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Myoclonus developing after vermisectomy in photosensitive Papio papio
82
Electroencephalography and Clinical Neurophysiology, 1978, 4 5 : 8 2 - - 8 9 © Elsevier/North-Holland Scientific Publishers, Ltd.
MYOCLONUS DEVELOPING AFTER VERMISECTOMY IN PHOTOSENSITIVE PAPIO PAPIO 1 S. BRAILOWSKY 2, Ch. MENINI and R. NAQUET 3
Laboratoire de Physiologie Nerveuse, Ddpartement de Neurophysiologie appliqude, C.N.R.S., 91190 Gif-sur-Yvette (France) (Accepted for publication: December 19, 1977)
This work describes the fortuitous finding of a spontaneous myoclonus induced by vermal ablation in photosensitive Papio papio. This operation was performed to investigate the influences of cerebellar lesions on the photic epilepsy in this species (Brailowsky et al. 1975). The search for an experimental myoclonus model dates back to the past century (Turtschaninow 1894). Substances which alter the excitability of the cerebral tissue as a whole have almost always been used (see ref. in Gastaut and Fischer-Williams 1959). However, there are also reports that localized lesions in systems with diffuse cortical projections, such as the thalamus (Milhorat 1967) or the reticular formation, can elicit muscular paroxysmal activity (see ref. in Halliday 1975). Nevertheless, to our knowledge this is the first report of an animal model of myoclonus which is associated with 'natural' epilepsy. As will be seen, this particular type of myoclonus raises problems regarding its origin.
1 This work was partially supported by a Grant from l'Institut National de la Sant6 et de la Recherche M6dicale (I.N.S.E.R.M., Grant No, 74.4.178.6). 2 Fellow of the French Government. Present address: Instituto de Investigaciones Biomedicas, Universidad Nacional A u t o n o m a de Mexico, Apartado postal 70228, Mexico 20, D.F., Mexico. 3 To whom reprint requests should be addressed.
Methods Experiments were performed on two adolescent photosensitive baboons. In the first operation metal electrodes were implanted in the skull under general anaesthesia (Killam et al. 1967), leaving free access to the posterior fossa. After 3 or 4 weeks recovery, during which control records were made, the cerebellar operation was performed under neurolept-analgesia. This operation consisted in removal of the vermis 4, sparing the hemispheres, down to the level of the floor of the 4th ventricle. Antibiotic treatment was given for 10 days after the operation. A 16~hannel polygraph was used, 8 channels for the EEG and the remainder to record EMGs, with the aid of wires implanted in the muscles (Basmajian and Stecko 1962), and mechanograms with an accelerometer attached to the animal. These traces were on occasion also displayed on an oscilloscope and filmed. Both animals were tested regularly with intermittent light stimulation (ILS), before and after surgical operation, and exhibited +1 and +3 photosensitivity according to the classification used by Killam et al. (1967). After completion of the experiments (12
4 With the collaboration of Dr. P. Derome (Service de Neurochirurgie, Centre M6dico-chirurgical Foeh, Suresnes, France) which is gratefully acknowledged.
SPONTANEOUS MYOCLONUS A F T E R VERMISECTOMY IN BABOON
and 16 months) the animals were killed; the brains were removed and the lesions verified histologically (Klfiver--Barrera stain). In both animals, the vermal portion was totally absent; in one animal the lesion was seen to be relatively simple with some neuronal degeneration in the Purkinje cell layer of the cerebellar hemispheres, but intact cerebellar nuclei; in the other animal there were some complications, including heavy demyelination of the white matter of the cerebellar hemispheres, neuronal changes in the dentate nucleus, probably caused by ischaemia, and destruction of a part of the fastigial nucleus.
Results After ablation of the vermis the animals showed acute atonia with strong postural disturbances, partially compensated by exaggerated limb splaying. These symptoms disappeared within 2--3 weeks. Myoclonus appeared a few days after the operation in one animal and a few months afterwards in the other. In both cases they persisted for the whole survival time of the animal. This myoclonus, consecutive to vermal ablation (called herein MVs), did not affect that induced by light stimulation (MLs). The two types of myoclonus were clearly distinguishable in both animals by their clinical and electrographical symptoms, by their sensitivity to different drugs and their mode of onset.
83
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Fig. 1. Time distribution of EMG discharges in various muscles during MV myoclonus. Ordinates: number of unit EMG discharges; abscissae: time in msec. Top trace: corresponding ECoG (frontocentral cortex). Time 0 is defined as the first appearance of the myographic discharge. Calibration, 50 pV.
followed occasionally by a prolonged tonic discharge (Figs. 1 and 2). The face and limb muscles showed less intense discharge, only lasting for 50 GO msec.
(2) EEG (Fig. 3) MLs were always preceded by large, simple or multiple fronto-rolandic spikes-and-waves, as reported b~ Fischer-Williams et al. (1968) and Menini and Laurent (1976). On the other
(1) Clinical observations MLs in all photosensitive baboons first began with tremor of the eyelids which spread to involve the face and then the rest of the body. MVs, on the other hand, first affected the muscles of the neck and trunk, especially those of the shoulder. Muscles of the face and limbs were secondarily involved 10--15 msec after the trunk musculature. In the trapezius, one of the first muscles to be affected, MVs were characterized by an intense muscular activity lasting 30msec on the average,
Fig. 2. Oscilloscopic records o f MV-type myoclonus. EEG, fronto-central record; ACC, mechanogram obtained by an accelerometer fixed on the animal's head; EMG, trapezius. Notice small accelerometric deflexion preceding myoclonus; this deflexion and the consecutive myoclonus were induced by animal's agitation. Calibration, 50/IV. Time base, 50 msec.
84
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Fig. 3. Comparison, in one baboon, of the 2 types of myoclonus (a and b). In both cases, upper trace is EMG of left trapezius and lower trace, right fronto-central EEG. a: MV myoclonus. EMG onset (marked by dashed line) precedes a small evoked potential with a latency of 10--15 msec. b: light induced myoclonus (ML). Onset of each cortical paroxysm, marked by dashed line, precedes EMG discharge.
hand, MVs were neither preceded nor accompanied by any sign o f paroxysmal EEG activity. The only noticeable EEG characteristic was a parietal somatic evoked potential, some 10--15 msec after the EMG discharge in the trapezius. This response was small and did n o t resemble the paroxysmal EEG discharge.
(3) Onset of MVs MVs appeared in isolation or in irregular bursts when the animal was agitated (Fig. 4). They did n o t occur while the animal was
resting or when it was making slow movements such as moving one limb. They were n o t triggered by passive limb movements b u t bursts of MVs were produced if the animal resisted this passive movement. MVs could also be triggered by tactile stimulation b u t the most effective triggers were either when the animal was trying to act against forced immobilization or, on the contrary, when his limb was forced to move by the experimenter. The role played b y the magnitude of the tactile stimulation was minimal, the fact that the animal had to be in a state of complete
SPONTANEOUS MYOCLONUS A F T E R VERMISECTOMY IN BABOON
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Fig. 4. Influence o f phases o f excitation after vermisectomy on spontaneous myoclonus (MV). The 3 records are consecutive. Abscissae: time in rain; ordinates: upper trace gives number of myoclonus (/sec);lower trace: state of the animal. AG, b o d y movements, spontaneous or induced; EO, eyes opened, without b o d y movement; EC, eyes closed, without b o d y movement.
alertness being more important; in this situation, even an air puff could elicit a muscular paroxysm. MVs disappeared during slow-wave sleep but could occasionally be seen during paradoxical sleep. The organization of sleep was studied in one of the two animals and did n o t reveal any abnormal pattern or distribution of its states.
(4) Effects of drugs Both MVs and MLs were facilitated by injection of 200 mg/kg allylglycine i.v. Both
were blocked during ketamine anaesthesia (5 mg/kg i.m.), but MVs reappeared during recovery from the anaesthesia whereas MLs and photosensitivity were depressed for a long time afterwards. Diazepam (1 mg/kg s.c.), which decreases photosensitivity and therefore blocks MLs, also greatly reduced the frequency of MVs which, nevertheless, could be seen during the brief active periods of the animal. This MV blockage by a strong reduction of the animal's motility was also observed after injection of 0.3 mg/kg amphetamine s.c. (Fig. 5).
86
S. BRAILOWSKY ET AL.
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Fig. 5. Modification of the frequency of spontaneous myoclonus after injection of amphetamine (s.c.). F r o m b o t t o m to top: number of spontaneous myoclonus (MVs); duration of periods of the animal's agitation; number of ocular movements (calculated from the EOG). Motility of the animal and spontaneous m y o clonus were reduced after the activation period which followed immediately the injection of amphetamine (0.3 mg/kg s.c.) (arrow).
Discussion
Photosensitive baboons with vermal ablation showed two types of myoclonus, and this is probably the first time that such an experimental model has been described. These two types of myoclonus were: (1) The classic myoclonus induced by intermittent light stimulation (ILS), shown by all photosensitive baboons and well described elsewhere (Killam et al. 1966, 1967; FischerWilliams et al. 1968; Menini 1976; Menini and Laurent 1976). In the photosensitive baboons submitted to ILS, the ECoG modifications invariably begin at the cortical level and are followed by myoclonus; this indicates that the cerebral cortex plays a more important role for the MLs than simply that of a general control as previously considered (Ascher et al. 1963; Ascher 1966; Halliday 1975). (2) MVs represent a different type of myoclonus, which in most cases arises 'sponta-
neously', that is, in the absence of any specific stimulation. This particular type does not seem to be facilitated by additional ablation of the cerebellar hemispheres (Brailowsky et al. 1975). MVs are akin to the action myoclonus of Wohlfart and Hook (1951), that is, brief contractions triggered by movement in a patient with a severe cerebellar syndrome. MVs are bilateral, 'massive', spontaneous and involuntary; they are neither accompanied nor preceded by any paroxysmal cortical activity. Recently, however, Shibasaki and Kuroiwa (1975) described in humans a type of myoclonus preceded by cortical events, revealed only when using an averaging technique. After ablation of the vermis in the baboons these events were not seen, but in our study averaged responses were not used. In any case, ablation of the vermis and the fact that no paroxysmal EEG discharge preceded or accompanied MVs led us to think that the origin of the descending generating discharge inducing the myoclonus is in the brain stem. An origin at this level in man was suggested for massive epileptic myoclonus (Gastaut 1968, 1973), but this type of myoclonus was generally accompanied by an EEG paroxysmal discharge. Using the international classification of myoclonus (Gastaut 1968), MVs which are not accompanied by any paroxysmal EEG activity could be considered as non-epileptic. In man, non-epileptic myoclonus exists, for example, as essential myoclonus or myoclonus of the velum (see BondueUe 1968 and Hallett et al. 1977b), and one must consider that they have no corticographic expression because either they are initiated very low in the brain stem (reticular reflex myoclonus of Hallett et al. 1977a), or they result from an inhibitory mechanism of their ascending propagation towards the cerebral cortex. On the contrary MLs are of an epileptic nature and resemble human epileptic myoclonus induced by light. If we follow the classification, we must admit that, in our baboons, the two types of myoclonus (epileptic and non-epileptic) may be associated in the same animal. In fact, MVs
SPONTANEOUS MYOCLONUSAFTER VERMISECTOMYIN BABOON are different from that induced experimentally by stimulation of the thalamic relay nuclei (Brookhart and Zanchetti 1956), by chloralose anaesthesia (Ascher et al. 1963) and also by topical application of penicillin to the cerebellum of the cat (FernandezGuardiola et al. 1976); in all these cases, the myoclonus was associated with paroxysmal discharge at the cortical level (cortical-loop reflex myoclonus, Hallett et al. 1977b). In our opinion, MVs, although they are action myoclonus, must be differentiated from the post-anoxic action myoclonus of Lance and Adams (1963). In addition to the EMG characteristics of the myoclonus, the aetiology, clinical EEG and neuroanatomical data also differ. The attenuating action of sleep and muscular relaxation on MVs emphasizes the importance of the somatic afferents in their development. The catecholaminergic character of these mechanisms could not be proved from our data, but is supported by results obtained with amphetamine administration in normal monkeys (Brailowsky and Naquet 1976). On the other hand, Myers et al. (1975) reported that cerebellar stimulation does not affect spontaneous or induced myoclonus in cats pretreated with epileptogenic agents, a fact which is inconsistent with earlier results (Myers and Bickford 1974). The animals used in this study were photosensitive and this does not seem to be a necessary condition for the appearance of MVs. Indeed, although ablation of the vermis greatly increases the frequency of MVs, they can be seen in intact Papio papio. During a mission to Senegal in 1968, Serbanescu (unpublished observations) noted that several young Papio papio showed myoclonus, appearing spontaneously or induced by tactile stimulation, and that this myoclonus had no particular correlation with the degree of photosensitivity of the animal; however, these are only behavioural data. In fact, it was shown that all these animals, photosensitive or not, belong to a group with a high predisposition to epilepsy (Wada et al. 1972; Da Costa et al. 1975).
87
The history of epilepsy, the cerebellar lesion and the symptomatology presented by our animals recall some hereditary degenerative cerebro-spinal human illness associated with epilepsy (e.g., dyssynergic cerebellar myoclonus (DCM), progressive myoclonus epilepsy (Ramsay--Hunt), etc; see Radermecker 1974; Tassinari et al. 1974). There are, however, significant differences; for example, Bergamasco et al. (1967) reported a case of DCM with an extensive disorganization of the nycthemeral cycle and absence of paradoxical sleep. In our experience, no significant alteration o f EEG sleep was seen.
Summary Two vermisectomized photosensitive baboons exhibited two different types of myoclonus, one induced by intermittent light stimulation (ILS) and the other occurring 'spontaneously'. The characteristics of these two types of myoclonus are described from a clinical and from an ECoG point of view. Myoclonus induced by ILS (ML) started at the eyelids and secondarily invaded the face and body; it was always preceded by frontorolandic "spike-waves or polyspike-waves. The 'spontaneous' myoclonus which followed vermisectomy (MV) was 'massive', but involved firstly the trunk and secondarily the face and limbs; no ECoG paroxysm accompanied this myoclonus, but we observed a parietal evoked potential of small amplitude, 10--15 msec after its onset. If MLs can be considered as consequences of the fronto-rolandic paroxysmal discharges, MVs seem to originate in the brain stem but appear similar to action myoclonus. This experimental situation showing two types of myoclonus resembles human hereditary degenerative syndromes (dyssynergic cerebellar myoclonus, progressive myoclonic epilepsy), without being exactly comparabl e . The conditions in which MVs were seen and their modifications during sleep and by different drugs are described. The relationships
88
between MVs and MLs epilepsy are discussed.
S. BRAILOWSKY ET AL.
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the manuscript and to Mrs. Riche and Ghilini for neuroanatomy.
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References
Myoclonies consdcutives d l'ablation du vermis chez des Papio papios photosensibles
Ascher, P. Lemniscal influences on m o t o r responses of extralemniscal origin. Brain Res., 1966, 2: 233--253. Ascher, P., Jassik-Gerschenfeld, D. et Buser, P. Participation des aires corticales sensorielles l'61aboration de r6ponses motrices extrapyramidales. Electroenceph. clin. Neurophysiol., 1963, 15: 246--264. Basmajian, V.J. and Stecko, G. A new bipolar electrode for electromyography. J. appl. Physiol., 1962, 17: 849. Bergamasco, B., Bergamini, L. and Mutani, R. Spontaneous sleep abnormalities in a case of dyssynergia cerebellaris myoclonica. Epilepsia (Amst.), 1967, 8: 272--281. Bonduelle, M. The myoclonias. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 6, Diseases of the Basal Ganglia. NorthHolland, Amsterdam, 1968: 761--781. Brailowsky, S. and Naquet, R. Effects of drugs modifying brain levels of catecholamines on photically-induced epilepsy in Papio papio. Epilepsia (Amst.), 1976, 17: 272--274. Brailowsky, S., Walter, S., Larochelle, L. et Naquet, R. Cervelet et ~pilepsie photosensible chez le Papio papio: effets de l~sions c~r~belleuses sur la photosensibilit4 et les potentiels ~voqu~s visuels. Rev. EEG Neurophysiol., 1975, 5: 247--251. Brookhart, J.M. and Zanchetti, A. The relation between electrocortical waves and responsiveness of the cortico-spinal system. Electroenceph. clin. Neurophysiol., 1956, 8: 427--444. Da Costa, L.M., Bostem, F. et Naquet, R. Des pointesondes spontan~es ~ predominance ant~rieure, aux manifestations paroxystiques induites par la SLI chez le Papio papio. R~flexions ~ propos d'un cas particulier. Rev. EEG Neurophysiol., 1975, 5: 47--51. Fernandez-Guardiola, A., Solis, H.J., Jurado, J.L., Salgado, A. e Jimenez, S. Application topica de penicilina en el lobulo anterior del cerebelo: un nuevo modelo de descarga mioclonica. Rev. Inst. nac. Neurol. (M~x.), 1976, 10: 157--163. Fischer-Williams, M., Poncet, M., Riche, D. and Naquet, R. Light induced epilepsy in the baboon Papio papio: cortical and depth recordings. Electroenceph, clin. Neurophysiol., 1968, 25: 557-569. Gastaut, H. S~m~iologie des myoclonies et nosologie analytique des syndromes myocloniques. Rev. neurol., 1968, 119: 1--30.
Deux babouins photosensibles pr6sentant des myoclonies, induites par la stimulation lumineuse intermittente (SLI), ont 6galement pr6sent6, apr6s ablation du vermis, un second type de myoclonies survenant spontan6ment. Les caract6ristiques cliniques et ECoG de ces deux types de myoclonies sont d6crites: Les myoclonies induites par la stimulation lumineuse (ML) int6ressent en premier lieu les paupi6res et envahissent secondairement la face et le reste du corps; elles sont toujours pr6cdd6es de pointes-ondes et de poly-pointesondes fronto-rolandiques. Les myoclonies spontandes cons6cutives ~ l'ablation du vermis (MV) sont massives mais int6ressent d'abord la musculature tronculaire puis secondairement la face et les membres; aucun 616ment paroxystique ECoG n'accompagne ces myoclonies, mais on observe un potentiel 6voqu6 pari6tal de faible amplitude, avec une latence de 10--15 msec apr6s la clonie. Si les ML peuvent 6tre consid6r6es comme secondaires h la d6charge paroxystique frontorolandique, les MV bien que semblables des myoclonies d'action, semblent avoir leur origine au niveau du tronc cdr6bral. Cette situation expdrimentale dans laquelle deux types de myoclonies sont associ6s rappelle certains syndromes h~r~do-d~g~n~ratifs humains (dyssynergie cdr6belleuse myoclonique, 6pilepsie myoclonique progressive), sans 6tre exactement semblable. Les conditions dans lesquelles les MV sont observdes et leurs modifications au cours du sommeil ou sous l'effet de diff~rentes drogues sont ddcrites. Les relations entre MV, ML et l'~pi-
lepsie myoclonique sont discut~es. We are very grateful to M. Raoul Guillon for his technical assistance, Mrs. Kandaroun for typing
SPONTANEOUS MYOCLONUS A F T E R VERMISECTOMY IN BABOON Gastaut, H. Dictionnaire de l'Epilepsie. OMS, Gen~ve, 1973, 80 pp. Gastaut, H. and Fischer-Williams, M. The pathophysiology of epileptic seizures. In: J. Field, H.W. Magoun and V.E. Hall (Eds.), Handbook of Physiology, sect. 1. Amer. Physiol. Soc., Baltimore, Md., 1959: 329--363. Hallett, M., Chadwick, D., Adam, J. and Marsden, C.D. Reticular reflex myoclonus. A physiological type of human post-hypoxic myoclonus. J. Neurol. Neurosurg. Psychiat., 1977a, 40: 253--264. Hallett, M., Chadwick, D. and Marsden, C.D. Ballistic movement overflow myoclonus, a form of essential myoclonus. Brain, 1977b, 100: 299--312. Halliday, A.M. The neurophysiology of myoclonic jerking; a reappraisal. In: M.H. Charlton (Ed.), Myoclonic Seizures. Excerpta Medica, Amsterdam, 1975: 1--29. Killam, K.F., Naquet, R. and Bert, J. Paroxysmal responses to intermittent light in a population of baboons (Papio papios). Epilepsia (Amst.), 1966, 7: 215--219. Killam, K.F., Killam, E.K. and Naquet, R. An animal model of light sensitive epilepsy. Electroenceph. clin. Neurophysiol., 1967, 22: 497--513. Lance, J.W. and Adams, R.D. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain, 1963, 86: 111--136. Menini, Ch. RSle du cortex frontal dans l'~pilepsie photosensible du singe Papio papio. J. Physiol. (Paris), 1976, 72: 5--44. Menini, Ch. et Laurent, H. D~charges paroxystiques EEG et EMG induites par la stimulation lumineuse intermittente chez le Papio papio photosensible. Rev. EEG Neurophysiol., 1976, 6: 502--505. Milhorat, T.H. Experimental myoclonus of thalamic origin. Arch. Neurol. (Chic.), 1967, 17: 365--378. Myers, R.R. and Bickford, R.G. Modulation of
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spontaneous and evoked chloralose myoclonus by cerebellar stimulation in the cat (relation to Ramsay-Hunt syndrome). In: I.S. Cooper, M. Riklan and R.S. Snyder (Eds.), Cerebellum, Epilepsy and Behavior. Plenum, New York, 1974: 217--227. Myers, R.R., Burchiel, K.J., Stokard, J.J. and Bickford, R.G. Effects of acute and chronic paleocerebellar stimulation on experimental models of epilepsy in the cat: studies with enflurane, pentylenetetrazol, penicillin and chloralose. Epilepsia, 1975, 16: 257--267. Radermecker, J. Epilepsy in the degenerative diseases. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 15. North-Holland, Amsterdam, 1974: 325--372. Shibasaki, H. and Kuroiwa, Y. Electroencephalographic correlates of myoclonus. Electroenceph. clin. Neurophysiol., 1975, 39: 455--463. Tassinari, C.A., Bureau-Paillas, M., Dalla-Bernardina, B., Grasso, E. et Roger, J. Etude ~lectroenc~phalographique de la dyssynergie c~r~belleuse myoclonique avec ~pilepsie (syndrome de RamsayHunt). Rev. EEG Neurophysiol., 1974, 4: 407-428. Turtschaninow, P. Experimentelle Studien fiber den Ursprungsort einiger klinisch wichtiger towischer Krampformen. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 1894, 34: 208--246. Wada, J.A., Terao, A. and Booker, H.E. Longitudinal correlative analysis of epileptic baboon Papio papio. Neurology (Minneap.), 1972, 22: 1271-1285. Wohlfart, G. and Hook, O.A. A clinical analysis of myoclonus epilepsy (Unverricht-Lundbord), myoclonia cerebellar dyssynergy (Hunt) and hepatolenticular degeneration (Wilson). Acta psychiat. neurol, scand., 1951, 26: 219--245.
Electroencephalography and Clinical Neurophysiology, 1978, 4 5 : 8 2 - - 8 9 © Elsevier/North-Holland Scientific Publishers, Ltd.
MYOCLONUS DEVELOPING AFTER VERMISECTOMY IN PHOTOSENSITIVE PAPIO PAPIO 1 S. BRAILOWSKY 2, Ch. MENINI and R. NAQUET 3
Laboratoire de Physiologie Nerveuse, Ddpartement de Neurophysiologie appliqude, C.N.R.S., 91190 Gif-sur-Yvette (France) (Accepted for publication: December 19, 1977)
This work describes the fortuitous finding of a spontaneous myoclonus induced by vermal ablation in photosensitive Papio papio. This operation was performed to investigate the influences of cerebellar lesions on the photic epilepsy in this species (Brailowsky et al. 1975). The search for an experimental myoclonus model dates back to the past century (Turtschaninow 1894). Substances which alter the excitability of the cerebral tissue as a whole have almost always been used (see ref. in Gastaut and Fischer-Williams 1959). However, there are also reports that localized lesions in systems with diffuse cortical projections, such as the thalamus (Milhorat 1967) or the reticular formation, can elicit muscular paroxysmal activity (see ref. in Halliday 1975). Nevertheless, to our knowledge this is the first report of an animal model of myoclonus which is associated with 'natural' epilepsy. As will be seen, this particular type of myoclonus raises problems regarding its origin.
1 This work was partially supported by a Grant from l'Institut National de la Sant6 et de la Recherche M6dicale (I.N.S.E.R.M., Grant No, 74.4.178.6). 2 Fellow of the French Government. Present address: Instituto de Investigaciones Biomedicas, Universidad Nacional A u t o n o m a de Mexico, Apartado postal 70228, Mexico 20, D.F., Mexico. 3 To whom reprint requests should be addressed.
Methods Experiments were performed on two adolescent photosensitive baboons. In the first operation metal electrodes were implanted in the skull under general anaesthesia (Killam et al. 1967), leaving free access to the posterior fossa. After 3 or 4 weeks recovery, during which control records were made, the cerebellar operation was performed under neurolept-analgesia. This operation consisted in removal of the vermis 4, sparing the hemispheres, down to the level of the floor of the 4th ventricle. Antibiotic treatment was given for 10 days after the operation. A 16~hannel polygraph was used, 8 channels for the EEG and the remainder to record EMGs, with the aid of wires implanted in the muscles (Basmajian and Stecko 1962), and mechanograms with an accelerometer attached to the animal. These traces were on occasion also displayed on an oscilloscope and filmed. Both animals were tested regularly with intermittent light stimulation (ILS), before and after surgical operation, and exhibited +1 and +3 photosensitivity according to the classification used by Killam et al. (1967). After completion of the experiments (12
4 With the collaboration of Dr. P. Derome (Service de Neurochirurgie, Centre M6dico-chirurgical Foeh, Suresnes, France) which is gratefully acknowledged.
SPONTANEOUS MYOCLONUS A F T E R VERMISECTOMY IN BABOON
and 16 months) the animals were killed; the brains were removed and the lesions verified histologically (Klfiver--Barrera stain). In both animals, the vermal portion was totally absent; in one animal the lesion was seen to be relatively simple with some neuronal degeneration in the Purkinje cell layer of the cerebellar hemispheres, but intact cerebellar nuclei; in the other animal there were some complications, including heavy demyelination of the white matter of the cerebellar hemispheres, neuronal changes in the dentate nucleus, probably caused by ischaemia, and destruction of a part of the fastigial nucleus.
Results After ablation of the vermis the animals showed acute atonia with strong postural disturbances, partially compensated by exaggerated limb splaying. These symptoms disappeared within 2--3 weeks. Myoclonus appeared a few days after the operation in one animal and a few months afterwards in the other. In both cases they persisted for the whole survival time of the animal. This myoclonus, consecutive to vermal ablation (called herein MVs), did not affect that induced by light stimulation (MLs). The two types of myoclonus were clearly distinguishable in both animals by their clinical and electrographical symptoms, by their sensitivity to different drugs and their mode of onset.
83
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Fig. 1. Time distribution of EMG discharges in various muscles during MV myoclonus. Ordinates: number of unit EMG discharges; abscissae: time in msec. Top trace: corresponding ECoG (frontocentral cortex). Time 0 is defined as the first appearance of the myographic discharge. Calibration, 50 pV.
followed occasionally by a prolonged tonic discharge (Figs. 1 and 2). The face and limb muscles showed less intense discharge, only lasting for 50 GO msec.
(2) EEG (Fig. 3) MLs were always preceded by large, simple or multiple fronto-rolandic spikes-and-waves, as reported b~ Fischer-Williams et al. (1968) and Menini and Laurent (1976). On the other
(1) Clinical observations MLs in all photosensitive baboons first began with tremor of the eyelids which spread to involve the face and then the rest of the body. MVs, on the other hand, first affected the muscles of the neck and trunk, especially those of the shoulder. Muscles of the face and limbs were secondarily involved 10--15 msec after the trunk musculature. In the trapezius, one of the first muscles to be affected, MVs were characterized by an intense muscular activity lasting 30msec on the average,
Fig. 2. Oscilloscopic records o f MV-type myoclonus. EEG, fronto-central record; ACC, mechanogram obtained by an accelerometer fixed on the animal's head; EMG, trapezius. Notice small accelerometric deflexion preceding myoclonus; this deflexion and the consecutive myoclonus were induced by animal's agitation. Calibration, 50/IV. Time base, 50 msec.
84
S. BRAILOWSKY ET AL.
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Fig. 3. Comparison, in one baboon, of the 2 types of myoclonus (a and b). In both cases, upper trace is EMG of left trapezius and lower trace, right fronto-central EEG. a: MV myoclonus. EMG onset (marked by dashed line) precedes a small evoked potential with a latency of 10--15 msec. b: light induced myoclonus (ML). Onset of each cortical paroxysm, marked by dashed line, precedes EMG discharge.
hand, MVs were neither preceded nor accompanied by any sign o f paroxysmal EEG activity. The only noticeable EEG characteristic was a parietal somatic evoked potential, some 10--15 msec after the EMG discharge in the trapezius. This response was small and did n o t resemble the paroxysmal EEG discharge.
(3) Onset of MVs MVs appeared in isolation or in irregular bursts when the animal was agitated (Fig. 4). They did n o t occur while the animal was
resting or when it was making slow movements such as moving one limb. They were n o t triggered by passive limb movements b u t bursts of MVs were produced if the animal resisted this passive movement. MVs could also be triggered by tactile stimulation b u t the most effective triggers were either when the animal was trying to act against forced immobilization or, on the contrary, when his limb was forced to move by the experimenter. The role played b y the magnitude of the tactile stimulation was minimal, the fact that the animal had to be in a state of complete
SPONTANEOUS MYOCLONUS A F T E R VERMISECTOMY IN BABOON
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Fig. 4. Influence o f phases o f excitation after vermisectomy on spontaneous myoclonus (MV). The 3 records are consecutive. Abscissae: time in rain; ordinates: upper trace gives number of myoclonus (/sec);lower trace: state of the animal. AG, b o d y movements, spontaneous or induced; EO, eyes opened, without b o d y movement; EC, eyes closed, without b o d y movement.
alertness being more important; in this situation, even an air puff could elicit a muscular paroxysm. MVs disappeared during slow-wave sleep but could occasionally be seen during paradoxical sleep. The organization of sleep was studied in one of the two animals and did n o t reveal any abnormal pattern or distribution of its states.
(4) Effects of drugs Both MVs and MLs were facilitated by injection of 200 mg/kg allylglycine i.v. Both
were blocked during ketamine anaesthesia (5 mg/kg i.m.), but MVs reappeared during recovery from the anaesthesia whereas MLs and photosensitivity were depressed for a long time afterwards. Diazepam (1 mg/kg s.c.), which decreases photosensitivity and therefore blocks MLs, also greatly reduced the frequency of MVs which, nevertheless, could be seen during the brief active periods of the animal. This MV blockage by a strong reduction of the animal's motility was also observed after injection of 0.3 mg/kg amphetamine s.c. (Fig. 5).
86
S. BRAILOWSKY ET AL.
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Fig. 5. Modification of the frequency of spontaneous myoclonus after injection of amphetamine (s.c.). F r o m b o t t o m to top: number of spontaneous myoclonus (MVs); duration of periods of the animal's agitation; number of ocular movements (calculated from the EOG). Motility of the animal and spontaneous m y o clonus were reduced after the activation period which followed immediately the injection of amphetamine (0.3 mg/kg s.c.) (arrow).
Discussion
Photosensitive baboons with vermal ablation showed two types of myoclonus, and this is probably the first time that such an experimental model has been described. These two types of myoclonus were: (1) The classic myoclonus induced by intermittent light stimulation (ILS), shown by all photosensitive baboons and well described elsewhere (Killam et al. 1966, 1967; FischerWilliams et al. 1968; Menini 1976; Menini and Laurent 1976). In the photosensitive baboons submitted to ILS, the ECoG modifications invariably begin at the cortical level and are followed by myoclonus; this indicates that the cerebral cortex plays a more important role for the MLs than simply that of a general control as previously considered (Ascher et al. 1963; Ascher 1966; Halliday 1975). (2) MVs represent a different type of myoclonus, which in most cases arises 'sponta-
neously', that is, in the absence of any specific stimulation. This particular type does not seem to be facilitated by additional ablation of the cerebellar hemispheres (Brailowsky et al. 1975). MVs are akin to the action myoclonus of Wohlfart and Hook (1951), that is, brief contractions triggered by movement in a patient with a severe cerebellar syndrome. MVs are bilateral, 'massive', spontaneous and involuntary; they are neither accompanied nor preceded by any paroxysmal cortical activity. Recently, however, Shibasaki and Kuroiwa (1975) described in humans a type of myoclonus preceded by cortical events, revealed only when using an averaging technique. After ablation of the vermis in the baboons these events were not seen, but in our study averaged responses were not used. In any case, ablation of the vermis and the fact that no paroxysmal EEG discharge preceded or accompanied MVs led us to think that the origin of the descending generating discharge inducing the myoclonus is in the brain stem. An origin at this level in man was suggested for massive epileptic myoclonus (Gastaut 1968, 1973), but this type of myoclonus was generally accompanied by an EEG paroxysmal discharge. Using the international classification of myoclonus (Gastaut 1968), MVs which are not accompanied by any paroxysmal EEG activity could be considered as non-epileptic. In man, non-epileptic myoclonus exists, for example, as essential myoclonus or myoclonus of the velum (see BondueUe 1968 and Hallett et al. 1977b), and one must consider that they have no corticographic expression because either they are initiated very low in the brain stem (reticular reflex myoclonus of Hallett et al. 1977a), or they result from an inhibitory mechanism of their ascending propagation towards the cerebral cortex. On the contrary MLs are of an epileptic nature and resemble human epileptic myoclonus induced by light. If we follow the classification, we must admit that, in our baboons, the two types of myoclonus (epileptic and non-epileptic) may be associated in the same animal. In fact, MVs
SPONTANEOUS MYOCLONUSAFTER VERMISECTOMYIN BABOON are different from that induced experimentally by stimulation of the thalamic relay nuclei (Brookhart and Zanchetti 1956), by chloralose anaesthesia (Ascher et al. 1963) and also by topical application of penicillin to the cerebellum of the cat (FernandezGuardiola et al. 1976); in all these cases, the myoclonus was associated with paroxysmal discharge at the cortical level (cortical-loop reflex myoclonus, Hallett et al. 1977b). In our opinion, MVs, although they are action myoclonus, must be differentiated from the post-anoxic action myoclonus of Lance and Adams (1963). In addition to the EMG characteristics of the myoclonus, the aetiology, clinical EEG and neuroanatomical data also differ. The attenuating action of sleep and muscular relaxation on MVs emphasizes the importance of the somatic afferents in their development. The catecholaminergic character of these mechanisms could not be proved from our data, but is supported by results obtained with amphetamine administration in normal monkeys (Brailowsky and Naquet 1976). On the other hand, Myers et al. (1975) reported that cerebellar stimulation does not affect spontaneous or induced myoclonus in cats pretreated with epileptogenic agents, a fact which is inconsistent with earlier results (Myers and Bickford 1974). The animals used in this study were photosensitive and this does not seem to be a necessary condition for the appearance of MVs. Indeed, although ablation of the vermis greatly increases the frequency of MVs, they can be seen in intact Papio papio. During a mission to Senegal in 1968, Serbanescu (unpublished observations) noted that several young Papio papio showed myoclonus, appearing spontaneously or induced by tactile stimulation, and that this myoclonus had no particular correlation with the degree of photosensitivity of the animal; however, these are only behavioural data. In fact, it was shown that all these animals, photosensitive or not, belong to a group with a high predisposition to epilepsy (Wada et al. 1972; Da Costa et al. 1975).
87
The history of epilepsy, the cerebellar lesion and the symptomatology presented by our animals recall some hereditary degenerative cerebro-spinal human illness associated with epilepsy (e.g., dyssynergic cerebellar myoclonus (DCM), progressive myoclonus epilepsy (Ramsay--Hunt), etc; see Radermecker 1974; Tassinari et al. 1974). There are, however, significant differences; for example, Bergamasco et al. (1967) reported a case of DCM with an extensive disorganization of the nycthemeral cycle and absence of paradoxical sleep. In our experience, no significant alteration o f EEG sleep was seen.
Summary Two vermisectomized photosensitive baboons exhibited two different types of myoclonus, one induced by intermittent light stimulation (ILS) and the other occurring 'spontaneously'. The characteristics of these two types of myoclonus are described from a clinical and from an ECoG point of view. Myoclonus induced by ILS (ML) started at the eyelids and secondarily invaded the face and body; it was always preceded by frontorolandic "spike-waves or polyspike-waves. The 'spontaneous' myoclonus which followed vermisectomy (MV) was 'massive', but involved firstly the trunk and secondarily the face and limbs; no ECoG paroxysm accompanied this myoclonus, but we observed a parietal evoked potential of small amplitude, 10--15 msec after its onset. If MLs can be considered as consequences of the fronto-rolandic paroxysmal discharges, MVs seem to originate in the brain stem but appear similar to action myoclonus. This experimental situation showing two types of myoclonus resembles human hereditary degenerative syndromes (dyssynergic cerebellar myoclonus, progressive myoclonic epilepsy), without being exactly comparabl e . The conditions in which MVs were seen and their modifications during sleep and by different drugs are described. The relationships
88
between MVs and MLs epilepsy are discussed.
S. BRAILOWSKY ET AL.
and
myoclonic
the manuscript and to Mrs. Riche and Ghilini for neuroanatomy.
Rdsum~
References
Myoclonies consdcutives d l'ablation du vermis chez des Papio papios photosensibles
Ascher, P. Lemniscal influences on m o t o r responses of extralemniscal origin. Brain Res., 1966, 2: 233--253. Ascher, P., Jassik-Gerschenfeld, D. et Buser, P. Participation des aires corticales sensorielles l'61aboration de r6ponses motrices extrapyramidales. Electroenceph. clin. Neurophysiol., 1963, 15: 246--264. Basmajian, V.J. and Stecko, G. A new bipolar electrode for electromyography. J. appl. Physiol., 1962, 17: 849. Bergamasco, B., Bergamini, L. and Mutani, R. Spontaneous sleep abnormalities in a case of dyssynergia cerebellaris myoclonica. Epilepsia (Amst.), 1967, 8: 272--281. Bonduelle, M. The myoclonias. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 6, Diseases of the Basal Ganglia. NorthHolland, Amsterdam, 1968: 761--781. Brailowsky, S. and Naquet, R. Effects of drugs modifying brain levels of catecholamines on photically-induced epilepsy in Papio papio. Epilepsia (Amst.), 1976, 17: 272--274. Brailowsky, S., Walter, S., Larochelle, L. et Naquet, R. Cervelet et ~pilepsie photosensible chez le Papio papio: effets de l~sions c~r~belleuses sur la photosensibilit4 et les potentiels ~voqu~s visuels. Rev. EEG Neurophysiol., 1975, 5: 247--251. Brookhart, J.M. and Zanchetti, A. The relation between electrocortical waves and responsiveness of the cortico-spinal system. Electroenceph. clin. Neurophysiol., 1956, 8: 427--444. Da Costa, L.M., Bostem, F. et Naquet, R. Des pointesondes spontan~es ~ predominance ant~rieure, aux manifestations paroxystiques induites par la SLI chez le Papio papio. R~flexions ~ propos d'un cas particulier. Rev. EEG Neurophysiol., 1975, 5: 47--51. Fernandez-Guardiola, A., Solis, H.J., Jurado, J.L., Salgado, A. e Jimenez, S. Application topica de penicilina en el lobulo anterior del cerebelo: un nuevo modelo de descarga mioclonica. Rev. Inst. nac. Neurol. (M~x.), 1976, 10: 157--163. Fischer-Williams, M., Poncet, M., Riche, D. and Naquet, R. Light induced epilepsy in the baboon Papio papio: cortical and depth recordings. Electroenceph, clin. Neurophysiol., 1968, 25: 557-569. Gastaut, H. S~m~iologie des myoclonies et nosologie analytique des syndromes myocloniques. Rev. neurol., 1968, 119: 1--30.
Deux babouins photosensibles pr6sentant des myoclonies, induites par la stimulation lumineuse intermittente (SLI), ont 6galement pr6sent6, apr6s ablation du vermis, un second type de myoclonies survenant spontan6ment. Les caract6ristiques cliniques et ECoG de ces deux types de myoclonies sont d6crites: Les myoclonies induites par la stimulation lumineuse (ML) int6ressent en premier lieu les paupi6res et envahissent secondairement la face et le reste du corps; elles sont toujours pr6cdd6es de pointes-ondes et de poly-pointesondes fronto-rolandiques. Les myoclonies spontandes cons6cutives ~ l'ablation du vermis (MV) sont massives mais int6ressent d'abord la musculature tronculaire puis secondairement la face et les membres; aucun 616ment paroxystique ECoG n'accompagne ces myoclonies, mais on observe un potentiel 6voqu6 pari6tal de faible amplitude, avec une latence de 10--15 msec apr6s la clonie. Si les ML peuvent 6tre consid6r6es comme secondaires h la d6charge paroxystique frontorolandique, les MV bien que semblables des myoclonies d'action, semblent avoir leur origine au niveau du tronc cdr6bral. Cette situation expdrimentale dans laquelle deux types de myoclonies sont associ6s rappelle certains syndromes h~r~do-d~g~n~ratifs humains (dyssynergie cdr6belleuse myoclonique, 6pilepsie myoclonique progressive), sans 6tre exactement semblable. Les conditions dans lesquelles les MV sont observdes et leurs modifications au cours du sommeil ou sous l'effet de diff~rentes drogues sont ddcrites. Les relations entre MV, ML et l'~pi-
lepsie myoclonique sont discut~es. We are very grateful to M. Raoul Guillon for his technical assistance, Mrs. Kandaroun for typing
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spontaneous and evoked chloralose myoclonus by cerebellar stimulation in the cat (relation to Ramsay-Hunt syndrome). In: I.S. Cooper, M. Riklan and R.S. Snyder (Eds.), Cerebellum, Epilepsy and Behavior. Plenum, New York, 1974: 217--227. Myers, R.R., Burchiel, K.J., Stokard, J.J. and Bickford, R.G. Effects of acute and chronic paleocerebellar stimulation on experimental models of epilepsy in the cat: studies with enflurane, pentylenetetrazol, penicillin and chloralose. Epilepsia, 1975, 16: 257--267. Radermecker, J. Epilepsy in the degenerative diseases. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 15. North-Holland, Amsterdam, 1974: 325--372. Shibasaki, H. and Kuroiwa, Y. Electroencephalographic correlates of myoclonus. Electroenceph. clin. Neurophysiol., 1975, 39: 455--463. Tassinari, C.A., Bureau-Paillas, M., Dalla-Bernardina, B., Grasso, E. et Roger, J. Etude ~lectroenc~phalographique de la dyssynergie c~r~belleuse myoclonique avec ~pilepsie (syndrome de RamsayHunt). Rev. EEG Neurophysiol., 1974, 4: 407-428. Turtschaninow, P. Experimentelle Studien fiber den Ursprungsort einiger klinisch wichtiger towischer Krampformen. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 1894, 34: 208--246. Wada, J.A., Terao, A. and Booker, H.E. Longitudinal correlative analysis of epileptic baboon Papio papio. Neurology (Minneap.), 1972, 22: 1271-1285. Wohlfart, G. and Hook, O.A. A clinical analysis of myoclonus epilepsy (Unverricht-Lundbord), myoclonia cerebellar dyssynergy (Hunt) and hepatolenticular degeneration (Wilson). Acta psychiat. neurol, scand., 1951, 26: 219--245.