t i o n s for t h e r e s u l t s o b s e r v e d w e r e a c c u m u l a t i o n
a t r e l e v a n t b r a i n s i t e s of a c a t e c h o l a m i n e or i t s m e t a b o l i t e s , w h i c h c o u l d
a l l e v i a t e d e p r e s s i o n 26 or ^ s y n c h r o n i z a t i o n of d i s t u r b e d b i o l o g i c a l r y t h m s1 7
.
In o u r p a t i e n t s a p o i n t c o u l d b e r a i s e d t h a t d e p r e s s i v e s y m p t o m s i m p r o v e d a s
a c o n s e q u e n c e of P D i m p r o v e m e n t , b u t t h i s i s h a r d l y t e n a b l e , a s P D s y m p t o m s
m a n t a i n e d t h e l o w e r s c o r e s for a l o n g e r p e r i o d a m e a n of 2 w e e k ( o r e v e n
l o n g e r for s o m e p a t i e n t s ) — a g a i n s t j u s t o n e w e e k for d e p r e s s i v e s y m p t o m s .
A s far a s P D s y m p t o m a t o l o g y i s c o n c e r n e d , t h e r e s u l t o b t a i n e d i n d i c a t e
a p o s i t i v e r e s p o n s e t o S D , w h i c h w a s m a n t a i n e d for at l e a s t 2 w e e k s . T h u s ,
S D h a s a b e n e f i c i a l e f f e c t 'per s e ' or w a s a b l e t o p o t e n t i a t e t h e e f f e c t s of t h e
d r u g s u s e d b y t h e p a t i e n t s . H o w e v e r t h e l a t t e r p o s s i b i l i t y i s l e s s l i k e l y , a s
t h e p a t i e n t s w e r e u s i n g d i f f e r e n t t h e r a p e u t i c s c h e d u l e s , i n v o l v i n g d r u g s w i t h
d i f f e r e n t m e c h a n i s m s of a c t i o n . A p l a c e b o e f f e c t s e e m e d a l s o n o t t o b e i n v o l v e d
a s t h e p a t i e n t s w e r e n o t t o l d t h a t a n i m p r o v e m e n t c o u l d o c c u r a f t e r S D .
F u r t h e r m o r e it w o u l d b e d i f f i c u l t t o e x p l a i n a p l a c e b o e f f e c t a c t i n g n o t o n l y
o n f u n c t i o n a l d i s a b i l i t y r a t i n g s c a l e , b u t a l s o o n o b j e c t i v e p a r a m e t e r s of t h e
r i g i d i t y , b r a d y k i n e s i a a n d g a i t a n d p o s t u r e d i s t u r b a n c e a n d , a t t h e s a m e t i m e ,
w i t h a v e r y s l i g h t a c t i o n o n t r e m o r . It s h o u l d a l s o b e m e n t i o n e d t h e w o r s e n i n g
of t h e L - D o p a d y s k i n e s i a s c a u s e d b y S D in 3 p a t i e n t s .
A t e n t a t i v e e x p l a n a t i o n for t h e r e s u l t s i s t h a t S D m a y a c t d i r e c t l y o n
d o p a m i n e r g i c r e c e p t o r s . R E M S D i n c r e a s e d a g g r e s s i v e b e h a v i o r i n d u c e d b y
d o p a m i n e r g i c a g o n i s t s 22; t h e u s e of a l p h a - m e t h y l - p - t y r o s i n e f a i l e d t o m o d i f y
the e x a g e r a t e d a p o m o r p h i n e r e s p o n s e in t h e R E M S D r a t s , a n d m e r e l y i n c r e a s i n g
b r a i n c o n c e n t r a t i o n of d o p a m i n e d i d n o t e n h a n c e d a p o m o r p h i n e e f f e c t s2 3
. A l l
t h e s e f i n d i n g s p o i n t t o a d o p a m i n e r e c e p t o r m e d i a t e d e f f e c t l e a d i n g t o t h e
h y p e r r e s p o n s i v e n e s s t o a p o m o r p h i n e o b s e r v e d in t h e S D a n i m a l s .
T h e p o s s i b i l i t y t h a t S D a c t s d i r e c t l y o n t h e d o p a m i n e r g i c r e c e p t o r s i s o n l y
a n s p e c u l a t i o n a t t h e m o m e n t . A l t h o u g h R E M S D r a t s h a v e s h o w n all t h e
a b o v e c h a n g e s in r e s p o n s i v e n e s s t o d o p a m i n e r g i c a g e n t s , t h e r e a r e n o t d a t a a t
p r e s e n t d e m o n s t r a t i n g t h e r e c e p t o r c h a n g e s . A l t h o u g h t h e m e c h a n i s m of
i m p r o v e m e n t p r e s e n t e d b y o u r p a t i e n t s r e m a i n s u n e x p l a i n e d , t h e r e s u l t s o b t a i n e d
i n d i c a t e t h a t S D m a y b e an u s e f u l a n d h a r m l e s s t h e r a p e u t i c p r o c e d u r e in P D .
SUMMARY
T w e l v e P a r k i n s o n d i s e a s e ( P D ) p a t i e n t s w e r e s u b m i t t e d t o a s i n g l e n i g h t
of t o t a l s l e e p d e p r i v a t i o n ( S D ) . D i s e a s e d u r a t i o n h a d a m e d i a n of 5.1 y e a r s
a n d all w e r e u s i n g e i t h e r a n t i c h o l i n e r g i c o r L - D o p a o r t h e c o m b i n a t i o n of b o t h
p o s t u r e d i s t u r b a n c e s a n d f u n c t i o n a l d i s a b i l i t y t h a t r e m a i n e d s i g n i f i c a n t for 2
w e e k s . N o e f f e c t w a s o b s e r v e d o n t r e m o r . C o n c e r n i n g d e p r e s s i v e s y m p t o m s ,
a s i g n i f i c a n t d i f f e r e n c e w a s n o t e d , t h a t r e m a i n e d f o r o n e w e e k . T h e s e r e s u l t s
s u g g e s t t h a t S D m a y b e a n u s e f u l p r o c e d u r e t o i m p r o v e P D s y m p t o m a t o l o g y .
It i s d i s c u s s e d a p o s s i b l e c h a n g e of d o p a m i n e r g i c r e c e p t o r s , i n d u c e d b y S D , t o
e x p l a i n t h e i m p r o v e m e n t .
RESUMO
Privação de sono total na doença de Parkinson.
D o z e p a c i e n t e s c o m d o e n ç a d e P a r k i n s o n ( D P ) f o r a m s u b m e t i d o s a p r i
-v a ç ã o d e s o n o t o t a l . A m é d i a d e i d a d e d o s p a c i e n t e s e r a 61 a n o s e a d u r a ç ã o
d a d o e n ç a e r a e m m é d i a d e 5,1 a n o s ( 1 , 5 a 12 a n o s ) . Q u a t r o d e l e s u s a v a m
a p e n a s a n t i c o l i n é r g i c o , 4 u s a v a m L - D o p a e 4 c o m b i n a ç ã o d e d r o g a s d e a m b o s
o s g r u p o s . A p ó s p r i v a ç ã o d e s o n o t o t a l p o r u m a ú n i c a n o i t e f o i v e r i f i c a d a
m e l h o r a n a r i g i d e z , b r a d i c i n e s i a , a l t e r a ç õ e s d e p o s t u r a e m a r c h a e i n c a p a c i d a d e
f u n c i o n a l c o m d u r a ç ã o d e d u a s s e m a n a s , e m c o m p a r a ç ã o c o m o s e s c o r e s q u a n d o
d a i n c l u s ã o n o e s t u d o . N ã o foi o b s e r v a d o e f e i t o s o b r e o t r e m o r . E m r e l a ç ã o
a o s s i n t o m a s d e p r e s s i v o s foi v e r i f i c a d a m e l h o r a c o m d u r a ç ã o d e a p e n a s u m a
s e m a n a . E s t e s r e s u l t a d o s s u g e r e m e f e i t o b e n é f i c o d a p r i v a ç ã o d e s o n o n a D P .
C o m b a s e e m e s t u d o s e x p e r i m e n t a i s j u l g a m o s q u e u m a e x p l i c a ç ã o p o s s í v e l p a r a
e s t e s r e s u l t a d o s s e j a a m o d i f i c a ç ã o d e r e c e p t o r e s d o p a m i n é r g i c o s .
R E F E R E N C E S
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