Epilepsia, 44(Suppl.
11):27–37, 2003
Blackwell Publishing, Inc.
C International League Against Epilepsy
!
Treatment Strategies for Myoclonic Seizures and Epilepsy
Syndromes with Myoclonic Seizures
∗ James W. Wheless and †Raman Sankar
∗ Department of Neurology and Pediatrics, Texas Comprehensive Epilepsy Program,University of Texas – Houston, Houston, Texas;
and †Department of Neurology and Pediatrics, Mattel Children’s Hospital at UCLA,University of California – Los Angeles,
Los Angeles, California, U.S.A.
Summary: Despite the availability of numerous treatment op-
tions, the diagnosis and treatment of myoclonic seizures con-
tinue to be challenging. Based on clinical experience, valproate
and benzodiazepines have historically been used to treat my-
oclonic seizures. However, many more treatment options exist
today, and the clinician must match the appropriate treatment
with the patient’s epilepsy syndrome and its underlying etiol-
ogy. Comorbidities and other medications must also be consid-
Single myoclonic jerks in patients with epilepsy have
long been recognized. Myoclonus comes from the Greek
myo, meaning muscle, and klonus meaning turmoil. While
this term was used by the Greeks to describe the erratic
movement often seen with myoclonic jerks, it aptly de-
scribes the current state of therapy for myoclonic seizures
and myoclonic epilepsies. Jeavons addressed the prob-
lem of nosology of the myoclonic epilepsies in 1977 (1),
suggesting that myoclonic epilepsies were as difficult to
classify as they were to treat. Myoclonus has become a de-
scription for many semiologically and nosologically dif-
ferent conditions. The treatment of myoclonic epilepsies
is still problematic 25 years later (2–7).
One task for clinicians is to establish whether or not
the paroxysmal episodes that the patient is experiencing
constitute epilepsy. The first step in this process is to
determine if a reversible etiology is present. The physi-
cian is then confronted with a clinical conundrum. My-
oclonus may only be one part of an epilepsy syndrome,
and several problems regarding its treatment exist: (a) not
all antimyoclonic drugs are antiepileptic, (b) only some
antiepilepsy drugs (AEDs) are antimyoclonic, (c) many
myoclonic epilepsies are refractory to treatment, and
(d) some AEDs may exacerbate myoclonus or induce my-
Address correspondence and reprint requests to Dr. J. W. Wheless at
Texas Comprehensive Epilepsy Program, University of Texas – Hous-
ton, 6431 Fannin St., Suite 7044, Houston, TX 77030, U.S.A. E-mail:
James.W.Wheless@uth.tmc.edu
27
ered when making decisions regarding treatment. Rarely, some
antiepileptic drugs may exacerbate myoclonic seizures. Most
epileptic myoclonus can be treated pharmacologically, but some
cases respond better to surgery, the ketogenic diet, or vagus nerve
stimulation. Because myoclonic seizures can be difficult to treat,
clinicians should be flexible in their approach and tailor therapy
to each patient. Key Words: Myoclonic seizures—Epilepsy—
Antiepileptic drug therapy.
oclonic seizures. If no reversible etiology is found, the
myoclonus, which is one component of an epilepsy syn-
drome, can be treated along with the syndrome. Accurate
definition of a patient’s epilepsy syndrome is an important
factor in treatment. Comorbidities and other medications
must also be considered when making decisions regarding
treatment.
Historically, valproate (VPA) and clonazepam (CZP)
have been used to treat myoclonic seizures based on
clinical experience. Both drugs work by promoting γ -
aminobutyric acid (GABA) action in the brain. However,
many more options are available today, and clinicians
must match the appropriate treatment with the epilepsy
syndrome and its underlying etiology. Most epileptic my-
oclonus is treated medically, but some cases may respond
to surgery, the ketogenic diet, or vagus nerve stimulation.
Animal models of myoclonic seizures have played a
role in evaluating the possible efficacy of drug therapy for
treatment of human myoclonic seizures. Animal models
can be classified as those involving provoked seizures and
those involving genetic models. Provocation of seizures
in the former is commonly accomplished by chemical
or electrical means, although other means, such as hy-
poxia and intermittent light stimulation, have also been
used. Classic pharmacologic screening involving rodents,
as used by the Anticonvulsant Screening Project of the
National Institute of Neurologic Disorders and Stroke, has
produced inconsistent information for predicting the effi-
cacy of potential therapeutic agents against myoclonus.
28 J. W. WHELESS AND R. SANKAR

With earlier-generation AEDs, models were only some-

what predictive of efficacy. Only CZP and VPA have
demonstrated efficacy in animal models for protection
against all three seizure provocations involving subcuta-
neous pentylenetetrazol, bicuculline, and picrotoxin (8).
Ethosuximide (ESM), which was only marginally ac-
tive against bicuculline, has been shown not to be a
useful antimyoclonic AED (8,9). Phenytoin (PHT) and
carbamazepine (CBZ) clearly distinguished themselves
as agents that were mainly active in the maximal elec-
troshock model (10). Among new-generation AEDs, fel-
bamate (FBM) has shown clinical utility in a variety
of myoclonic seizures and was also active in protect-
ing rats against subcutaneous pentylenetetrazol, subcu-
taneous bicuculline, and subcutaneous picrotoxin (11).
Gabapentin (GBP), the next agent to arrive on the United
States market, has been shown to be ineffective in sub-
cutaneous bicuculline and picrotoxin provocations in the
rodent (12) and appears to be clinically useful only for par-
tial and secondarily generalized seizures (13). Vigabatrin
(VGB), like GBP, has not demonstrated significant activity
against subcutaneous bicuculline or picrotoxin challenge,
and is not a clinically useful agent for most syndromes
involving myoclonic seizures (14). Experience with GBP
highlights another difficulty in the use of animal mod-
els for screening compounds to treat myoclonus. Kan-
FIG. 1. A: Baboon in the primate chair for EEG recording.
thasamy et al. (15) found GBP to be antimyoclonic in a B: EEG demonstrating a photomyoclonic response in Papio
posthypoxic rodent model, but not for myoclonus induced hamadryas anubis, cynocephalus, an animal model for photosen-
by administration of p,p# -DDT (1,1,1-trichloro-2,2-bis(p- sitive epilepsy. (Figure courtesy of Dr. C. Akos Szabo, University of
Texas Health Sciences Center, San Antonio, TX, U.S.A., reprinted
chlorophenyl)ethane). with permission.)
Experience with other new-generation AEDs has also
revealed many inconsistencies. Lamotrigine (LTG), which
has an animal testing profile resembling that of PHT (16), in the baboon (25), suggesting that the baboon model also
has demonstrated clinical utility for treating some patients has limitations in its ability to predict the clinical utility
with juvenile myoclonic epilepsy (JME) (17). Paradox- of test AEDs. This model is apparently not routinely used
ically, LTG is also known to exacerbate myoclonus in in screening, and many of the new-generation AEDs have
some patients (18–20). Topiramate (TPM), another new- no published literature describing their use in this model.
generation agent, has been shown to be ineffective in Another well-characterized genetic model involves the
blocking chemically induced seizures (21). Nevertheless, tottering mouse. The tg locus causes a delayed-onset re-
this medication may be of value in treating a variety of cessive neurological disorder in the mouse, featuring a
syndromes that involve myoclonus, as is discussed later stereotyped triad of ataxia, intermittent focal myoclonic
in this article. seizures, and bursts of generalized 6- to 7-Hz spike waves.
The most extensively described genetic model of This model has not been routinely used in screening for
epilepsy involves Papio papio, the photosensitive baboon AEDs; hence, its reliability for this purpose is unknown.
(Fig. 1A). Killiam et al. (22) first reported that when these Other genetic models of inherited myoclonus include a
animals were subjected to intermittent light stimulation, disorder of the inhibitory glycine receptor that results in
paroxysmal discharges in the form of spikes and waves spontaneous and stimulus-sensitive myoclonus in Polled
or polyspikes and waves resulted (Fig. 1B). Behaviorally, Hereford calves (26) and spontaneous and photically in-
bilateral and synchronous myoclonic jerks appeared and duced myoclonus in a mutant strain of Fayoumi chickens
were followed by generalized convulsive seizures. The in- (27). The possible importance of the glycine receptor in
volvement of the GABAergic system in this model was de- some myoclonic disorders is highlighted by the recent de-
scribed in detail by Meldrum and Wilkins (23). This model velopment of a transgenic mouse model of hyperekplexia,
correctly predicted GBP’s lack of efficacy in human my- which involves a mutation in the gene for the α 1 sub-
oclonic epilepsies (24). However, VGB was shown to be unit of the glycine receptor (28). However, the cost and
effective in blocking photically induced epileptic activity inconsistent availability of these animals precludes their

Epilepsia, Vol. 44, Suppl. 11, 2003

 MYOCLONUS TREATMENT STRATEGIES
routine use for developing highly specific antimyoclonic
drugs. Economic forces continue to drive the development
of AEDs for partial seizures, with subsequent adoption of
some AEDs to treat myoclonic seizures based on clinical
experience.
No controlled clinical trials have solely evaluated the
efficacy of treatment for myoclonic seizures; rather, they
have evaluated the effect of treatment on epilepsy syn-
dromes that may include myoclonus. This practice has
resulted from the difficulty in accurately quantifying my-
oclonic seizures before and after treatment in controlled
clinical trials. This limitation must be acknowledged when
evaluating drug treatment strategies for myoclonic epilep-
sies. In this review of treatment options, the American
Academy of Neurology Quality Standards Subcommit-
tee practice guidelines (29) are used to classify the levels
of evidence for each treatment. These recommendations
are based on the following levels of evidence for thera-
peutic modalities: (a) class I—controlled clinical trials;
(b) class II—case-controlled and cohort studies; and (c)
class III—evidence provided by case series, case reports,
and expert opinions. For most epilepsy syndromes with
myoclonic seizures, the controlled trial data (class I evi-
dence) only applies to the overall treatment of the epilepsy
syndrome, not specifically to the myoclonic component.
As a result, most information presented in this article is
based on class II or class III evidence for the treatment of
myoclonic seizures. Additionally, all the information pre-
sented herein regarding therapies that may cause exacer-
bation of myoclonic seizures is based on class III evidence
(typically case series).
EPILEPSY SYNDROMES
WITH MYOCLONIC SEIZURES
Syndromes of infancy and early childhood
Myoclonic seizures that begin in infancy are typi-
cally associated with both poor response to treatment and
poor ultimate prognosis (3). Included in this category are
early myoclonic encephalopathy (neonatal myoclonic en-
cephalopathy), infantile spasms, and severe myoclonic
epilepsy in infancy (Dravet syndrome). Benign myoclonic
epilepsy of infancy is an exception in that it can have a
good response to treatment and a favorable prognosis. For
infants and young children, there are few conditions that
fall between these two ends of the spectrum.
Massive or axial bilateral myoclonias are the myoclonic
features of early myoclonic encephalopathy. This rare syn-
drome has onset during the first month of life and is often
fatal by 1 year of age. The electroencephalogram (EEG)
in patients with this condition reveals a burst-suppression
pattern and may evolve toward typical hypsarrhythmia. No
controlled clinical trials have investigated the treatment of
early myoclonic encephalopathy. Treatment options are all
based on anecdotal reports, and although drug therapy has
29
demonstrated some efficacy, response to treatment is typ-
ically poor and seizure freedom is rarely achieved. None
of the conventional AEDs, adrenocorticotropic hormone
(ACTH) gel, prednisone, or pyridoxine has been effec-
tive in treating this syndrome (30). The myoclonias of this
syndrome gradually decrease with age.
The treatment of infantile spasms is based on the under-
lying etiology of the spasms (31,32). With respect to both
seizure control and developmental outcome, infants who
have underlying focal cortical dysplasia, porencephalic
cysts, or (rarely) a brain tumor may show the best re-
sponse to epilepsy surgery. Anecdotal and controlled trial
data indicate that VGB is the treatment of choice for in-
fantile spasms associated with tuberous sclerosis complex
(33–37). Children with cryptogenic infantile spasms show
the best response to ACTH in clinical trials (32,38). Use
of VGB (32–35,39) and nitrazepam (NTZ) (40) to treat
cryptogenic infantile spasms has also been evaluated in
clinical trials. In Japan, pyridoxine is typically admin-
istered as initial therapy for infantile spasms but has a
low response rate (41–43). Other treatment options that
have been pursued in case series include VPA, prednisone,
FBM, LTG, TPM, and zonisamide (ZNS) (38,39,44,45).
The ketogenic diet has recently shown success in children
with refractory infantile spasms (cryptogenic and symp-
tomatic etiologies) (46). Children with symptomatic eti-
ologies are often treated with the same medications, but the
response rate is much lower than in children with a cryp-
togenic etiology (32,38,39,44). As such, in patients with
symptomatic etiologies, a risk/benefit assessment must be
made for each therapeutic option and discussed with the
child’s parents.
Severe myoclonic epilepsy in infancy (Dravet syn-
drome) begins with partial or generalized, often pro-
longed, febrile seizures in normal infants before 1 year
of age. Myoclonus occurs between the ages of 1 and 4
years, typically upon awakening. Children progress to ex-
perience multiple seizure types, and their psychomotor de-
velopment becomes retarded after the second year of life.
Photoparoxysmal effects are common in this syndrome.
Recent placebo-controlled, multicenter studies have eval-
uated the efficacy of stiripentol in the treatment of severe
myoclonic epilepsy in infancy (Dravet syndrome) (47,48).
In one study by Chiron et al. (47), children were typically
treated with VPA and clobazam during the baseline phase
(Fig. 2). They were then randomized to treatment with
Stiripentol (n=21)
Valproate, clobazam Stiripentol
0 to 4 weeks 50 to 100 mg/kg/d
Baseline
Placebo (n=20)
8 weeks
FIG. 2. Severe myoclonic epilepsy in infancy (47) study design.
Epilepsia, Vol. 44, Suppl. 11, 2003
30 J. W. WHELESS AND R. SANKAR
stiripentol (STP) or placebo for 8 weeks. Subsequently,
patients entered an open-label phase, during which they
were treated with STP at dosages of 50–100 mg/kg/day.
Responder rates (i.e., proportions of patients experienc-
ing a >50% decrease in seizure frequency) were sig-
nificantly greater for the STP group (71%) than for the
placebo group (5%). The proportion of patients who were
free from generalized clonic and generalized tonic-clonic
seizures during the study was also significantly greater
in the STP group (43%) than in the placebo group (0%).
Aside from documenting the efficacy of STP in this very
difficult-to-treat childhood epilepsy syndrome, this study
demonstrated the use of a multicenter group to determine
a drug’s efficacy in a relatively uncommon epilepsy syn-
drome, for which recruiting enough patients at a single
center to complete a trial would likely be impossible. Be-
fore this trial, treatment of severe myoclonic epilepsy in
infancy was based on anecdotal evidence for the efficacy
of drugs, such as VPA, CZP, methsuximide (MSM), TPM,
and intravenous gammaglobulin. Both LTG and CZP are
reported to exacerbate seizures in this condition (18).
Benign myoclonic epilepsy of infancy is the only
epilepsy syndrome associated with myoclonic seizures in
infancy or childhood that can have a favorable prognosis.
Seizures are characterized by symmetric myoclonus, and
this is the only seizure type associated with this syndrome
(with the exception of occasional febrile convulsions).
Generalized tonic-clonic seizures may develop later dur-
ing adolescence. The EEG background for individuals
with this syndrome is normal, and the myoclonus is ac-
companied by a generalized spike or polyspike and slow-
wave complex. There have been no controlled trials to
evaluate treatment options for this syndrome, but anec-
dotal evidence suggests that VPA, TPM, LTG, and CZP
are effective (49). Some children may require relatively
brief therapy (i.e., 1–2 years), while others may require
longer-term therapy.
The ability of a drug to effectively treat Lennox-Gastaut
syndrome has often been considered the gold standard
for declaring an AED to have broad-spectrum efficacy in
childhood epilepsy. VPA has been used to treat Lennox-
Gastaut syndrome for 25 years, and there is a wealth of
clinical evidence indicating its efficacy in open-label tri-
als, although no double-blind trials have been performed
(31,50–54). It was not until ∼15 years after the intro-
duction of VPA in the United States that a successful
controlled clinical trial was conducted to investigate the
treatment of Lennox-Gastaut syndrome; FBM was the
first drug to show efficacy in this manner (55,56). Un-
fortunately, potential side effects of FBM have limited
its use in Lennox-Gastaut syndrome, but the drug is still
recommended as a third- or fourth-line agent. FBM is
particularly efficacious in controlling the drop attacks
associated with Lennox-Gastaut syndrome. Two other
drugs (i.e., LTG and TPM) have also emerged as broad-
Epilepsia, Vol. 44, Suppl. 11, 2003
spectrum AEDs with demonstrated efficacy in the treat-
ment of Lennox-Gastaut syndrome in controlled clinical
trials (57–63). The availability of these two drugs has been
a major asset to pediatric neurologists who previously had
only VPA available. Additionally, there have been anec-
dotal reports of success in treating Lennox-Gastaut syn-
drome with ZNS, steroids, CZP, MSM, and NTZ (51).
Nonpharmacologic treatments can also be of benefit in
treating Lennox-Gastaut syndrome. Both the ketogenic
diet and vagus nerve stimulation may be particularly use-
ful in the treatment of drop attacks associated with this
condition (64–69). Vagus nerve stimulation has been so
efficacious in the treatment of drop attacks that corpus
callosotomies are seldom performed. However, when such
procedures are performed, there appears to be a synergis-
tic effect in patients who had previously received vagus
nerve stimulation (70). Interestingly, GABAergic drugs,
such as VGB and GBP, may exacerbate the myoclonic
seizures specifically associated with Lennox-Gastaut syn-
drome (71,72). Epileptic myoclonus in Lennox-Gastaut
syndrome originates from a stable generator in the frontal
cortex and spreads to other cortical areas, whereas the
myoclonus in Doose syndrome appears to be a primary
generalized epileptic phenomenon (73).
Doose syndrome (myoclonic-astatic epilepsy of early
childhood) occurs in children between 2 and 5 years of
age. The jerks associated with this syndrome, followed
by atonia, often lead to abrupt falling and injury. No for-
mal clinical trials have documented the efficacy of AEDs
in treating Doose syndrome, and information regarding
its treatment is based on anecdotal experience. FBM ap-
pears to play a special role in the treatment of Doose syn-
drome, as many patients with this condition are uniquely
responsive to the drug. Other AEDs that have been used
in treating Doose syndrome include ESM, ACTH, VPA,
CZP, TPM, and LTG (2,74–76). Additionally, the keto-
genic diet and vagus nerve stimulation have been used as
nonpharmacologic agents for treatment of intractable drop
attacks sometimes associated with this condition. Exacer-
bation of myoclonic astatic seizures has been reported in
patients treated with PHT, CBZ, and VGB (77).
Syndromes of late childhood, adolescence,
and adulthood
Three of the late-childhood and adolescent-onset ab-
sence epilepsy syndromes may be associated with my-
oclonic seizures. Juvenile absence epilepsy is typically
treated with VPA, but LTG and CZP also appear to be
efficacious (74,78–81). TPM is probably less efficacious
in the treatment of absence seizures than either LTG or
VPA (61,82). As such, if absence seizures are a major
component of the patient’s childhood epilepsy syndrome,
the situation warrants use of LTG over that of TPM. The
GABAergic agents VGB and tiagabine have also been re-
ported to exacerbate absence seizures associated with this
 MYOCLONUS TREATMENT STRATEGIES
condition (74,77). Tassinari syndrome (epilepsy with my-
oclonic absences) has been treated with VPA, CZP, LTG,
TPM, ESM, and phenobarbital (PB) (2,83). A similar
condition, Jeavons syndrome (eyelid myoclonia with ab-
sences), has been treated with VPA, CZP, ESM, and LTG
(2,84). The last two are uncommon epilepsy syndromes;
therefore, no clinical trials have investigated treatment for
them.
JME is the most common adolescent primary gener-
alized epilepsy syndrome. Approximately 18 years ago,
the unique sensitivity of this syndrome to treatment with
VPA was first proposed (85). Since then, although no for-
mal clinical trials have been conducted, there have been
numerous open-label reports documenting VPA’s clinical
efficacy in this condition (86–88). Only one controlled
clinical trial has investigated the treatment of JME. This
trial evaluated the efficacy of adjunctive therapy with TPM
in patients with primary generalized tonic-clonic seizures,
a subgroup of which had JME (61,89). In the TPM-treated
JME patients, primary generalized tonic-clonic seizures
were reduced >50% in 73% of patients, versus 18% of
placebo-treated patients (p = 0.03). Open-label experi-
ence in the treatment of JME with LTG, ZNS, FBM, and
CZP has also been reported (2,7). Older AEDs, such as
primidone, PB, acetazolamide (ACZ), MSM, and ESM,
were also used to treat JME before the introduction of
VPA. Reports indicate that ACZ, though at times effective
for controlling generalized tonic-clonic seizures, is rarely
effective for controlling myoclonic seizures (90). Benzo-
diazepines (BZDs) may be very effective in controlling the
myoclonus associated with JME (88); however, this may
deprive the patient of the warning jerks before the onset
of a generalized tonic-clonic seizure. PHT, CBZ, LTG,
and VGB have all been associated with exacerbation of
myoclonic seizures in JME (34,77,91–93).
Guerrini et al. recently proposed a new epilepsy syn-
drome linked to chromosome 2p11.1–q12.2, which they
defined as autosomal dominant cortical myoclonus and
epilepsy (ADCME) (94). Eight individuals from a single
pedigree presented with a nonprogressive disorder with
onset between the ages of 12 and 50 years. Most indi-
viduals had rare seizures. The disorder is characterized
by predominantly distal semicontinuous rhythmic my-
oclonus and generalized tonic-clonic seizures (all patients)
and complex partial seizures (three patients). Myoclonic
seizures are not a prominent feature. This syndrome has
some clinical and neurophysiological characteristics that
are similar to familial adult myoclonic epilepsy (FAME),
including generalized EEG abnormalities. All patients
treated with CBZ had severe worsening of their my-
oclonus. CZP, VPA, and PB, drugs combining antiepilep-
tic and antimyoclonic properties, produced the most ben-
efit. Patients with this syndrome may be misdiagnosed as
having JME, and the cortical tremor, if interpreted as a
31
simple tremor, may be considered a side effect of VPA
therapy.
FAME is characterized by adult-onset myoclonus in
the extremities (cortical tremor), generalized myoclonic
jerks, rare generalized tonic-clonic seizures, generalized
EEG abnormalities, and normal IQ (95,96). A locus for
this form of epilepsy has been mapped to chromosome
8q24 in Japanese families (95,96), although a European
pedigree did not have this linkage (97), suggesting ge-
netic heterogeneity of this condition. Clinical and EEG
characteristics suggest that FAME is a form of idiopathic
generalized epilepsy akin to JME (95–97). CZP was ef-
fective in all treated FAME patients (97).
The progressive myoclonic epilepsies (PMEs) are a
challenging group of disorders, both from a treatment and
a diagnostic standpoint (98,99). The treatments used in
these conditions often are symptomatic and may improve
seizure control or myoclonus, allowing the patient greater
mobility or quality of life. However, such treatments do
not reverse the underlying etiology and the progressive
encephalopathy associated with these conditions. Despite
this major limitation, treatments are often very benefi-
cial to the patient and the family, as they allow patients
to be mobile for as long as possible and decrease the
number of injuries secondary to myoclonic seizures. No
formal clinical trials have been conducted in the treat-
ment of PME; however, open-label studies and anecdo-
tal reports provide evidence for the usefulness of some
drugs. Open-label clinical trials have reported the effi-
cacy of ZNS in the treatment of PMEs (100–102). In the
treatment of myoclonus epilepsy with ragged-red fibers
(MERRF), both carnitine and coenzyme Q10 may help
improve seizure control (103). LTG has reported special
efficacy in the treatment of neuronal ceroid lipofuscinosis
(104,105). Other medical therapies that have been used
in the treatment of PMEs include piracetam, levetirac-
etam (LEV), CZP, and VPA (106,107). Historically, both
alcohol and N-acetylcysteine have been helpful in some
patients with PMEs (108,109). However, a recent report
has shown variable response and some notable side effects
during treatment with N-acetylcysteine and has suggested
that a multicenter, controlled trial be performed (110).
Single case reports indicate that vagus nerve stimulation
can improve seizures in patients with PME (111). PHT
has been reported to exacerbate the seizures specifically
associated with Unverricht-Lundborg disease (112); this
effect may possibly occur in other PMEs, although it has
not been reported.
The recently described epilepsy syndrome, generalized
epilepsy with febrile seizures plus (GEFS+), has a pheno-
type with a significant component of myoclonic seizures
(113,114). No formal clinical trials have been conducted,
but anecdotal evidence suggests efficacy of VPA and
BZDs for the treatment of this condition (113,114).
Epilepsia, Vol. 44, Suppl. 11, 2003
32 J. W. WHELESS AND R. SANKAR
SPECIAL SITUATIONS
Chromosomal encephalopathies, metabolic disorders,
and anoxic insults may be associated with refractory my-
oclonic seizures. Down’s syndrome (trisomy 21) may
present in infancy or early childhood with myoclonic
seizures or infantile spasms. Typically, the seizures show a
good response to treatment with AEDs, steroids, or ACTH
(44,115–118). Late-onset myoclonic epilepsy in Down’s
syndrome should be considered in the differential diag-
nosis of adult-onset PMEs (119). Wolf-Hirschhorn syn-
drome (partial monosomy 4p or 4p-) is a chromosomal
defect that may affect the alpha-2 and the beta-1 genes for
the GABAA receptor (120). Reduction in the amount of
gene product could contribute to the high epileptogenic-
ity of this syndrome. Wolf-Hirschhorn syndrome shows
some similarities with the electroclinical findings of An-
gelman syndrome. As such, GABAergic drugs (VPA and
BZDs) usually control the seizures, while CBZ may exac-
erbate the seizures in this syndrome (120,121). Angelman
syndrome (partial monosomy 15Q) is another chromo-
somal defect that affects the GABA receptor by elimi-
nating a cluster of GABAA receptor genes. The resultant
decreased inhibition has been suggested to lead to cortical
hyperexcitability (121). BZDs, VPA, and TPM may con-
trol the seizures associated with Angelman syndrome, and
piracetam has been reported to decrease the tremulous-
ness (probable cortical myoclonus) associated with this
gene abnormality (122). Again, CBZ has been reported to
worsen the myoclonic seizures in this syndrome (121).
Two other chromosomal abnormalities have been asso-
ciated with myoclonic seizures, although no specific ther-
apeutic approaches have been reported. In trisomy 1p-,
three voltage-gated potassium channel genes are clustered
together in the 12p13 band. TPM is the only AED that is
known to affect the potassium receptor and potentially
could show efficacy in this condition. Patients with an
inverted duplicated chromosome 15 have three GABAA
receptor subunit genes that may be altered. Although no
drugs have specifically been tested, GABAergic agents
may have potential efficacy in this condition.
Several metabolic disorders are associated with my-
oclonic seizures. Some of these disorders, such as
pyridoxine-dependent epilepsy and biotin deficiency, may
require life-long treatment with the necessary cofactor
(42,43). Other disorders may respond to specific dietary
manipulation. Glucose transporter protein deficiency re-
sponds uniquely to the ketogenic diet, and this diet must
be maintained throughout the patient’s life (123,124). Spe-
cific dietary treatment is also used for treatment of maple
syrup urine disease. Unfortunately, peroxisomal disorders,
molybdenum cofactor deficiency, and nonketotic hyper-
glycinemia segmental myoclonic jerks all must be treated
symptomatically because no other therapies are available
at this time.
Epilepsia, Vol. 44, Suppl. 11, 2003
Postanoxic myoclonus has historically been treated
with VPA or BZDs. No controlled clinical trials have been
conducted in the treatment of this condition; however, re-
cent clinical reports have suggested good efficacy of LEV
(125–127).
AED THERAPY FOR MYOCLONIC SEIZURES
The administration of VPA as one of the primary treat-
ments for myoclonic seizures is based on a long history of
clinical experience (Fig. 3) (1,53). Although VPA is gen-
erally regarded as the drug of choice for Lennox-Gastaut
syndrome, seizures are effectively controlled in only 10–
30% of patients (1). VPA has also been used to treat
Doose syndrome, myoclonic absence, photomyoclonic
epilepsy, eyelid myoclonia with absence seizures, JME,
and postanoxic myoclonus (49,128,129). The availability
of an intravenous formulation of VPA allows rapid loading
for treatment of myoclonus status epilepticus associated
with any of these epilepsy conditions (130). Before intra-
venous VPA was available, the only intravenous formula-
tion available for the treatment of myoclonic epilepsy was
a BZD.
LTG was introduced as a second broad-spectrum AED,
and controlled clinical trials have demonstrated the drug’s
efficacy for myoclonic epilepsy as part of the treatment
for Lennox-Gastaut syndrome (57). In addition, anecdo-
tal reports have shown the efficacy of LTG in infantile
spasms, Doose syndrome, seizures associated with Rett
syndrome, Jeavons syndrome, JME, Tassinari syndrome,
juvenile absence epilepsy, photosensitive epilepsy, and
neuronal ceroid lipofuscinosis (17,81,131–134). A con-
trolled double-blind trial of LTG in JME is currently
being conducted. Interestingly, the combination of VPA
with LTG appears to be synergistic (135), making this
a useful combination for epilepsy syndromes associated
with refractory seizures. However, one study has shown
that LTG may aggravate severe myoclonic epilepsy in
infancy (18).
TPM has been extensively evaluated in treating many
epilepsy syndromes (59–62,89,122,136,137). Controlled,
100
Percentage of Patients Who
71%
70%
Were Seizure Free
53%
50
18%
0
0%
Myoclonic LGS (n=38) Jeavons JME (n=23) BMEI
Absence Syndrome (n=17)
(n=6) (n=19)
FIG. 3. Treatment of myoclonic seizures: valproate monother-
apy (53). JME, juvenile myoclonic epilepsy; BMEI, benign my-
oclonic epilepsy of infancy; LGS, Lennox-Gastaut syndrome.
 MYOCLONUS TREATMENT STRATEGIES 33

100 NONPHARMACOLOGIC THERAPY

≤ 50% 100% FOR MYOCLONIC SEIZURES
68%
Any type of focal cortical lesion can cause focal cor-
Patients (%)

53%
50
9%
0
GTC Myoclonic GTC
(n=34) (n=36) (n=34)
FIG. 4. Treatment of Lennox-Gastaut syndrome with open-label
topiramate (59): seizure reduction for ≥6 months. GTC, general-
ized tonic-clonic.
double-blind trials have demonstrated TPM’s efficacy in
the treatment of Lennox-Gastaut syndrome (59,62) and
primary generalized tonic-clonic seizures, including JME
(Figs. 4 and 5) (61,89). Efficacy of TPM as add-on open-
label therapy has been shown in the treatment of severe
myoclonic epilepsy in infancy and other childhood my-
oclonic epilepsies (60,122,136,137).
ZNS has multiple mechanisms of action, suggesting
it may also be a broad-spectrum AED. Anecdotal re-
ports suggest efficacy of ZNS in treating Lennox-Gastaut
syndrome, the PMEs, and the infantile epileptic en-
cephalopathies (45,100–102,138–144).
Piracetam is effective and well tolerated as add-on ther-
apy for the treatment of myoclonus associated with the
PMEs (107,145). The drug’s efficacy is reported to be
highest within the first 12 months and subsequently stabi-
lizes (146–149). Treatment is usually initiated at a dosage
of 3.2 g/day, divided in three doses and increased by
2.4 g/day every week to a stable clinical response or a
maximum dosage of 20 g/day (mean = 13.5 g/day), ex-
ceptionally up to 40 g/day.
LEV is chemically similar to piracetam and is effective
in preventing the photoparoxysmal response in patients
with photosensitive epilepsy (150), which may predict its
efficacy in myoclonic seizures. Anecdotal reports suggest
efficacy of LEV for myoclonus in postencephalitic and
postanoxic myoclonus, Unverricht-Lundborg disease, and
treatment-resistant JME (106,125–127,151).
100
≤ 50%
63%
67%
Patients (%)
tical myoclonus (e.g., angiomas, tumor, or encephalitis).
Rarely, focal cortical dysplasia may be associated with
14% cortical myoclonus. Surgical excision of the excitable
tissue can cure the myoclonus. Patients with congenital
Myoclonic
hemiplegia due to vascular causes or congenital brain mal-
(n=36) formations may show asymmetric myoclonic seizures as
part of their epilepsy syndrome. Successful hemispherec-
tomy resolves the myoclonus along with the other seizure
types. Epilepsy partialis continua is considered a par-
ticularly treatment-resistant form of cortical myoclonus
but may be alleviated by functional hemispherectomy
in patients with Rasmussen’s encephalitis. Patients with
hypothalamic hamartomas may display generalized my-
oclonic seizures as part of their epilepsy syndrome. The
ketogenic diet, vagus nerve stimulation, surgical resec-
tion, or gamma knife treatment may improve the seizures
(152–156). The more complete the resection, the better
the result.
Vagus nerve stimulation has also been reported to im-
prove seizure frequency in Lennox-Gastaut syndrome,
symptomatic generalized epilepsy, and Unverricht-
Lundborg disease, although no prospective, controlled
studies have investigated its use in any of these
seizure/epilepsy types (65–69,111,152,157–159). Fur-
thermore, such treatment primarily leads to improvement
in generalized convulsive seizures, rather than improve-
ment in myoclonus.
Finally, the ketogenic diet has shown efficacy in the
treatment of myoclonic seizures associated with differing
etiologies and is the treatment of choice for glucose trans-
porter protein deficiency (46,64,65,160–162). The keto-
genic diet has also been useful in treating Lennox-Gastaut
syndrome, for which its efficacy may be comparable to
drug therapy (65,161). Additionally, open-label studies
have demonstrated that the ketogenic diet can produce dra-
matic improvements for children with symptomatic my-
oclonic epilepsy and infantile spasms (46,162).
CONCLUSIONS
Despite the availability of numerous treatment options,
100% the diagnosis and treatment of myoclonic seizures con-
tinue to be challenging. First, the clinician must determine

if the events that a patient experiences are indeed my-

50 48%
oclonic seizures. Next, it is important to define the etiology
33%
of the episodes. For some rare conditions, special diets or
16%
10% vitamins may be used to treat the underlying etiology, and
0 no other therapies may be needed. However, most cases
GTC
(n=96)
Myoclonic
(n=21)
Absence
(n=50)
GTC
(n=96)
Myoclonic
(n=21)
Absence
(n=50)
require other treatments, and identification of the epilepsy
syndrome and its etiology is critical for making decisions
FIG. 5. Primary generalized epilepsy treated with topiramate:
seizure reduction for ≥6 months (61). GTC, generalized tonic- regarding therapy. Comorbidities must also be considered,
clonic. and treatment should be individualized for each patient.

Epilepsia, Vol. 44, Suppl. 11, 2003

34 J. W. WHELESS AND R. SANKAR

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