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Cortical myoclonus in angelman syndrome.

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Cortical Myoclonus in Angelman Syndrome
Renzo Guerrini, MD,* Timothy M. De Lorey, PhD,? Paolo Bonanni, MD,* Anne Moncla, MD,f
Charlotte Dravet, MD,S Georges Suisse, MD," Marie Odile Livet, MD,S Michelle Bureau, MD,$
Perrine Malzac, PhD,$ Pierre Genton, MD,S Pierre Thomas, MD," Ferdinand0 Sartucci, MD,'
Paolo Simi, PhD,' and Josi. M. Serratosa, M D t
Angelman syndrome (AS) results from lack of genetic contribution from maternal chromosome 15qll-13. This region
encompasses three GABA,, receptor subunit genes (p3, a 5 , and y3). The characteristic phenotype of AS is severe mental
retardation, ataxic gait, tremulousness, and jerky movements. We studied the movement disorder in 11 As patients,
aged 3 to 28 years. Two patients had paternal uniparental disomy for chromosome 15, 8 had a > 3 Mb deletion, and
1 had a microdeletion involving loci D15S10, D15S113, and GABRB3. All patients exhibited quasicontinuous rhythmic
myoclonus mainly involving hands and face, accompanied by rhythmic 5- to 10-Hz electroencephalographic (EEG)
activity. Electromyographic bursts lasted 35 f 13 msec and had a frequency of 11 f 2.4 Hz. Burst-locked EEG averaging
in 5 patients, generated a premyoclonus transient preceding the burst by 19 +- 5 msec. A cortical spread pattern of
myoclonic cortical activity was observed. Seven patients also demonstrated myoclonic seizures. No giant somatosensory
evoked potentials or C-reflex were observed. The silent period following motor evoked potentials was shortened by 70%,
indicating motor cortex hyperexcitability. Treatment with piracetam in 5 patients significantly improved myoclonus. We
conclude that spontaneous, rhythmic, fast-bursting cortical myoclonus is a prominent feature of AS.
Guerrini R, De Lorey TM, Bonanni P,Moncla A, Dravet C, Suisse G, Livet MO, Bureau M, Malzac P,
Genton P,Thomas P, Sartucci F, Simi P, Serratosa JM. Cortical myoclonus
in Angelman syndrome. Ann Neurol 1996;40:39-48
Angelman syndrome (AS) [I] is a neurogenetic disorder resulting from lack of genetic contribution from
maternal chromosome 15qll-I3 [2, 31. Sixty percent
of AS patients demonstrate a chromosome 15qll- 13
cytogenetic or molecular deletion. The remaining patients have either no detectable deletion (-35%) or
uniparental disomy (- 5%) where both chromosome
15 alleles are contributed by the father [4].Affected
patients present with severe mental retardation, absent
speech or very poor language skills, microbrachycephaly, inappropriate laughter, seizures, abnormal electroencephalographic (EEG) activity, and a characteristic
"puppetlike" motor pattern consisting of ataxic gait,
tremulousness, and jerky limb movements [ 1, 5- lo].
Although the movement disorder is present in almost all patients [b] and represents a major diagnostic
criterion, it has not been studied neurophysiologically
and, to date, there is no rational treatment.
We present a clinical and neurophysiological study
of 11 unrelated AS patients confirmed by genetic analysis. Our findings indicate that the tremulous move-
ment disorder of AS is related to a unique pattern of
fast-bursting cortical myoclonus (FBCM) and that antimyoclonic treatment with piracetam can produce
marked functional improvement.
From the *Institute of Child Neurology and Psychiatry, University
of Pisa-IRCCS Stella Maris Foundation, 'Department of Neurop h y s i o l o ~Institute
~
Of
and
Of Generics,
Institute of Pediatrics, University of Pisa, Pisa, Italy; ?Department
of Pharmacology, UCLA School of Medicine, and California Comprehensive Epilepsy Program, Los Angeles, CA; and $Department
of Medical Genetics, H6pital de la Timone, and Scentre Saint
Paul, Marseille, and !'Departments of Neurophysiology and Neurology, H8pital Pasteur, Nice, France.
Received Sep 27, 1995, and in revised form Dec 20. Accepted for
publication Jan 25, 1996.
Address correspondence to Dr Guerrini, Institute of Child Neural.
ogy and Psychiatry, University of Pisa, Via dei Giacinti 2, 56018
Calambrone, Pisa, Italy,
Patients and Methods
Patients
Eleven patients ( 5 male, 6 female), aged 3 to 28 years, were
included in the study (see Table I). Ten patients are new
to this study and one has been previously described by
Robinson and colleagues [I 11. To be included in this study,
patients were required to be clinically diagnosed with AS and
show either a maternal deletion or uniparental disomy on
chromosome 15. Clinical diagnosis of AS was based on the
presence of the characteristic physical and behavioral phenotype [ l , 6, 91. Follow up varied from 2 to 24 years (mean,
17 years; median, 18 years).
Genetic Analysis
High-resolution chromosome studies were performed on 10 patients using a synchroHIGH-RESOLUTION BANDING.
Copyright 0 1996 by the American Neurological Association
39
nization method [ 121. RHG banding was obtained by heatcontrolled denaturation followed by Giemsa staining.
FISH was
performed on chromosomal spreads from 10 patients using
the GABRB3 probe and the PML chromosome 15q22 control probe (ONCOR, Inc).
FLUORESCENT I N SII‘U HYBRIDIZATION (FISH).
rw7i METHYLATION ANALYSIS. The D15 S63 locus was
analyzed for rnethylation using the PW71 probe. Genomic
DNA was digested with Hind111 and HpnTI and hybridized
with the PW71 probe, as previously described [13].
MICKOSAI‘ELLITE MARKER ANALYSIS. The polymerase
chain reaction (PCR) was used to amplify total genomic
DNA in 10 patients and their parents. Haplotypes were constructed using the following microsatellite markers: IR4 3-R
(D15Sll), 3-21 (D15S10), LS6-1 (Dl5Sl13), 155 and 85
(Dl5S51 l), DlSS128, D15S210, D15S122, GABRB3,
GABRA5, D15S156, and D15S165 114, 151. These markers
cover a 13 cM interval in chromosome 15qll-13.
Clinical and Video-ELectropbysioLogicaL Studies
All patients were cvaluated by long-term video-EEG and simultaneous surface electromyographic (EMG) monitoring
with bipolar and referential montages using silver-silver
chloride surface electrodes. Recordings were carried out in
two centers (ICNP-Pisa for Patients 1 to 6 and CSP-Marseille for Patients 7 to 11). Scalp electrode placement was
performed according to the international 10-20 system.
EMG activity was recorded using pairs of electrodes applied
3 cm apart over the masseter, orbicularis oris, deltoids, biceps, and finger flexors and extensors. Back averaging of EEG
activity related to the EMG bursts was performed in the 5
patients (1-4 and 6; age range, 7-25 years) for whom artifact-free EEG and EMG could be recorded on computer for
later analysis. The EEG signal was filtered using a bandpass
of 1 to 100 Hz, and digitalized at the sampling rate of 1,024
Hz. The average of 100 to 120 consecutive 300-msec artifact-free EEG epochs centered at the onset of the EMG burst
(burst-locked EEG averages) was computed. At least two averages were generated for each patient to ensure reliability
between trials. Averages of 100 to 120 consecutive 300-msec
artifact-free EEG epochs related to the onset of the EMG
silence (silence-locked EEG averages) were generated from
the same EEG data.
Somatosensory evoked potentials (SEPs) were recorded in
the 6 patients studied at ICNP-Pisa (1-6; age range, 7-27
years) from central (C3’, C4’) and frontal (F3, F4) regions,
from a point at the level of the seventh cervical spine (C7S),
and from Erb’s point (EP) using referential montages. The
median nerve was electrically stimulated at the wrist using
an intensity strong enough to produce a twitch of the thenar
muscle and a frequency of 0.5 and 1 Hz. The EEG signal
was filtered with a bandpass of 1 to 2,000 Hz. Blocks of
500 consecutive artifact-free responses were averaged. The
C-reflex was sought by applying a 0.5-msec electrical stimulus to the median nerve at the wrist at motor threshold intensity and by recording EMG activity from the abductor pol-
40 Annals of Neurology Vol 40
No 1
July 1996
licis brevis at rest. Blocks of 50 consecutive stimuli were
averaged. Trials were replicated to ensure reproducibility of
the responses. Twenty healthy subjects aged 18 to 30 years
(mean t SD, 23.4 ? 2.5) were used as control group for
Patients 2, 3, and 5. Three groups of 15 healthy subjects
(aged 14-18, 12-14, and 6-8 years) were used as control
groups for Patients 1, 4, and 6, respectively.
Transcranial Magnetic Stimulation
A Novametrix Magstim ME magnetic device was used to
obtain motor evoked potentials (MEPs) in the 6 patients
studied at ICNP-Pisa (1-6; age range, 7-27 years). A flat,
single round coil (inner diameter of 9.5 cm) was placed on
the vertex. The EMG surface electrodes were placed in the
abductor digiti minimi, at the hypothenar eminence, and at
the tibialis anterior. The effects of peripheral nerve, cervical,
and transcranial magnetic stimulation (TMS) on the rhythmic EMG bursting pattern of hand myoclonus and on voluntary motor contraction were analyzed in 4 patients (1-3
and 5; age range, 15-27 years). Single T M S were delivered
to the contralateral side of the scalp. The stimulus intensity
was 100% of the stimulator’s output (1.5 T), approximately
1.2 times the motor threshold for the MEPs. Cervical stimulation was delivered with the coil centered over the C7S.
Peripheral nerve stimulation was delivered with the coil centered over the EP. The EMG surface electrodes were positioned over the right wrist extensors and flexors. Trials were
replicated to ensure reproducibility of the responses. Normal
data for TMS (including central motor conduction time
[CMCT], amplitude of responses, and post-MEPs silent
period) were obtained from 20 healthy subjects aged 15 to 30
years (mean ? SD, 25.6 2 2.3 years). Although Patient 6 was
aged below the age range of controls, we considered C M C T
values to be comparable as no significant variations in this parameter are generally observed after the age of 2 [ 161.
Neuroimaging
Nine patients underwent brain magnetic resonance imaging
using a 0.5- or 1-T instrument. Spin echo, inversion recovery, and gradient echo-weighed sequences were obtained in
the axial, sagittal, and coronal planes. T h e remaining 2 patients underwent brain computed tomographic (CT) scan.
Treatment of Myoclonus with Piracetarn
Various drugs, alone or in combinations, had been given
chronically to all patients to achieve control of seizures, myoclonus, or both. Piracetam was added to previous drug regimes in 5 patients (clobazam [CLB] in Patient 1, CLB
phenobarbital [PB] in Patient 2, CLB
PB ethosuximide
valproate in Patient 5, and clonazepam
in Patient 3, CLB
in Patient 6). The initial dose was 2.4 gm/day and was increased until a stable benefit was observed. Clinical benefit
was assessed 2 to 4 weeks after a stable dosage was reached,
using rating scales for motor impairment, functional disability, and global impression of disability I17, 181 adapted to
AS. Motor impairment was evaluated by obtaining a score
that resulted from the addition of the following three subscores: spontaneous myoclonus, frequency of action myoclonus, and severity of action rnyoclonus. In the subscore scale
+
+
+
+
for spontaneous myoclonus the following 5 body areas were
considered: face, right and left arm, and right and left leg.
Each body area was scored as follows: 0 for no spontaneous
myoclonus, 1 for spontaneous myoclonus occurring only
during part of the day, 2 for spontaneous myoclonus occurring less frequently than once every 3 minutes, 3 for spontaneous myoclonus occurring every 1 to 3 minutes, or 4 for
spontaneous myoclonus occurring more often than once every minute. The subscore to assess the frequency of action
myoclonus was obtained by having the patient grasp an object with either hand 4 times and rated as follows: 0 for no
action-activated jerking, and 1, 2, 3, and 4 for action activated jerking occurring in 1 of 4, 2 of 4, 3 of 4, or in all
4 movements, respectively. The severity of action myoclonus
was assessed on the same test on a scale from 0 to 4 with
0, 1, 2, 3, and 4 representing no myoclonus, myoclonus that
never, occasionally, frequently, or completely interfered with
function, respectively. The latter two scores resulted from
the sum of the scores obtained for each hand. The functional
disability was scored, based on the simple task of drinking
a glass of water, by using the following rating scale: 0 for
no myoclonus, 1 for mild myoclonus, 2 for moderate interference, 3 for severe interference, and 4 for complete interference making impossible the task. The global impression of
disability was scored as follows: 0 for no myoclonus; 1 for
mild myoclonus not annoying the patient; 2 for moderate
myoclonus annoying the patient; 3 for severe myoclonus
causing distress; and 4 for marked myoclonus causing great
distress. To assess the treatment effect, pretreatment scores
were compared with those obtained on piracetam, using the
Wilcoxon two-sample rank-sum test. Tests were two-tailed
with significance being at 5%. Epistat software was used for
the analysis.
Results
Table 1 summarizes the clinical, neurophysiological,
and genetic findings of the 11 patients.
Genetics
Eight patients (2-5, 8-1 1) were shown to have a deletion extending more than 3 Mb on maternal chromosome 15ql1-13 as determined by high-resolution
banding, FISH, and molecular analyses. High-resolution banding and methylation pattern were normal in
Patient 7;but molecular analysis showed a small deletion involving loci D15Sl0, D15S113, and GABRB3
(GABRA5 was noninformative and D 15s156 was nondeleted). Patient 1 showed paternal uniparental disomy
for chromosome 15 as demonstrated by lack of maternal inheritance for GABRB3, GABRA5, LS6-1, 155,
and 85 and a normal FISH pattern with probes
GABRB3 and PML. Patient 6 also had paternal disomy for chromosome 15 and a 46,XYl47/XY,+inv
dup( 15)(pter+q11 :ql1+) karyotype, with a ratio of
40160, as reported by Robinson and colleagues [ l l ] .
This patient’s extra chromosome appeared to contain
mostly or only heterochromatic p arm material, which
should have no phenotypic effect [ l l ] .
Clinical and Edeo-ElectropbysiologicalAnalysis
of Myoclonus
Different manifestations of myoclonus were identified.
These could coexist in the same patient and often overlapped to form a continuum.
All 11 patients presented with very rapid jerking of
fluctuating amplitude, which caused a coarse distal
tremor combined with dystonic limb posturing. Jerks
occurred at rest in prolonged runs and were enhanced
by voluntary movement. EMG showed synchronous
bursting of agonist and antagonist muscles with a mean
frequency of 11 2 2.4 Hz (range, 5-24 Hz) and a
mean burst duration of 35 2 13 msec. Each burst
alternated with a period of EMG silence or near silence. Stable bursting at 10 to 15 Hz was accompanied
by dystonic limb posturing that persisted for 20 to 40
seconds, then ceased abruptly and reappeared spontaneously or upon voluntary movement. Jerking at rest
usually started in one hand or the face and spread homolaterally, or contralaterally, to homologous body
segments. Muscle recruitment followed a rostrocaudal
sequence passing down the brainstem and spinal cord
(Fig 1). Bilateral jerks were asynchronous, with a mean
latency of 8 +- 5 msec (Fig 2). Rest EEG activity consisted of a 5- to 7-Hz irregular background. Myoclonus
was accompanied by contralateral or bilateral asynchronous, rhythmic 5- to 10-Hz sinusoidal or sharp activity, which could be hemispheric or of frontocentral
predominance (Fig 3). Although this rhythmic EEG
activity was somatotopically related to the opposite part
of the body, on visual inspection of EEG traces the
individual waves did not appear to be time locked to
myoclonic potentials (Fig 4A). This impression was
confirmed by the fact that the 5- to 10-Hz activity
disappeared on burst-locked EEG averaging, studied in
5 patients (Fig 4B). In contrast, back-averaging generated a reproducible positive-negative biphasic transient
in the hemisphere contralateral to the jerking hand
(Figs 4C and 5). This reproducible waveform could be
identified in all patients and averages analyzed. Since
the EEG potential was time locked to EMG activity,
it showed exactly the same frequency as the latter and
was recognizable in averaged responses as a larger positive-negative wave within a sequence of waves. T h e
premovement positivity had a mean duration of 32.5
2 4.4 msec; peak latency was 19 & 5 msec when EMG
bursts were recorded from the belly of the wrist extensors. T o assess whether responses were truly consistent,
we used the coefficient of variability (CV), in terms of
the ratio between standard deviation of each sample of
measurements of peak latencies and relative mean [CV
= (SDImean) X 1001. A threshold of 5% was set to
Guerrini et al: Cortical Myoclonus in Angelman Syndrome 41
Table 1. Main Electroclinical and Genetic Characteristics on I I Patients with Angelman Syndrome
Age at
Patient
Seizure
No.lSex Onser
Age at
O n w of Age at
FBCM
Fullow-up
-10yographyl
E t G Ahnoimalitics
Frequency
of Myoclonus
M u l r i f o d , 8-15 H,,
MRIiCT
Cyrogenetics and FISH
Molecular
Normal
Normal
UPD
Mulrifocal, 8-15 Hz. Myoclonic abscnccs
rhythmic
Mild brain
atrophy
15qll-13 dcl
mat dcl > 3 M b
C3, (:4,5-8 H L
rhythm; diffuse SWc
Multifocnl, 5-10 H7,
arrhvthmir
Myoclonic abscnccs,
Mild hrain
ariophy
15qll-1.3 del
mat del
> 3 Mb
> 3 Mb
llM
-
7 yr
15 yr
C3. C4, 8-10 H r
2iF
hmo
jyr
25 y r
C3, C4. 5-10 H r
rhythni; diffuse SWs
31M
4
8 Inlo
18 y r
rhyrhni
1110
Cmctica
Assoiiarcd Srizuirr
rhythmic
c h i c , inyoilunii
irarur
4iF
5/F
61M
10 nio
3
V I
4 yr
7iF
5 yr
8iM
17 mo
3 yr
13 yr
Fp1, Fp2. 5-8 Hc
rhythm; diffuse SWs
Mulrifocal, 7-10 Hz,
rhythmic
Myoclonic
Perivenrricular
high signal
15qll-13 del
mat dcl
2 yr
27 y r
C3, C4, 5-8 H z
rhythm .irid SWr
Moltifncd, 7-10 HL,
My"Clo,,K
NornA
15q11-13 dcl
init
C3, (74,5-10 H L
ihythm, diffiise SWI
MultIfocal, 8-15 H7,
rhyrhniic
Myoclonic
Mild venrricular
aryninierry
'46,XYi47/XY,+inv
dup
UPD
2 yr
7 yr
del > 3 M b
~hyrhmic,sinusoidal
(l5)(pter+qll:qll+)
yr
28 y,
C3, C4, 5-10 Hr
rhyrhm a n d SW.y
Mulrifocal, 5-10 Hz,
rhythmic, rinusoidal
GTC, clan^,
myoclnnic status
Normal
Nor&
m.it dcl Sl 0,
S113,
2 yr
12 yr
(:3, C4. 5-10 IIZ
ihyrhiii and SWs
Multifocal, 8-15 Hz,
GTC,
Mild brain
15qll-13 del
mat
del
> 3 Mh
C3, C4, 5-10 H z
rhyrhm .and SWF
Mulrifoial, R-15 H L ,
rhyrhmic, sinusoidal
Myoclonic,
Normal
myoclonic s t a r u ~
15qll-13 dcl
mar del
> 3 Mh
C3, C4, 8-10
Mulrifocal. 8-15 Hz.
rhythmic, iinumidal
Chic
Mild brain
dtlophy
15qll-13 dcl
mat del
> 3 JMh
rhythm and SWs
C3, C4, 5-1 0 H,
r h y t h m , diffuse 5Ws
Mulrifocal, 8-15 Hz,
rhythmic, cinusaidal
Clonic, myoclonic,
Mild brain
atruphy
15qll-13 del
mar drl
> 3 Mb
12
GABRB3
9iF
4 mo
2 yr
20 y r
l0iM
4 mu
6 ino
3 yr
lllF
1 yr
12 y,
20 yi
Hz
rhythmic, sinusoidrl
ahsence srarus
myoclunic ,tatus
arrophy
'Genetic analyais reported by Robinson and collcaguec 11 11
EEG = e1ecrroencephalogr.iphic; FFK:M = fast-bursting cortical myvLlonux M N = nugneiic resonance imaging; CI' = computed tomogiaphy; FISI I = Ruoiescent in siru hyhridlration; Hz = Hertz; UPD = uniparenral disuiny; del = delerion: mat = maternal; Mb = megabase; SWs = ryiki and waver; GTC = generalized tonic clonic, Gen = generalized.
define the measurements as statistically reproducible.
Table 2 shows the high level of reproducibility for each
patient. Mean interhemispheric latency between peaks
of premyoclonus spikes was 8.3 t 2.6 msec (range,
5.5-12.3 msec) (see Fig 2). Silence-locked EEG averages did not generate a potential related to the EMG
silence in any of the 5 patients (Fig 6). Polygraphic
sleep recordings, obtained in 7 patients, showed attenuation and disappearance of myoclonus during sleep.
The age at onset of this fast-bursting myoclonus was
between age 8 months and 12 years. There was no
correlation of intensity of jerking with age. There was
a strict relationship between severity of myoclonus and
that of ataxia. Two patients experienced periods, lasting
weeks, during which myoclonus occurred bilaterally in
such a continuous and intense way that it could be
classified as myoclonic status.
Seven patients developed myoclonic seizures or
myoclonic absences between the ages of 4 months and
5 years. These were intractable and often presented as
status epilepticus up to the age 10 to 14 years. Afterwards they occurred sporadically in 3 patients and
ceased in the others. Myoclonias were represented by
rhythmic jerking accompanied by 2- to 2.5-Hz-spike
waves phase reversing over the frontorolandic regions
and often spreading to both hemispheres (see Fig 3).
Mean interhemispheric latency between peaks of premyoclonus spikes, studied in 4 patients, was 11.05 2
0.6 msec (range, 9.51-12.56 msec). The leading side
42
Annals of Neurology
Vol 40
No 1 July 1996
could vary from one discharge to another. EMG burst
duration, obtained from the rectified averages of 100
consecutive bursts time locked with the EEG spikes,
was 39 k 15 msec. The premyoclonus spikes had a
mean duration of 66.2 2 10.1 msec (range, 35-86.2
msec) and preceded the burst by -39 2 15 msec
(range, 20.3-57.3 msec). There was a wide withinpatient variability in delay (for example, Patient 3 had
the widest range, from 28.5 to 57.3 msec and Patient
2 the narrowest, from 30.5 to 43.9) with a coefficient
of variability > 10.8%. Bursts were followed by a postmyoclonic silence time locked with a slow wave of
equal duration (219 It 21 msec). Myoclonus involved
the limbs, more intensely in the proximal areas, and
could cause jerky drop attacks or head drops, or simply
cause spontaneous movements to become jerky. Since
jerks were mild at rest but markedly enhanced by
movement, they resembled action myoclonus.
Evoked Potentials
SEPs were normal in 1 patient and showed prolonged
central conduction times in 5. We did not observe giant SEPs or C-reflex in any patient.
Transcranial Magnetic Stimulation
MEPs showed increased CMCTs in 2 patients, low
amplitude responses in 5, and no abnormalities in 1
patient. TMS induced a post-MEP silent period (SP)
lasting 43 2 10 msec. These values were markedly
A
Masseter
0. Oris
Del t
c4
A
CZ
_I----J\II\*-
c3
L. Est
R.Est
LNPEPisa
(15~v
Flex
20 ms
I NPE- Pi sa
Fig 1. Putient 1. Rectified electromyogmphic activity. Average
of 30 spontaneous jerks of fast-bursting corticul myoclonus. All
muscles recorded from one side ure involved, following u rostrocuudul pattern of recruitment. This indicutes thut the
impulses generating the myoclonus puss down the bruinstem.
The masseter @fib cruniul nerve) is activuted before the orbicularis oris (seventh cruniul nerve), which is in turn uctivuted
before the more caudal muscles. 0. Oris = orbiculuris oris;
Delt = deltoid; Tric = triceps; Bic = biceps; Ext = wrist
extensors; Flex = wrist flexors.
shortened with respect to those obtained in controls
(135 2 37 msec). The EMG activity following the SP
resumed immediately the rhythmic bursting pattern of
the prestimulus period.
Neuroimaging
Results of neuroimaging are reported in Table 1.
Treatment of Myoclonus with Piracetam
Five patients treated with piracetam showed a marked
reduction in myoclonus with the drug being well tolerated. Daily doses ranged from 4.8 to 9.6 gm/day
(114-160 mg/kg/day). There was a significant improvement in all scores during piracetam treatment ( p
< 0.05). The antimyoclonic effect was stable after 4
to 12 months of treatment. Attempts to reduce CLB
comedication in 2 patients resulted in an intolerable
exacerbation of myoclonus. There was no exacerbation
of seizures during piracetam treatment in the 3 patients
with active epilepsy who received this drug.
100 ms
Fig 2. Putient 2. Buck-uveruged electroencephalogruphic
(EEG) activity (n = 100) preceding the onset of u briefelectromyogruphic (EMG) burst. E M G uctivicy in the Left wrist
extensor precedes thut o f the contruluterul homologous muscle
by about 8 msec. The sume time difference is found between
the premyoclonus EEG trunsients recorded fiom the right central (C4) und lefi centrul (C3) ureas.
Discussion
The 11 patients presented here showed the abnormal
jerky, tremulous, or dystonic motor pattern typical of
AS [6]. Since AS patients are severely mentally retarded
and frequently hyperkinetic, it may be difficult to recognize the individual components of the abnormal
movement. Using long-term video-EEG and polygraphic monitoring we observed that the movement
disorder was related to cortical myoclonus.
Most patients exhibited both myocloiiic seizures or
myoclonic absences and FBCM. Eight patients had experienced myoclonic seizures or myoclonic absences
sometime in their life. These seizure types occurred either as short attacks or as status epilepticus and consisted of transitory events during which habitual motor
behavior was disrupted and cortical spiking, time
locked with bilateral jerking, was demonstrable with
standard polygraphic procedures. In addition, all patients presented with almost continuous focal or multifocal fast jerking or twitching, often manifested as
dystonic limb posturing. Jerks were either spontaneous or action related and did not appear to be stimulus
sensitive. The typical pattern of myoclonus, consisting
of brief bursts occurring synchronously in agonist and
antagonist muscles at a mean frequency of 11 Hz was
observed in the EMG. The jerking involved mainly
the hands and face following a pattern consistent with
intrahemispheric cortical spread [ 191. Bilateral jerks
Guerrini et al: Cortical Myoclonus in Angelman Syndrome 43
Z.S.
25 yrs
INPE-Pisa
Fig 3. Patient 2. Surface electroencephalographic-electromyographic (EEG-EMG) polygrphic recording. Rhythmic 12- to 1 5 - H ~
myoclonus (fast-bursting cortical myoclonus [FBCM]) involving all muscles recorded is acconzpanied by difise, rhythmic, 5- t o
8-Hz sharp EEG activiry. A discharge of generalized polyspike and wave complexes, lasting 2.5 seconds, is accompanied by rhythmic EMG bursts of 2 t o 4 myoclonic potentials, each time locked with the spikes. This generalized discharge accompanies a short
myoclonic absence. AJter the absence, both EEG and EMG resume the rhythmic pattern of FBCM, which disappears 3 seconds
later on the right hemisphere and l e j muscles, whereas it persists f i r 3 more seconds contralaterally.
were never synchronous as observed in minipolymyoclonus [2O], but they had a latency consistent with
interhemispheric transfer [ 191. Myoclonus was accompanied by rhythmic, somatotopically related 5- to 10Hz EEG activity well recognizable on conventional recordings, similar to that described by Kelly and associates [21] in action myoclonus. By back averaging EEG
recordings related to onset of the EMG burst, in 5
patients, this rhythmic activity disappeared, indicating
that it was not time locked to the muscle discharges.
O n the other hand, back averaging revealed a reproducible EEG potential arising from the contralateral
sensorimotor cortex and preceding the EMG burst by
a short interval appropriate to conduction through corticomotoneuronal pathways [ 2 2 ] .Negative myoclonus
[23]was ruled out because back averaging EEG activiry
related to the onset of the silent periods between two
bursts did not reveal a cortical potential. The influence
of a long-loop was also excluded, since the C-reflex
could not be elicited. Therefore, all patients presented
with a type of myoclonus resembling cortical tremor
44 Annals of Neurology
Vol 40
No 1 July 1996
[24, 251, but with some peculiarities that make it
unique to AS, which we have designated as FBCM. A
transition into a peculiar form of myoclonic status,
with bilateral 12- to 15-Hz jerking was seen in 2 patients, which strengthens the evidence for a continuum
of manifestations within the spectrum of cortical tnyoclonus [26, 271.
We found the time between cortical spiking and
subsequent EMG burst during myoclonic seizures or
myoclonic absences to be considerably longer than during focal jerking (39 i- 15 vs 19 i- 5 msec). Since in
both instances the delay was consistent with conduction in rapidly conducting corticospinal pathways, the
difference in latency could be attributed to the time
required by myoclonic activity to generalize throughout the motor cortex via corticocortical connections
[ 19, 281. Because these patients presented multifocal
jerking, the cortical area from which myoclonic activity
could arise and spread may have varied from one generalized jerk to another. It follows that the first muscles
to be activated during generalized myoclonus might
F4
100 ms
P4
B
F4
I5vV
L. Ext
I25 PV
cz
100 ms
c3 -----.&-+d
L. Ext
125 pv
INPE-Pisa
TNPE-Pisa
100 ms
Fig 4. Patient 2. (A) Suface electroencephalogvaphic-electromyographic (EEG-EMG) recording reproduced after E M G
has been rectijed. Rhythmic EEG activity is not time locked
to E M G bursts. (B) After 20 averages of EEG activity preceding the onset of the E M G burst, rhythmic EEG activity disappears and is replaced by more irregular wavefoovms. (C) After
80 averages, a positive-negative EEG transient, time locked
to E M G onset, is well recognizable.
vary from one jerk to another, and differ from those
recorded. The wide within-patient variability in latencies of generalized myoclonus (CV > 10.8%) seems
to confirm this possibility. We demonstrated interhemispheric corticocortical spread of myoclonic activity based upon right to left latencies of both EMG
burst and cortical correlates. Unfortunately, we could
not record from leg muscles of these hyperkineric patients, and we therefore could not measure variations in
latency of activation of widely separated muscle groups,
providing timing evidence for intrahemispheric spread
(19, 281.
Piracetam has proven to be an effective and safe drug
for symptomatic treatment of cortical myoclonus [ 18,
291. Used in association with VPA or benzodiazepines
in 5 patients, piracetam produced considerable overall
functional improvement. This resulted from a reduc-
100 Ins
Fig 5. Patient 3. Back-averaged electroencephalographicactivity (n = 100; Oz reference; rectijed electromyograrn) in
relation to a spontaneous jerk involving lefi wrist extensor
muscles (L. Ext). A positive-negative potential, well recognizable over tbe C4 electrode, precedes the jerk by 20 msec.
tion in myoclonus, as well as from improvement in
dystonic limb posturing and ataxic gait. The mechanism of action of piracetam in cortical myoclonus is
not known, but it is probably not due to modulation
of the effect of other antimyoclonic drugs since it is
also effective in monotherapy [18]. However, in 2 of
our patients we were unable to switch to piracetam
monotherapy because myoclonus worsened during
benzodiazepine withdrawal.
The multiple small twitches typical of FBCM may
originate from small distinct areas within a hyperexcitable motor cortex. These areas could generate multiple
small spikes leading to tremulous muscle activity [30].
Since we found neither giant SEPs nor C-reflex, it is
conceivable that FBCM is produced by discharges originating spontaneously in the motor cortex [31], without simultaneous involvement of the parietal cortex.
However, we cannot exclude sensitivity to nontested
sensory inputs such as muscle stretch, touch, and pressure [32]. The short post-MEP-SPs observed in our
patients after TMS would indicate that central motor
Guerrini et al: Cortical Myoclonus in Angelman Syndrome 45
Table 2. Electrophysiolozic Findings in Fast-Burstin‘? Cortical Myoclonus
EMG Burst
Back-Averaged EEG
Latency of Premovement
Positivity (msec)
Patient No.
Positivity
Duration (msec)
(Hz)
Duration
(msec)
Mean
SD
cv (Yo)
Mean
SD
Mean
SD
Mean
SD
-23.19
-22.14
-21.21
- 18.24
-13.17
0.18
0.21
0.32
0.1 0
0.15
0.78
0.95
1.51
0.55
1.14
31.6
30.5
1.5
0.5
0.2
0.5
1.5
12.0
12.8
10.7
9.1
11.7
2.6
0.5
0.2
0.5
1.5
25.0
26.0
48.6
47.0
28.0
1.o
1.o
1.5
0.9
1.0
CV = (SD/mean) X 100; threshold at 5%.
electromyographic; CV
EEG = electroencephalographic; EMG
40.4
30.0
30.3
=
inhibitory mechanisms are impaired [33] and provide
further evidence that the motor cortex is hyperexcitable.
The only neuropathologic study from an AS patient
has revealed marked cerebellar atrophy with loss of
Purkinje and granule cells with extensive Bergmann’s
gliosis 1341. Neurochemical study of the abnormal cerebellar cortex showed markedly reduced GABA content, possibly related to failure to develop or a loss of
Purkinje cells and inhibitory GABAergic interneurons.
Although these findings should be considered cautiously because that patient had received phenytoin
treatment, loss of inhibitory cerebellar influence on
motor cortical function is a possible cause of cortical
myoclonus [ 311.
The majority of AS patients have a large deletion
on maternal chromosome 15ql1- 13, which eliminates
a cluster of GABA, receptor genes (p3, a5, ~ 3 )A.
similar situation is also observed in the mutant mouse
pcp (p locus cleft palate), which exhibits a chromosomal deletion that likewise eliminates the same
GABA, receptor cluster [35].This deleted murine region is considered to be syntenic to the one associated
with AS in humans [35]. The mutant mouse pcp displays seizure activity, tremor, and a jerky gait [36].A
significant reduction ( 6 0 4 0 % ) in benzodiazepine
binding in most brain regions of this mouse has also
been observed [35]. A similar receptor abnormality
may be present in AS, resulting in a decrease in the
inhibitory control mechanisms exercised by GABAergic
nonpyrainidal cells. These cells inhibit intrinsically
bursting neurons located in human neocortical layers
IV and V, which generate a stereotyped clustering of
action potential bursts with a frequency of 5 to 15 Hz,
in response to intracellular threshold stimuli [37].
Since this frequency is similar to the spiking accompanying FBCM, it is possible that cortical myoclonus in
AS results from enhanced firing properties of intrinsically bursting neurons. Studies using the GABA, recep-
46
Frequency
Annals of Neurology
Vol 40
No 1 J d y 1996
coefficient of variability.
c4
L. Ext
I 25 $7
L. Flex
I NPE- Pi sa
loo Ins
Fig 6 Patient 3. Back-averaged electroencephalographic
(EEG) activity (n = 100; Oz reference; rectified electromyogram) in relation to the onset o f the EMG silence following a
burst. Averages do not generate a potential related to the
silence. The premyoclonic potential is still visible, became it is
time locked with the burst immediately preceding the EMG
silence. Since myoclanic bursts and postmyoclonic silences are
temporally related and have a high-frequency rhythmicity,
back-averaging EEG activiq related to one of the two does
not allow complete elimination of EEG activity related t o the
other. L. = lefi; Ext = wrist exteyisors; Flex = wi+istJexors.
tor inhibitor penicilline have demonstrated that cortical
layers IV and V have the lowest threshold for epileptogenesis [38], Numerous experimental [39-411 and
clinical data [42, 431 demonstrate that loss of GABAergic inhibition can produce myoclonus, especially of
cortical origin.
The observation that the deleted region in AS is always of maternal origin suggests that this region is subject to genetic imprinting [44].The presence of FBCM
in our 2 patients with uniparental disomy, suggests that
the gene(s) implicated with FBCM is also an imprinted
phenomena. Furthermore, FBCM is fully expressed
in a patient with a microdeletion restricted to 3-21
(D15S10), LS6-1 (D15S113), and GABRB3, making
it probable that a genic abnormality responsible for ASassociated myoclonus is localized in this small region.
GABA fi3 is [he only gene of known funct-ion mapped
to this region [45, 461. To demonstrate whether this
gene plays a role in FBCM, it will be necessary to
perform neurophysiological studies in those rare patients bearing deletions in which the p3 gene is apparently intact [47,
481 and in those where the p3 gene is
deleted while a5 is not [46, 491. However, one cannot
exclude the possibility that nondeleted genes are inactivated and that a yet unidentified gene(s) in the AS
deletion region may be responsible for AS-associated
myoclonus. That we found the same pattern of myoclonus in 5 AS patients with no demonstrable genetic
abnormality (not included in this study) indicates thzt
myoclonus is similarly expressed in deleted and nondeleted patients [7,101.
In our experience, the powerful antimyoclonic and
antiabsence action of benzodiazepines, which is based
on their GABAergic properties, is also confirmed in
AS. Based on this rationale, new antiepileptic molecules designed €or enhancing GABAergic inhibition,
such as Vigabatrin (VGB) (a GABA-T blocker) or Tiagabine (TGB) (which blocks GABA reuptake), could
in theory also be effective in treating AS-associated seizures. However, in experimental models of absence seizures, VGB has shown negative effects [50]. Clinical
trials have confirmed such findings and have also
shown that myoclonic seizures may worsen with VGB
1511. No experimental or clinical experience on absence
or myoclonic seizures has been gathered with TGB as
yet [52].Therefore, a t the current state of‘ knowledge,
there is no convincing evidence showing whether these
new drugs could be effective in treatment of seizures
in AS.
In conclusion, our findings demonstrate that AS patients present with a continuum of manifestations
within the spectrum of cortical myoclonus. FBCMassociated jerking causes severe disability and is a major
component of the motor pattern observed in AS.
Treatment with pitacetam, used as an add-on drug,
induced considerable functional improvement and
should be considered in those AS patients in which
cortical myoclonus is a prominent manifestation.
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