Continuous Spike Web during Sleep - (CSWS)

CONTINEOUS SPIKE WAVE IN
SLOW SLEEP(CSWS)
Presenter:
Dr Sanjida Ahmed
MD Phase B student
Pediatric Neurology & Neurodevelopment BSMMU

Sami, 6 year old female child, Only issue of non-
consanguineous parents, hailing from Mirpur, Dhaka got
admitted on 25th September with the complaints of
recurrent seizure since 1 and 1/2 years of age,
progressive deterioration of intelligence for 2-3 years,
hyperactive behavior for last 1 year. Seizure was initially
manifested as turning of head toward right side followed
by bilateral tonic clonic convulsion involving both upper
and lower limbs without bladder bowel dysfunction or
loss of consciousness. It occurred always during sleep at
5-6 months interval . Each episode persisted for 5-15
minutes..

For this illness she was treated by local doctor with Tab. PBN and Per rectal
Diazepam intermittently without any significant improvement. Then Na Valproate
was added in adequate doses but the frequency of seizure was gradually
increasing and one episode of status epilepticus occurred 6 months back which
persisted for 1 hour associated with bladder bowel dysfunction and loss of
consciousness.
At that time she visited a qualified pediatric neurologist and an EEG was done as
per advice which revealed frequent burst of epileptiform discharge in wake state
and continuous spike wave discharges with right temporal predominance in sleep
state. Then dose of Na Valproate was increased to highest level and Levetiracetam
and Clobazam was added without any significant improvement.

After that she developed multiple type of seizure during last 6 months manifested as
recurrent jerky movement in every night, recurrent fall during walking and recurrent
attack of brief arrest of activity accompanied by staring several times in a day.
Her birth history was uncomplicated and was developmentally age appropriate upto one and
half years of age. She has progressive cognitive deterioration manifested as poor school
performance and hyperactive behavioral abnormality as well. Now she reads in Play Group
and has been in the same class for the last two years.
On examination, Sami was conscious, co-operative , vitals were within normal limit, skin
survey normal. anthropometry was normal. Developmental assessment revealed normal
except cognitive impairment, neurological examination revealed poor intelligence and
behavior abnormality manifested as excessive talking, running, jumping otherwise normal.
Other systemic examinations revealed normal findings. Provisional diagnosis was Epilepsy
with Continuous spike- wave during sleep (CSWS).

After admission EEG was done which was suggestive of Continuous Spike
-Wave during Sleep. Her psychological assessment was done . It revealed
cognitive delay for 23 months (42 months level at 65 months). Behavior
assessment was done by DSM V for ADHD and result was positive. Final
diagnosis was Epilepsy with continuous spike -wave during sleep.
She was treated with inj. Midazolam drip for 3 days without any significant
improvement in EEG. Then Inj. Methyle prednisolone was given for 5 days
at a dose of 30mg/kg/day. EEG findings was improved. She was discharged
with oral prednisolone at a dose of 2mg/kg/day for 4 weeks and then gradual
tappering over 2 weeks and to continue Na Valproate and Levetiracetam
and Resperidone with plan to do MRI before next follow up.

22/9/2018 – Before Treatment
Awake EEG Sleep EEG

3/10/2018 – After Treatment
Awake EEG Sleep EEG

Introduction
• Continuous spikes and waves during slow sleep (CSWS) is an age-
related, self-limiting disorder . It was first described as “subclinical
electrical status epilepticus induced by sleep in children” in1971,
when Patry et al. (1971) described a peculiar EEG pattern occurring
almost continuously during sleep in six children, characterized by apparent
“subclinical” spike and-wave complexes lasting from months to years. Five
of the children were mentally retarded and two had no acquired language.

• Epilepsy with continuous spikes and waves during sleep (CSWS) and Landau-
Kleffner syndrome (LKS) are recognized as specific epilepsy syndromes by
International League Against Epilepsy (ILAE). They were first classified as
epilepsies and syndromes, undetermined as to whether they are focal or
generalized.
• They are now classified as epileptic encephalopathy, defined as disorders in
which the epileptic activity itself may contribute to severe cognitive and
behavioral impairment above and beyond what might be expected from the
underlying pathology alone (such as a cortical malformation), and that these
impairments may worsen over time.
• LKS and CSWS are also considered special syndromes of status epilepticus.

CSWS is characterized by:
• (1) Seizures,
• (2) Neurocognitive regression, and
• (3) An electroencephalography (EEG) pattern of electrical status
epilepticus during sleep (ESES).

EPIDEMIOLOGY
• It is a rare condition and represents approximately 0.5% to 0.6% of all childhood
epilepsy cases seen at tertiary referral epilepsy centers.
• The classical presentation at around 5 years of age, typically between age 4 and 7
years. Rarely beyond age 10–12 years.
• Onset during the first 2 years of life has been described. (Guzzetta et al., 2005;
Inutsuka et al., 2006; Ohtsuka et al., 2002).
• Boys seem to be affected more often than girls :3:2
(Eksioglu et al., 2009; Morikawa et al., 1989)

CLINICAL PRESENTATION
The classic clinical presentation :
• A child around 5 years old
• Presents with new-onset seizures
• Mild developmental problems
• Mild regression
• Behavior abnormality

What do seizures in this syndrome look like?
• Approximately 80% patient present with seizure.
• The most common seizure type seen in CSWS is focal motor .
• Focal seizures can progress to affect both sides of the brain. When this happens, the
seizure becomes focal with bilateral, usually tonic clonic seizures.
• Other seizure types include typical absence, atypical absence, atonic.
• Seizures usually happen during sleep.
• Daily or more frequent seizures are initially rare.
• When the ESES pattern appears approximately 60% of cases have several seizure types
and 70% of cases suffer several seizures per day .

Neuropsychological regression:
• Neuropsychological regression and ESES on EEG appear 2 to 3 years after
seizure onset, approximately around 7 years of age.
• Neuropsychological deficits are reported as presenting symptom in
approximately 20% of patients.
(Bureau, 1995b; Morikawa et al., 1995).

The neuropsychological deterioration involves a wide spectrum of
developmental and neurocognitive milestones:
• Decrease in overall intelligence quotient
• language deterioration in the form of a fluctuating aphasic disorder
• Hyperactive and impulsive behavior
• Learning disorders
• Memory problems
• Reduced attention span
• Aggressive or compulsive behavior
• Poor interpersonal contact
• Emotional liability
(Sarco and Takeoka, 2009; Tassinari et al., 2000, 2005; Van Hirtum-Das et al., 2006)

• Fine and gross motor skills may also be affected and dystonia, dyspraxia, ataxia,
unilateral motor deficits, and negative myoclonus are frequently considered as
most disabling problem.
(Sarco and Takeoka, 2009; Tassinari et al., 2000).

Clinical Stages of CSWS
Dormant Stage: From birth to seizure
onset.
Prodromal Stage: From seizure onset
to neuropsychologic regression
Acute Stage: From regression to
seizure freedom.
Residual Stage: After seizure
freedom.
EEG findings and cognitive
dysfunction correlate with these
clinical stages.

Investigation
• EEG
• Neuroimaging
• Psychological assessment
• Behavior assessment
• Developmental assessment

EEG
• Electroencephalographic features during wakefulness, the EEG shows
focal/multifocal spikes that increase in frequency during the acute stage.
• The hallmark EEG feature of CSWS is ESES.
• ESES is characterized by (1) marked potentiation of epileptiform discharges
during non-REM sleep, leading to (2) a (near)-continuous, bilateral, or
occasionally lateralized slow spikes and waves, (3) and these spikes and waves
occur “during a significant proportion” of the non-REM sleep with a threshold
ranging from 25% to 85%.
(Beaumanoir, 1995; Boel and Casaer, 1989; Bureau, 1995a; Dalla Bernardina et al., 1978; Hirsch et al., 1990; Inutsuka et al.,
2006; Laurette and Arfel, 1976; Loddenkemper et al., 2009b; Patry et al., 1971; Saltik et al., 2005; Tassinari et al., 2000, 2005;
Van Hirtum-Das et al., 2006; Yan Liu and Wong, 2000; Yasuhara et al., 1991)

EEG
Spike-Wave Index Assessment:
• The spike-wave index (SWI) quantifies the frequency of spiking in the EEG tracing.
• Most authors loosely refer to this term as the percentage of non-REM sleep occupied by
spike waves, without defining the exact method for calculating it.
• Others define the SWI as the percentage of 1-second bins with at least one spike and
wave relative to the total 1-second bins in non-REM sleep.
The SWI is higher in the first sleep cycles, and progressively decreases through the night.
(Inutsuka et al., 2006; Tassinari et al., 2000, 2005; Saltik et al., 2005).
(Aeby et al., 2005; Tas et al., 2009).

EEG
Cut-Off Value:
• The initial definitions of ESES proposed that no less than 85% of the total
duration of slow sleep should be occupied by spike-waves .
• This cut-off value has been followed by several authors while other authors used lower
cut-off percentages.
• The International League Against Epilepsy does not refer to any particular threshold
and only requires that spike-waves be “continuous” and “diffuse” which leads to
heterogeneous and variable use of cut-off values by the professionals caring for these
children.
(Commission on Classification and Terminology of the International League Against
Epilepsy, 1989).

For example:
• In a series of 15 patients with ESES pattern (Inutsuka et al., 2006), an SWI of at least 60%
was required to meet the diagnosis.
• A case report (Kobayashi et al., 2006) considered an EEG with an SWI of 41.4% compatible
with CSWS.
• A series of 102 children with sleep activated spikes and waves (Van Hirtum-Das et al., 2006)
considered an SWI of 25% or more as an inclusion criterion.
• Others have also included sleep-potentiated spiking as “sleep overactivation pattern” or “near-
ESES” referring to patients electroclinically highly suspected for CSWS, but with an SWI below
the 85% threshold (Saltik et al., 2005).
• Tassinari et al.. suggested assessment with three different EEGs over a period of at least 1
month for diagnosis.

Etiology and Pathophysiology
Regarding the aetiology, the ILAE classification reported that “it is unknown whether these
conditions are idiopathic, symptomatic or both”.
The exact cause of CSWS is unknown, but there are two factors that have been implicated.
• First: Early developmental lesions of the brain has been shown.
• Second : an increasing number of genetic associations of unclear significance have also been
described.
• Many (62%–74%) patients reportedly have normal neuropsychological
and motor function before the onset of ESES.
(Morikawa et al., 1989; Tassinari et al., 1992), associated structural defects (Buzatu et al., 2009;
Guerrini et al)

Etiology and Pathophysiology
• Early developmental lesions: Perinatal vascular lesions and related conditions
• Cortical malformations
• Prenatal or perinatal thalamic lesions
• Abnormal/delayed myelination and
• Rare cases have also been associated with neurodegenerative disorders and the
use of topiramate (Montenegro and Guerreiro, 2002).
(Guzzetta et al., 2005; Rudolf et al., 2009; Tassinari et al., 2000; Das et al., 2006).

Management
To Treat or Not to Treat Epileptiform Activity:
• The relationship of epileptiform activity in the EEG with neuropsychological function
is a matter of debate. Near-continuous epileptiform discharges are considered to be
related to neurocognitive regression in CSWS.
• Many studies demonstrate that epileptiform activity is deleterious for learning and
memory under certain experimental conditions, indirectly supporting the option of
treatment.
Modification of the Natural Course of the Disease by Treatment:
• Treatment goals of CSWS include not only improved seizure control, but also a
reduction in EEG abnormalities and potentially improvement of neurocognitive
function or at least prevention of further regression.
• Several studies suggest that long-term neurocognitive function can significantly
improve once epileptiform discharges are reduced.
However, to date, there is no scientific evidence for or against treatment of
interictal spikes.

TREATMENT
• Antiepileptic Drugs: The most common antiepileptic drugs used are
Steroids, valproic acid or high dose diazepam,
clobazam, ethosuximide, levetiracetam.
• Ketogenic diet may be benificial.
• Surgery :If seizures persist despite medication, surgeries such as multiple
subpial transections, lesionectomy and hemispherectomy may be done.

Na Valproate
• Valproate, ethosuximide, and several benzodiazepines may be first-line
antiepileptic drugs based on case series.
(Inutsuka et al., 2006; Larrieu et al.,1986; Van Lierde, 1995; Yasuhara et
al.,1991)
• Recently, Inutsuka et al. (2006) studied the effects of traditional AEDs on
the EEG pattern of 15 patients. VPA monotherapy was initially up-
titrated until the serum level was above 100 g/mL, if no side effects
occurred. ESES/CSWS disappeared completely in seven patients (47%)
and no relapses occurred.
• Since the first description of ESES/CSWS by Patry et al. (1971), high-dose
valproate (VPA) has been considered to be a first-line therapy for patients
with CSWS syndrome.

Benzodiazepine
• Inutsuka et al. (2006), in a recent comparative study, investigated the effects of a short
cycle of DZP therapy (0.5-1 mg/kg per day, given orally or rectally before nocturnal
sleep for 6-7 days) in four patients in whom VPA or a combination of VPA and ESM had
failed. DZP was initially effective in two cases, but both relapsed within a year. It was
suggested that short-term treatment with DZP in ESES/CSWS patients can be valuable
but, due to a lack of sustained long-term benefit, treatment should be repeated after any
relapse. This approach has the advantage of avoiding long-term side effects.
• The same conclusion was reached by Kramer et al. (2008) who used DZP at a dose of
0.75-1 mg/kg/day orally for three weeks in eight patients with ESES/CSWS. Only three
patients (37%) responded to DZP and they all relapsed within six months.

Benzodiazepine
• Uncontrolled case series of nighttime high-dose oral or rectal diazepam
(1 mg/kg up to doses of 30 mg per dose) have been reported to
decrease nocturnal spiking by several authors although frequent relapses
prompt new cycles of treatment.
• Among high-dose benzodiazepines, the preferred drug (41.3%) was diazepam 1
mg/kg for one night followed by 0.5 mg/kg/day. The second choice (16.9%) was
clobazam 1 mg/kg for one night followed by 0.5 mg/kg/day. More than half of
the respondents indicated that high-dose benzodiazepines were maintained for
1–3 months and tapered over 1–3 months.
(Epilepsia, 55(7):1099–1108, 2014)
• Epilepsia, 55(7):1099–1108, 2014
• Epilepsia, 55(7):1099–1108, 2014

Sulthiame
• The use of sulthiame (STM) was first assessed in 2006 (Wirrell et al., 2006) in a five-
year-old male with language delay, nocturnal seizures and ESES/CSWS. After only
one month of STM therapy (10 mg/kg/day), ESES/CSWS disappeared completely and
language improved significantly. The authors suggested that STM may be indicated in
cases resistant to VPA. One advantage of STM is that it can be titrated up quickly and its
effect on EEG can be assessed within four weeks.
• It was suggested that a brief trial of STM should be considered before using steroids in
“idiopathic” ESES/CSWS cases. Despite the suggestion that the use of STM for
ESES/CSWS is acceptable, it is difficult to infer general conclusions from a single case.

Levetiracetam
• Levetiracetam (LEV), seem to be effective as treatment for ESES/CSWS.
• In 2003, Hoppen et al. (2003) described a five-year seven-month-old boy with
pharmacological refractory ESES/CSWS which rapidly disappeared after
treatment with LEV.
• One year later, Capovilla et al. (2004) used LEV in three children with
symptomatic focal epilepsy and ESES/CSWS pharmacoresistant to old AEDs.
ESES/CSWS disappeared completely in two children, while in the third child
there was only a mild improvement of the EEG pattern during sleep.

Levetiracetam
• Abbey et al. (2005) studied the effects of LEV in 12 patients (seven pharmacoresistant and
five nonpharmacoresistant) using a titration scheme consisting of 25 mg/kg/day during the
first two weeks, followed by 50 mg/kg/day for six more weeks. Seven children (58.3%)
showed a significant improvement on EEG.
• In 2011, Chhun et al. (2011) studied 102 patients with refractory seizures in a prospective
open-labelled trial in order to study the efficacy and safety of LEV as adjunctive therapy. Six
patients were diagnosed with ESES/CSWS syndrome. At three and six months, patients with
ESES/CSWS exhibited the highest responder rate (67%; 4/6). Three patients were seizure-
free, one had 92% seizure reduction and showed behavioural and cognitive improvement, two
had normal EEG, and two had persisting ESES/CSWS. The authors concluded that, in spite of
a small sample, ESES/CSWS is a good candidate for a randomisedcontrolled trial with LEV.

Levetiracetam
• Another paper published in 2011 (Atkins et al., 2011) evaluated the add-on effect of
LEV treatment on the EEG and clinical status of 20 children with ESES/CSWS
refractory to other conventional AEDs (VPA, CLB, STM, LTG, and ESM). The
population was composed of seven cryptogenic, seven symptomatic and six
idiopathic cases. All children received 45-50 mg/kg/day of LEV as add-on
treatment for a follow-up time of 18-53 months. The authors observed an
electroencephalographic response in 11 patients; eight patients demonstrated a
response lasting for more than 12 months and three children showed only a partial
response from six to 12 months. The authors concluded that add-on therapy with LEV
is more effective in children with ESES/CSWS resulting from a known underlying
structural brain lesion.

Immune Modulation Therapy
• Corticosteroids and intravenous immunoglobulins have shown
improvement in selected cases and, in some cases, lead to
complete resolution of CSWS. Once CSWS is recognized,
usually during the acute phase, corticosteroid treatment should
be considered.

• Okuyaz et al. (2005) reported a four-year-old girl with ESES/CSWS and epilepsy
refractory to several AEDs, including VPA, BDZ, and LTG. She was treated successfully
with high-dose intravenous methylprednisolone (the first three days at 30 mg/kg/day,
the following two days at 20 mg/kg/day, and then gradually reduced from 10
mg/kg/day to 5 mg/kg/day over four consecutive days) with VPA, CLB, and LTG being
continued at the same dose during and after corticosteroid therapy. On day seven, a
dramatic clinical and EEG improvement was observed. After high-dose intravenous
methylprednisolone, prednisolone was administered orally (2 mg/kg, daily) for two
months and then gradually discontinued. Even after 6 months followup no ESES was
found.

• In a series of 44 children with a pattern of ESES and clinical presentations
of variable severity, prolonged corticosteroid treatment (hydrocortisone 5
mg/kg/day during the first month, 4 mg/kg/day during the second month, 3
mg/kg/day during the third month, and 2 mg/kg/day during the next 9
months, followed by slow withdrawal for a total treatment duration of 21
months) led to reductions of seizures or neuropsychological improvement
in 34/44 (77.3%) cases, with 34 achieving complete control of seizures
and normalization of EEG abnormalities in 21 patients.

Six Months Dosing Schedule for Oral Prednisone
2 mg/kg/day for 1 month (maximum dose 60 mg)
1.5 mg/kg/day for 1 month
1 mg/kg/day for 1 month
1 mg/kg every other day for 1 month
0.75 mg/kg every other day for 1 month
0.5 mg/kg every other day for 1 month
Ref. (Veggiotti P, Pera MC, et al…)

• The intramuscular administration of 0.001–0.04 mg/kg/day of
adrenocorticotrophic hormone was reported to be effective in 1 out of 4 patients.
The side effects of corticosteroid treatments usually limit its long-term use.
• Intravenous immunoglobulin treatment was associated with improvements in 3
out of 9 patients with CSWS. In another series, the neurocognitive function
of 1 out of 3 patients with CSWS improved following the administration of
intravenous immunoglobulins. However, there is probably a publication bias of
positive results, and the high cost and risk of complications associated with
immunoglobulins make their role in the treatment of CSWS unclear.

Ketogenic diet
• Recently, the ketogenic diet (KD) was also assessed as a potential therapy for
ESES/CSWS.
• In 2009, Nikanorova et al. (2009) tested the KD in five children aged between
eight and 13 years with ESES/CSWS refractory to conventional AEDs,
including LEV and steroids. Concomitant AED treatment remained unchanged
during the diet. EEG monitoring after 24 months showed remission of
ESES/CSWS in one child and a mild decrease of SWI in another child. The
KD did not seem to influence neuropsychological outcome since IQ scores were
unchanged at the end of the follow-up period.

Other Drugs
• Other drugs with therapeutic success in case reports or small case series
included lamotrigine, acetazolamide and clonazepam.
• Because of the severity of the seizure disorder, polytherapy is frequently
necessary.
(Guerrini et al., 1998; Van Lierde, 1995,; Aeby et al., 2005; Wang et al., 2008), ),

Carbamazepine, Phenytoin, and Phenobarbitone are usually avoided because
they are thought to lack efficacy or may worsen CSWS.
Carbamazepine has been associated with generalization of spike and waves.
(Capizzi et al., 1995; Lerman, 1986,De Negri, 1997; Guzzetta et al., 2005; Okuyaz et al., 2005; Van
Lierde, 1995)

Surgery
• Surgical management should be considered in patients with an early
unilateral brain lesion, even if the EEG epileptiform activity is generalized.
• Multiple subpial transection consists of multiple small superficial parallel
cuts in the cortex, severing only the local corticocortical connections in an
attempt to disrupt local epileptic circuitry, and has been reported to recover
age appropriate speech in seven of a series of 14 patients with AEA .
(Morrell et al., 1995), whereas a less-dramatic language improvement was found in other
series (Cross and Neville, 2009; Irwin et al., 2001)

Surgery
• Hemispherectomy and focal resective epilepsy surgery have been shown
to be highly beneficial in controlling seizures and improving the EEG
pattern in small series of patients with ESES of structural etiology.
• Furthermore, a tendency toward neurocognitive improvement was found
in three of five patients after surgery (Loddenkemper et al., 2009b). Data
on the long-term neuropsychological outcome of surgically managed
patients are not available.
(Battaglia et al., 2009; Guzzetta et al., 2005; Loddenkemper et al., 2009b).

Epileptic Disord, Vol. 14, No. 1, March 2012

SUGGESTED INITIAL THERAPY TO CONTROL ESES AS RAPIDLY AS POSSIBLE
NONLESIONAL CAUSE:
Clobazam, for 3 months; if this does not work, follow with corticosteroids
Corticosteroids:
First: pulse IV methylprednisolone (20 mg/kg/day for 3 days) and monthly for 5 to 6 months; followed
by either ethosuximide or levetiracetam
If only partial response, or adverse effects preclude ongoing therapy, clobazam plus ethosuximide, or
sulthiame, or levetiracetam
SYMPTOMATIC/ LESIONAL CAUSE:
Corticosteroids initially; refer to previously listed corticosteroid material for nonlesional cause.
Ref. (Veggiotti P, Pera MC, et al…)

Outcome
• The natural history of seizures suggests that clinical seizures cease
spontaneously, typically around puberty.
• The natural history of the electrographic finding of ESES suggests that ESES
ceases around age 11 years and thus has been described as a self-limited
condition.
• The EEG subsequently can continue to show focal discharges. Typically,
improvement of clinical seizures and ESES is associated with cognitive
improvement, though most patients continue to demonstrate some degree of
impairment.
• It has been proposed that frequent EEG spikes and ESES patterns are
associated with poor neurocognitive outcome; thus, it has been presumed that
improving the EEG appearance may positively impact cognitive outcome.
• According to some reports, duration of ESES seems to be the main predictor
of neurocognitive function,

Conclusions
• Continuous spike and wave during slow wave sleep (CSWS) is an
epileptic encephalopathy that presents with neurocognitive regression and
clinical seizures, and that demonstrates an electroencephalogram (EEG)
pattern of electrical status epilepticus during sleep.
• While the pathophysiology is not completely understood. There are known
genetic and developmental associations with this condition.
• Traditional anticonvulsants as well as hormonal therapies are used with
mixed results.
• The end goal of treatment remains to preserve neurocognitive
development.

Continuous Spike Web during Sleep - (CSWS)

Continuous Spike Web during Sleep - (CSWS)

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