ARTICLE
Auteur(s) : Julia Larch, Iris Unterberger, Gerhard Bauer,
Johannes Reichsoellner, Giorgi Kuchukhidze, Eugen Trinka
Department of Neurology, Medical University
of Innsbruck, Austria
Article reçu le 9 Avril 2009, accepté le 18 Novembre 2009
Juvenile myoclonic epilepsy (JME) is one of the most common age
related idiopathic generalized epilepsies (IGEs; Janz, 1997). The
syndrome is characterized by myoclonic seizures (MS), generalized
tonic clonic seizures (GTCS) and absence seizures (AS). MS appear
as shock-like jerks, affecting mainly shoulders and arms. They may
occur as a single myoclonic jerk or repetitivelywith irregular
frequency and varying intensity. Although they are usually
bilateral, some asymmetries may be observed. Patients may be fully
conscious or experience some impairment of consciousness to a
variable degree (Janz, 1957a; Christian, 1980). Seizures are
clearly related to the sleep/waking cycle and occur predominantly
in the morning hours after awakening or in drowsy state during the
day. MS may present frequently as repeated jerks lasting for
minutes with or without transition to a GTCS. Very rarely, they may
last for more than 30 minutes fulfilling the formal criteria
(Walker et al., 2005) for myoclonic status epilepticus (MSE),
termed “impulsive-petit mal status” in the original
descriptions.
The occurrence of MS and MSE is mostly provoked by trigger
factors such as sleep deprivation, alcohol intake, non-compliance
with or inappropriate antiepileptic drugs (AEDs) (Thomas
et al., 2006; Panayiotopoulos et al., 1994). However, MSE
is seemingly a rare event in JME. Available literature is limited
to single case reports or small series (Badhwar et al., 2002;
Terzano et al., 1978; Grüneberg and Helmchen, 1969; van
Leeuwen et al., 1969; Schneemann et al., 1969). We aimed
to analyze incidence, precipitating factors and clinical course of
MSE by studying a cohort of patients with JME from a large
outpatient epilepsy clinic.
Patients and methods
In this retrospective hospital based study we reviewed all patients
with JME (n = 247) for a history of MSE. Patients were treated at
the outpatient epilepsy clinic, Department of Neurology, Medical
University Innsbruck, Austria between 1970 and 2007.
The diagnosis of JME was based on the criteria of the
International League against Epilepsy (ILAE) (Commission on
Classification and Terminology of ILAE, 1989). MSE was diagnosed if
myoclonic jerks lasted for at least 30 minutes (Walker
et al., 2005). In six of seven patients the EEG during MSE was
available for re-evaluation. For one patient only, a written report
with a clear description of ongoing ictal activity was
available.
We analyzed sex, age at time of MSE, age at seizure onset,
seizure types, EEG and CT/MRI findings. Seizure outcome refers to
the last visit at the outpatient clinic. We extracted all available
data from patients’ charts and reviewed available EEGs during MSE
and the responsiveness to AEDs, as well as the course of the
disease after the MSE.
Statistical analysis
Data processing and analysis was performed with SPSS 12.0 and
EXCEL for Windows 11.0. We used descriptive methods (average values
and standard deviations). Incidence rate in person years was
calculated in relation to the total number of patients at risk
observed over time.
Results
Study population
Seven of 247 JME patients (five women and two men) had a
history of MSE, yielding a percentage of 3% or an incidence of
3.2/1,000 patient years. The median age at the time of MSE was
31 years (range 17-73). The mean duration of epilepsy before
MSE was 26.4 (± 17) years and median was 26 years (range
10-58). The median age at seizure onset was 14 years (range
3-35). Four out of seven patients had three seizure types (MS, AS,
GTCS). Three patients had only MS and GTCS. Demographic data are
summarized in table 1.
Table 1 Clinical characteristics and treatment of
MSE.
|
Patient No (sex, age at time of MSE)
|
Age at seizure onset
|
Seizure types
|
AED at time of MSE (mg/day)
|
Semiology of MSE
|
Precipitating factors
|
Treatment of MSE (mg/day)
|
AED after MSE (mg/day)
|
Repeated MSE
|
|
1 (M, 31)
|
14
|
MS, GTCS, AS
|
None
|
MS with GTCS
|
AED withdraw
|
CLZ (4) IV
|
VPA (900)
|
Lost for FU
|
|
2 (W, 62)
|
35
|
MS, GTCS, AS
|
PHT (750)
|
GTCS with myoclonic absence status
|
Inappropriate treatment (PHT)
|
DZP (20) IV
|
VPA (900)
|
No
|
|
3 (W, 54)
|
17
|
MS, GTCS, AS
|
CBZ (600)
|
MS with GTCS
|
Inappropriate treatment (CBZ)
|
DZP (20) IV
|
VPA (1500)
|
No
|
|
4 (W, 17)
|
7
|
MS, GTCS
|
None
|
MS only
|
AED withdraw
|
DZP (20) IV
|
VPA (1000)
|
No
|
|
5 (W, 29)
|
3
|
MS, GTCS, AS
|
VPA (2000) PRM (750)
|
GTCS with myoclonic absence status
|
-
|
CLZ (4) PO
|
VPA (2500) PRM (750)
|
No
|
|
6 (W, 73)
|
15
|
MS, GTCS
|
None
|
MS with GTCS
|
AED withdraw
|
LZP (2) IV
|
VPA (1500)
|
No
|
|
7 (M, 23)
|
13
|
MS, GTCS
|
TPM (400)
|
MS only
|
AED withdraw Alcohol intake
|
LZP (2) IV
|
TPM (500)
|
Yes (same clinical type)
|
Semiology of MSE
According to the observed seizure semiology, we distinguished three
types of MSE:
- – Type (1) only MS (n = 2): in one patient upper and
lower extremities were affected, only upper extremities were
affected in the other patient. Consciousness was not impaired in
these two patients;
- – Type (2) MSE with GTCS (n = 3): in three patients MSE
was observed immediately after termination of a GTCS. It was
impossible to determine whether the GTCS preceded MS since
consciousness was impaired in these patients. In one of the
patients, myoclonic jerks involved upper and lower extremities and
in the other two cases only upper extremities were affected. In all
patients consciousness was impaired;
- – Type (3) GTCS with myoclonic absence status (n = 2):
consciousness was clearly impaired in a discontinuous way. In both
cases, the jerks were limited to the upper extremities without
involvement of head or lower extremities.
Ictal EEG patterns
An EEG during MSE was available in six out of seven patients (figures 1-3).
Generalized polyspike-wave activity and spike-wave activity was
recorded in all EEGs. In three patients, generalized epileptiform
discharges presented repeatedly throughout the whole recording with
changes in intervals and morphology (figure 1). The EEG during
myoclonic absence status was characterized by bursts of generalized
3-4 Hz spikes and waves as well as polyspikes and waves during
the whole recording time (figure 2). In one patient,
epileptiform activity occurred periodically with short
interruptions (figure
3). One patient’s EEG exhibited an asymmetry of generalized
epileptiform discharges with the higher amplitude over the left
hemisphere.
Treatment
At the time of MSE, chronic AED treatment consisted of valproic
acid (VPA) for two patients, and topiramate (TPM), phenytoin (PHT)
and carbamazepine (CBZ) for three other patients, respectively. PHT
and CBZ treatments were started several months before first
admission to our institution. For two of the seven patients, drugs
were withdrawn three and four years, respectively, before the
occurrence of MSE.
MSE ceased in six patients treated with intravenous
benzodiazepines (diazepam, clonazepam and lorazepam); in one
patient oral treatment with clonazepam was sufficient. After MSE,
six patients were treated with VPA and one with TPM.
Details of treatment are given in table
1.
Precipitating factors
In six out of seven patients, precipitating events were identified.
Two out of six patients deliberately discontinued chronic
antiepileptic treatment due to non-compliance, and for one of these
patients, additional triggers, aside from AED discontinuation, were
alcohol intake and sleep deprivation.
Two other patients stopped medication despite ongoing seizures
and medical advice for three and four years prior to MSE,
respectively. In these last two cases, an immediate triggering
factor was not evident.
The other two patients received inappropriate treatment (CBZ,
PHT) at the time when MSE occurred.
Course of epilepsy after MSE
For one of the seven patients, follow-up was discontinued six
months after MSE. The other six patients had a median follow-up of
10 years (range 2-19). Only one patient had multiple episodes
of MSE over the years. Two of six patients were free of seizures at
the last follow-up. Four had recurrent GTCS and MS. In two cases
this was presumably due to non-compliance. The remaining two
patients had rare GTCS and MS. After MSE, none of the patients had
any neuropsychiatric disorders during the follow-up time.
Discussion
MSE was observed in 3% of our population with JME. The incidence
was comparatively low with a rate of 3.2/1,000 patient years.
Precipitating factors were identified in six out of seven patients.
AED withdrawal, inappropriate treatment with CBZ and PHT, as well
as sleep deprivation, were the most important factors. MSE was
readily controlled in all patients with low doses of intravenous
benzodiazepines and none of them experienced a deterioration in the
course of the seizure disorder or related psychiatric disturbances
after MSE. In contrast to postanoxic myoclonic status, which is
most often refractory, MSE in the context of JME is easy to treat.
In addition to benzodiazepines, intravenous valproate or
levetiracetam are treatment options which have been used
successfully in open uncontrolled series (Trinka, 2007; Trinka and
Dobesberger, 2009). Previous studies on MSE in patients with JME
report a widely varying frequency ranging from 1.4% (Dziewas
et al., 2002; Panayiotopoulos et al., 1994) to 42% of
patients (Asconape and Penry, 1984). These discrepancies might be
explained by several factors such as small sample size or selection
bias. The occurrence of MSE is clearly associated with trigger
factors. In the present study, two out of seven patients were each
treated with either CBZ or PHT which are considered as
inappropriate AEDs for the treatment of JME. In other retrospective
series, 19 out of 28 (68%) patients with JME who were
treated with CBZ and six out of 16 (38%) who were treated with
PHT, experienced seizure aggravation, which resulted in two
patients with MSE (Genton et al., 2000). Another retrospective
series reported 14 patients with absence status epilepticus or
MSE. Four JME patients in this series were treated with CBZ and
lamotrigine (LTG), which may also aggravate seizures in IGE (Thomas
et al., 2006). In another small series, three patients
developed absence status epilepticus with mild myoclonic components
after replacement of VPA with LTG. After reinstitution of VPA, the
clinical course was favourable (Trinka et al., 2002). Drug
withdrawal is another important triggering factor. In a prospective
study of patients with JME, only one out of 66 (1.5%) had MSE.
This patient was among the seven who underwent discontinuation of
treatment (Panayiotopoulos et al., 1994). In our study, four
out of seven patients did not take any AED at the time of MSE (two
of them due to non compliance leading to acute withdrawal and two
due to non-compliant withdrawal, years before MSE). Semiology of
MSE can be variable and three types of MSE can be distinguished.
- – Patients with bilateral myoclonic jerks synchronous
with generalized polyspike-wave discharges on EEG and without
impairment of consciousness represent the form of MSE designated as
“impulsive petit mal status epilepticus” (SE) or “typical MSE”
(Thomas et al., 2006; Dziewas et al., 2002; Christian,
1980; Janz, 1957b). In the latest classification of SE, typical MSE
is termed “myoclonic status epilepticus” (Engel, 2006).
Preservation of consciousness is emphasized. In the recent
definition of the ILAE, MSE can also occur in a variety of other
epilepsy syndromes like Dravet syndrome or non-progressive
myoclonic epilepsies in infancy. However, MSE definition by the
ILAE does not include status myoclonicus in coma after
cardiorespiratory arrest.
- – MSE may be preceded, followed or interrupted by a
GTCS. The consciousness of these patients is mostly impaired after
GTCS. A condition with impairment of consciousness and mild
myoclonic jerks after a GTCS can be misinterpreted as postictal
confusion. A routinely performed EEG can detect the ictal
nature and govern parenteral AED treatment of SE (Bauer
et al., 1982; Bauer, 1975).
- – Absence status with superimposed myoclonic jerks is
another form of SE. Jerks can be very prominent in the eyelids with
variable involvement of the upper extremities. Consciousness is
moderately impaired in these patients. Myoclonic jerks are rarely
time-locked with polyspike-wave discharges on EEG (Engel, 2006).
The boundaries between MSE and myoclonic absence status and their
relationship to different epilepsy syndromes are not well
delineated and they may represent a biological continuum.
A combination of type 2 and 3 of SE can also be observed and
this has been referred as “atypical MSE” and might have important
therapeutic consequences (Schneemann et al., 1969; Thomas
et al., 2006).
There are limited data about sequelae of MSE in JME. Cerebral
damage caused by non-convulsive SE is discussed controversially
(Shorvon and Walker, 2005). In a case report, Grüneberg and
Helmchen (1969) described the occurrence of paranoid psychosis
after an untreated MSE which lasted for days. The patient had
frequent MSE but recovered completely. In contrast, none of our
patients had psychiatric problems or cognitive deficits after
MSE.
In conclusion, MSE in JME is a rare event related most often to
inappropriate drug treatment. MSE in JME is easily controlled by
benzodiazepines without any following permanent sequelae.
Disclosure
None of the authors has any conflict of interest to disclose.
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