Epileptic syndromes in infancy and childhood
Rima Nabbouta,b and Olivier Dulaca,b
a
Department of Neuropediatrics, Centre de référence
épilepsies rares, Hôpital Necker-Enfants malades,
APHP, Necker-Enfants malades and bUniversity Paris
Descartes, Paris, France
Correspondence to Rima Nabbout, MD, PhD,
Department of Neuropediatrics, Centre de référence
épilepsies rares, Hôpital Necker-Enfants malades,
APHP, 149 rue de Sèvres, Paris Cedex 15, F-75743,
France
Tel: +33 1 42192695; fax: +33 1 42192692;
e-mail: [email protected],
[email protected]
Current Opinion in Neurology 2008, 21:161–166
Purpose of review
The aim of this article is to review new epilepsy syndromes, acquire a new
understanding of older ones and emphasize the impact of this concept on basic
research regarding aetiology and treatment.
Recent findings
In addition to those included in the classification of the International League Against
Epilepsy, new epilepsy syndromes comprise febrile seizures plus, benign familial
neonatal–infantile seizures (BFNIS), benign infantile focal epilepsy with midline spikes
and waves during sleep (BFIS), malignant migrating partial seizures in infancy,
devastating epilepsy in school age children and late onset cryptogenic spasms.
Genetics played a central role in identifying some new entities (BFNIS, BFIS with
choreoathetosis), to delineate older syndromes (Dravet syndrome and myoclonic astatic
epilepsy) and determine their mechanisms (infantile spasms, pyridoxine dependent
seizures, neonatal encephalopathy with suppression bursts).
Summary
A significant number of children, mainly infants, do not fit in any of the described epilepsy
syndromes. Still many patients with infantile epilepsy require the identification of cause
or recognition of an epilepsy syndrome.
Keywords
classification, epilepsy genetics, epilepsy syndrome, epileptic encephalopathies
Curr Opin Neurol 21:161–166
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540
Introduction
The course of epilepsy in children is most variable and the
prognosis cannot be determined on the basis of age of onset,
seizure types, interictal condition, electroencephalography
(EEG) pattern or cause. The combination of age of onset,
seizure types, interictal condition and EEG pattern, called
epilepsy syndrome, however, does give some clue regarding cause and prognosis. It allows refined communication
between caregivers. It is useful for research regarding
treatment strategy and aetiology, including the eventual
genetic background. Recent advances in basic epileptology
reinforced this concept and led to the identification of
specific cause for a given syndrome.
We will focus on new understanding of previously recognized syndromes and on new epilepsy syndromes.
Benign familial neonatal–infantile seizures
This condition is intermediate between benign familial
neonatal convulsions (BFNCs) and benign familial infantile convulsions (BFICs), called benign familial neonatal–
infantile seizures (BFNIS) [1]. The identification of these
families is based on the mean age of onset, which ranges
from that of BFNC to BFIC, from 2 days to 6 months. To
date, a total of 10 families with mutations in SCN2A were
reported. An Italian family with a strict phenotype of
BFIC and a mutation in SCN2A suggested that BFNIS
and BFIC show overlapping clinical features [2]. No
SCN2A mutations are reported in families with BFNC
although the neonatal onset is emphasized by a recent
review of the clinical spectrum [3].
Familial infantile convulsions and
choreoathetosis
Benign familial infantile seizures with paroxysmal choreoathetosis inherited as an autosomal dominant trait
were first recognized in 1997 [4]. Over 20 families have
since been reported in different countries. Seizures
appear at 3–12 months, and are partial and may secondarily generalize as previously described [5]. Seizures
soon stop but paroxysmal choreoathetosis starts between
5 and 9 years. It occurs in paroxysmal attacks, at rest or
induced by exercising and anxiety. Neurological examination and EEG tracings between these attacks are
normal, as is psychomotor development. Genetic studies
reveal a strong evidence of linkage to the pericentromeric
region of chromosome 16. No causative gene has been
found to date.
1350-7540 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
162 Seizure disorders
Benign infantile focal epilepsy with midline
spikes and waves during sleep
Seizures onset is between 4 and 30 months. Seizure
manifestations are typical, characterized by cyanosis,
staring and rare lateralizing signs, of short duration. There
is a strong EEG marker, a spike followed by a bell-shaped
slow-wave, localized in the midline regions, present in all
subjects only during sleep. The prognosis is naturally
favourable and the majority of patients do not require
antiepileptic drugs (AEDs) [6].
Epileptic encephalopathy with suppression
bursts
This severe condition begins within the first 3 months of
life. EEG demonstrates bursts of paroxysmal activity
(polyspikes) lasting several seconds and alternating with
episodes of flat or low amplitude tracing, a combination
called suppression bursts. This pattern is present in both
awake and sleep states, or mainly during sleep. It is
associated with partial seizures variably combined with
myoclonus or spasms.
The classification of the International League Against
Epilepsy [7] recognized two conditions with suppression
bursts: the early infantile epileptic encephalopathy
(EIEE) or Ohtahara syndrome [8] and the neonatal
myoclonic encephalopathy (EME) [9].
In EIEE, there are spasms and the suppression burst
pattern is often asymmetrical, mainly affecting the side
of a cortical malformation, usually hemimegalencephaly or
focal cortical dysplasia [8]. Aicardi syndrome, olivarydentate dysplasia and schizencephaly are other conditions
in which such tracings are encountered [10]. In EME,
there is no radiological evidence of a brain lesion, the
patients exhibit erratic and massive myoclonus and there is
familial recurrence [11]. Non-ketotic hyperglycinaemia,
Menkes disease, pyridoxine and pyridoxal phosphate
dependencies, and glutamate transporter defect [12]
may be involved and share excess of glutamate transmission. Antiquitin, the gene for pyridoxine dependency
causes an excessive renal excretion of a-aminoadipicsemi-aldehyde that chelates pyridoxine and causes the
defect [13].
Although the distinction between both entities is important from both the aetiologic and the therapeutic points
of view, it may be difficult for a given patient since
myoclonus and spasms may be confused at that age,
because suppression bursts may be an early variant of
fragmented hypsarrhythmia, and since all patients do
not fulfil the criteria for either EIEE or EME [14].
Recently, a polyalanine expansion in the ARX gene
(Aristales-related homeobox), longer than for infantile
seizures, was observed in two unrelated cases of EIEE
with normal brain MRI [15].
Infantile spasms and West syndrome
The combination of clusters of spasms, psychomotor
deterioration and hypsarrhythmia defines West syndrome
that occurs mainly between 3 and 12 months of age.
Cryptogenic cases account for 9–15% of the cases, the rest
being symptomatic. The symptomatic cases are associated
with several prenatal, perinatal and postnatal factors. Various brain dysgenesis (lissencephaly, hemimegalencephaly, focal cortical dysplasia, septal dysplasia or callosal
agenesis), chromosomal (including Down syndrome,
del1p36) or single gene (mutations of ARX or STK9 gene)
[16,17] causes are reported. Untreated phenylketonuria,
tetrahydrobiopterine deficiency and mitochondrial cytopathy including the NARP mutation are occasionally
observed. Infantile spasms are particularly frequent in
the course of Menkes disease.
Vigabatrin and steroids are the basis of treatment. Early
treatment results in a better outcome [18]. Controlled
studies in patients with other conditions than tuberous
sclerosis found better short term but similar long term
effect of steroids compared to vigabatrin, due to the high
relapse rate with hormonal treatment [19–21]. Radiological work-up should be performed for surgery before going
to topiramate that may have some effect [22], although
worsening has been reported [23]. The place of the
ketogenic diet also needs to be determined [24].
We reported a transient decrease of diffusion in subcortical structures in six patients with pharmacoresistant
West syndrome of unknown cause. The eventuality of
toxic lesions, including some inborn error of metabolism
or drug toxicity, was considered but the contribution of
the epileptic encephalopathy appears the most likely
[25].
Cryptogenic late-onset epileptic spasms
When cryptogenic, late onset epileptic spasms beginning
between 12 and 48 months of age have a particular pattern
that is intermediary between West and Lennox–Gastaut
syndromes [26]. EEG does not show classical hypsarrhythmia but a temporal or temporofrontal slow wave or
spike focus combined with slow spike-waves. Ictal events
combine spasms in clusters, tonic seizures and atypical
absences. Ictal EEG discloses a generalized high-voltage
slow wave followed by diffuse voltage attenuation with
superimposed fast activity, typical of the epileptic spasms,
occurring in clusters. The classical treatment of infantile
spasms was efficient in almost half the cases.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Epileptic syndromes in childhood Nabbout and Dulac 163
This newly delineated cryptogenic syndrome is not merely
a late variant of infantile seizures but could correspond to
maturation dysfunction of the temporal lobes, in contrast
with West syndrome combined with posterior and Lennox–Gastaut syndrome with anterior maturation features.
Malignant migrating partial seizures in
infancy
First reported in 1995 in 14 infants [27], malignant
migrating partial seizure in infancy (MMPSI) is an epileptic encephalopathy characterized by onset in the first
6 months of life, of rapidly progressive partial seizures
that become subcontinuous. Their onset migrates from
one area of the cortex to the other and major deterioration
of the psychomotor abilities appears. Cases were later
identified in European, Asian and American countries.
Early seizures have motor and autonomic components,
later seizures are more polymorphic, varying from one
seizure to the next in a given patient. Seizures last several
minutes longer than usual partial seizures in infancy.
They tend to be more frequently generalized as time
goes by. Myoclonus is rare, and spasms exceptional. By
the end of the first year of life, seizures become almost
continuous and occur in clusters: seizures lasting several
weeks, during which the infant deteriorates considerably,
and followed by disappearance of seizures during a few
weeks with slow improvement of the condition. Microcephaly progressively occurs.
To date, no cause has been identified by historical,
biochemical, radiological or histological investigations.
No familial case or consanguinity has been reported. A
genetic study failed to find mutations in sodium (SCN1A,
SCN2A), potassium (KCNQ2, KCNQ3), and chloride
(CLCN2) ion channels in three children with migrating
partial seizures in infancy [28].
The course is most severe because seizures never come
under control. For the rare patients whose seizures are
controlled before the end of the first year of life, walking is
possible. Only a single patient, however, is said to have had
normal development at age 7 years [29] and levetiracetam
was reported recently in a possible case with early neonatal
onset [30]. This contrast in the course raises doubts regarding the syndromic diagnosis for these patients. Open data
on the effect of the combination of clonazepam and
stiripentol have been reported. Bromide may be efficient
but AEDs for partial epilepsy, mainly carbamazepine and
vigabatrin, seem to worsen the condition.
Dravet syndrome
First described in 1978, Dravet syndrome is characterized
by the occurrence, in an otherwise normal infant, of
generalized or unilateral clonic or tonic–clonic seizures,
mostly with fever, in the first year of life [31]. Later, other
seizure types occur, including myoclonus, atypical
absences and partial seizures. Developmental delay progressively appears from the second year. Seizures remain
fever sensitive and tend to evolve to status epilepticus
[32]. The term Dravet syndrome is preferred to that of
severe myoclonic epilepsy in infancy since all patients do
not develop myoclonia. The first seizure can be mistaken
for complex febrile seizures, although early recurrence
allows the distinction. This sensitivity to fever seizures
led to the identification of mutations in SCN1A [33],
a gene first described in families with generalized
epilepsy with febrile seizures plus (GEFSþ) [34].
Febrile seizures plus (FSþ) defined febrile seizures
lasting beyond 6 years or associated with non-febrile
seizures [35]. Dravet syndrome was proposed as the most
severe form of the spectrum of the FSþ linked epilepsies.
SCN1A mutations account for 75% of Dravet syndrome
cases. Recently, almost 10% of patients with reported
negative mutations showed partial or complete deletion
of the gene and less frequently duplication [36,37].
Inherited cases were also reported with parental mosaicism [38,39]. SCN1A mutations were shown to cause
vaccine encephalopathies [40].
Seizures in Dravet syndrome are highly pharmacoresistant. The ultimate goal is to reduce seizures, mainly
status epilepticus, during the first years [41]. A prospective randomized trial [42] proved the efficacy of the
association of clobazam, valproate and stiripentol in reducing status epilepticus and the frequency of tonic–clonic
seizures. In patients responding partially, the adjunction
of topiramate or levetiracetam might be effective.
The incidence of hippocampal lesions [43] could be underestimated. A T2 weighted coronal MRI performed after
the second or third year of life could help in disclosure.
The mechanism of sudden death that is particularly
frequent in this syndrome may result from the SCN1A
mutation [44].
Myoclonic astatic epilepsy
The patients collected under the term ‘centrencephalic
myoclonic–astatic petit mal’, because they were supposed
to share a genetic predisposition related to idiopathic
generalized epilepsy, combine generalized tonic–clonic
seizures, myoclonus and generalized spike-waves [45].
The condition consists of an aetiological concept sharing
features of the Lennox–Gastaut syndrome although there
is no brain lesion, pharmacoresistance, episodes of status
epilepticus and impact on cognitive functions. It comprises
several subgroups, each subgroup consisting of an epilepsy
syndrome reported as the Dravet syndrome [32], ‘benign
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
164 Seizure disorders
myoclonic epilepsy in infancy’ [32], and cases that begin in
school age with myoclonic-astatic seizures.
Myoclonic astatic epilepsy (MAE) begins between 2 and
5 years, often explosively, with either tonic–clonic seizures or drop attacks. A first tonic–clonic seizure at that
age requires an EEG and treatment in cases of spike wave
activity. Multiple seizure types include myoclonic–astatic, tonic–clonic and absences. Non-convulsive status
epilepticus is a classically underdiagnosed complication.
Tonic seizures are a risk factor for poor prognosis [46].
Cognitive deterioration is distinct from that observed in
Lennox–Gastaut and usually combines apraxia and dysarthria. This predominance is explained by the major
involvement of the rolandic strip that contributes to
generate the myoclonus.
A genetic predisposition plays a role in MAE. Very few
cases were reported in families affected by febrile seizures plus with mutations in GEFSþ genes [34,47]. In a
study of 22 sporadic patients affected with MAE, however, no mutation was found in the three major GEFSþ
genes (SCN1A, SCN1B and GABRG2) [48]. MAE has a
different genetic background than Dravet syndrome and
may be inherited as a polygenic disorder involving different families of genes.
The course is variable. Most patients recover within 1–
3 years but others develop myoclonic status and major
cognitive decline in the context of an epileptic encephalopathy. Therapy for epilepsy with myoclonic–astatic
seizures in early childhood remains empirical. Some
compounds may worsen the condition: phenytoin, carbamazepine, and vigabatrin [49]. Valproate, ethosuximide
and benzodiazepines (clobazam more than clonazepam)
have been used successfully. The most efficient combination, however, seems to be valproate with lamotrigine
[50]. The use of benzodiazepines should be restricted to
episodes of myoclonic status epilepticus. Pharmacoresistance is frequent, however, in patients who develop
epileptic encephalopathy, in the sense of cognitive and
motor deterioration with ongoing tonic and myoclonic
seizures. A ketogenic diet should be started as soon as
such a course is identified [51,52]. In non-responders to
the diet and in those who do not tolerate it, the indication
of steroids should be considered. The dose needs to be
moderate, however, in order to avoid precipitation of
convulsive seizures. The treatment needs to be prolonged in order to prevent relapse during the period of
risk, which lasts 1–2 years.
Epileptic encephalopathy with continuous
spike waves in slow sleep
This condition was initially reported with over 85% of
slow wave sleep with spike waves. It was later recognized
to occur with lower spiking activity in various conditions,
namely worsening of idiopathic focal epilepsy in childhood
also called atypical benign focal epilepsy, with negative
myoclonus or facial dyspraxia [53,54], symptomatic
epilepsy usually due to vascular prenatal or perinatal
lesions involving the rolandic area and eventually the
thalamus, cryptogenic involving the temporal lobe with
aphasia and auditory agnosia [55,56] or the frontal lobes
with frontal syndrome [57]. The story of a clear motor or
cognitive deterioration is crucial for diagnosis and therapeutic strategy. Expressive dysphasia has been related to
an SRPX2 monogenic mutation [58].
Devastating epileptic encephalopathy in
school aged children
Devastating epileptic encephalopathy in school aged children (DESC) presents in previously normal children as
intractable convulsive status epilepticus lasting several
weeks and followed without a silent period by pharmacoresistant perisylvian epilepsy associated with a dramatic
deterioration of cognitive function that predominates on
temporal lobe function [59]. It begins between 4 and 11
years, with fever without evidence of intracranial infection,
and intractable status epilepticus followed immediately
by pharmacoresistant epilepsy with clinical and EEG
evidence of perisylvian involvement, bilateral temporal
and frontal dysfunction on neuropsychological tests predominating on limbic structures, consistent with MRI and
PET findings. This condition easily goes unrecognized
since it presents in a febrile setting and can be easily
diagnosed as ‘grey matter encephalitis’ [60,61].
There is no evidence of brain inflammation whereas
status epilepticus causes bilateral temporal epileptogenic lesions: it may merely be a previously overlooked
epileptic encephalopathy. Another non-inflammatory
epileptic encephalopathy triggered by fever with
massive involvement of both frontal lobes has been
reported [62].
Conclusion
The concept of epilepsy syndromes, developed four
decades ago by the school of Marseille [63] and established
by the International League Against Epilepsy [7], remains
a golden standard in paediatric epileptology. The Dravet
syndrome was described on clinical and EEG criteria long
before the basic mechanism, a mutation in SCN1A gene
was recently identified. Clinical and EEG delineation from
MAE was confirmed by a different genetic background.
This concept allows the identification of new syndromes
such as DESC and MMPS, based mainly on clinical and
EEG criteria. Advances in neuroimaging and genetics
have by no means contradicted this concept. Therapeutic
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Epileptic syndromes in childhood Nabbout and Dulac 165
trials based on this approach have generated specific
indications, such as vigabatrin for infantile spasms and
stiripentol for Dravet syndrome. The recent description
of epilepsy syndromes in adults adds to this validation.
Autosomal dominant lateral temporal lobe epilepsy
(ADLTLE) and autosomal-dominant nocturnal frontal
lobe epilepsy (ADNFLE) may be idiopathic and not be
amenable to surgery.
17 Guerrini R, Moro F, Kato M, et al. Expansion of the first PolyA tract of ARX
causes infantile spasms and status dystonicus. Neurology 2007; 69:427–
433.
Authors refine the phenotype and the frequency of ARX mutations in infantile
seizures in boys. The ‘classical’ phenotype is that of infantile seizures with severe
dyskinetic quadriparesis. They suggest that ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence
of a consistent perinatal history.
18 Eisermann MM, DeLaRaillere A, Dellatolas G, et al. Infantile spasms in Down
syndrome: effects of delayed anticonvulsive treatment. Epilepsy Res 2003;
55 (1–2):21–27.
19 Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for
infantile spasms: a randomized, prospective study. Epilepsia 1997; 38:
1270–1274.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 213–214).
1
Berkovic SF, Heron SE, Giordano L, et al. Benign familial neonatal-infantile
seizures: characterization of a new sodium channelopathy. Ann Neurol 2004;
55:550–557.
2
Striano P, Bordo L, Lispi ML, et al. A novel SCN2A mutation in family with
benign familial infantile seizures. Epilepsia 2006; 47:218–220.
3
Herlenius E, Heron SE, Grinton BE, et al. SCN2A mutations and benign
familial neonatal-infantile seizures: the phenotypic spectrum. Epilepsia 2007;
48:1138–1142.
4
Szepetowski P, Rochette J, Berquin P, et al. Familial infantile convulsions
and paroxysmal choreoathetosis: a new neurological syndrome linked to the
pericentromeric region of human chromosome 16. Am J Hum Genet 1997;
61:889–898.
5
Vigevano F. Benign familial infantile seizures. Brain Dev 2005; 27:172–
177.
6
Capovilla G, Beccaria F, Montagnini A. ‘Benign focal epilepsy in infancy with
vertex spikes and waves during sleep’. Delineation of the syndrome and
recalling as ‘benign infantile focal epilepsy with midline spikes and waves
during sleep’ (BIMSE). Brain Dev 2006; 28:85–91.
7
Commission on Classification and Terminology of the International
League Against Epilepsy/Proposal for revised classification of epilepsies
and epileptic syndromes. Epilepsia 1989; 30:389–399.
8
Ohtahara S. Clinico-electrical delineation of epileptic encephalopathies in
childhood. Asian Med J 1978; 21:499–509.
9
Aicardi J, Gouttières F. Encéphalopathie myoclonique néonatale. Rev EEG
Neurophysiol 1978; 8:99–101.
20 Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile
Spasms Study comparing vigabatrin with prednisolone or tetracosactide
at 14 days: a multicentre, randomised controlled trial. Lancet 2004; 364:
1773–1778.
21 Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms
Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised
trial. Lancet Neurol 2005; 4:712–717.
22 Zou LP, Ding CH, Fang F, et al. Prospective study of first-choice topiramate
therapy in newly diagnosed infantile spasms. Clin Neuropharmacol 2006;
29:343–349.
23 Mikaeloff Y, Saint-Martin A, Mancini J, et al. Topiramate: efficacy and tolerability in children according to epilepsy syndromes. Epilepsy Res 2003;
53:225–232.
24 Kossoff EH, Pyzik PL, McGrogan JR, et al. Efficacy of the ketogenic diet for
infantile spasms. Pediatrics 2002; 109:780–783.
25 Desguerre I, Marti I, Valayannopoulos V, et al. Transient magnetic resonance
diffusion abnormalities in West syndrome: a toxic effect or the radiological
expression of non convulsive status epilepticus? Dev Med Child Neurol
(in press).
26 Eisermann MM, Ville D, Soufflet C, et al. Cryptogenic late-onset epileptic
spasms: an overlooked syndrome of early childhood? Epilepsia 2006;
47:1035–1042.
This paper delineates this new syndrome and distinguishes it from a simple late
occurrence of infantile seizures. It is striking that this syndrome comprises temporal
predominance of interictal paroxysmal activity and begins between the ages of
onset of West and Lennox–Gastaut syndromes. It increases the evidence of an
age-dependent developmental continuum showing anterior migration of epileptogenicity, consistent with the physiological posterior to anterior gradient of brain
maturation.
27 Coppola G, Plouin P, Chiron C, et al. Migrating partial seizures in infancy: a
malignant disorder with developmental arrest. Epilepsia 1995; 36:1017–
1024.
11 Dalla Bernardina B, Dulac O, Fejerman N, et al. Early myoclonic epileptic
encephalopathy (EMEE). Eur J Pediatr 1983; 140:248–252.
28 Coppola G, Veggiotti P, Del Giudice EM, et al. Mutational scanning of
potassium, sodium and chloride ion channels in malignant migrating partial
seizures in infancy. Brain Dev 2006; 28:76–79.
Although it is a small series, authors ruled out the role of ionic channels already
reported in childhood epilepsies in this new defined syndrome.
12 Molinari F, Raas-Rothschild A, Rio M, et al. Impaired mitochondrial glutamate
transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum
Genet 2005; 76:334–339.
29 Marsh E, Melamed SE, Barron T, Clancy RR. Migrating partial seizures in
infancy: expanding the phenotype of a rare seizure syndrome. Epilepsia 2005;
46:568–572.
10 Robain O, Dulac O. Early epileptic encephalopathy with suppression bursts
and olivary-dentate dysplasia. Neuropediatrics 1992; 23:162–164.
13 Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with
pyridoxine-dependent seizures. Nat Med 2006; 12:307–309.
Mutations in the antiquitin gene were reported in pyridoxine dependent seizures
(PDS). Antiquitin activity as a d1-piperideine-6-carboxylate (P6C)-a-aminoadipic
semialdehyde (a-AASA) dehydrogenase is abolished. The accumulating P6C
inactivates pyridoxal 50 -phosphate (PLP) and produces the pyridoxine deficiency.
The important implication is that the simple measurement of urinary a-AASA
provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene
analysis provides a means for prenatal diagnosis.
14 Schlumberger E, Dulac O, Plouin P. Early infantile syndromes: nosological
considerations. In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf
P, editors. Epileptic syndromes in infancy, childhood and adolescence, 2nd
ed. London: John Libbey; 2005. pp. 35–42.
15 Kato M, Saitoh S, Kamei A, et al. A longer polyalanine expansion mutation in
the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). Am J Hum Genet 2007; 81:361–
366.
This is the first genetic common predisposition between Ohtahara syndrome and
infantile seizures. This finding is compatible with the clinical and EEG continuum of
these two syndromes.
16 Scala E, Ariani F, Mari F, et al. CDKL5/STK9 is mutated in Rett syndrome
variant with infantile spasms. J Med Genet 2005; 42:103–107.
30 Hmaimess G, Kadhim H, Nassogne MC, et al. Levetiracetam in a neonate with
malignant migrating partial seizures. Pediatr Neurol 2006; 34:55–59.
31 Dravet C. Severe epilepsies in infancy and childhood [in French]. Vie Médicale
1978; 8:548–1548.
32 Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy
(Dravet syndrome). In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA,
Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence,
4th ed. London: John Libbey; 2005. pp. 89–114.
33 Claes L, Del-Favero J, Ceulemans B, et al. De novo mutations in the sodiumchannel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum
Genet 2001; 68:1327–1332.
34 Escayg A, MacDonald BT, Meisler MH, et al. Mutations of SCN1A, encoding a
neuronal sodium channel, in two families with GEFSþ2. Nat Genet 2000;
24:343–345.
35 Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A
genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120
(Pt 3):479–490.
36 Mulley JC, Nelson P, Guerrero S, et al. A new molecular mechanism for severe
myoclonic epilepsy of infancy: exonic deletions in SCN1A. Neurology 2006;
67:1094–1095.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
166 Seizure disorders
37 Madia F, Striano P, Gennaro E, et al. Cryptic chromosome deletions involving
SCN1A in severe myoclonic epilepsy of infancy. Neurology 2006; 67:1230–
1235.
The authors describe deletions of SCN1A as a cause for Dravet syndrome. In this
case, sequencing cannot detect the genetic abnormality and these patients were
diagnosed as mutation free.
51 Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of
myoclonic-astatic epilepsy of early childhood. Neuropediatrics 2002; 33:
122–132.
38 Depienne C, Arzimanoglou A, Trouillard O, et al. Parental mosaicism can
cause recurrent transmission of SCN1A mutations associated with severe
myoclonic epilepsy of infancy. Hum Mutat 2006; 27:389.
The authors describe a parental mosaicism that can give inherited cases of Dravet
syndrome. This paper exposes the possibility of somatic or germinal mosaicism
and give new insights in the possible transmission of Dravet syndrome.
53 Dalla Bernardina B, Sgrò V, Caraballo R, et al. Sleep and benign partial
epilepsies of childhood: EEG and evoked potentials study. Epilepsy Res
Suppl 1991; 2:83–96.
39 Marini C, Mei D, Cross H, Guerrini R. Mosaic SCN1A mutation in familial
severe myoclonic epilepsy of infancy. Epilepsia 2006; 47:1737–1740.
40 Berkovic SF, Harkin L, McMahon JM, et al. De-novo mutations of the sodium
channel gene SCN1A in alleged vaccine encephalopathy: a retrospective
study. Lancet Neurol 2006; 5:488–492.
This paper suggests the role of SCN1A mutations in the post-vaccine encephalopathies.
41 Cassé-Perrot C, Wolff M, Dravet C. Neuropsychological aspects of severe
myoclonic epilepsy in infancy. In: Jambaqué I, Lassonde M, Dulac O, editors.
Advances in behavioural biology (50). New York, Boston, London: Kluwer
Academic, Plenum publishers; 2001. pp. 131–140.
42 Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy
in infancy: a randomised placebo-controlled syndrome-dedicated trial.
STICLO study group. Lancet 2000; 356:1638–1642.
43 Siegler Z, Barsi P, Neuwirth M, et al. Hippocampal sclerosis in severe
myoclonic epilepsy in infancy: a retrospective MRI study. Epilepsia 2005;
46:704–708.
44 Nabbout R. Can SCN1A mutations account for SUDEP? Epilepsia (in press).
45 Doose H, Gerken H, Leonhardt R, et al. Centrencephalic myoclonic-astatic
petit mal. Clinical and genetic investigation. Neuropadiatrie 1970; 2:59–
78.
46 Kaminska A, Ickowicz A, Plouin P, et al. Delineation of cryptogenic LennoxGastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res 1999; 36:15–29.
47 Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized
epilepsy associated with a mutation in the Naþ-channel beta1 subunit gene
SCN1B. Nat Genet 1998; 19:366–370.
48 Nabbout R, Kozlovski A, Gennaro E, et al. Absence of mutations in major
GEFSþ genes in myoclonic astatic epilepsy. Epilepsy Res 2003; 56 (2–3):
127–133.
49 Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of
worsening seizures. Epilepsia 1998; 39:5–17; Review.
50 Panayiotopoulos CP, Ferrie CD, Knott C, et al. Interaction of lamotrigine with
sodium valproate. Lancet 1993; 341:445.
52 Caraballo RH, Cersósimo RO, Sakr D, et al. Ketogenic diet in patients with
myoclonic-astatic epilepsy. Epileptic Disord 2006; 8:151–155.
54 Aicardi J, Chevrie JJ. Atypical benign partial epilepsy of childhood. Dev Med
Child Neurol 1982; 24:281–292.
55 Landau W, Kleffner FR. Syndrome of acquired aphasia with convulsive
disorder in children. Neurology 1957; 7:523–530.
56 Rapin I. Acquired aphasia in children. J Child Neurol 1995; 10:267–270;
Review.
57 Roulet E, Deonna T, Gaillard F, et al. Acquired aphasia, dementia, and
behavior disorder with epilepsy and continuous spike and waves during sleep
in a child. Epilepsia 1991; 32:495–503.
58 Roll P, Rudolf G, Pereira S, et al. SRPX2 mutations in disorders of language
cortex and cognition. Hum Mol Genet 2006; 15:1195–1207.
The authors report a genetic basis to the link between the rolandic (sylvian) seizure
disorders and speech and cognitive impairments, a well known clinical association
albeit poorly understood. The involvement of SRPX2 in these disorders suggests
an important role for SRPX2 in the perisylvian region critical for language and
cognitive development.
59 Mikaeloff Y, Jambaqué I, Hertz-Pannier L, et al. Devastating epileptic ence phalopathy in school-aged children (DESC): a pseudo encephalitis. Epilepsy
Res 2006; 69:67–79.
The authors describe a new epilepsy syndrome. There is no evidence of brain
inflammation. Status epilepticus causes bilateral temporal epileptogenic lesions
and seems to be the first expression of an epileptic encephalopathy. The identification of this syndrome should prevent useless aetiological work-up.
60 Kramer U, Shorer Z, Ben-Zeev B, et al. Severe refractory status epilepticus
owing to presumed encephalitis. J Child Neurol 2005; 20:184–187.
61 Sahin M, Menache CC, Holmes GL, et al. Prolonged treatment for acute
symptomatic refractory status epilepticus: outcome in children. Neurology
2003; 61:398–401.
62 Takanashi J, Oba H, Barkovich AJ, et al. Diffusion MRI abnormalities after
prolonged febrile seizures with encephalopathy. Neurology 2006; 66:1304–
1309.
This paper reports a non-inflammatory acute encephalopathy in which massive
neocortical involvement affects mainly the frontal lobes and seems to result from
‘glutamergic’ mechanisms.
63 Gastaut H. Clinical and electroencephalographical classification of epileptic
seizures. Clinical and electroencephalographical classification of epileptic
seizures. Epilepsia 1969; 10 (Suppl):2–13.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.