NON-EPILEPTIC MYOCLONUS AND MITOCHONDRIAL
ENCEPHALOMYOPATHY
A. CUKIERT * — F. G. M. NAYLOR ** — H. B. SCAPOLAN * — M. M. VILELA * F. S. ALOE * — J. O. SIFFERT * — ANA M. TSANAGLIS *** — MONICA HADDAD *
TERESA C. MACHADO * — MARY CARVALHO-ALEGRO *** — J. A. LEVY *** L. MARQUES-ASSIS *
S U M M A R Y — T w o b r o t h e r s p r e s e n t e d t o u s w i t h a p r o g r e s s i v e m y o c l o n i c s y n d r o m e w i t h s l i g h t c e r e b e l l a r s y m p t o m s . N e u r o l o g i c a l e x a m i n a t i o n d i s c l o s e d m o d e r a t e c e r e b e l l a r s i g n s a n d p a l e o p t i c d i s c s ; a s y m m e t r i c , a s y n c h r o n o u s a n d a r h y t h m i c m y o c l o n u s , a n a r t h r e s t h e s i c d e f i c i t a n d n o m u s c u l a r w e a k n e s s . E E G b a c k g r o u n d a c t i v i t y w a s m o d e r a t e l y s l o w w i t h n o i r r i t a t i v e d i s c h a r g e s . C T w a s n o r m a l in b o t h c a s e s , I n t e r m i t e n t p h o t i c s t i m u l a t i o n i n c r e a s e d t h e freq u e n c y o f t h e m y o c l o n i c j e r k s , w h i c h b e c a m e b i l a t e r a l a n d s y n c h r o n o u s , p r o g r e s s i n g t o a g e n e -r a l i z e d t o n i c - c l o n i c s e i z u -r e . E P s a n d M R I i n o n e c a s e w e -r e n o -r m a l . A n t i c o n v u l s a n t d -r u g s w e -r e i n e f f e c t i v e . T h e d i a g n o s i s o f m i t o c h o n d r i a l e n c e p h a l o m y o p a t h y w a s b a s e d o n t h e f i n d i n g , in m u s c l e s p e c i m e n s , o f t h i c k e n e d b a s e m e n t m e m b r a n e s w i t h m y o f i b r i l l a r y d e g e n e r a t i o n a n d i n c r e a s e d n u m b e r o f m i t o c h o n d r i a p e r i p h e r a l l y d i s t r i b u t e d a n d w i t h a d e n s e g r a n u l a r m a t r i x a n d s o m e v a c u o l e s . T h e c l i n i c a l a n d E E G d a t a s u g g e s t a. s u b c o r t i c a l o r i g i n f o r t h i s t y p e o f m y o c l o n i c s y n d r o m e .
Mioclonias não epilépticas e encefalomiopatia mitocondrial.
R E S U M O — F o r a m e x a m i n a d o s d o i s i r m ã o s p o r t a d o r e s d e u m a s í n d r o m e m i o c l ô n i c a p r o g r e s s i v a c o m d i s c r e t o s s i n t o m a s c e r e b e l a r e s . O e x a m e n e u r o l ó g i c o m o s t r a v a s i n a i s c e r e b e l a r e s m o d e r a d o s e p a p i l a s p á l i d a s ; m i o c l o n i a s a s s í n c r o n a s , a r r í t m i c a s e a s s i m é t r i c a s , u m d é f i c i t a r t r e s t é s i c o e a u s ê n c i a d e f r a q u e z a m u s c u l a r . A a t i v i d a d e d e b a s e d o E E G e r a m o d e r a d a m e n t e l e n t a e s e m a t i v i d a d e i r r i t a t i v a . A T C e r a n o r m a l e m a m b o s o s c a s o s . A e s t i m u l a ç ã o f ó t i c a i n t e r m i t e n t e a u m e n t a v a a f r e q ü ê n c i a d o s a b a l o s m i o c l ô n i c o s q u e s e t o r n a v a m b i l a t e r a i s e s i n c r o n o s , p r o g r e
-d i n -d o p a r a u m a c r i s e t ô n i c o - c l ô n i c a g e n e r a l i z a -d a . P o t e n c i a i s e v o c a -d o s e R M N e m u m c a s o f o r a m n o r m a i s . D r o g a s a n t i c o n v u l s i v a n t e s f o r a m i n e f i c a z e s n o c o n t r o l e d a s m i o c l o n i a s . O d i a g n ó s t i c o d e e n c e f a l o m i o p a t i a m i t o c o n d r i a l f o i r e a l i z a d o a t r a v é s d o a c h a d o e m e s p é c i m e s m u s -c u l a r e s d e m e m b r a n a s b a s a i s e s p e s s a d a s , -c o m d e g e n e r a ç ã o m i o f i b r i l a r e u m n ú m e r o e l e v a d o d e m i t o c o n d r i a s d i s t r i b u í d a s p e r i f e r i c a m e n t e e c o m u m a m a t r i z d e n s a , g r a n u l a r e c o m a l g u n s v a c ú o l o s . O s a c h a d o s c l í n i c o s e e l e t r o g r á f i c o s s u g e r e m u m a o r i g e m s u b c o r t i c a l p a r a esta s í n d r o -m e -m i o c l ô n i c a .
Some cases of mitochondrial encephalomyopathy ( M E M ) may present the hallmarks for the diagnosis of a progressive myoclonic epilepsy ( P M E ) : a convulsive syndrome, myoclonus and mental deterioration. Likewise in other forms of P M E , myoclonus can
have a subcortical origin. Yet, each individual element of the aforementioned triad can also be originated in the cerebral cortex. In this paper two cases 01 M h M are reported that had signs and symptoms of a P M E in which the anatomophysiological
basis of its clinical manifestations may primarily involve subcortical structures.
F a c u l t y o f M e d i c i n e , U n i v e r s i t y o f S ã o P a u l o ( F M U S P ) a n d H o s p i t a l d a s C l í n i c a s , F M U S P : * D i v i s i o n o f N e u r o l o g y ; ** D i v i s i o n o f F u n c t i o n a l N e u r o s u r g e r y ; *** N e u r o l o g y I n v e s t i g a t i o n C e n t e r .
M A T E R I A L , A N D M E T H O D S
T w o male brothers, G S and M S , aged 29 and 49 respectively, presenting a P M E syndrome were submitted to a thorough clinical examination, prolonged E E G tracings, C A T , C S F analysis,
E K G , hematologic and blood biochemistry exams.
Skin and muscle biopsies (biceps) were performed in both patients and were analised by optic and electron microscopy. GS was submitted to visual and somatosensory evoked
potentials, a polisomnography, N M R I and E E G recordings with photostimulation under hypnosis and curarization in order to avoid myoclonic born electrographic artifacts.
R E S U L T S
GS, a 29 year-old countryman born in the State of Pernambuco first presented simple visual secondarily generalized tonic-clonic seizures at the age of eighteen. I n the interictal periods there were arhythmic, asymmetric and asynchronous myoclonic jerks. Three other brothers suffered from the same illness, and one of them is described below. Mental deterio-ration was evident at a regular interview and the patient w a s not amenable to standard neuropsychological testing. Neurological examination showed no muscle weakness, a cerebellar syndrome with pastpointing, decomposition of movements of the four limbs, a slurred speach and a sensitive syndrome characterized by abnormal joint position sensation with normal vibration sense. Fundoscopic examinations displayed slightly pale papilae bilaterally. L o w frequency, arhythmic, asynchronous and asymmetric myoclonus predominantly in the face and upper limbs muscles occurred with eyes open and became more severe with eyes closed or in dark places. A t one occasion, a generalized tonic-clonic seizure w a s triggered b y a three minute long dark-room exposure. E K G , C S F analysis and a hematological survey were normal. Prolonged E E G tracings disclosed only a few periods of delta and theta waves bilaterally over the frontaJ regions and no definite epileptic elements were recorded. Background activity was slightly slow and interspersed with muscle artifacts. Hyperventilation yielded no substantial E E G changes. L o w frequency photostimulation (1 H z ) provoked a clear increase in both fre-quency and amplitude of the myoclonus, which at a certain point became bilateral, synchronous and symmetric, progressing to generalized tonic-clonic seizure. There was no E E G correlate to the myoclonic jerks. E E G recording under curarization and hypnosis showed periods of delta and theta waves over both frontal regions and no additional abnormal elements were recorded under low frequency photostimulation. A polisomnognaphic record showed a decreased R E M sleep density. Visual evoked potentials showed a slight enhanced latency period. Somatosensory evoked potentials were normal. C T and M R I disclosed signs of a cortico-subcor-tical atrophy. Immunofluorescence studies of a skin biopsy were normal. Optic microscopy studies of muscle specimens were unable to demonstrate the presence of ragged-red fibers ( R R F s ) . Electronic microspopy examination of muscle biopsies showed small areas of focal fibrosis and myofibrillary degeneration. W a v y and thickened sarcolemmae were frequent. Elongated mitochondria with a dense and heterogeneous matrix were seen in a great number as well as large agglomerates of mitochondria in a subsarcolemmal position (Figures 1 and 2 ) .
MS, a 49 year-old countryman born in the State of Pernambuco presented asynchronous, arhythmic and asymmetric myoclonus since the age of fourteen. A t the a g e of eighteen he noticed a progressive gait disturbance. Sporadic episodes of loss of consciousness (apparently generalized tonic-clonic seizures) were reported b y the patient. A t a regular interview mental deterioriation was evident and the patient was not suitable for neuropsychological testing. Neurologic examination showed normal muscle power, a cerebellar syndrome characterized by an ataxic gait, disarthric speech, past-pointing and movement decomposition in the four limbs. Abnormal point position with normal vibration sensations w a s noticed. Fundoscopic examina-tion showed slightly atrophic papilae. Arhythmic, asynchronous and asymmetric myoclonus of small amplitude predominating in the upper limbs could be seen. E y e s closure did not alter myoclonus characteristics. C S F analysis and hematologic exams were reported normal. A n E K G showing a sinusal bradychardia of 40 b p m with a few supraventricular P V C s and anterior left halfblockade was recorded. Sorologic reactions for Chagas' disease were negative and
Schistosoma mamsoni eggs were found in the feces. E E G was normal but C T scanning showed
signs of cortico-subcortical atrophy. Skin and muscle biopsy examinations under optic and electronic microscopy yielded findings similar to the first case ( G S ) .
C O M M E N T S
The EEG findings in both cases suggest a subcortical origin of the myoclonic jerks in this form of M E M . The clinical progression of the seizure reported for case 1 suggests a subcortico-cortico-subcortical loop as the underlying anatomophysiolo-gical basis for this epileptic syndrome as opposed to the usual cortico-subcortico-cortical loop as seen in many non-progressive forms of epilepsy. About thirty cases of M E M presenting as a P M E were so far reported and in many of them the E E G clearly showed diffuse epileptic abnormalities. In these cases previously reported, the E E G changes appear to relate to the epileptic syndrome but there was no E E G correlate for the myoclonic syndrome.
The definitive diagnosis of M E M is based on the findings of abnormal mitochon-dria mainly in muscle specimens. RRFs are frequently found in optic microscopy examination and one negative sample does not rule out completely the diagnosis of MEM. Yet, other samples from different muscles may yield positive results. In addition to that, the abscence of RRFs does not rule out the diagnosis of other forms of M E M . The most common histopathologic findings in M E M correspond to a selective neuronal loss specially in the dentate cerebellar nucleus and olivary nucleus with simultaneous degeneration of the superior cerebellar peduncles and dorsal
funi-culli with disseminated cerebellar and brain stem g l i o s i s1 2
-1 6
.
PME-like M E M has been denominated MERRF (myoclonus epilepsy and ragged--red fibers). However, some controversy has arisen recently in the current literature since cases similar to ours with no RRFs have also been called MERRF 7. The authors prefer to name the latter as M E M presenting as a P M E with no RRFs. In both cases reported here no RRFs were observed. Additional muscle biopsies obtained from different muscles could have yielded different results. So far, no mitochondrial changes were recorded in C N S cells in cases of M E M . The actual difficulty to obtain adequate samples and different histopathologic responses of both C N S and other tissues may account for this failure, hurthermore, it is not possible so far to assure that C N S manifestations are caused by a nervous cell respiratory blockade. The search for specific biochemical mitochondrial defects has led to the demonstration of such abnormalities in at least three out of five distinct respiratory mitochondrial enzymatic complexes 3 , i i , i 5 . Nonetheless, it has not been possible to relate any specific biochemical deficits to a distinct clinical picture.
Many syndromes described in the past are now classified as MEMs. Ramsay-Hunt
syndrome 2
<&, Friedreich ataxia associated to c o n v u l s i o n s a n d Leigh syndrome 4
>1 8
were found to show mitochondrial abnormalities. The cases reported by Ekbom 6 and May and White as well as many others described as multisystem degeneration may represent distinct examples of M E M s 9. Other MEMs as the M E L A S (mitochon-drial myopathy, encephalopathy, lactic acidosis and stroke like episodes) 13 possess a different clinical progression.
Due to the broad clinical spectrum of the M E M s1 4
, these are very likely to be underdiagnosed in tlie current practice. A more accurate classification of the specific phenotypes and their associated biochemical deficits will lead to a better understanding of these disorders.
R E F E R E N C E S
1. B e r k o v i c S F , A n d e r m a n n F , C a r p e n t e r S, W o l f e S — P r o g r e s s i v e m y o c l o n u s e p i l e p s i e s : s p e c i f i c c a u s e s a n d d i a g n o s i s . N E n g l J M e d 315 : 296, 1986.
2. B i r d T D , S h a w C M — P r o g r e s s i v e m y o c l o n u s e p i l e p s y w i t h d e n t a t o r u b r a l d e g e n e r a t i o n : a c l i n i c o p a t h o l o g i c a l s t u d y o f t h e R a m s a y - H u n t s y n d r o m e . J N e u r o l N e u r o s u r g P s y c h i a t 41 : 140, 1978.
3. B y r n e E , T r o u n c e I — O x i g e n e l e c t r o d e s t u d i e s w i t h h u m a n s k e l e t a l m u s c l e m i t o c h o n d r i a i n v i t r o : a r e a p p r a i s a l . J N e u r o l S c i 69 : 319, 1982.
4. C r o s b y T W , C h o u S M — ' R a g g e d - r e d ' f i b e r s in L e i g h d i s e a s e . N e u r o l o g y 24 : 49, 1974. 5. D i M a u r o S, B o n i l l a E , Z e v i a n i M , N a g a k a w a M , D e V i v o D — M i t o c h o n d r i a l m y o p a t h i e s .
A n n N e u r o l 17 : 521, 1985.
6. E k b o m K — H e r e d i t a r y a t a x i a , p h o t o m y o c l o n u s , s k e l e t a l d e f o r m i t i e s a n d l i p o m a . A c t a N e u r o l S c a n d 51 : 393, 1975.
8. H u n t J R — D y s s i n e r g i a c e r e b e l l a r i s m y o c l o n i c a : p r i m a r y a t r o p h y o f t h e d e n t a t e s y s t e m . A c o n t r i b u t i o n t o t h e p a t h o l o g y a n d s y m p t o m a t o l o g y o f t h e c e r e b e l l u m . B r a i n 44 : 490, 1921. 9. K a r p a t i G, C a r p e n t e r S, L a r b r i s s e a u A , L a f o n t a i n e R — T h e K e a r n s - S h y s y n d r o m e : a
m u l t i s y s t e m d i s e a s e w i t h m i t o c h o n d r i a l a b n o r m a l i t y d e m o n s t r a t e d i n s k e l e t a l m u s c l e a n d akin. J N e u r o l Sci 19 : 133, 1973.
10. M a y D L , W h i t e HH — F a m i l i a l m y o c l o n u s , c e r e b e l l a r a t a x i a a n d d e a f n e s s . A r c h N e u r o l 19 : 331, 1968.
11. M o r g a n - H u g h e s J A — M i t o c h o n d r i a l d i s e a s e s . T r e n d s in N e u r o s c i e n c e 9 : 15, 1986. 12. N a k a n o T , S a k a i H , A m a r o N , Y a g i s h i t a S, I t o Y — A n a u t o p s y c a s e o f d e g e n e r a t i v e t y p e
o f m y o c l o n u s e p i l e p s y a s s o c i a t e d w i t h F r i e d r e i c h ' s a t a x i a a n d m i t o c h o n d r i a l m y o p a t h y . B r a i n a n d N e r v e 34 :321, 1982.
13. P a v l a k i s S G , P h i l l i p s P C , D i M a u r o , S, D e V i v o D C , R o w l a n d L P — M i t o c h o n d r i a l m y o p a t h y , e n c e p h a l o p a t h y , l a c t i c a c i d o s i s a n d s t r o k e l i k e e p i s o d e s : a d i s t i n c t i v e c l i n i c a l s y n d r o m e . A n n N e u r o l 16 : 481, 1984.
14. P e t t y R K H , H a r d i n g A E , M o r g a n - H u g h e s J A — T h e c l i n i c a l f e a t u r e s o f m i t o c h o n d r i a l m y o p a t h y B r a i n 109 : 915, 1986.
15. R i g g s J E , S c h o c h e t SS, F a k a d e j A V , P a p a d i m i t r i o u A , D i M a u r o S, C r o s b y T W , G u t m a n n L , M o x l e y R T — M i t o c h o n d r i a l e n c e p h a l o m y o p a t h y w i t h d e c r e a s e d s u c c i n a t e - c y t o c h r o m e C r e d u c t a s e a c t i v i t y . N e u r o l o g y 34 : 48, 1984.
16. S a z a k i H , K u z u h a r a S, K a n a z a w a I , N a k i n i s h i T , O g a t a T — M y o c l o n u s , c e r e b e l l a r d i s o r d e r , n e u r o p a t h y , m i t o c h o n d r i a l m y o p a t h y a n d A C T H d e f i c i e n c y . N e u r o l o g y 33 : 1288, 1983. 17. S m i t h N J , E s p i r M L E , M a t t r e w s W B — F a m i l i a l m y o c l o n i c e p i l e p s y w i t h a t a x i a a n d
n e u r o p a t h y w i t h a d d i t i o n a l f e a t u r e s o f F r i e d r e i c h a t a x i a a n d p e r o n e a l m u s c u l a r a t r o p h y . B r a i n 101 : 461, 1978.
18. W a l t e r G F , B r u c h e r J M , M a r t i n J J , C e n t e r i c k C, P i l z P , F r e u n d M . — L e i g h ' s d i s e a s e - ¬ s e v e r a l n o s o l o g i c a l e n t i t i e s w i t h i d e n t i c a l h i s t o p a t h o l o g i c a l c o m p l e x ? N e u r o p a t h o l A p p l N e u r o b i o l 12 : 95, 1986.
