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Juvenile myoclonic epilepsy of Janz: clinical observations in 60 patients
Seizure 1992; 1: 291-298
Juvenile myoclonic epilepsy observations in 60 patients M.P. CANEVINI, R. CANGER
of Janz: clinical
R. MAI, C. DI MARCO, C. BERTIN, L. MINOTTI, V. PONTRELLI,
A. SALTARELLI
&
Regional Center for Epilepsy, University of Milan, Chair of Clinical Neurophysiology, S. Paolo Hospital, Milan, Italy Correspondence
to Dr M.P. Canevini, Centro Regionale Epilepsia, Ospedale San Paolo, Via A. Di Rudini, 8, 20142 Milano, Italy
We studied 60 patients with juvenile myoclonic epilepsy (JME). There was a high positive family history for epilepsy (33.3%). Age at onset of epilepsy ranged from 4 to 18 years with an average of 13.9 years. 86.3% of patients were seizure-free. The most effective drug was valproate. In eight patients drug withdrawal was attempted but all patients relapsed during a follow-up period of 1 year. Video-EEG studies were performed in eight newly diagnosed patients; myoclonic jerks were recorded in five patients. Key words: epilepsy; video-EEG; juvenile myoclonic epilepsy.
INTRODUCTION Juvenile myoclonic epilepsy (JME) or impulsive petit ma1 was first described by Janzl in 1957. JME has been neglected, especially in the English language literature, for many years. During the last 5 years, however, articles appearing in the literature about JME2-7 and research into the genetics of epiof lepsies s,‘, have confirmed the individuality the syndrome. Most patients who refer to special centres have had a generalized tonicclonic seizure (GCTS) and only when specifically questioned do they report also having had occasional myoclonic jerks initially, or separately. Some of the misunderstanding about this syndrome may be related to the different terms that have been used: the term ‘myoclonit’ may be misleading; in fact it may lead us to think of a syndrome with constant myoclonic characteristics and not a syndrome in which we must recognize the seizures characterized by myoclonias that can occur singly or in close succession of a few jerks. Janz’ attempted to clarify the intermittent nature of the jerks and their critical characteristic as minor seizures, naming the myoclonic seizures ‘impulsive petit mal’ (impulsio = jerk). It is likely that the terminology used up until now has not contributed to greater 1059-131 l/92/040291 +08
$08.00/O
knowledge of this syndrome, one that can be recognized and diagnosed only if its characteristics are definitively known, characteristics that make it possible to question patients appropriately. JME has been considered a benign form of epilepsy”. In any case, the ILAE international classification did not keep the adjective ‘benign’11,i2. The differing descriptive terms may have contributed to the discrepancy in the epidemiological data on JME. In fact, there have been reports of incidence as different as less than 1% of myoclonic seizures (including myoclonic seizures in childhood)13 to 7.5%14, 10.7%4 and 11.3%15. The purpose of this report is to present the data regarding our population of patients with JME. We report also the video-electroencephalographic (Video-EEG) recordings performed on eight newly diagnosed patients.
Definition The revised
classification of Epilepsies and defines JME as follows: ‘JME appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance
Epileptic
SyndromeI
@ 1992 Baillibre Tindall
M.P. Canevini et al.
292 Febrile seizures (3 potients11~5,0,,
(33 Fig. 1: Incidence
of seizures
in family
members
Afebrile Ttients)
patients) of patients
+ febrile
(20
seizures
patients)
with JME.
of consciousness is noticeable. Often, there are GTCS and, less often infrequent absences. The seizures usually occur shortly after awakening and are often caused by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular spike-waves (SW) and polyspike-waves (PSW); there is no close phase correlation between EEG spikes and jerks. Frequently the patients are photosensitive. The disorder may be inherited and sex distribution is equal. Response to appropriate drugs is good.’ MATERIALS AND METHODS Sixty patients who were referred to our clinic from 1983 to 1990, were included and studied prospectively using a uniform protocol. All patients were re-interviewed, EEG records were re-examined and a conventional EEG was recorded for all patients during the survey. Eight new patients who were diagnosed for the first time, had video-EEG recording, after a night of sleep deprivation, during spontaneous morning sleep and at awakening, using polygraphy. The following exclusion criteria were applied: abnormal CT brain scan, clinical or EEG evidence of myoclonic jerks secondary to brain anoxia, metabolic and progressive diseases, other structural brain abnormalities. Electroencephalography Conventional EEG was performed in all patients. Longitudinal and transverse montages were utilized in all patients and the lo20 international system was utilized with an
OTE (standard) 16 channel EEG machine. In all patients a 5min overbreathing COB), numerous eye-closures (EC) and intermittent photic stimulation UPS) test was performed. Patients were studied without modification of drug regimen. Video-EEG studies Video-EEG studies were performed in all eight new patients with a Transvideo System. Two cameras were used (one for the EEG and one for the patient) as well as a mixer in order to synchronize the two images. Each study was performed during sleep and after awakening and was attended by at least one investigator. Polygraphic recordings, usually of the upper limbs surface EMG, were obtained in all patients. Antigravity postures were tested during repeated eye closures and during IPS. Consciousness was tested by administering one or more acoustic stimulations and by asking the awakened patient to report on which simulations had been administered. RESULTS From a total of 242 patients who were firsttime referrals to our Centre during the years 1988-89, there were 21 JME patients, representing 8.6% of the total. Of the 60 patients we have studied, 40 (66.7%) were females and 20 (33.3%) males. Their age on referral varied from 15 to 55 (mean 25.6 +- 7.7 sd) years. A positive family history (Fig. 1) for epilepsy was only, in close and distant relatives, reported in 20 patients (33.3%). A positive
Juvenile
myoclonic
epilepsy
of Janz
family history for epilepsy and febrile seizures was reported in four patients (6.7%). A positive family history for febrile seizures only was reported in 3 patients (5%). In 16 patients (26.7%) a dystocic delivery was reported. Psychomotor development (motor language and function) was normal in all patients. Neurological and physical examination was normal in all patients with the exception of one male patient (congenital retinal angioma). Brain CT scan was performed in 19 patients (31.7%) and was normal in all; one patient had signs of slight cortical atrophy (age 25 years). The average age at onset of epilepsy was 13.9 (+ sd 2.8, range 4-18) years. The average age at onset of myoclonic jerks was 15.1 (+ sd 3.1; range 9-25) years, of GTCS 15.7 (+ sd 3.4; range 7-26) years (Fig. 2) and of absences 17.4 (* sd. 7.9; range 4-37) years.
Years
Fig. 2: Seizure types by age of onset. Myoclonic jerks -, GTCS . . ., absences - - - -.
All 60 patients had myoclonic jerks mainly or exclusively shortly after awakening. Fig. 3 shows the seizure types of our population: one patient (1.7%) had myoclonic jerks and absences, seven patients (11.7%) had myoclonit jerks only, 17 (28.3%) patients had myoclonit jerks, absences and GTCS and 35 (58.3%) patients had myoclonic jerks and GTCS. No neonatal convulsions were reported. Simple febrile convulsions were reported in nine patients (15%) (5 females, 4 males). No complex febrile convulsions were reported. All the facts provided are based on the anamnestic records given by the patients and their relatives.
Myoclonic jerks Myoclonic jerks were reported by 55 (91.7%) patients as symmetrical, bilateral and synch-
293
ronous, mainly affecting the upper limbs. Five patients (8.3%) reported myoclonic jerks of their upper limbs as lateralized; among these in four patients jerks were lateralized to the upper limbs corresponding to the dominant manual limb (2 patients right-handed, 2 lefthanded). Handedness was tested with Oldfield’s battery 16. In 23 patients the upper limb jerks were reported to be located in the proximal area, in 30 cases the jerks were reported to be located in the distal area and in both proximal and distal areas in the remaining seven subjects. Thirty-five (58.3%) patients reported they had had jerks also in the lower limbs. None of the patients reported having had lateralized jerks in the lower limbs. Twenty-three (38.3%) patients reported having had at least one fall owing to jerks in the lower limbs, and in one of these, the jerks were always accompanied by a fall. The jerks of the lower limbs were reported in the proximal area in 20 patients and in the distal area in 15 patients. Apparently, the likelihood of a fall was in strict relation to the intensity of patient’s jerks. Fifteen (25%) patients reported having sometimes had the sensation of impaired awareness during the jerks. Ten patients reported that on some occasion the jerks also involved their trunk and 13 patients their heads: among these, six patients reported having had jerks of both trunk and head. Before the beginning of regular treatment jerks occurred daily in 18 patients, weekly in 21 patients, almost monthly in six patients and only occasionally in 15 patients. A circadian incidence was present in 22 patients exclusively at awakening, in 13 patients in the morning and evening, in 12 patients in the morning, in three patients only in the evening and 10 patients did not confirm a connection with circadian rhythm. In those subjects who did not report any relationship with the circadian rhythm it is important to note that in seven patients lack of sleep and sudden awakening were the main precipitating factors; the remaining three patients who were controlled by therapy after a few seizures, did not report any precipitating cause. Thirty-six patients related jerks to lack of sleep, 27 patients to stressful situations, 21 patients to sudden awakening, one to relaxed evenings and one to TV-watching. In four females the jerks related to the menstrual cycle. Eight patients (13.3%) reported myoclo-
M.P. Canevini et al.
294
(28.3%)
MJ +AS+ GTCS (17 patients) Fig. 3: Clinical characteristics of patients with JME. MJ = Myoclonic jerks; AS = absence seizures; GTCS = generalized tonicclonic seizures. (35 patients)
nit jerks on eye closure, particularly shortly after awakening, whilst washing their faces. Myoclonic status epilepticus occurred in two (3.3%) patients: in one patient it followed a sudden withdrawal of a drug, in the second the cause was poor compliance. Generalized tonic-clonic
seizures
In 52 patients who experienced this seizure type, GTCS had its onset between the ages of 7 and 26 years. In 16 (26.7%) patients the seizures appeared at the beginning of the illness, i.e. before the start of myoclonic jerks. In five they appeared as the first clinical event, immediately preceded by myoclonic jerks. Thirty-two (53.3%) patients reported GTCS immediately preceded by myoclonic jerks in series, particularly in the upper limbs, but sometimes even in the lower limbs, with consciousness often preserved until the beginning of GTCS. Jerks were also reported of increasing intensity before GTCS. In 18 (30%) patients GTCS appeared only once. Among the reported precipitating factors for GTCS were: lack of sleep (19 patients), no factors (14 patients), sudden awakening (8 patients), drug withdrawal or poor compliance (8 patients), video-watching (7 patients), hyperthermia (1 patient). None of the patients reported GTCS in connection with alcohol abuse. A predominant circadian incidence of GTCS was subdivided as follows: 16 patients on awakening, 11 in the evening, 10 no relationship to different daytimes (but with irregular life-style there could still be a relation to awakening and to relaxing situations), nine in the morning, five in the morning and evening.
The patients’ relatives often reported a particularly long tonic phase with marked cyanosis. Absences Absences were present in 17 (28.3%) patients, associated with the other two types of seizures and in one patient combined only with myoclonit jerks. In one female, the absences started at 4 years of age and consisted of a classical childhood absence epilepsy (EEG with SW at 3 Hz). The patient was treated with ethosuximide (ESM), which controlled the absences and, at the age of 10 years (she was taking ESM), the first myoclonic jerks appeared. In another female, absences began at the age of 8 years with the characteristics of pyknolepsy, but old EEGs were not available. In another patient absences appeared at the age of 15 years; she did not have any drug therapy, and at the age of 17 years, myoclonic jerks on awakening appeared. In all the other patients absences appeared either contemporarily with (5 patients) or after the myoclonic jerks. In all patients the absences were simple, of short duration, not accompanied by motor or evident neurovegatative signs. Specific precipitating factors were reported by five patients only. One male patient reported video-watching as a precipitating factor. Among the female patients only two reported a connection with the menstrual cycle. EEG All patients had normal background activity. The most common abnormality
EEG was
Juvenile myoclonic
epilepsy
of Janz
the presence of a paroxysmal, generalized symmetrical SW and/or PSW pattern with maximum voltage over frontal regions. In all patients, previous EEGs presented anomalies on at least one occasion. In our survey recordings critical anomalies were only demonstrated for five patients, all newly diagnosed (see below, video-EEG). The interictal anomalies were subdivided as follows: in 20 patients, EEG recordings were completely normal, also during activating manoeuvres; in 20 the basal EEG showed paroxysmal anomalies (SW in 9, PSW in 11). Of the remaining 20 patients, OB was effective in 15 (SW in 13, PSW in 2) and IPS was effective in five (SW in 3, PSW in 2). Eye closure (EC) was effective in five (3 females, 2 males) patients only; in four of these IPS was ineffective. In only seven patients were both OB and IPS effective.
Video-EEG recordings Video-EEG recording was performed in eight: for all we recorded interictal anomalies while in five patients we recorded a total of about 30 myoclonic jerks. Among these patients, seven presented a characteristic pattern with SW and PSW at 3.5-4Hz, while only one patient presented rare SW at 3.5Hz. During the paroxysmal discharges, both ictal and interictal, consciousness has been tested by acoustic stimulation and/or analysis of performance of patients in counting, reading and recall tasks. In only one patient we recorded an increase in the latency between the acoustic stimulus and the answer: two patients appeared hesitant, with a brief discountinuation of the activity, but immediately resumed counting. In the remaining patients, the previous activity was neither interrupted nor altered. In addition, no patient admitted subjective changes during subclinical discharges. In two cases, however, we recorded, with video-EEG monitoring, myoclonic jerks in series after awakening, and the patients could not respond during jerks, but could recall being stimulated at the end of a series of them. One patient, after a bilateral and symmetrical myoclonic jerk of the upper limbs (evident both with video-EEG and on surface EMG recording) spontaneously reported a unilateral jerk of the right upper limb (right-handed patient). Figure 4 shows the polygraphic EEG record-
ing of an 18 year old patient with myoclonit jerks at awakening, precipitated by EC. From the electroencephalographical viewpoint, awakening was definitely activating for both interictal anomalies and myoclonic jerks, particularly if associated with OB and IPS. Polygraphic recordings (deltoid muscles) and video-EEG consistently demonstrated bilateral jerks always concomitant with PSW discharges without a constant relationship with the spikes on EEG.
Therapy In Fig. 5 we report treatment results related to the therapy administered. Fifty-three (88.3%) patients were controlled by drugs, and only seven (11.7%) patients were not controlled. Of those patients who were not controlled, four presented all three seizure types and three presented jerks and GTCS. In the eight patients newly diagnosed, all were controlled (minimum 1 year follow-up) by the first drug prescribed (valproic acid (VPA), 7 patients; primidone (PRM), 1 patient). In 8 patients drug withdrawal was attempted, but all relapsed during the follow-up period of between 6 months and 1 year.
DISCUSSION The incidence of JME is usually reported to be between 3 and 5.4% of all epilepsies 1-3,5, 15,17, ‘s. A higher incidence, 11.4%, was found by Wolf and Goosesi Tsuboi and Christianlg found 7.5%, and Obeid and Panayiotopoulos4 found a similar incidence. The incidence of 8.7% that we found in our study is similar to these latter studies. We think that the incidence of JME is very likely to be higher than the 3 to 5% reported in retrospective studies. Since JME is an age-dependent syndrome, an additional factor that might be relevant in this respect is the age composition of the samples studied. In fact our incidence data come from a population formed mainly of adult patients. A knowledge of the syndrome should stimulate clinicians to ask the right questions; in fact, many patients do not mention the jerks spontaneously, and even if they are reported, very often neurologists underestimate the significance of these myoclonic jerks5. The mean age of onset of the syndrome in our
M.P. Canevini et al.
296
.IA
.n
EC
J
J
J
J
J
Fig. 4: Precipitation of a polyspike-wave discharge by eye closure in an 18 year old patient with JME, shortly after awakening (video-EEG recorded).
patients overlaps with that of other studies’5, lo and this is at puberty. Myoclonic jerking as the sole expression of this form of epilepsy, was found in a few patients (11.7% in our study), as in previous studies29 18,20. Such cases probably are much more frequent, but often remain undiagnosed since both the patients and their physicians tend to dismiss the occasional morning jerks as ‘nervousness’ and attribute them to irregularities in the patient’s life, which may in fact be
an initiating factor5. The majority of patients (86.6%) in our study presented with associated GTCS, in accordance with the data in the literaturelP5’ lo. Frequently GTCS were the reason for referral. In accord with Janz’s original description, our findings confirm the fact that both the minor and major seizures occur most often in the morning on awakening, or in the evening during relaxing periods. Notably, in eight patients (13.3%) the time at which the myoclo-
Juvenile
myoclonic
epilepsy of Jane
PB
PB+ESM PRM+VPA VPM PB+VPA VPA+ESM
Fig. 5: Treatment results. Controlled El, not controlled m.
nit jerks most frequently occurred was during the morning when the patients closed their eyes whilst washing their faces. The EEG pattern, which was always pathological in untreated patients, can provide confirmatory information at the onset of the syndrome, especially after sleep-deprivation. Interictally, the background activity in our patients is normal, as in previous studies1-3,6v lo. The epileptic discharges are characteristically represented by irregular discharges of bilaterally synchronous SW and PSW complexes, at a frequency greater than 3 Hz and usually at 3.5 to 4.5 Hz~-~, “3 “9 20. Video-EEG and surface EMG recordings were very helpful in detecting subclinical seizures. Genetic factors are very important in JME. Between 17 to 49% of patients with JME have relatives with epileptic seizures1,3p4,14,20,21,22. A positive family history for epilepsy was reported in 33.3% patients in our study. Recognition of this syndrome is important because of the good response to therapy. In particular 95% of our patients were completely seizure-free on monotherapy with VPA. This is in accordance with the reports of Janz7 and other authors2-4*23,24. Although the syndrome is benign and the response to therapy is excellent, difficulty is often encountered when attempting to reduce or withdraw therapy. In fact, all eight patients in whom drug withdrawal was attempted, relapsed, and similar results were reported by Janz (92% relapses2?, and by Baruzzi (95% relapses2Y. Our cases were characterized by a high percentage of female patients (66.7%). A slight prevalence of females also was noted in previous studies2,22, but is not discussed in the JME definition of ILAE12. This finding needs to be further studied and we believe that it merits
297
particular attention, especially in relation to genetic data. One of our patients had myoclonic jerks on awakening and rare absences, but never had GTCS: the literature has not previously reported cases with such characteristics. Further, we found a high percentage of patients (38.3%) who reported having experienced at least one fall in consequence of myocionic jerks. These patients report that they fell when the intensity of the jerks was greatest. Previous studies20,27 have indicated the possibility that in the context of JME jerks may occur in only one arm. Five patients in our study (8.5%) reported myoclonic jerks in the upper limbs as lateralized. We tested the hypothesis that the lateralization was subjective, i.e. that patients reported myoclonic jerks lateralized to the dominant manual limb and in four of these patients, jerks were lateralized to the upper limb corresponding to the dominant manual limb. This opinion is supported by our video-EEG and polygraphic recording mentioned above. We believe that in the context of a generalized syndrome, such as JME, the jerks are always bilateral in reality and manual dominance together with a different intensity of jerks in the two limbs may condition the subjective sensation of lateralization. Eye closure is an important precipitating factor both for myoclonic jerks and for interictal anomalies. Eye-closure after awakening bothin the EEG laboratory and in daily life are the most effective combination of precipitating factors. For this reason patients should always be asked whether they have myoclonic jerks shortly after awakening while washing their faces. In conclusion the purpose of this paper is to draw the physician’s attention to a relatively common form of generalized epilepsy, which given its excellent response to pharmacological therapy, should always be recognized. ACKNOWLEDGEMENT
We wish to thank Professor D. Janz for a critical reading of the manuscript. REFERENCES 1.
Janz, Deutsch
D. and Christian, Zeitschrift
W. Impulsiv-Petit mal. 1957; 176:346-
Nervenheilkunde
386. 2. Asconap&, J. and Penry, J.K. Some clinical
and EEG
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3. 4. 5. 6. 7. 8.
9.
10.
aspects of benign juvenile myoclonic epilepsy. Epilepsia 1984; 25: 108-114. Delgado-Escueta, A.V. and Enrile-Bacsal, F. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34:285294. Obeid, T. and Panayiotopoulos, C.P. Juvenile myoclonit epilespy: a study in Saudi Arabia. Epilepsia 1988; 29(3):280-282. Jam, D. Epilepsy with impulsive petit-ma1 (juvenile myoclonic epilespy). Actu Neurologica Scandinu~icu 1985; 72:449-459. Dreifuss, F.E. Juvenile Myoclonic Epilepsy: characteristics of a primary generalized epilepsy. Epilepsiu 1989; 3O(Suppl4):Sl-S7. Janz, D. Juvenile myoclonic epilepsy-epilepsy with impulsive petit mal. Cleveland Clinical Journal of Medicine 1989; 56: 23-33. Greenberg, D.A. Delgado-Escueta, A.V., Widelitz, H. el al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. American Journal of Medical Genetics 1988; 31:185-192. Weissbecker, K.A., Durner, M., Janz, D., Scaramelli, A., Sparkes, R.S. and Spence, M.A. Confirmation of linkage between juvenile myoclonic epilepsy locus and the HLA region of chromosome 6. American Journal of Medical Genetics 1991; 38: 32-36. Wolf, P. L’Epilepsie myoclonique juveile benigne. In: Les syndromes cent. (Eds J.
11.
12.
13.
14.
15.
epileptiques
de l’enfunt
et de l’Adoles-
Roger, C. Dravet, M. Bureau, F.E. Dreifuss and P. Wolf) Paris, John Libbey Eurotext, 1984: pp 255-256. Commission on classification and terminology of the International League Against Epilepsy. Proposal for Classification of Epilepsy and Epileptic Syndromes. Epilepsia 1985; 26~268-278. Commission on classification and terminology of the International League Against Epilepsy. Proposal for revised classification of Epilepsies and Epileptic Syndromes. Epilepsiu 1989; 30:389-399. Sander, J.W.A.S., Hart, Y.M., Johnson, A.L. and Shorvon, SD. National General Practice Study of Epilepsy: newly diagnosed epileptic seizures in a general population. Luncet 1990; 336: 1267-1271. Tsuboi, T. and Christian, W. On the genetics of the primary generalized epilepsy with sporadic myoclonias of impulsive petit ma1 type. Human Genetics 1973; 19:155-182. Wolf, P. and Gooses, R. Relation of photosensitivity to epileptic syndromes. Journal of Neurology Neurosurgery and Psychiatry 1986; 49:1368-1391.
16. Oldfield, R.C. The assessment and analysis of handedness-Edinburgh Inventory. Neuropsychologiu 1971; 9:97-113. 17. Gastaut, H., Gastaut, J.A., Gastaut, J.L., Roger, J. and Tassinari, C.A. Epilepsie generalisbe primaire grand mal. In: Evolution and prognosis of epilepsies. (Eds E. Lugaresi, P. Pazzaglia, and C.A. Tassinari). Bologna, Au10 Gaggi, 1973. 18. Simonsen, M., Mollgaard, V. and Lund, M. A controlled clinical and electroencelphalographic study of myoclonic epilepsy (Impulsive-Petit mall. In Epileptology (Ed. D. Janz) Stuttgart, Thieme, 1976. 19. Tsuboi, T. Epilepsy. A clinical, electroencephalographic, and statistical study of 466 patients. Springer, Berlin, Heidelberg, New York, 1976. 20. Janz, D. Die Epilepsien. Stuttgart, Thieme, 1969. 21. Beck-Mannagetta, G., Hensen, J. and Janz, D. Seizure type in epilepsy patients with a history of febrile convulsions. In: Advances in Epileptology. (Eds P. Wolf, D. Janz, F. Dreifuss, and M. Dam) XVIth Epilepsy International Symposium. New York, Raven Press, 1988. 22. Salas-Puig, X., Camara da Silva, A.M., Dravet, Ch. and Roger, J. L’epilepsie myoclonique juvenile dans la population du Centre Saint-Paul. Epilepsies 1990; 2:108-113. 23. Penry, J.K., Dean, C. and Riela, A.R. Juvenile Myoclonit Epilepsy: long-term response to therapy. Epilepsia 1989; 30 (Suppl. 4): 19-23. 24. Covanis, A., Gupka, A.K. and Jeavons, P.M. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982; 23: 693-720. 25. Janz, D. When should antiepileptic drug treatment be terminated? In: Advances in Epileptology, Vol. 16. (Eds. P. Wolf et al.) New York, Raven Press, 1987: pp. 365-372. 26. Baruzzi, A., Procaccianti, G., Tinuper, P. and Lugaresi, E. Anti-epileptic drug withdrawal in childhood epilepsy: preliminary results of a prospective study. In: Diagnostic leptology.
and
Therapeutic
Problems
in Pediatric
Epi-
(Eds. G. Faienza and G.L. Prati). Amsterdam, New York, Oxford, Excerpta Medica, 1988: pp. 117-123. 27. Guirao Bringas, I.P., Behl, I. and Wolf, P. Epileptic discharge after eye closure: relation to epileptic syndromes. In: Advances in Epileptology, Vol. 16 (Eds P. Wolf et al.) New York, Raven Press, 1987: pp. 255-258.
Juvenile myoclonic epilepsy observations in 60 patients M.P. CANEVINI, R. CANGER
of Janz: clinical
R. MAI, C. DI MARCO, C. BERTIN, L. MINOTTI, V. PONTRELLI,
A. SALTARELLI
&
Regional Center for Epilepsy, University of Milan, Chair of Clinical Neurophysiology, S. Paolo Hospital, Milan, Italy Correspondence
to Dr M.P. Canevini, Centro Regionale Epilepsia, Ospedale San Paolo, Via A. Di Rudini, 8, 20142 Milano, Italy
We studied 60 patients with juvenile myoclonic epilepsy (JME). There was a high positive family history for epilepsy (33.3%). Age at onset of epilepsy ranged from 4 to 18 years with an average of 13.9 years. 86.3% of patients were seizure-free. The most effective drug was valproate. In eight patients drug withdrawal was attempted but all patients relapsed during a follow-up period of 1 year. Video-EEG studies were performed in eight newly diagnosed patients; myoclonic jerks were recorded in five patients. Key words: epilepsy; video-EEG; juvenile myoclonic epilepsy.
INTRODUCTION Juvenile myoclonic epilepsy (JME) or impulsive petit ma1 was first described by Janzl in 1957. JME has been neglected, especially in the English language literature, for many years. During the last 5 years, however, articles appearing in the literature about JME2-7 and research into the genetics of epiof lepsies s,‘, have confirmed the individuality the syndrome. Most patients who refer to special centres have had a generalized tonicclonic seizure (GCTS) and only when specifically questioned do they report also having had occasional myoclonic jerks initially, or separately. Some of the misunderstanding about this syndrome may be related to the different terms that have been used: the term ‘myoclonit’ may be misleading; in fact it may lead us to think of a syndrome with constant myoclonic characteristics and not a syndrome in which we must recognize the seizures characterized by myoclonias that can occur singly or in close succession of a few jerks. Janz’ attempted to clarify the intermittent nature of the jerks and their critical characteristic as minor seizures, naming the myoclonic seizures ‘impulsive petit mal’ (impulsio = jerk). It is likely that the terminology used up until now has not contributed to greater 1059-131 l/92/040291 +08
$08.00/O
knowledge of this syndrome, one that can be recognized and diagnosed only if its characteristics are definitively known, characteristics that make it possible to question patients appropriately. JME has been considered a benign form of epilepsy”. In any case, the ILAE international classification did not keep the adjective ‘benign’11,i2. The differing descriptive terms may have contributed to the discrepancy in the epidemiological data on JME. In fact, there have been reports of incidence as different as less than 1% of myoclonic seizures (including myoclonic seizures in childhood)13 to 7.5%14, 10.7%4 and 11.3%15. The purpose of this report is to present the data regarding our population of patients with JME. We report also the video-electroencephalographic (Video-EEG) recordings performed on eight newly diagnosed patients.
Definition The revised
classification of Epilepsies and defines JME as follows: ‘JME appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance
Epileptic
SyndromeI
@ 1992 Baillibre Tindall
M.P. Canevini et al.
292 Febrile seizures (3 potients11~5,0,,
(33 Fig. 1: Incidence
of seizures
in family
members
Afebrile Ttients)
patients) of patients
+ febrile
(20
seizures
patients)
with JME.
of consciousness is noticeable. Often, there are GTCS and, less often infrequent absences. The seizures usually occur shortly after awakening and are often caused by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular spike-waves (SW) and polyspike-waves (PSW); there is no close phase correlation between EEG spikes and jerks. Frequently the patients are photosensitive. The disorder may be inherited and sex distribution is equal. Response to appropriate drugs is good.’ MATERIALS AND METHODS Sixty patients who were referred to our clinic from 1983 to 1990, were included and studied prospectively using a uniform protocol. All patients were re-interviewed, EEG records were re-examined and a conventional EEG was recorded for all patients during the survey. Eight new patients who were diagnosed for the first time, had video-EEG recording, after a night of sleep deprivation, during spontaneous morning sleep and at awakening, using polygraphy. The following exclusion criteria were applied: abnormal CT brain scan, clinical or EEG evidence of myoclonic jerks secondary to brain anoxia, metabolic and progressive diseases, other structural brain abnormalities. Electroencephalography Conventional EEG was performed in all patients. Longitudinal and transverse montages were utilized in all patients and the lo20 international system was utilized with an
OTE (standard) 16 channel EEG machine. In all patients a 5min overbreathing COB), numerous eye-closures (EC) and intermittent photic stimulation UPS) test was performed. Patients were studied without modification of drug regimen. Video-EEG studies Video-EEG studies were performed in all eight new patients with a Transvideo System. Two cameras were used (one for the EEG and one for the patient) as well as a mixer in order to synchronize the two images. Each study was performed during sleep and after awakening and was attended by at least one investigator. Polygraphic recordings, usually of the upper limbs surface EMG, were obtained in all patients. Antigravity postures were tested during repeated eye closures and during IPS. Consciousness was tested by administering one or more acoustic stimulations and by asking the awakened patient to report on which simulations had been administered. RESULTS From a total of 242 patients who were firsttime referrals to our Centre during the years 1988-89, there were 21 JME patients, representing 8.6% of the total. Of the 60 patients we have studied, 40 (66.7%) were females and 20 (33.3%) males. Their age on referral varied from 15 to 55 (mean 25.6 +- 7.7 sd) years. A positive family history (Fig. 1) for epilepsy was only, in close and distant relatives, reported in 20 patients (33.3%). A positive
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family history for epilepsy and febrile seizures was reported in four patients (6.7%). A positive family history for febrile seizures only was reported in 3 patients (5%). In 16 patients (26.7%) a dystocic delivery was reported. Psychomotor development (motor language and function) was normal in all patients. Neurological and physical examination was normal in all patients with the exception of one male patient (congenital retinal angioma). Brain CT scan was performed in 19 patients (31.7%) and was normal in all; one patient had signs of slight cortical atrophy (age 25 years). The average age at onset of epilepsy was 13.9 (+ sd 2.8, range 4-18) years. The average age at onset of myoclonic jerks was 15.1 (+ sd 3.1; range 9-25) years, of GTCS 15.7 (+ sd 3.4; range 7-26) years (Fig. 2) and of absences 17.4 (* sd. 7.9; range 4-37) years.
Years
Fig. 2: Seizure types by age of onset. Myoclonic jerks -, GTCS . . ., absences - - - -.
All 60 patients had myoclonic jerks mainly or exclusively shortly after awakening. Fig. 3 shows the seizure types of our population: one patient (1.7%) had myoclonic jerks and absences, seven patients (11.7%) had myoclonit jerks only, 17 (28.3%) patients had myoclonit jerks, absences and GTCS and 35 (58.3%) patients had myoclonic jerks and GTCS. No neonatal convulsions were reported. Simple febrile convulsions were reported in nine patients (15%) (5 females, 4 males). No complex febrile convulsions were reported. All the facts provided are based on the anamnestic records given by the patients and their relatives.
Myoclonic jerks Myoclonic jerks were reported by 55 (91.7%) patients as symmetrical, bilateral and synch-
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ronous, mainly affecting the upper limbs. Five patients (8.3%) reported myoclonic jerks of their upper limbs as lateralized; among these in four patients jerks were lateralized to the upper limbs corresponding to the dominant manual limb (2 patients right-handed, 2 lefthanded). Handedness was tested with Oldfield’s battery 16. In 23 patients the upper limb jerks were reported to be located in the proximal area, in 30 cases the jerks were reported to be located in the distal area and in both proximal and distal areas in the remaining seven subjects. Thirty-five (58.3%) patients reported they had had jerks also in the lower limbs. None of the patients reported having had lateralized jerks in the lower limbs. Twenty-three (38.3%) patients reported having had at least one fall owing to jerks in the lower limbs, and in one of these, the jerks were always accompanied by a fall. The jerks of the lower limbs were reported in the proximal area in 20 patients and in the distal area in 15 patients. Apparently, the likelihood of a fall was in strict relation to the intensity of patient’s jerks. Fifteen (25%) patients reported having sometimes had the sensation of impaired awareness during the jerks. Ten patients reported that on some occasion the jerks also involved their trunk and 13 patients their heads: among these, six patients reported having had jerks of both trunk and head. Before the beginning of regular treatment jerks occurred daily in 18 patients, weekly in 21 patients, almost monthly in six patients and only occasionally in 15 patients. A circadian incidence was present in 22 patients exclusively at awakening, in 13 patients in the morning and evening, in 12 patients in the morning, in three patients only in the evening and 10 patients did not confirm a connection with circadian rhythm. In those subjects who did not report any relationship with the circadian rhythm it is important to note that in seven patients lack of sleep and sudden awakening were the main precipitating factors; the remaining three patients who were controlled by therapy after a few seizures, did not report any precipitating cause. Thirty-six patients related jerks to lack of sleep, 27 patients to stressful situations, 21 patients to sudden awakening, one to relaxed evenings and one to TV-watching. In four females the jerks related to the menstrual cycle. Eight patients (13.3%) reported myoclo-
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(28.3%)
MJ +AS+ GTCS (17 patients) Fig. 3: Clinical characteristics of patients with JME. MJ = Myoclonic jerks; AS = absence seizures; GTCS = generalized tonicclonic seizures. (35 patients)
nit jerks on eye closure, particularly shortly after awakening, whilst washing their faces. Myoclonic status epilepticus occurred in two (3.3%) patients: in one patient it followed a sudden withdrawal of a drug, in the second the cause was poor compliance. Generalized tonic-clonic
seizures
In 52 patients who experienced this seizure type, GTCS had its onset between the ages of 7 and 26 years. In 16 (26.7%) patients the seizures appeared at the beginning of the illness, i.e. before the start of myoclonic jerks. In five they appeared as the first clinical event, immediately preceded by myoclonic jerks. Thirty-two (53.3%) patients reported GTCS immediately preceded by myoclonic jerks in series, particularly in the upper limbs, but sometimes even in the lower limbs, with consciousness often preserved until the beginning of GTCS. Jerks were also reported of increasing intensity before GTCS. In 18 (30%) patients GTCS appeared only once. Among the reported precipitating factors for GTCS were: lack of sleep (19 patients), no factors (14 patients), sudden awakening (8 patients), drug withdrawal or poor compliance (8 patients), video-watching (7 patients), hyperthermia (1 patient). None of the patients reported GTCS in connection with alcohol abuse. A predominant circadian incidence of GTCS was subdivided as follows: 16 patients on awakening, 11 in the evening, 10 no relationship to different daytimes (but with irregular life-style there could still be a relation to awakening and to relaxing situations), nine in the morning, five in the morning and evening.
The patients’ relatives often reported a particularly long tonic phase with marked cyanosis. Absences Absences were present in 17 (28.3%) patients, associated with the other two types of seizures and in one patient combined only with myoclonit jerks. In one female, the absences started at 4 years of age and consisted of a classical childhood absence epilepsy (EEG with SW at 3 Hz). The patient was treated with ethosuximide (ESM), which controlled the absences and, at the age of 10 years (she was taking ESM), the first myoclonic jerks appeared. In another female, absences began at the age of 8 years with the characteristics of pyknolepsy, but old EEGs were not available. In another patient absences appeared at the age of 15 years; she did not have any drug therapy, and at the age of 17 years, myoclonic jerks on awakening appeared. In all the other patients absences appeared either contemporarily with (5 patients) or after the myoclonic jerks. In all patients the absences were simple, of short duration, not accompanied by motor or evident neurovegatative signs. Specific precipitating factors were reported by five patients only. One male patient reported video-watching as a precipitating factor. Among the female patients only two reported a connection with the menstrual cycle. EEG All patients had normal background activity. The most common abnormality
EEG was
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the presence of a paroxysmal, generalized symmetrical SW and/or PSW pattern with maximum voltage over frontal regions. In all patients, previous EEGs presented anomalies on at least one occasion. In our survey recordings critical anomalies were only demonstrated for five patients, all newly diagnosed (see below, video-EEG). The interictal anomalies were subdivided as follows: in 20 patients, EEG recordings were completely normal, also during activating manoeuvres; in 20 the basal EEG showed paroxysmal anomalies (SW in 9, PSW in 11). Of the remaining 20 patients, OB was effective in 15 (SW in 13, PSW in 2) and IPS was effective in five (SW in 3, PSW in 2). Eye closure (EC) was effective in five (3 females, 2 males) patients only; in four of these IPS was ineffective. In only seven patients were both OB and IPS effective.
Video-EEG recordings Video-EEG recording was performed in eight: for all we recorded interictal anomalies while in five patients we recorded a total of about 30 myoclonic jerks. Among these patients, seven presented a characteristic pattern with SW and PSW at 3.5-4Hz, while only one patient presented rare SW at 3.5Hz. During the paroxysmal discharges, both ictal and interictal, consciousness has been tested by acoustic stimulation and/or analysis of performance of patients in counting, reading and recall tasks. In only one patient we recorded an increase in the latency between the acoustic stimulus and the answer: two patients appeared hesitant, with a brief discountinuation of the activity, but immediately resumed counting. In the remaining patients, the previous activity was neither interrupted nor altered. In addition, no patient admitted subjective changes during subclinical discharges. In two cases, however, we recorded, with video-EEG monitoring, myoclonic jerks in series after awakening, and the patients could not respond during jerks, but could recall being stimulated at the end of a series of them. One patient, after a bilateral and symmetrical myoclonic jerk of the upper limbs (evident both with video-EEG and on surface EMG recording) spontaneously reported a unilateral jerk of the right upper limb (right-handed patient). Figure 4 shows the polygraphic EEG record-
ing of an 18 year old patient with myoclonit jerks at awakening, precipitated by EC. From the electroencephalographical viewpoint, awakening was definitely activating for both interictal anomalies and myoclonic jerks, particularly if associated with OB and IPS. Polygraphic recordings (deltoid muscles) and video-EEG consistently demonstrated bilateral jerks always concomitant with PSW discharges without a constant relationship with the spikes on EEG.
Therapy In Fig. 5 we report treatment results related to the therapy administered. Fifty-three (88.3%) patients were controlled by drugs, and only seven (11.7%) patients were not controlled. Of those patients who were not controlled, four presented all three seizure types and three presented jerks and GTCS. In the eight patients newly diagnosed, all were controlled (minimum 1 year follow-up) by the first drug prescribed (valproic acid (VPA), 7 patients; primidone (PRM), 1 patient). In 8 patients drug withdrawal was attempted, but all relapsed during the follow-up period of between 6 months and 1 year.
DISCUSSION The incidence of JME is usually reported to be between 3 and 5.4% of all epilepsies 1-3,5, 15,17, ‘s. A higher incidence, 11.4%, was found by Wolf and Goosesi Tsuboi and Christianlg found 7.5%, and Obeid and Panayiotopoulos4 found a similar incidence. The incidence of 8.7% that we found in our study is similar to these latter studies. We think that the incidence of JME is very likely to be higher than the 3 to 5% reported in retrospective studies. Since JME is an age-dependent syndrome, an additional factor that might be relevant in this respect is the age composition of the samples studied. In fact our incidence data come from a population formed mainly of adult patients. A knowledge of the syndrome should stimulate clinicians to ask the right questions; in fact, many patients do not mention the jerks spontaneously, and even if they are reported, very often neurologists underestimate the significance of these myoclonic jerks5. The mean age of onset of the syndrome in our
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.IA
.n
EC
J
J
J
J
J
Fig. 4: Precipitation of a polyspike-wave discharge by eye closure in an 18 year old patient with JME, shortly after awakening (video-EEG recorded).
patients overlaps with that of other studies’5, lo and this is at puberty. Myoclonic jerking as the sole expression of this form of epilepsy, was found in a few patients (11.7% in our study), as in previous studies29 18,20. Such cases probably are much more frequent, but often remain undiagnosed since both the patients and their physicians tend to dismiss the occasional morning jerks as ‘nervousness’ and attribute them to irregularities in the patient’s life, which may in fact be
an initiating factor5. The majority of patients (86.6%) in our study presented with associated GTCS, in accordance with the data in the literaturelP5’ lo. Frequently GTCS were the reason for referral. In accord with Janz’s original description, our findings confirm the fact that both the minor and major seizures occur most often in the morning on awakening, or in the evening during relaxing periods. Notably, in eight patients (13.3%) the time at which the myoclo-
Juvenile
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PB
PB+ESM PRM+VPA VPM PB+VPA VPA+ESM
Fig. 5: Treatment results. Controlled El, not controlled m.
nit jerks most frequently occurred was during the morning when the patients closed their eyes whilst washing their faces. The EEG pattern, which was always pathological in untreated patients, can provide confirmatory information at the onset of the syndrome, especially after sleep-deprivation. Interictally, the background activity in our patients is normal, as in previous studies1-3,6v lo. The epileptic discharges are characteristically represented by irregular discharges of bilaterally synchronous SW and PSW complexes, at a frequency greater than 3 Hz and usually at 3.5 to 4.5 Hz~-~, “3 “9 20. Video-EEG and surface EMG recordings were very helpful in detecting subclinical seizures. Genetic factors are very important in JME. Between 17 to 49% of patients with JME have relatives with epileptic seizures1,3p4,14,20,21,22. A positive family history for epilepsy was reported in 33.3% patients in our study. Recognition of this syndrome is important because of the good response to therapy. In particular 95% of our patients were completely seizure-free on monotherapy with VPA. This is in accordance with the reports of Janz7 and other authors2-4*23,24. Although the syndrome is benign and the response to therapy is excellent, difficulty is often encountered when attempting to reduce or withdraw therapy. In fact, all eight patients in whom drug withdrawal was attempted, relapsed, and similar results were reported by Janz (92% relapses2?, and by Baruzzi (95% relapses2Y. Our cases were characterized by a high percentage of female patients (66.7%). A slight prevalence of females also was noted in previous studies2,22, but is not discussed in the JME definition of ILAE12. This finding needs to be further studied and we believe that it merits
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particular attention, especially in relation to genetic data. One of our patients had myoclonic jerks on awakening and rare absences, but never had GTCS: the literature has not previously reported cases with such characteristics. Further, we found a high percentage of patients (38.3%) who reported having experienced at least one fall in consequence of myocionic jerks. These patients report that they fell when the intensity of the jerks was greatest. Previous studies20,27 have indicated the possibility that in the context of JME jerks may occur in only one arm. Five patients in our study (8.5%) reported myoclonic jerks in the upper limbs as lateralized. We tested the hypothesis that the lateralization was subjective, i.e. that patients reported myoclonic jerks lateralized to the dominant manual limb and in four of these patients, jerks were lateralized to the upper limb corresponding to the dominant manual limb. This opinion is supported by our video-EEG and polygraphic recording mentioned above. We believe that in the context of a generalized syndrome, such as JME, the jerks are always bilateral in reality and manual dominance together with a different intensity of jerks in the two limbs may condition the subjective sensation of lateralization. Eye closure is an important precipitating factor both for myoclonic jerks and for interictal anomalies. Eye-closure after awakening bothin the EEG laboratory and in daily life are the most effective combination of precipitating factors. For this reason patients should always be asked whether they have myoclonic jerks shortly after awakening while washing their faces. In conclusion the purpose of this paper is to draw the physician’s attention to a relatively common form of generalized epilepsy, which given its excellent response to pharmacological therapy, should always be recognized. ACKNOWLEDGEMENT
We wish to thank Professor D. Janz for a critical reading of the manuscript. REFERENCES 1.
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