Dravet syndrome, what is new?

Raidah S. Al-Baradie, MD.

ABSTRACT

.

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.
Dravet syndrome (DS) is one of the most severe genetic
epilepsies of childhood. Charlotte Dravet described
severe myoclonic epilepsy in infancy in 1978. Shortly
after the initial report, many cases were published.
Most of the cases have the SCN1A mutation. A variant
of DS called borderline severe myoclonic epilepsy in
infancy has similar clinical and electrographic features
without myoclonus. The prevalence of DS is 3-6% of
epilepsy cases in infancy, and the incidence is less than
one per 40,000 infants. Also, there is a rare mutation
in the GABARG2 and SCN1B genes. Usually, affected
patients have normal developmental milestones
during infancy. Then after 1-4 years of age, they
start to develop refractory mixed seizure types (tonic
seizures are exceptional) and psychomotor retardation,
ataxia, and hyperkinesias. The EEG reveals focal or
multifocal epileptic discharges and it commonly
shows photosensitivity. The treatment of the seizures
is challenging. The combination of stiripentol, valproic
acid, clobazam, and topiramate is promising.
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From the Neuroscience Center, King Fahd Specialist Hospital, and the
Department of Pediatrics, Dammam University, Dammam, Kingdom
of Saudi Arabia.
Address correspondence and reprint request to: Dr. Raidah S. Al-Baradie,
Department of Pediatrics, Dammam University, PO Box 5473,
Dhahran 31311, Kingdom of Saudi Arabia. Fax. +966 (3) 8431111
Ext. 2915. E-mail: Raidah_albaradie@hotmail.com

istorical introduction. Severe myoclonic epilepsy

in infancy (SMEI) was first described in 1978
by Charlotte Dravet at Marseille, and it was briefly
reported in a French medical journal.1 Soon afterward,
it was recognized in Italy by Bernardo Dalla Bernardina
and they together presented the first 42 cases diagnosed
in Marseille at the International Epilepsy Congress in
Kyoto in 1981.2 It became subsequently obvious that
some patients exhibited overlapping characteristics,
with the exception of myoclonic seizures, which led to
the subdivision of typical and atypical, or borderline
(SMEIB) forms, without an obvious difference in
the prognosis. For this reason, and because this form
of epilepsy was not limited to infancy, the name
was changed to the eponym Dravet syndrome (DS)
(Commission on Classification and Terminology of the
International League Against Epilepsy [ILAE], 1989).
It starts in the first year of life with febrile seizures
(FS) in an, otherwise, normal infant. The FS usually
are atypical. This is followed by refractory and mixed
type of seizures. The most common seizure types are
myoclonic, atypical absence, and focal seizures. Later on,
the infant develops regression in his developmental and
cognitive functions, and he begins to have behavioral
difficulties. Various degrees of variability are seen in the
symptoms of patient with DS; namely, they might not
have myoclonic seizures.3-5 In addition, they may have
characteristics in the EEG that vary from one patient to
another, and on the other hand they may carry the same
prognosis as patients with myoclonic seizures. These
patients are classified as the borderline form (SMEIB). It
is considered as one of the channelopathies after finding
the mutation of SCN1A in affected patients with DS.6
It is still not clear if there are different forms of one

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Dravet syndrome, what is new? Al-Baradie

disease, which may carry various mutations, and also it

is not known whether there is any relationship between
epilepsy and psychomotor development in these
patients. According to the ILAE,7 the DS is considered
as an epileptic encephalopathy, defined as a disease in
which there is progressive cognitive dysfunction caused
by epileptic discharges. It is yet not known whether the
cognitive delay noted early in the disease is considered
to be an early stage of the disease.
Definition. The ILAE classification,8 typical form
of DS, is defined by a refractory and mixed seizure
disorder (most commonly myoclonus, atypical absence,
and partial seizures) which starts after different types
of febrile and afebrile seizures in an, otherwise, healthy
infant. In the second year of life, the child develops
cognitive and behavioral difficulties.
Severe myoclonic epilepsy in infancy (Dravet
syndrome) 30 years later. Thirty years after its
first description, DS is considered as a model of
channelopathy that raises wide interest in the scientific
and medical community. However, clinical and
experimental implications related to the syndrome
spectrum have a much wider meaning than was
originally foreseen in SMEI. The animal models of the
syndrome that have been developed are convincing
and have already provided important insights on
the mechanisms of epileptogenesis.9-11 Additional
insights are emerging on the gait disorder that may
accompany the clinical syndrome and, hopefully, on
the mechanisms underlying cognitive impairment.12
There are encouraging progresses in treatment as new
molecules have emerged that allow a better control
of seizures and that decrease the episodes of status
epilepticus (SE) in a significant proportion of patients.
Unfortunately, seizure freedom remains an exception.
Early mortality, often due to sudden unexpected death
in epilepsy (SUDEP), is a big concern, but has been
seldom studied.
Epidemiology. Severe myoclonic epilepsy of infancy
is an uncommon disorder with an incidence of one per
2,000 to one per 40,000 children, and a prevalence of
6% of epilepsies starting below 3 years of age.13,14 Despite
the increased recognition of DS, it is still considered to
be rare, especially below 15 years of age where it is as
low as 1.4%.15
The genetics of Dravet syndrome. A strong family
history of epilepsy or FS was seen, which is variable
from approximately 25-71%. In many studies, the
relationship with genetic abnormalities was not
investigated. The mutation found in genetic analysis
is variable from 27% in patients with an SCN1A
mutation,16 to 62.5% that demonstrate no mutation.17

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Sodium channel a 1 subunit gene (SCN1A) and

Dravet syndrome. Early on, the SCN1A mutation was
found in patients with FS plus (GEFS+).18 Currently,
more than 500 mutations have been found associated
with DS and they are randomly distributed along the
gene.19 Various mutations are found in patients with
DS, 70% of cases have sequencing mutation, 40% have
missense mutation, 40% have spliced-site changes, and
5-10% of cases are familial mutation, which is commonly
missense in nature.20 An important genetic counseling
issue is that several families have been reported with more
than one child with DS. However, mosaicism might be
found in approximately 7% of families with DS.21 A
patient with similar clinical features of DS who tested
negative for the SCN1A mutation can have SCN1A
exonic deletion or chromosomal rearrangements, which
involve the contiguous gene and SCN1A.22 This type of
mutation is seen in 2-3% of all DS cases and 12.5% of
patients with DS with negative mutation.23
Associated pathology. Dravet syndrome is rarely
associated with other disorders, for example, Rud
syndrome, neurofibromatosis type 1, congenital heart
disease, growth hormone deficiency, and hemophilia.14
Clinical presentation at onset. The onset of DS is
usually in the first year of life. It starts with atypical
FS, but they may have seizures, which may be related
to vaccination, or it may not be related to fever. All
authors indicate an age at onset between 2 and 12
months, and rarely after the age of one year.4 The
febrile convulsive seizures can be variable occurring
in 28-68%.11,14 In one series, these afebrile seizures
usually occurred in the context of a vaccination or of
an infectious episode, or after a bath, and later on, they
were associated with FS. In 25-49% of children with
DS, the seizures are prolonged and it may or may not
be related to fever.14,24 The first seizures can be focal.
In some patients, isolated episodes of focal myoclonic
jerking are noted by the parents either some weeks or
some days before the appearance of the first convulsive
seizure. The myoclonic jerks may start in the hours
before the convulsive seizure, and it may be associated
with hyperthermia. Shortly after the first FS (2 weeks
to 2 months), other FS occur and afebrile seizures also
appear. The child with DS develops mixed seizure types
and starts to show features of psychomotor delay and
then reaches a steady state between age one and 4 years.
These seizure types are variable, mixed, and resistant to
antiepileptic drugs such as erratic or massive myoclonic
seizures, atypical absences, generalized tonic-clonic
or uni-or bilateral clonic seizures, and focal seizures
with or without secondary generalization. Episodes
of obtundation or nonconvulsive SE with or without

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Dravet syndrome, what is new? Al-Baradie

erratic myoclonus is commonly noted. To differentiate

it from Lennox-Gastaut syndrome (LGS), tonic seizures
are very uncommon, in addition to typical EEG features.
A) Myoclonic seizures. Myoclonic seizures are
considered as one of the defining features of DS.
However, patients with DS appear not to present any
myoclonic seizures.4,25 Such cases have been grouped
as borderline cases of SMEI(SMEIB). Massive
myoclonias have been reported for 77% of patients,4
and erratic myoclonias for about one-third of patients
studied;2,3 some patients may experience both massive
and erratic myoclonia.4 Myoclonic seizures are variable
and usually involve the axial muscles and cause drop
attacks if severe or head, shoulder, and trunk jerks when
mild. They occur commonly in the minutes before
the convulsion upon awakening from sleep. They are
provoked by subtle light intensity,4 or more intense or
continuous stimulation.2 Interestingly in approximately
25% of patients, seizures can be triggered either by
interfering with a light source or observing patterns.4,26,27
The majority of massive myoclonias were associated with
bursts of irregular spike-waves or polyspike-waves.4 This
has been observed in half of the individuals studied by
Doose et al,28 it was less commonly observed by others.3
Myoclonic seizures can be erratic or segmental, which
may involve the distal part of the face and limbs and
result in muscle twitch. Movement enhances erratic
myoclonias, and they are particularly common during
periods of severe and frequent convulsions; however,
they also occur at rest. The seizures are seldom intense,
and may be more palpable than visible; however,
imbalance and disturbances of fine coordination may
occur. Interestingly, there might not be associated EEG
changes associated with erratic myoclonias, which is not
the case in massive myoclonias.
B) Atypical absences. Approximately 40-90% of
children with DS have atypical absence.3,4,25 These
appear as absence seizures with myoclonic jerks of
the upper limbs, a simple fall of the head, or drop
attacks. The EEG recordings identify brief discharges
or irregular spike-waves. Typically during the atypical
absences, which are usually prolonged and it may lasts
hours or days, these patients have variable degrees of
obtundation, and ataxia.2,4
C) Convulsive seizures. The convulsive seizures can
be focal or generalized at any time of the diagnosis.
Most of the seizures appear to be focal with rapid
secondary generalization and not generalized in onset
as demonstrated by video-EEG recording in patients
with DS. Interestingly, the seizures are hemiclonic
ones that evolve to status as noted in young children.29
These seizures tend to become briefer and it alternates

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from one side to another as the patient becomes older.

It is commonly associated with Todds paralysis and
asymmetric EEG features.
D) Focal seizures. More than 50% of children
with DS have focal seizures, which may or may not
secondarily generalize.
E) Tonic seizures. They are unusual in this
syndrome. They may look like tonic seizures with or
without a myoclonic component as seen in LGS, which
are commonly sporadic. The ictal EEG shows either
a decremental event or low amplitude rapid rhythms,
followed by slow waves. In a recent study,30 they
recorded tonic seizures in 5 patients and described an
interictal EEG pattern consisting of frontal, slow, bi, or
tri spikes, followed or not by slow waves, when awake,
activated by sleep. They may have other epileptic events,
which can be very difficult to classify.
Developmental and cognitive features. Most patients
with DS have various degrees of cognitive deficits and
behavioral difficulties, which are usually noted very
clearly from the second year of age.31 As a rule, children
start walking at a normal age but an unsteady gait
develops for an unusually long period. Language also
starts at a normal age, but progresses very slowly, and
many patients do not reach the stage of constructing
elementary sentences. Patients fine motor abilities
are disturbed by segmental myoclonus and by poor
eye-hand coordination. The most apparent problems
in children with DS that hinder them from learning
are attention deficit hyperactivity and difficulties in
concentration. These patients are not interested in
playing with educational toys and participating in the
usual activities of their age group and do not listen to
adults. However, they can complete puzzles and watch
cartoons repetitively. Not all these traits are present
in all patients, and the traits tend to be less severe in
those with a recent diagnosis.24 In the first studies, the
degree of impairment appeared to be correlated with
the severity of epilepsy during the first 2 years of life.32
The EEG features. Interictal EEG recordings
are generally normal during the first months of the
disease, despite the frequent seizures (unlike the slow
spike-waves observed for LGS). As the patient gets
older, various EEG features start to be evident such as
multifocal, focal, or generalized epileptiform activities.
In addition, the background of the EEG activity
starts to become slower.4,28 From the second year of
life, generalized discharges of fast spike-wave or poly
spike-wave complexes appear in bursts or in isolation,
sometimes with a unilateral predominance. Focal or
multifocal spikes are often observed. In later life, the
EEG patterns observed are variable. Multifocal spikes

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Dravet syndrome, what is new? Al-Baradie

or sharp-wave discharges become more common, and

background tracings become slower, especially during
seizure clusters. The paroxysmal EEG abnormalities
are activated during slow sleep. Then the epileptic
discharges later on remit and instead the EEG shows
more diffuse slowing. In the few reported cases of DS
during adolescents, the EEG showed frontal slowing
with 2-3 Hz epileptic discharges, which are activated
during sleep and become paroxysmal lasting for several
seconds without clinical features associated with the
EEG.30
Neuroimaging and neuropathology. Brain MRI
studies in patients with Dravet syndrome and SCN1A
mutations have shown abnormal findings in a small
minority of patients. Some of the abnormalities noted
in the brain of patients with DS are hippocampal
sclerosis, cortical dysplasia, and atrophy. It is not clear
if these abnormalities are specific and related to the
duration, age of onset, and the frequency of the seizures
in this disorder. An immunomediated etiology in DS
was proposed since the few reported cases of Rasmussen
syndrome and hemiconvulsive-hemiplegia syndrome
have the SCN1A mutation. One has to consider severe
epileptic encephalopathy in these cases.33
SPECT findings. Only a few SPECT or PET studies
have been performed DS. A SPECT study showed areas
of hypoperfusion in 8 out of 10 patients; the finding
was limited to one hemisphere in 5 patients and was
bilateral in the remaining 3. Areas of hypoperfusion did
not clearly correlate with EEG findings.34 In terms of
neuropathological findings seen in patients with DS,
there is a subtle brain malformation, which is found in
some cases. It is not clear if these findings correlate with
SCN1A gene dysfunction. It is worth pursuing further
animal and human prospective studies to find out if
early diagnosis and seizure control in patients with DS
may alter the clinical, imaging, or pathologic picture.35
Differential diagnosis. Febrile seizures. It is always
important to distinguish the diagnosis of FS from DS at
the onset of FS. The following points are in favor of DS (a)
onset is always early (before one year of age); (b) seizure
type is clonic and often unilateral instead of generalized
and tonic; (c) seizure episodes are more prolonged and
frequent, even when treated; and (d) temperature is not
very high. Dravet syndrome is commonly associated
with alternating focal seizures. Then, the diagnosis
becomes evident with the development of mixed seizure
types and the photoparoxysmal spike-wave epileptic
discharges noted in these children.14 Some studies have
proposed a screening test that can be used before the
end of the first year.
Benign (idiopathic) myoclonic epilepsy in infancy.
The first events are brief generalized myoclonic seizures,

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which remain the only ictal manifestations even

without treatment. Usually, these children have normal
development and they respond well to antiepileptic
medications. Their EEG show generalized epileptic
discharges associated with myoclonic jerks. They
carry a good prognosis, and the reflex seizures resolve
spontaneously.36
The epilepsy with myoclonic-astatic seizures (Doose
syndrome). It is defined by the association of GTCS and
frequent drop attacks, which are unusual DS, and, as
a rule, it starts after the age of 2 years and has a different
course. Atypical absence status with myoclonic jerks
occurs, but there are no focal seizures and no focal EEG
abnormalities. The outcome is variable with complete
cure in >50% of the cases.37
Progressive myoclonus epilepsy. Mainly ceroid
lipofuscinosis, can be evoked in the second year when
neurologic and behavioral signs appear. These patients
usually have visual abnormalities, abnormal evoked
potential, and retinal abnormalities. A mitochondrial
encephalomyopathy must be considered in the most
severe cases and in the presence of metabolic changes
induced by AEDs.38
Lennox-Gastaut syndrome. It is characterized by
mixed seizure types such as atypical absences, drop
attacks, and most commonly tonic seizures, in addition
to typical EEG features. Febrile seizures are very rare in
infancy. An onset of atypical FS and focal seizures can
be seen in patients with early cryptogenic focal epilepsy.
They may not have myoclonic or absence seizures. The
EEG features are typical of focal abnormalities. The
presence of hemiclonic and alternating seizures makes
this diagnosis less likely.39 Interestingly, a few cases of
focal epilepsy that carry similar clinical characteristics
of DS may have the SCN1A mutation, such as epilepsy
of infancy with migrating focal seizure.
Generalized epilepsy with febrile seizures plus
family. One member may have DS. The typical clinical
feature is prolonged and atypical FS, which refractory
to antiepileptic drugs (AEDs) followed by psychomotor
retardation. Recently, mutations in PCDH19, the gene
encoding the protocadherin 19 on the X chromosome,
were discovered in some of the SCN1A-negative female
patients presenting with a clinical picture resembling
the borderline SMEI, which was described as Epilepsy
and mental retardation limited to females (EFMR).40
It is considered to be a variant of DS, which carry a
different mutation. Therefore, in patients who are less
than one year who develop atypical and frequent FS, the
diagnosis of DS should be considered, which is further
confirmed by the development of other mixed seizure
types, photosensitivity, and developmental delay. The

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Dravet syndrome, what is new? Al-Baradie

borderline form of DS should also be considered when

the SCN1A mutation is found.
Treatment. There is no single effective treatment used
for these patients. This makes the treatment modalities
in children with DS limited. As a preventative measure,
hot baths should be avoided in young children and
sunglasses or any other method to reduce photo-and
pattern-sensitivity, when present, may prove useful.
Vigorous treatment of febrile diseases might be of
uncertain value. In general, there is a lack of controlled
trials regarding the efficacy of available antiepileptic
drugs (AEDs). Many AEDs have no effect and may be
at the origin of adverse effects, such as carbamazepine41
and vigabatrin,4 which can favor or even induce
myoclonic seizures and lamotrigine,42 particularly for
young patients. For older patients, polytherapy should
be avoided, and the specific action of each AED should
be considered. The AEDs that have been shown to
have therapeutic value against DS include valproate,13
levetiracetam,43 zonisamide,44 and topiramate,45
especially in patients who were unsatisfactorily treated
with stiripentol alone.46 Stiripentol is a new AED
that recently received conditional approval from the
European Medicines Agency to be used throughout
the European Union, in conjunction with clobazam
and valproate as adjunctive therapy for refractory
generalized tonic-clonic seizures in patients with
DS.47 When administered as an add-on, stiripentol
demonstrates a positive effect on reducing the frequency
of seizures.47 A systematic review and meta-analysis
of individual data demonstrated a positive effect of
stiripentol in patients with DS using 23 uncontrolled
studies and 2 randomized controlled trials. The efficacy
of stiripentol in patients with DS is ~70% compared
with placebo.48 This seems to have promising results.
Other treatment modalities used in patients with DS
include vagus nerve stimulation (VNS), ketogenic diet
(KGD), bromide, immunoglobulins, and steroids.49,50
Most of the preceding reports refer to anecdotal cases
or to open studies.
Comorbid
conditions.
Autism
spectrum
characteristics and communication impairments. Many
surveys in the literature demonstrated the developmental
delay, psychomotor regression, behavioral difficulties,
language and communication problems, autistic
features, and sensory integration abnormalities in
affected patients with DS.51
Cardiovascular. Various cardiac abnormalities have
been described in patients with DS and their families,
which includes prolonged Q-T interval, tachycardia
or bradycardia, tricuspid atresia, bicuspid aortic valve,
atrial septal defect, and pulmonary stenosis. These

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associated abnormalities may resolve spontaneously in

the first year of life.51
Dental health. These patients may have malocclusion
(13%), delayed teething (20%), bruxism (20%), and a
few children with DS may have malformed teeth and
oral infections.51
Dysautonomia. Autonomic dysfunction is seen
commonly in children and families with DS such as
papillary dilatation, episodes of flushing, stomach
emptying difficulties, regulation of body temperature,
and sweating.52
Coordination, growth, and nutrition. It is very
common for patients with DS to have failure to thrive
(22%), feeding difficulties, and an orthopedic disorder
such as pes planus and/or pes valgus foot deformities.
They also may have hypotonia (56%), hypertonia
(14%), joint laxity (21%), ataxia, and constipation
(29%).52
Infections and immune dysregulation. Infections of
the respiratory tract are frequently reported; gastritis
and urinary tract infections are also of concern. Thirteen
percent of patients with DS are found to have immune
problems.52
Sleep. Sleep disorders are seen commonly in these
patients, which include insomnia (20%), premature
awakening (28%), nocturnal seizures (50%), and sleep
apnea (52%).
Mortality and sudden unexpected death in epilepsy.
The mortality rate was reported as 3.7%.52 The mean age
of death was 4.6 years (range 10 months to 17 years);
the most frequent age of death was 2 years. The causes
of death are SUDEP (61%), and SE (32%). Few died
from ketoacidosis and seizure-related accidents. There
was no significant relationship between death, gender,
or country of residence. In 2009, the death rate by year
joined ranged from 2.3-4.9%.52
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Authorship entitlement
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