SUBACUTE SCLEROSING LEUCOENCEPHALITIS: A N
EPIDEMIO-LOGICAL, CLINICAL AND BIOCHEMICAL STUDY OF 31 CASES
HORÁCIO M . C A N E L A S * ; A N T Ô N I O B . L E F È V R E * * * ; W A L D I R A . T O G N O L A * * * * ; L I N E U C . F O N S E C A * * * * * * ;
O . FREITAS J U L I Ä O * * ; J . L A M A R T I N E DE A S S I S * * * ; FRANCISCO B . DE J O R G E * * * * * ; A . X A V I E R - L I M A * * * * * *
Subacute sclerosing leucoencephalitis ( S S L E ) is lately deserving the attention of several investigators in what concerns its biochemical, immunolo-gical and patholoimmunolo-gical aspects, these latter including studies by electron microscopy.
Contrasting with a well defined clinical picture, essentially characterized by the binomial consisting of psychiatric disorders and myoclonus or loss of tonus, controversies remain in regard to its pathological background, formerly
described either as an inclusion body encephalitis ( D a w s o n5
-6
) , a panence-phalitis (Pette D ö r i n g2 3
) or a subacute sclerosing leucoencephalitis (Van Bo-g a e r t2 9
) . The current trend, however, is to take these forms as variants of the same disease "> 1 8
>2 2 - 2 7
which Tariska 2 6
proposed to call subacute progressive panencephalitis. Though w e affiliate to the unicist view, the more widely used designation proposed by V a n Bogaert will be adopted.
T h e etiology is still unknown. Nevertheless, some facts point to a viral determination of the disease: 1) presence in the glia and neurons of Cowdry
type A intranuclear inclusion bodies 4
.1 6 >2 5
, similar to those found in herpes simplex encephalitis and c y t o m e g a l y2 3
; 2 ) intracytoplasmic bodies in the o
astrocytes, 500 to 8 0 0 A wide, morphologically resembling the viruses, which could signify, however, an abnormal metabolite of the endoplasmic reti-culum of the glia c e l l s1 1
; since the biologic properties of these inclusion bodies have not so far been demonstrated, the name virion (Caspar et al., cited by Howatson et a l .1 4
) could be extended to them; 3 ) transmission to the monkey through inoculation of biopsic material of human cases (in two
P a p e r r e a d a t t h e V I I t h N e u r o l o g i c a l C o n g r e s s o f A r g e n t i n a , h e l d i n B u e n o s A i r e s in 2 7 - 2 9 O c t o b e r 1 9 6 6 .
animals an encephalitis developed, and in one of them it had the features of S S L E , including the presence of intranuclear inclusion b o d i e s1 2
) ; 4) The relationship, in some cases, between the onset of the disease and the death of household animals 2
-3 0 .
Nevertheless, K o l a r et a l .1 5
give special emphasis to the immunopathologic mechanisms, particularly to the extraneural reticulo-endothelial system in the development of S S L E . These mechanisms would be implicated in the preva-lence of the disease in males. On the other hand, the correlation between thymus activity, adolescence, and the prevailing age period of S S L E led Kolar et al. to perform a pneumomediastinography in 7 cases of the disease, a hyperplasia being found in 4. Evidently, Kolar's hypothesis needs a decisive confirmation and therefore can not refute the arguments in favor of the viral etiology of S S L E .
Electroencephalography and the electrophoresis of the proteins of the cere-brospinal fluid ( C S F ) and blood are significant aids in the diagnosis of S S L E . T h e marked increase of C S F gamma-globulins with C S F / b l o o d ratios two or more times greater than the normal figures, seems to b e a constant in the disease. Though the immunologic studies are not conclusive yet, those glo-bulins are seemingly produced in situ. T h e presence of a number of plasma cells in the neuropil of one case studied by Gonatas 1 1
was assumed as related to the formation of antibodies.
The questions which still remain to be solved in regard to the etiopatho-genesis of S S L E are responsible for the failure of the therapeutic schemes so far tried.
A s a contribution to the epidemiological, clinical and biochemical study of S S L E the experience of the Departments of Neurology of the Universities of São Paulo and Campinas Medical Schools will be analyzed *.
M A T E R I A L A N D M E T H O D S
T h e clinical m a t e r i a l is m a d e up by 3 1 cases, t h e first one diagnosed in 1954 ( T a b l e 1 ) .
In T a b l e s 2 and 3 the paraclinical criterion used for the diagnosis is s u m m a -rized. A s it can be seen in T a b l e 2, in 16 a m o n g 18 cases w i t h o u t p o s t m o r t e m confirmation, alter ation s of the p r o t e i n o g r a m ( m a r k e d increase of the C S F g a m m a -globulins, usually w i t h C S F / b l o o d ratios o v e r 1.0) and a typical electroencepha-lographic pattern were associated. In 2 cases the diagnosis w a s based on the clinical and electroencephalographic characteristics alone.
R e g a r d i n g the pathological study, i n t r a c e l l u l a r inclusion bodies w e r e found in 8 of 1 3 cases submitted to p o s t m o r t e m e x a m i n a t i o n . A s t o t h e cerebral biopsy, a picture of encephalitis w a s evidenced in 4 of 7 cases, in o n e of t h e m inclusion bodies being found. Contrary to w h a t could be expected f r o m t h e reported pre-v a l e n c e of t h e lesions in the parieto-occipital r e g i o n1 8
,1 9
, encephalitis w a s found in 3 of t h e 4 frontal biopsies and in only 1 of the 3 occipital biopsies .
R E S U L T S A N D C O M M E N T S
Age — T h e mean age w a s 11.7 years, with the limits of 3 and 22 years
(fig. 1 ) ; this upper limit is seldom recorded in the l i t e r a t u r e2 0 -3 1
. In 2 7 pa-tients the age varied between 6 and 15 years. These findings agree with those of Canal and Torek 2
( 7 5 % of their patients were f r o m 6 to 12 years old, with a m e a n age of 9.1 years) and~Hamoen et a l .1 2
Race — A l l patients were white.
Provenance — Patients coming from rural zones were more afflicted (77,4%) than those living in large cities, in a rate completely opposite the general distribution in the outpatient service (Table 5 ) . M o s t of cases lived in hinterland counties with low demographic density, a fact also found
by Canal and Torek 2
in Belgium, and by Glasgow and W r i g h t o n (apud Canal and Torek 2
) in N e w Zealand.
Geographic distribution — T h e distribution of cases in the State of São Paulo and in the North of the State of Paraná (a region intimately bound to the State of São Paulo) was scattered, though some prevalence could be noted in the W e s t e r n region (fig. 2 ) . Canal and Torek 2
found a predomi-nance of cases of S S L E coming from the Northern and W e s t e r n regions of Belgium, which present significant geographic differences, especially con-cerning altitude.
There are no studies on the frequency and distribution of cases of S S L E in other States of Brazil. Most of the cases studied in the State of Guanabara
(actually a large city and not a state), however, came from the suburban zones 1
.
Climate and seasons — N o correlation between incidence of S S L E and climate could be stated.
Like Canal and Torek 2
and Usunoff et a l .2 1
, no seasonal prevalence of
the onset of the disease was found (Table 6 ) .
months. H a m o e n et a l .1 2
found an average of 13 months and a range from 3
to 27 months. Usunoff et a l .2 7
report the range from 3.5 to 18 months. Lehmannn and U l e1 7
found a significant correlation between age and duration of the disease; in our material, however, a non significant negative correlation was found (r = — 0.376; tr . = 1.518).
Clinical picture — In the symptomatology (Table 7) the constancy of myoclonus or losses of tonus, and psychiatric disorders was evidenced. T h e losses of tonus can not be clinically distinguished from myoclonus, and it is also hard to decide on the existence of lapses of consciousness. Myoclonus occurred as the first symptom in 35.5% of cases (fig. 3 ) , a rate very similar
to those reported by Usunoff et a l .2 8
(a third of the cases) and Hamoen et a l .1 2
( 3 0 . 4 % ) .
In 3 cases the existence of psychiatric alterations could not be stated, owing to doubtful or lacking anamnestic data. Concerning this aspect, Hasaerts and V a n Geertruyden 1 3
pathologic character of the initial psychiatric manifestations. These occurred as the first symptom of the remaining 2 8 patients in a proportion of 55.6% and, up to the fifth month of disease, they were manifest in the great majority of cases. In Usunoff et a l . ' s2 8
series (45 cases) psychiatric disorders were the first symptom in two thirds of the cases.
Grand m a l seizures occurred in 48.4% of the patients. In 33.3% of the cases they were the first symptom, a rate very greater than that reported by Usunoff et a l .2 8
( 6 . 6 % ) . The high figure w e found m a y be due to the fact that the parents or relatives could have overlooked the other symptoms, par-ticularly the initial psychiatric disorders.
Muscle hypertonus occurred in 8 3 . 3 % of the cases during the course of the disease. Usually an extrapyramidal stiffness was evidenced but it ulti-mately evolved to a decerebrate or decorticate rigidity, whose onset was coin-dent with the subsidence of the hyperkinesis.
T h e ophtalmoscopic examination disclosed alterations in a third of cases (Table 8 ) , consisting of a slight edema or pallor of the optic disk; in one case
there was choroiditis associated with pallor. Osetowska and T o r e k2 0
found edema or pallor of the disk, or else retinitis pigmentosa, in 3 7 % of the cases.
In cases 30 and 31 the onset of the disease was concomitant with an epizootic in household chicken. Seemingly this kind of relationship could be detected in other patients provided w e had not directed our attention to his question only in the last cases of our series.
Copper, ceruloplasmin, magnesium and sulfur concentrations in the blood serum (Table 9) — T h e determinations of the total blood copper in 8 cases always showed high contents, ranging from 123 to 310 ^ g / 1 0 0 ml (mean 210 ju.g/100 m l ) , associated with slight changes in the ceruloplasmin levels; this finding suggests that the hypercupremia is consequent to increment of the
free copper. These results agree with those of Cernacek et al. 3
T h e blood levels of sulfur, determined only m 3 cases, were high. The blood concentrations of magnesium showed a variable behavior, in 4 cases being over and in 2 being under the normal limits.
S U M M A R Y
T h i r t y - o n e c a s e s o f S S L E a r e r e p o r t e d . T h e d i a g n o s i s w a s b a s e d o n
t h e c l i n i c a l p i c t u r e , t h e m a r k e d i n c r e a s e o f g a m m a g l o b u l i n s in t h e c e r e b r o s
-p i n a l fluid, t h e t y -p i c a l e l e c t r o e n c e -p h a l o g r a -p h i c -p a t t e r n , a n d t h e -p a t h o l o g i c a l
e x a m i n a t i o n . I n t r a c e l l u l a r i n c l u s i o n b o d i e s w e r e f o u n d at t h e p o s t m o r t e m
e x a m i n a t i o n o f 8 a m o n g 13 c a s e s a n d in 1 o f 7 c e r e b r a l b i o p s i e s . T h e m e a n
a g e w a s 11.7 y e a r s , w i t h t h e l i m i t s o f 3 a n d 2 2 y e a r s . M a l e s p r e v a i l e d
m a r k e d l y o v e r f e m a l e s ( 2 3 : 8 ) . P a t i e n t s f r o m r u r a l r e g i o n s w e r e t h e b u l k o f
t h e series ( 7 7 . 4 % ) . N o d e f i n i t e r e g i o n a l p r e d o m i n a n c e w a s d e m o n s t r a t e d b y
t h e a n a l y s i s o f t h e g e o g r a p h i c d i s t r i b u t i o n . A s e a s o n a l i n f l u e n c e w a s n o t
e v i d e n c e d . I n 16 p a t i e n t s f o l l o w e d u p t o d e a t h , t h e a v e r a g e d u r a t i o n o f t h e
d i s e a s e w a s 7 m o n t h s , w i t h a r a n g e f r o m 2 t o 2 0 m o n t h s . I n t h e c l i n i c a l
p i c t u r e t h e c o n s t a n c y o f m y o c l o n u s o r l o s s e s o f t o n u s , a n d p s y c h i a t r i c d i s o r d e r s
w a s e v i d e n c e d . T h e first s y m p t o m w a s t h e p s y c h i a t r i c a l t e r a t i o n in 5 5 . 6 %
o f t h e c a s e s , m y o c l o n u s in 3 5 . 5 % a n d g r a n d m a l s e i z u r e s in 3 3 . 3 % . R i g i d i t y
a n d p y r a m i d a l signs w e r e v e r y f r e q u e n t , w h i l e t h e c e r e b e l l a r s y n d r o m e w a s
r a r e . O p h t a l m o s c o p i c a l t e r a t i o n s ( e d e m a t o u s o r p a l e d i s k , c h o r o i d i t s ) w e r e
f o u n d i n a t h i r d o f t h e c a s e s . I n t w o c a s e s an e p i z o o t i c o f h o u s e h o l d c h i c k e n
w a s c o i n c i d e n t w i t h t h e o n s e t o f t h e d i s e a s e . T h e b l o o d c o p p e r c o n c e n t r a t i o n s
d e t e r m i n e d in 8 c a s e s w e r e a l w a y s a b o v e t h e n o r m a l r a n g e , w h i l e c e r u l o ¬
p l a s m i n r e m a i n e d w i t h i n t h e n o r m a l l i m i t s . T h e b l o o d s u l f u r l e v e l s w e r e
h i g h in 3 p a t i e n t s s t u d i e d . T h e b l o o d m a g n e s i u m l e v e l s w e r e v a r i a b l e in
6 p a t i e n t s s t u d i e d .
R E S U M O
Leucoencefalite esclerosante subaguda: estudo epidemiológioco, clínico e
bioquímico de 31 casos
S ã o a p r e s e n t a d o s 31 c a s o s d e l e u c o e n c e f a l i t e e s c l e r o s a n t e s u b a g u d a , c u j o
d i a g n ó s t i c o se b a s e o u n o q u a d r o c l í n i c o , n o a c e n t u a d o a u m e n t o d a s g l o b u l i n a s y
n o l í q u i d o c e f a l o r r a q u e a n o , n a s c a r a c t e r í s t i c a s a l t e r a ç õ e s d o e l e t r e n c e f a l o g r a ¬
m a e n o e s t u d o a n á t o m o - p a t o l ó g i c o . F o r a m e n c o n t r a d o s c o r p ú s c u l o s d e
in-c l u s ã o i n t r a in-c e l u l a r m e d i a n t e o e s t u d o n e in-c r o s in-c ó p i in-c o d e 8 e n t r e 13 in-c a s o s e o
e x a m e h i s t o p a t o l ó g i c o d e 1 e n t r e 7 b i o p s i a s c e r e b r a i s . A m é d i a e t á r i a foi d e
11,7 a n o s , c o m o s l i m i t e s de 3 a 22 a n o s . O s e x o m a s c u l i n o p r e d o m i n o u
niti-d a m e n t e s o b r e o f e m i n i n o ( 2 3 : 8 ) . O s p a c i e n t e s p r o v e n i e n t e s niti-d a z o n a r u r a l
f i c a n ã o d e m o n s t r o u p r e d o m í n i o r e g i o n a l d e f i n i d o . N ã o foi o b s e r v a d a i n
-f l u ê n c i a e s t a c i o n a l s ô b r e o i n í c i o d a m o l é s t i a . E m 16 c a s o s a c o m p a n h a d o s a t é
o ó b i t o , a d u r a ç ã o m é d i a foi d e 7 m e s e s , c o m u m a f a i x a d e 2 a 2 0 m e s e s . N o
q u a d r o c l í n i c o s o b r e s s a i u a p r e s e n ç a e o n s t a n t e d e m i o c l o n i a s o u p e r d a s d e
t o n o , e d e a l t e r a ç õ e s p s í q u i c a s . O p r i m e i r o s i n t o m a f o i r e p r e s e n t a d o p o r
d i s t ú r b i o s p s í q u i c o s e m 5 5 , 6 % d o s p a c i e n t e s , p o r m i o c l o n i a s e m 35,5%o e p o r
c o n v u l s õ e s d o t i p o g r a n d e m a l e m 3 3 , 3 % . R i g i d e z e sinais p i r a m i d a i s f o r a m
m u i t o f r e q ü e n t e s , s e n d o r a r a a s í n d r o m e c e r e b e l a r . A l t e r a ç õ e s o f t a l m o s c ó p i c a s
( e d e m a o u p a l i d e z d e p a p i l a , c o r o i d i t e ) f o r a m v e r i f i c a d a s e m u m t e r ç o d o s
c a s o s . E m 2 c a s o s o i n í c i o da m o l é s t i a c o i n c i d i u c o m u m a e p i z o o t i a d e
g a l i n h a s . O s v a l o r e s d o c o b r e s a n g ü í n e o , d e t e r m i n a d o s e m 8 c a s o s , s i t u a r a m - s e
s e m p r e a c i m a d a f a i x a n o r m a l , e n q u a n t o a c e r u l o p l a s m i n a p e r m a n e c e u d e n t r o
d o s l i m i t e s n o r m a i s . O s v a l o r e s d o e n x o f r e s a n g ü í n e o r e v e l a r a m - s e e l e v a d o s
e m 3 p a c i e n t e s e x a m i n a d o s . O s n í v e i s d a m a g n e s e m i a m o s t r a r a m - s e v a r i á v e i s
e m 6 p a c i e n t e s e s t u d a d o s .
R E F E R E N C E S
1 . A L E N C A R , A . A . — P e r s o n a l c o m m u n i c a t i o n . S ã o P a u l o , O c t o b e r 1 9 6 6 .
2 . C A N A L , N . & T O R C K , P . — A n e p i d e m i o l o g i c a l s t u d y o f s u b a c u t e s c l e r o s i n g
l e u c o e n c e p h a l i t i s in B e l g i u m . J. n e u r o l . S c i . 1 : 3 8 0 - 3 8 9 , 1 9 6 4 .
3 . C E R N Á C E K , J.; K O B S A , K . ; B R A C H T L O V Á , M . & M A J E R O V Á , A . — S e r u m ¬
- c o p p e r l e v e l in s u b a c u t e s c l e r o t i s a n t l e u k o e n c e p h a l i t i s . P s y c h i a t . N e u r o l . 1 4 7 :
3 2 1 - 3 2 6 , 1 9 6 4 .
4 . C O W D R Y , E . V . — T h e p r o b l e m o f i n t r a n u c l e a r i n c l u s i o n s in v i r u s d i s e a s e s .
A r c h . P a t h . ( C h i c . ) 1 8 : 5 2 7 - 5 4 2 , 1 9 3 4 .
5 . D A W S O N , J. R . — C e l l u l a r i n c l u s i o n s in c e r e b r a l l e s i o n s o f l e t h a r g i c e n c e
-p h a l i t i s . A m e r . J. P a t h . 9 : 7 - 1 6 , 1 9 3 3 .
6 . D A W S O N , J. R . — C e l l u l a r i n c l u s i o n s in c e r e b r a l l e s i o n s o f e p i d e m i c e n c e
-p h a l i t i s ( s e c o n d r e -p o r t ) . A r c h . N e u r o l . P s y c h i a t . ( C h i c . ) 3 1 : 6 8 5 - 7 0 0 , 1 9 3 4 .
7 . D e J O R G E , F . B . .& C A N E L A S , H . M . — C o n t r i b u i ç ã o a o e s t u d o d a c e r u l o
-p l a s m i n a . I : V a l o r e s n o r m a i s n o s ô r o s a n g ü í n e o . A r q . N e u r o - -p s i q u i a t . ( S .
P a u l o ) 2 2 : 2 7 1 - 2 7 6 , 1 9 6 4 .
8 . D e J O R G E , F . B . ; C A N E L A S , H . M . & S P I N A F R A N C A , A . — C o n t r i b u i ç ã o
a o e s t u d o d o m e t a b o l i s m o d o c o b r e . I I : V a l o r e s n o r m a i s d e c o b r e n o s a n g u e ,
l í q u i d o c e f a l o r r a q u e a n o e u r i n a . R e v . p a u l . M e d . 6 2 : 1 2 5 - 1 2 8 , 1 9 6 3 .
9 . D e J O R G E , F . B . ; C A N E L A S , H . M . & Z A N I N I , A . C . — M e t a b o l i s m o d o
m a g n é s i o . I I : V a l o r e s n o r m a i s n o s o r o , p l a s m a , s a n g u e t o t a l , l í q u i d o c e f a
-l o r r a q u e a n o , u r i n a e f e z e s . R e v . p a u -l . M e d . 6 5 : 9 5 - 1 0 5 , 1 9 6 4 .
1 0 . D e J O R G E , F . B . ; C A N E L A S , H . M . & Z A N I N I , A . C . — M e t a b o l i s m o d o e n
-x o f r e . I I : V a l o r e s n o r m a i s n o s ô r o s a n g ü í n e o , l í q u i d o c e f a l o r r a q u e a n o , s a l i v a ,
1 1 . G O N A T A S , N . K . — S u b a c u t e s c l e r o s i n g l e u c o e n c e p h a l i t i s : e l e c t r o n m i c r o s
-c o p i -c a n d -c y t o -c h e m i -c a l o b s e r v a t i o n s o n a -c e r e b r a l b i o p s y . J. N e u r o p a t h . 2 5 :
1 7 7 - 2 0 1 , 1 9 6 6 .
1 2 . H A M O E N , A . M . ; H E R N G R E E N , H . ; S T O R M V A N L E E U W E N , W . & M A G
-N U S , O . — E n c é p h a l i t e s u b a i g u ë p r o g r e s s i v e : c o n s t a t a t i o n s c l i n i q u e s e t e l e c t r o ¬
e n c é p h a l o g r a p h i q u e s d a n s 2 3 c a s . R e v . n e u r o l . 9 4 : 1 0 9 - 1 1 9 , 1 9 5 6 .
1 3 . H A S A E R T S , E . & V A N G E E R T R U Y D E N , E . — C a r a c t è r e s e t é t a p e s d e l a
d é t é r i o r a t i o n p s y c h i q u e d a n s l a l e u c o - e n c é p h a l i t e s c l é r o s a n t e s u b a i g u ë ( 1 4
o b s e r v a t i o n s ) . E n c é p h a l e 4 7 : 3 1 - 7 2 , 1 9 5 8 .
1 4 . H O W A T S O N , A . F.; N A G A I , M . & Z U R H E I N , G . M . — P o l i o m a - l i k e v i r i o n s
in h u m a n d e m y e l i n a t i n g b r a i n d i s e a s e . C a n a d . m e d . A s s . J. 9 3 : 3 7 9 - 3 8 6 , 1 9 6 5 .
1 5 . K O L A R , O . ; M U S I L , J. & F U N T A L O V A , M . — A c o n t r i b u t i o n t o p r o b l e m s
o f s e x u a l d i f f e r e n c e i n s u s c e p t i b i l i t y t o s u b a c u t e s c l e r o s i n g l e u c o e n c e p h a l i t i s .
A c t a n e u r o l . p s y c h i a t . b e l g . 6 6 : 7 3 2 - 7 4 1 , 1 9 6 6 .
1 6 . K U R T Z K E , J. F . — I n c l u s i o n b o d y e n c e p h a l i t i s : a n o n f a t a l c a s e . N e u r o l o g y
( M i n n e a p . ) 6 : 3 7 1 - 3 7 6 , 1 9 5 6 .
1 7 . L E H M A N N , H.-J. & U L E , G . — S u b a k u t e E n c e p h a l i t i s f o r m e n u n b e k a n n t e r
Ä t i o l o g i e : ü b e r d i e n o s o l o g i s c h e S t e l l u n g d e r L e u k e n c e p h a l i t i s ( v a n B o g a e r t )
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