Review

Approach to refractory childhood seizures

Up to 40% of children with epilepsy will not achieve seizure freedom with antiepileptic drugs. Refractory
epilepsy has devastating consequences, both for the child and their carers. Early recognition of those with
refractory epilepsy, in order to minimize these consequences, has proven difficult. Currently, most patients
with refractory epilepsy wait many years before being referred for evaluation at a specialist center. The
clinicians taking care of children with epilepsy must have a clear approach to both the diagnosis and
appropriate pathways for investigation of patients with refractory seizures. We present a structured
approach to both the diagnosis and evaluation of refractory seizures; we review the current therapeutic
options available to treat those suffering from refractory seizures and explore potential therapeutic options
for the future.

keywords: children n deep-brain stimulation n diet n epilepsy n refractory n surgery Bláthnaid McCoy†
n vagal-nerve stimulation
& Selim R Benbadis1
1
Departments of Neurology
Epilepsy, defined as recurrent unprovoked sei­ a definition of refractory seizures that one hopes & Neurosurgery, University of South
Florida School of Medicine, Tampa
zures, occurs in 1–2% of the pediatric popu­ will provide clarity and improve time­liness of General Hospital, FL, USA
lation [1,2] . The peak incidence of childhood these referrals. It requires the clinician who is †
Author for correspondence:
Division of Neurology, the Hospital for
epilepsy occurs in the first year of life, which taking care of the child with epilepsy to have a Sick Children, 555 University Avenue,
coincides with a critical time in neuronal clear approach to both the diagnosis and appro­ Toronto, M5G 1X8, Ontario, Canada
Tel.: +1 416 813 7500
development [1,2,3] . priate pathways for investigation of patients Fax: +1 416 598 2092
Up to 40% of children with epilepsy will suffering from refractory seizures. blathmccoy@yahoo.co.uk;
not achieve seizure freedom with antiepileptic In order to develop a successful approach to blathnaid.mccoy@sickkids.ca

drugs (AEDs) [4–7] . Early diagnosis of refrac­ refractory seizures, we must first answer two
tory seizures is vital, as is recognition of the next questions for each patient. Does this patient have
appropriate therapeutic step for the patient. epilepsy, and is it refractory?
Refractory epilepsy has devastating conse­
quences. It impacts upon every aspect of the Re-evaluating the diagnosis
child’s development, including their academic of epilepsy
performance and social development [8,9] . It The diagnosis of epilepsy is often difficult [20] .
affects those involved in caring for the child, It has been estimated that 20–30% of patients
with many carers experiencing comorbid com­ referred for management of refractory seizures
plications, commonly depression [9,10] . Siblings do not have epilepsy [21,22] . Many paroxysmal
often experience a negative impact [10] and, events may be mistaken for seizures, such as
within the classroom, many teachers fail to rec­ syncope, tics or migraine [23] .
ognize the impact of seizures on education [11–15] . Studies of patients investigated for possible
Uncontrolled seizures can result in a decline in diagnosis of epilepsy demonstrated that between
school performance, even when they are brief 10 and 40% of those investigated had non­
and involve subtle symptoms [8,15] . epileptic seizures [24–26] . In one study, over a third
Patients with refractory seizures are exposed of the children who had a diagnosis of intractable
to multiple AEDs, often many drugs in combi­ seizures and were referred to a specialist center for
nation, which has a significant negative impact management, were subsequently diagnosed with
on cognition [8,10,15] . Early recognition of those nonepileptic events [27] ; many were on multi­
with refractory epilepsy, to minimize these ple AEDs. Psychogenic nonepileptic seizures
consequences, has proven difficult [4,16–19] . (PNES) are events that clinically resemble epi­
Currently, most patients with refractory epi­ leptic seizures, without electrographic evidence of
lepsy wait many years before being referred for seizure on an EEG. The events are psycho­logical
evaluation at a specialist center. Recently, the in nature and often thought of as a conversion
International League Against Epilepsy presented disorder. The incidence of PNES is highest in

10.2217/THY.10.51 © 2010 Future Medicine Ltd Therapy (2010) 7(5), 497–506 ISSN 1475-0708 497
Review McCoy & Benbadis

people aged 15–24 years, with a strong female definition. It does not allude to seizure frequency
preponderance described [28] . Nonepileptic sei­ as part of the definition, acknowledging the fact
zures are more common in patients with epilepsy; that infrequent seizures can have a significant
therefore, clinicians caring for children with epi­ impact on lifestyle, wellbeing and independence.
lepsy that is difficult to treat, must pay heed to a Key to accurate and early detection of refrac­
change in seizure semiology or particular features tory seizures is determination of patients most
suggestive of nonepileptic events. Correct diag­ at risk. Several factors have been investigated
nosis and appropriate treatment of PNES will as predictors of development of intractability
avoid inappropriate exposure to AEDs and their (Box 2) . Failure of response to the first AED accu­
potential side effects, and may avoid escalation rately predicts those who will develop intractable
of underlying psychological issues. seizures [32,33] . Certain epilepsy syndromes are
A careful history of the events and triggers associated with a higher risk of medical intrac­
may lead a clinician to suspect them to be tability in children, for example West syndrome
non­epileptic in nature, but the conclusive test and Landau–Kleffner syndrome [34–37] .
involves video EEG monitoring to capture one A retrospective study, examining 10 years of
or two typical events on both EEG and video. patients at a Canadian center, concluded that
Previous authors have suggested guidlines for multiple seizure types (hazard ratio of  6.5),
clinicians for detecting features suspicious for mental retardation at onset of seizures (hazard
PNES [29] . A recent presentation at the American ratio of 7.2) and seizure recurrence in the first
Academy of Neurology Meeting presented a 6–12  months of treatment were predictive of
simple scoring system that can aid clinicians intractability [38] . Similar risk factors have been
in identifying those who may witness clinical reported by others [39] .
events that are suspicious for nonepileptic sei­ The age of onset of seizures is not as clearly
zures  [30] . Their scoring system for a witnessed predicative. An initial study by one group con­
event included eight clinical features to assist cluded that seizure onset in the first year of life
in recognizing a likely nonepileptic event: wax­ was the predominant predictor of the develop­
ing and waning symptoms, eye closure, side- ment of intractability; their subsequent ana­lysis
to-side head movements, duration longer then of the patients, according to their syndromic
3  min, pelvic thrusting, crying, out-of-phase diagnosis, did not support this finding [4] . Other
limb movements and patients carrying an age- authors have also concluded that seizure onset in
inappropriate soft toy. Commonly encountered the first year of life is not clearly associated with
clinical features suggestive of either PNES or the development of intractability [37] .
epileptic seizures are reviewed in Box 1. The predictive features in Box 2 are apparent
within the first few months of the patient’s epi­
Establishing those with refractory lepsy in many instances. Once two appropriate
seizures at an early stage AEDs have been trialed in adequate doses and are
Refractory epilepsy was recently defined by the unsuccessful in controlling seizures, the chance
International League Against Epilepsy as fail­ of a third agent being successful and providing
ure to achieve sustained remission following a seizure freedom is less than 5–10% [18,33,37,40,41] .
trial of two or three appropriate drugs [31] . This Diagnosis or suspicion of intractability, which
is similar to the definition used by many clini­ leads to referral to a tertiary center for specialist
cians prior to this, defining refractory seizures assessment for the consideration of surgical or
as failure of two or more AEDs and the occur­ other interventions is delayed by many years in
rence of one or more seizures per month over most. Of the patients referred for epilepsy sur­
18 months  [19] . The new definition, from the gery in the USA, the average duration of their
International League Against Epilepsy, specifies seizures prior to referral was 18 years, with a
selection of the appropriate AED as part of the range from 2–58 years [42] .
Ongoing medical therapy exposes the patient
Box 1. Clinical features of events suspicious for psychogenic to increased risk of adverse drug responses and
nonepileptic seizures versus epileptic seizures. side effects, and prolonged medical therapy with
ƒƒ Psychogenic nonepileptic seizure: AEDs can lead to development of tolerances,
-- Tongue-tip bite, longer then 3 min, eyes closed, side-to-side head movement, which may explain the loss of drug efficacy of
gradual onset, fluctuating and no injury most AEDs with prolonged use [43,44] . Undue
ƒƒ Epileptic seizure: prolongation of medical therapy, despite poor
-- Severe tongue bite/mouth injury, eyes open, automatisms, injury seizure control, is not justified in the face of
and incontinence viable surgical options to treat these children [45] .

498 Therapy (2010) 7(5) future science group

 Approach to refractory childhood seizures Review
It is probably an oversimplification to assign Box 2. Predictors of development of refractory seizures.
patients to being either refractory or not, given ƒƒ Patient factors:
the heterogeneous nature of those patients with -- Intellectual or developmental delay at presentation
epilepsy. Several studies of the natural history of -- Structural malformation evident on imaging
epilepsy have found that patients with epilepsy -- Seizure onset under 1 year of age
may fit into each of these categories at different ƒƒ Epilepsy factors:
periods in time. This finding is particularly true -- Epileptic syndrome associated with intractability, multiple seizure types,
when one considers seizures in children. A study status epilepticus and failure to respond to first antiepileptic drug
carried out in Finland followed 144 children pre­
senting with seizures from diagnosis for an average unit offers many advantages. Tapering of AEDs,
of 37 years  [46] . Only 16% of the patients were often required to ensure seizures are obtained
immediately seizure free and remained so, unin­ during the stay, can be safely undertaken in
terrupted by relapse, and only 19% were treatment the hospital setting with close nursing care and
resistant throughout, without ever experiencing access to emergency treatment. Video EEG
a remission. The remaining patients had some allows lateralization and localization of the epi­
periods of seizures and some periods of remission. leptogenic zone. Seizure semiology from video
recording can allow classification of the patient’s
Evaluating children with seizure type and may guide therapy. At times,
refractory seizures subtle, brief or nocturnal seizures are identified
„„ Presurgical evaluation that were not previously recognized. Prolonged
All patients with refractory seizures should be recording of the interictal activity during wake­
referred to a specialist center for further inves­ fulness and sleep is obtained. It offers an objective
tigation of their seizures and for advice regard­ way of assessing response when new treatments
ing therapy. An approach to their assessment is are introduced.
outlined in Box 3. Newer methods of EEG ana­lysis, such as
A comprehensive history must be obtained; dipole ana­lysis and EEG source imaging, exist.
a detailed drug history is important for iden­ These provide us with additional ability to local­
tifying if appropriate AEDs were received, and ize the epileptogenic zone, particularly in patients
adequate doses and therapeutic drug levels were with extratemporal-lobe epilepsy, who can be a
obtained. Physical examination may lead to very difficult group to undertake surgery in,
further investigations, such as the detection of owing to the epileptogenic zone being located
neuro-cutaneous stigmata, suggesting tuberous near to the eloquent motor, sensory and language
sclerosis, or the presence of subtle asymmetry in regions of the brain [51,52] .
power or fine motor skills, indicating a possible Analysis of video EEG categorizes the patient
laterality of seizures causing functional deficits. with refractory seizures as having focal or gener­
Further investigation of etiology is often patient alized onset of seizures [53] . For the patient with
specific, but will generally include baseline blood generalized onset epilepsy, the options for fur­
and urine ana­lysis for inborn errors of metabolism, ther therapy decision may be considered once
karyotype ana­lysis, fragile‑X and cerebro­spinal appropriate imaging and video EEG monitoring
fluid (CSF) ana­lysis. A child presenting with has been performed. They may be a candidate
treatment-resistant atypical absence seizures and for further medication trial (with low chance
a history of early morning seizure clustering may of success), vagal-nerve stimulation (VNS) or
have glucose transporter 1 deficiency syndrome
and a low ratio of CSF to serum glucose. Many Box 3. Approach to refractory seizures.
advocate that CSF ana­lysis should be performed
ƒƒ Referral to specialist epilepsy center
in all children with refractory seizures to outrule
ƒƒ History and physical examination
this condition, which has a favorable response to
ƒƒ Directed diagnostic investigations
treatment with the ketogenic diet [47,48] . A recent ƒƒ Scalp video EEG monitoring
review of the clinical and genetic spectrum of ƒƒ Neuroimaging – brain MRI (epilepsy protocol)
glucose transporter 1 deficiency highlights the ƒƒ Functional assessment – language lateralization and neuropsychology
importance of lumbar-puncture testing, as it can ƒƒ Review results with expert panel
dramatically reduce diagnostic delay and allow an ƒƒ Not surgical candidate – consider vagal-nerve stimulation or dietary options
early start of the ketogenic diet [49] . ƒƒ If potential surgical candidate
Video EEG monitoring forms the cornerstone -- Palliative – corpus callosotomy and multiple subpial transections
of any assessment for refractory seizures [50] . -- Curative – lesionectomy/magnetoencephalography clusterectomy/invasive EEG
Admission to an in-patient epilepsy monitoring monitoring and resection

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Review McCoy & Benbadis

the ketogenic diet. For children with intrac­ field is not distorted by the skull defects and CSF
table seizures that cause drop attacks, a corpus collections, which can lead to false localization
callosotomy may be considered as a palliative on scalp EEG [57] .
surgery procedure. These patients often have Functional imaging with ictal SPECT and PET
many seizure types and the drop attacks can scans are established techniques in epilepsy local­
occur multiple times per day, leading to repeated ization. The imaging reflects the seizure-related
injury necessitating a protective helmet be worn. changes of cerebral perfusion, glucose metabolism
Significant improvement of quality of life can and neuro-receptor status. These techniques are
be obtained with callosotomy; although seizure increasingly available in many centers and can be
freedom is rare. especially useful where there is no MRI-detected
If the ana­lysis of video EEG monitoring lesion. Further detailed discussion is beyond the
shows a focal/lateralized onset of seizure activity, scope of this review; an up-to-date publication on
workup for potentially curative epilepsy surgery the topic is recommended [58] .
is appropriate. This is best performed in a spe­ Functional assessment with lateralization of
cialist center with appropriate expertise to per­ language and assessment of memory function is
form and analyze the detailed imaging sequences imperative. Neuropsychological assessment is per­
required. Neuroimaging provides detailed formed for each patient. The Wada test has rou­
structural ana­lysis to identify discrete lesions or tinely been used to assess and lateralize language
regions of potential cortical malformation that and memory before epilepsy surgery [59] . This
may represent epileptogenic zones. It can also study requires an intra-carotid injection of amo­
be used to provide details of eloquent regions of barbital sodium. Blood oxygen level-dependent
the brain involved in motor, sensory, language functional MRI provides a noninvasive method
and memory function. It provides us with a of assessing language lateralization and memory.
non­invasive technique to assess the relationship Many studies have demonstrated that functional
between these eloquent regions and the epilepto­ MRI is a suitable noninvasive replacement for
genic zone. MRI is better for the detection of Wada testing of language lateralization  [60,61] . A
subtle structural abnormalities than CT. MRI recent study has demonstrated functional MRI
with a specified epilepsy protocol is the imaging can also be used instead of Wada to predict
study of choice and is the mandatory primary postoperative memory changes in temporal-lobe
imaging modality according to the International epilepsy surgery patients [62] .
League Against Epilepsy guidelines [54] . Once the investigations are complete, a multi­
Newer 3‑Tesla magnetic resonance machines disciplinary group in a specialist epilepsy surgery
have finer imaging resolution to identify subtle center should review the data. From this review of
focal abnormalities in epilepsy patients. MRI the data, a number of possible recommendations
techniques, such as diffusion tensor imaging, can arise. First, the patient is not a suitable can­
allow detailed views of white-matter tracts and didate for surgery and options of VNS, ketogenic
detection of subtle abnormalities in white mat­ diet or continued medical therapy are discussed,
ter  [55] . The absence of a lesion or structural and a specific plan is tailored for each patient.
abnormality on imaging does not preclude sur­ Second, the patient may be a surgical candidate
gery. Other tests, such as scalp, and invasive but further details are required regarding the
EEG monitoring and magnetoencephalogra­ localization of the epileptogenic zone and of its
phy (MEG), can be utilized to provide adequate relationship to the eloquent cortex. In these cases,
localization information for resective surgery. invasive EEG monitoring is recommended with
Magnetoencephalography is an increasingly subdural EEG electrode placement. Information
available neuroimaging technique, which is use­ obtained from invasive monitoring is used to guide
ful in evaluating intracranial neural activity and specific resections. Third, the patient is a candi­
functional mapping. It is a technique that maps date for resective surgery of a structurally abnor­
interictal magnetic dipole sources onto MRI mal region, which is remote from the eloquent
to produce magnetic source imaging. A recent cortex. This resection may also include a cluster
review of MEG outlined its role in epilepsy sur­ as defined by MEG. Finally, the surgery may be
gery, both in localizing the epileptogenic zone considered as a palliative procedure rather than a
and in functional mapping of the eloquent cor­ potentially curative one. As discussed previously,
tex [56] . MEG is also useful in those with per­ corpus callosotomy may be performed for drop
sistent seizures following resective surgery. In attacks or multiple sub-pial transections may be
these patients, it has been suggested that MEG performed when resective surgery is not possible,
is superior to scalp EEG, because the magnetic owing to the location of the epileptogenic zone in

500 Therapy (2010) 7(5) future science group

 Approach to refractory childhood seizures Review
relation to the eloquent cortex. Any recommen­ profile. Its efficacy has been reported in a recent
dation is discussed in detail with the patient and double-blind randomized placebo-controlled
their family with appropriate discussion of risks study [66] . Glauser et al. reported a 32% reduc­
and benefits, and a consensus decision is reached. tion in seizure frequency with rufinamide and a
For those patients in whom surgical resection low incidence of adverse effects [66] . This novel
is possible, they have the best chance of obtain­ agent provides hope in the treatment of devastat­
ing seizure freedom. For those patients who are ing refractory epilepsy and is suitable for many
not candidates for potentially curative surgery, seizure types, which may lead to broadening of its
the decision regarding the appropriate next step applications in the future.
can be difficult. Deciding on an AED versus
considering a trial of ketogenic diet or implan­ „„ Vagal-nerve stimulation
tation of a VNS device must be tailored for each Vagal-nerve stimulation is a useful treatment in
patient. Seizure freedom is difficult to obtain in refractory seizures. It utilizes a small implanted
this group, but significant improvements in sei­ device that stimulates the left vagus nerve inter­
zure frequency and seizure duration and overall mittently with an electrical stimulus. The exact
quality of life can be obtained. mechanism of its antiseizure action is not known
but it has been demonstrated to affect blood flow
When epilepsy surgery is not to different parts of the brain and to affect cer­
an option tain neurotransmitters. The device is generally
„„ Pharmacotherapy well tolerated with side effects described as an
The last decade has seen a significant increase in alteration in quality of voice when the stimulus
the number of AEDs available for the treatment is being delivered to the vagus nerve, hoarseness,
of epilepsy [63] . These newer agents are associated cough, dyspnoea and parasthesia. Seizure free­
with fewer side effects; however, they have not dom is rarely achieved, but it is associated with
shown an improved efficacy. improvement in seizure frequency and improved
Despite the low chance of a third AED being quality of life. The reduction in seizure fre­
successful if two have failed, many more AEDs quency achieved is similar to that achieved with
are often trialed in patients where no other options newer add-on drug therapies for refractory epi­
are deemed appropriate or when they have been lepsy [67,68] . The improvement in quality of life is
trialed and been without success. Any previous not clearly established. A recent prospective study
medication or combination of medications that examined VNS efficacy and reported that almost
had some success are often trialed. The pediat­ half of those treated with VNS had a greater than
ric neurologist caring for these children is always 50% reduction in their seizure frequency [69] .
seeking novel medications that may show promise. The same group examined the impact of VNS
One example of refractory and catastrophic on the quality of life for the patients, and did
epilepsy of childhood is Lennox–Gastaut syn­ not detect a significant improvement with VNS
drome. Considered by many as an epileptic after 1 year. The authors acknowledge that their
encephalopathy, this is a symptomatic general­ study population represents children with severe
ized epilepsy syndrome. Children present with intractable epilepsy, which may not be represen­
multiple seizure types and nonconvulsive status tative of the entire population treated with VNS.
epilepticus is common. They have significant cog­ Furthermore, they suggest the lack of statistically
nitive impairment with moderate-to-severe intel­ significant improvement in 1 year may represent
lectual disability and behavioral disorders, such as a cessation in further deterioration in quality of
autism, are common. Lennox–Gastaut syndrome life, and warrants longer follow-up. Anecdotally,
is difficult to treat [64] . Many of these children are it is our observation that a significant majority
exposed to poly­pharmacy in an attempt to treat of parents report an observed improvement in
seizures. Some novel AEDs are emerging for this the level of alertness and responsiveness when
condition. One such AED is rufinamide, which their child has a VNS placed, independent of an
was approved by the US FDA for the treatment objective reduction in seizure frequency.
of Lennox–Gastaut syndrome in children over
4 years of age, in January 2009. It is structurally „„ Ketogenic diets
different from other AEDs. Its exact mechanism The ketogenic diet, modified Atkins diet and
of action is unknown, but it has been reported to low-glycemic-index diet provide us with an
act on sodium channels and prolong their state additional therapeutic option for children with
of inactivation, preventing repetitive firing [65] . intractable seizures. Most clinical data exist for
Rufinamide has good safety and a low side-effect the traditional or classic ketogenic diet. The more

future science group www.futuremedicine.com 501

Review McCoy & Benbadis

modern adaptations, such as the modified Atkins first 11 years from 1986 to 1997 with the most
diet, demonstrates a greater than 50% reduc­ recent 11 years from 1998 to 2008. They found
tion in seizure burden in 40–50% of patients the most recent period showed more patients
after 3–6 months [70–75] . Compared with VNS, to be seizure free up to 5 years postsurgery and
the ketogenic diet appears to work faster, typi­ there were fewer complications among this
cally within 2–4 weeks [76] . Its benefits extend group compared with the earlier years [91] .
beyond seizure control, with improvements in
development and behavior reported [77] . The Future perspective
effect of the ketogenic diet can be long lasting, There have been major leaps made in imaging
with many patients experiencing sustained ben­ and therapeutic options over the last decade
efit, even after returning to a normal diet [78,79] . for patients with refractory seizures and the
The International Ketogenic Diet Study Group trajectory is set to continue. These can be con­
have recently produced a consensus paper that sidered as improvements to help streamline
sets forth clear recommendations for those existing therapeutic options and develop novel
administering the diet [80] . therapeutic options.

Outcome of refractory seizures „„ Streamlining current

Sudden unexplained death in pediatric patients therapeutic options
with epilepsy is rare [81,82] . However, risk of sud­ For those patients being evaluated for potential
den unexpected death in epilepsy is of particular epilepsy surgery, the advances in imaging modal­
concern in those with ongoing refractory seizures. ities mean that the detection of subtle changes in
Outcome data for patients with refractory sei­ structure that would previously have gone unrec­
zures are most impressive for those who undergo ognized are now being detected and widening
resective surgery. Excellent short-term outcomes the potential for surgical intervention for these
are published, with the best outcomes reported children. A rapid expansion in the techno­logy
for temporal-lobe resections [83,84] . One large available has increased precision in resective sur­
study shows 65% of patients to be seizure free gery. Image fusion allows accurate identification
following temporal-lobe resection performed for of imaging abnormalities previously assessed by
focal epilepsy of the temporal lobe. Evidence MRI, eloquent cortex identified by functional
from extratemporal surgery is weaker. Long- mapping, MEG spike clusters and diffusion ten­
term outcome following surgery was recently sor imaging of white tracts. These techniques are
reported in patients followed for a mean or constantly being refined. A recent report details
median of at least 5 years after their resective a new patient-specific method of surgical naviga­
surgery [85] . Similar to short-term studies, the tion and image integration. They describe a min­
outcome for temporal-lobe surgery remains imally invasive frameless stereotactic guidance
good, with 66% of patients becoming seizure system that utilizes a patient-specific mouth­
free. For extra­temporal groups, seizure freedom piece, which was used in the operating room to
is sustained in 46% with occipital and parietal allow repetitive non­invasive localization of the
resections, and 27% with frontal resections. patient’s anatomy during imaging integration
The same group reported improved psycho­ and during surgery [92] .
social outcomes with epilepsy surgery, includ­ Our understanding of the mechanism that
ing employment, education, driving status, may underlie the development of pharmaco­
satisfaction and quality of life [86] . Long-term resistance is improving, and we hope to utilize
outcome in patients with focal epilepsy, who this for improved AED delivery to the patients
were investigated for possible epilepsy surgery brain. It has been suggested that overexpression
and deemed not to be suitable candidates, of multi­d rug transporters in the blood–brain
are also reported  [87] . Following their surgical barrier is responsible for producing pharmaco­
assessment, 21% of patients were seizure free for resistance, by decreasing the AED concentration
at least 4 years. Quality of life assessments dem­ and, hence, its effectiveness. Therefore, novel
onstrate that quality of life in those still experi­ methods of administration of AEDs may be
encing seizures is poorer than that measured in successful in bypassing the blood–brain bar­
patients with other chronic conditions, such as rier. One such mechanism is intranasal admin­
diabetes or hypertension [88–90] . In recent years, istration of AEDs. There are few studies on this
the outcome figures have improved. A recent method of drug administration but some recent
publication examined pediatric epilepsy surgery data have emerged on this topic in the literature,
outcomes over a 22 year period – comparing the which may show future promise [93] .

502 Therapy (2010) 7(5) future science group

 Approach to refractory childhood seizures Review
„„ Novel therapies randomized; half received stimulation and half
For patients whom surgery is not an option or no stimulation during a 3‑month blinded phase;
is not successful in treating their seizures, the then all received unblinded stimulation. The
ketogenic diet and VNS offer real options to stimulated group had a 29% greater reduction
improve their seizure control and their qual­ in seizures versus the control group (p = 0.002).
ity of life. Newer AEDs, such as rufinamide, Complex partial and ‘most-severe’ seizures were
offer hope, with similar outcome data reported significantly reduced by stimulation. By 2 years,
for many of these agents as with both diet 54% of patients had a seizure reduction of at
and VNS. least 50% and 14 patients were seizure free for at
Deep-brain stimulation is another prom­ least 6 months. Complication rates were modest.
ising modality of treatment for refractory This study demonstrates the efficacy and safety
seizures  [94,95] . A multicenter, double-blind, of this therapy in refractory seizures. Further
randomized trial of deep-brain stimulation studies are ongoing in many centers to add clar­
in adults with refractory seizures has recently ity regarding which patients are likely to benefit
been reported  [95] . A total of 110 patients were best from this.

Executive summary
Impact of refractory seizures
ƒƒ Up to 40% of those treated with antiepileptic drugs (AEDs) for epilepsy will not achieve sustained seizure freedom.
ƒƒ Refractory seizures have devastating consequences for the child and their carers.
ƒƒ Treatment with AEDs exposes the patient to potentially harmful AED side effects/drug toxicity from multiple AEDs.
ƒƒ It is not reasonable to continue medication trials that have failed when epilepsy surgery is available.
ƒƒ Epilepsy surgery provides the best chance of seizure freedom in those with refractory seizures.
ƒƒ Early referral to specialist centers is necessary to maximize outcome and minimize continued exposure to AEDs.
Diagnosis of epilepsy/refractory epilepsy
ƒƒ Of those referred for management of refractory seizures, 20–30% do not have epilepsy.
ƒƒ Re-evaluation of all patients not responding to AED therapy is vital.
ƒƒ Psychogenic nonepileptic seizures may be suspected by observing key clinical features but must be confirmed with video
EEG monitoring.
ƒƒ Early identification of those with refractory seizures will maximize outcome – developmental delay at presentation, multiple seizure types
and failure to respond to first AED all predict development of refractory seizures.
ƒƒ The International League Against Epilepsy have defined refractory seizures as failure to achieve remission following trial of two or three
appropriate AEDs.
Presurgical evaluation
ƒƒ All patients with refractory seizures after treatment with two appropriate AEDs should be referred to a specialist epilepsy center
for evaluation.
ƒƒ A comprehensive history, including drug history and physical examination, is performed to guide the investigations.
ƒƒ Baseline metabolic evaluation of blood and urine, karyotype ana­lysis and fragile X should be considered.
ƒƒ Analysis of cerebrospinal fluid is recommended for all patients with refractory seizures.
ƒƒ Prolonged video EEG monitoring and appropriate magnetic resonance brain imaging with specific epilepsy protocol sequences should be
performed for all.
ƒƒ Magnetoencephalography allows further localization of focal epilepsy.
ƒƒ Multidisciplinary input is required to interpret the results and tailor a patient-specific plan.
ƒƒ Invasive monitoring with subdual electrodes allows precise localization of the epileptogenic zone and identification of eloquent cortical
regions and their relation to each other.
ƒƒ Timely evaluation and action is important.
When epilepsy surgery is not an option
ƒƒ Most therapies are aimed at minimizing the impact of seizures by reducing seizure frequency and severity and improving quality of life.
ƒƒ Novel AEDs have been demonstrated to have success in some particular instances, and may be considered.
ƒƒ The ketogenic diet and modern forms, such as the modified Atkins diet, offer a seizures reduction of greater than 50% in almost half of
patients with some achieving seizure freedom.
ƒƒ Vagal-nerve stimulation has similar seizure reduction rates as ketogenic diet, although seizure freedom is rare and it can be slow in
its effects.
Future perspective
ƒƒ Better understanding of the mechanism of development of drug intractability may allow us to develop drugs and drug delivery systems
that can bypass these obstacles.
ƒƒ There has been a significant increase in the number of AEDs available and in development for the treatment of epilepsy.
ƒƒ Deep-brain stimulation is a promising modality of treatment for refractory seizures, with good early data published on outcomes.

future science group www.futuremedicine.com 503

Review McCoy & Benbadis

Financial & competing interests disclosure or entity with a financial interest in or financial conflict
S Benbadis serves as a consultant and a speaker for with the subject matter or materials discussed in the
Cyberonics, GSK, Lundbeck, Pfizer, Sleepmed, UCB manuscript apart from those disclosed.
pharma and XLTEK. The authors have no other relevant No writing assistance was utilized in the production of
affiliations or financial involvement with any organization this manuscript.

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