With many types of epilepsy now alleviated or controlled by surgery,
inte-rest has shifted to other seizure types that are not traditionally
amenable to surgical therapy. This trend is particularly evident at pediatric
centers where seizure presentations are diverse and often extremely severe.
Many present as severe electroclinical syndromes with adverse prognoses
that are well studied [1, 2]. Thus, without definitive intervention, the
long-term outlook for affected patients is poor, and provides justification
for seeking innovative and radical solutions.
To a great extent, the ability to identify seizure origin in non-traditional
surgical candidates is technology driven. Advances in structural and functional
imaging, EEG monitoring and surgical techniques now offer a more detailed
understanding of the basis and expression of the epileptic focus in a
variety of clinical settings, and permit accurate localization . Further
advances in imaging and monitoring hold promise for even wider patient
This review focuses on recent trends in surgery for medically resistant
seizures. Until recently, many affected patients were rarely considered
for surgical therapy. This group typically experiences seizure onset in
the first two decades and has significant neurobehavioral deterioration.
With more powerful tools for preoperative evaluation, and a more sophisticated
knowledge base of their natural history, it is likely that the number
of surgical candidates will increase in the future.
Infantile spasms are the hallmark of West Syndrome, a major cause of
early childhood epileptic encephalopathy. The spasms consist of brief
bilateral flexion or extension contractions of the trunk and limbs, often
occurring in clusters, and associated with EEG hypsarrhythmia and developmental
regression. They typically begin in the first year of life, usually between
ages 4-10 months. Standard antiepileptic drugs (AED) rarely result in
complete seizure remission, and oral or parenteral corticosteroid therapy
is typically employed for short-term seizure relief. Once the spasms remit,
other seizure patterns supervene, and long-term prognosis for seizure
control and normal mentation remains poor.
Infantile spasms are traditionally regarded as an age-specific, generalized
epilepsy. The hypsarrhythmic EEG is believed to represent a global epileptic
and functional disturbance by virtue of its high amplitude, poorly organized
background activity, multifocal epileptiform transients and suppression-burst
activity. These electrographic features are widespread throughout both
cerebral hemispheres, and support the concept of bilateral cortical and
An association between infantile spasms and focal brain pathology was
initially observed in three infants with West syndrome who presented with
unilateral, non-hemorrhagic, cerebral infarcts . Similar observations
were subsequently confirmed in a larger series , giving rise to the
novel view that the widespread electrographic disturbances of West syndrome
may actually be originating within relatively circumscribed cortical regions.
Malformations of cortical developmental and acquired tumors are identified
in a small proportion of patients (figure
1). The restricted region of cortical dysfunction is not inextricably
linked to gross structural pathology as some patients with EEG hypsarrhythmia
show microscopic changes and a normal MRI. The potential preoperative
pool thus includes all patients with evidence of focal cortical dysfunction,
with or without a discrete anatomic abnormality.
The utilization of excisional procedures for West syndrome is facilitated
by high resolution MRI detection of cortical dysplasia and other subtle
malformations of cortical development. In non-lesional cases, PET studies
may reveal focal hypometabolic regions that ultimately prove to be foci
of cortical dysplasia. The ability to functionally identify abnormally
metabolic cortex is especially critical in patients lacking gross structural
lesions . Localized cerebral hypoperfusion may also be demonstrated
by SPECT . For reasons unknown, gross dysplastic cortical lesions have
a predilection for the posterior cerebral hemispheres, whereas a frontal
lobe location is less common.
The surgical treatment of West syndrome was first carried out in infants
with well-documented infantile spasms and localized hypometabolism on
PET. Patients did not exhibit focal anatomic lesions and resections
were based primarily on evidence of localized metabolic abnormality. The
resected tissue demonstrated histopathologic findings consistent with
cortical dysplasia. More recently, Shewmon et al.  confirmed
the efficacy of surgery in 28 infants who were experiencing active spasms
at the time of surgery. Twenty-six (93%) obtained immediate postoperative
seizure relief, while only three relapsed. At long-term follow-up, 11
patients were seizure-free, with 5 still taking medication.
There are no universally accepted criteria for selecting patients with
infantile spasms for surgery. Perfectly symmetric spasms are rare and
it is important to document clinical and electrographic features suggesting
a lateralized process. Apart from clinical features such as hemiparesis,
successful candidates should manifest partial seizures or asymmetric spasms,
with or without asymmetry of the hypsarrhythmic EEG . Asymmetric spasms
and partial seizures can coexist as the principal seizure pattern, or
occur concurrently . Partial seizures trigger spasms in some patients
The prognostic importance of clinical and electrographic lateralization
is unclear. EEG asymmetry and asynchrony appear reliably in a small but
significant group of patients [12, 13]. PET scanning is currently available
at only a few select epilepsy centers. The identification of a clear hypometabolic
region on PET aids the selection process, although a positive PET scan
does not guarantee surgical selection. Patients with bitemporal hypometabolism,
for example, often go on to manifest language disturbance and autism,
rendering the value of surgery questionable for this population .
Considering the poor prognosis facing patients with West syndrome, the
control or elimination of seizures via the excision of epileptogenic cortex
represents a significant advance over palliative medical strategies. Improved
adaptive capacity in communication skills, daily living and socialization,
accompany seizure-freedom . Long-term benefits are equal or superior
to those in children treated with ACTH, vigabatrin, the benzodiazepines
or sodium valproate. Earlier surgery correlates with superior developmental
Catastrophic partial seizures
Tailored excisional procedures can be employed effectively to treat
extremely young patients exhibiting severe partial seizures and neurobehavioral
deterioration. Epileptogenesis predisposes to significant dysfunction
in the developing brain , and the trend towards early referral of
young, medically-resistant seizure patients is likely to continue.
Until recently, hemispherectomy or multilobar resections were more frequent,
but are now less common without evidence of widespread hemispheric neurological
deficit (hemiparesis, homonomous hemianopia etc). Techniques that precisely
delineate primary epileptogenic cortex facilitate more selective elimination
of the epileptogenic region and minimize damage to critical cortical tissue.
Several theoretical and practical concerns impact the decision to limit
the resection plane in young patients. The benefits of procedures designed
to spare eloquent or future eloquent cortical regions during early postnatal
life are difficult to predict. While neural plasticity and recovery of
function are prominent features of immature cortex, it may be argued that
more aggressive treatment assures better seizure control. However, while
early ablation is associated with superior functional recovery compared
to older patients , it should not be assumed that all aspects of higher
cortical function recover equally.
Given the uncertainties of future mental functioning, minimizing tissue
removal would appear advantageous as long as the probability of seizure-freedom
is high. Candidates for tailored procedures should therefore be selected
on an individualized basis, with hemispherectomy and large resections
reserved for extensive malformations of cortical development. Infants
with primary epileptic involvement of motor or visual cortex may also
not benefit from highly tailored excisions. In contrast, highly localized
cortical malformations and discrete developmental tumors in non-critical
cortex are more appropriate surgical targets.
A further methodological concern is whether eloquent cortical regions
can be successfully identified in very young patients. Mapping sensorimotor
cortex is now possible in infants using a dual stimulation paradigm that
alternates increments in stimulus intensity and pulse duration . With
this procedure, even small infants can be mapped successfully and referred
for tailored resections.
Tailored resection for catastrophic localization-related seizures in
infancy was initially performed in 5 patients under one year of age .
Three became seizure-free and two improved significantly; there were no
post-surgically acquired deficits. The beneficial effects of resections
guided by focal seizure patterns and functional mapping data have been
confirmed repeatedly . Wyllie et al.  described 12 infants
undergoing neocortical resection or hemispherectomy. Ten had abnormal
MR imaging and two had regions of cortical dysplasia localized by interictal
SPECT. At follow-up, six were seizure-free, three had rare seizures, and
two showed worthwhile improvement. Catch-up development occurred with
parents reporting rapid acquisition of new skills after surgery.
In another series , 6 of 26 infants became seizure-free, and 4 or
more had a greater than 90% reduction. There were no significant differences
with respect to seizure-freedom after hemispherectomy or multilobar resection
versus lobar resection, or between temporal versus extratemporal resection
confirming that outcome is independent of the amount of neocortex removed.
The presence of a discrete lesion predicts a more favorable outcome.
Intraoperative subdural EEG monitoring is often necessary to define
the boundaries of epilptogenic cortex in tailored excisions. Without this
technology, improvement in seizure status is less certain. Patients with
focal cortical dysplasia have the least favorable prognosis .
Despite admittedly excellent recovery after early ablation in the majority
of cases, the neurobehavioral and social benefits of earlier seizure-freedom
remain the most compelling reasons for contemplating immediate intervention.
Tuberous sclerosis complex
Epilepsy affects 90% of patients with tuberous sclerosis complex (TSC)
and often begins in the first decade of life . There is a significant
incidence of infantile spasms, although partial seizures affect a much
higher proportion of patients . Seizures are often refractory to medication
and may be associated with significant developmental regression. Status
epilepticus unresponsive to aggressive pharmacological intervention has
been observed as early as two days of age .
The TSC population is unique in that while intractable focal epilepsy
is often viewed as being either lesional or non-lesional, TSC patients
are more precisely characterized as "multi-lesional" in that several lesions
could be epileptogenic. Despite these concerns, removing a single tuber
often successfully improves or alleviates seizures. The preoperative evaluation
is therefore oriented towards the identification of the epileptogenic
surgical tuber while simultaneously assessing the epileptogenic potential
of other lesions.
Both the identification and removal of a candidate tuber can be accomplished
by standard preoperative investigational and planning protocols. Video/EEG
is particularly helpful for characterizing primary seizure origin and
functional spread patterns. Ictal recording may be used to localize seizure
onset in rapid secondarily generalized tonic spasms  and to lateralize
apparent bilaterally synchronous discharges .
Hyperperfused cortical regions on ictal SPECT help corroborate electrographic
seizure origin, and are highly localizing if the EEG demonstrates sustained
rhythmic focal fast discharges or spiking . More recently, alpha methyl
l-tryptophan PET studies have revealed regions of increased isotope
corresponding to single tubers associated with ictally-confirmed seizure
origin . A significant proportion of surgical candidates experience
a good outcome when MRI, EEG and SPECT findings are convergent, while
the risk of developing a new focus postoperatively is acceptably small
[31-33]. Early seizure control reverses profound mental retardation and
severe autism [34, 35].
The long-term prognosis for recurrence in TSC patients rendered seizure-free
by surgery is incompletely known. While other tubers could potentially
activate in later life, similar risks may be attributed to surgery for
other malformations of cortical development. Alternatively, it is also
possible that removal of the primary epileptogenic region could modify
potential secondary epileptogenic areas as has been described for other
brain lesions . The persistence of multifocal abnormalities in some
patients  underscores the need for caution and long-term seizure surveillance.
Early infantile epileptic
encephalopathy (Ohtahara syndrome)
Early infantile epileptic encephalopathy (EIEE), also known as Ohtahara
Syndrome, is a severe early onset, age-specific catastrophic epilepsy
syndrome. The disorder typically begins within hours or days of birth
with frequent generalized seizures, usually in the form of tonic spasms,
and a burst-suppression EEG characterized by high amplitude spikes, sharp
wave discharges and slow activity followed by up to nine seconds of electrical
silence. This EEG pattern is invariant in all behavioral states, and unreactive
to extrinsic stimulation [37, 38]. Developmental brain malformations underlie
the majority of affected patients  including an unusual, stereotyped
hindbrain malformation consisting of dentato-olivary dysplasia . The
outlook is extremely poor with persistent seizures, severe delay and early
death being common.
Despite the apparently generalized nature of EIEE, an association with
focal cortical dysplasia suggests that EIEE, like infantile spasms, is
a developmentally based, partial seizure disorder that shows an age-dependent
tendency towards rapid secondary generalization. The identification and
elimination of focally dysplastic cortical tissue was first performed
in a patient with a region of thickened, right frontoparietal cortex that
was believed to be the epileptogenic source . Following its elimination,
the patient had had only one febrile seizure at the two-year postoperative
follow-up, and the neurological examination revealed only minor developmental
delay and slight left-sided weakness.
A further association of EIEE and suppression-burst EEG was reported
in a patient with focal cortical dysplasia of the left prefrontal cortex
. Ictal SPECT revealed focal hyperperfusion within the lesion, and
the EEG evolved to a hypsarrhythmic pattern with significant hemispheric
asymmetry. Lesionectomy was performed at age 4 months under ECoG guidance.
Short-term follow-up indicated overall improvement in developmental functioning.
The success of limited excisional procedures in EIEE is notable. The
extent of the cerebral dysgenesis may not be apparent on neuroimaging
despite widespread underlying architectural disturbances . Disruption
of normal myelination is thought to partially de-afferent the cortex leading
to the characteristic suppression-burst EEG.
Syndrome of gelastic epilepsy and hypothalamic hamartoma
The syndrome of gelastic seizures and hypothalamic hamartoma is characterized
by laughing seizures in infancy or early childhood, in association with
a hamartoma of the posterior hypothalamus. The lesion consists of heterotopic
and hyperplastic tissue arising in the interpeduncular cistern or within
the hypothalamus near the tuber cinereum and mamillary bodies . Patients
go on to manifest complex partial seizures or motor convulsions in the
form of tonic, atonic or clonic movements . Few patients are controlled
by medication. Precocious puberty in some patients indicates a neurosecretory
potential for the lesion. Progressive mental decline during the second
decade of life is the rule.
Despite the uniform presence of the hypothalamic lesion in affected
patients, it has been difficult to prove unequivocally that the hamartoma
is intrinsically epileptogenic. Supportive evidence has come from several
sources. Ictal SPECT during gelastic seizures reveals hyperperfusion within
the hamartoma, hypothalamus and thalamus but not the cortex [45, 46].
Direct EEG recording from the hamartoma reveals focal spiking [46, 47],
while electrical stimulation of the hamartoma reproduces gelastic seizures
Both surgical excision [48, 49] and radiofrequency lesioning  successfully
alleviate seizures. Seizure-freedom facilitates progressive improvement
in the EEG and eventual disappearance of the paroxysmal activity [48,
49]. Improved cognitive ability and behavior has also been reported .
In contrast, focal resection of epileptogenic cortical regions in this
group of patients is rarely beneficial . The rationale for corticectomy
is based on the demonstration of abnormal cortical epileptogenic activity,
and the belief that ictal laughter and confusion are cortically organized,
complex, partial seizure manifestations. Patients with hypothalamic hamartomas
also manifest extralesional abnormalities of gray and white matter throughout
the hemispheres , but while these regions form aberrant intraneuronal
networks, their elimination is insufficient for seizure-freedom.
It should be emphasized that despite the remarkable advances in surgical
technique, elimination of the hypothalamic hamartoma is not without risk.
Hypothalamic disturbance and Korsakoff's dementia are consequences of
damage to the mamillary bodies and sessile hamartomas are technically
challenging. Gamma knife may provide a noninvasive alternative for ablating
small deep-seated lesions  (figure
Neuronal migration disorders
Virtually all forms of neuronal migration disorders (NMD) are capable
of producing epileptic seizures. Seizures may begin at any time from neonatal
life to adulthood, and often respond poorly to AED. There is a wide spectrum
of involvement spanning the histopathologic features of focal cortical
dysplasia, to gross malformation of the cerebral hemisphere leading to
hemimegalencephaly, lissencephaly or schizencephaly. Despite differences
in appearance, all share similar pathologic findings in the form of bizarre
giant neurons and glial elements, cortical dyslamination and neuronal
Disorders of neuronal migration are the most frequently cited pathologic
abnormality in tissue resected in pediatric patients [21, 54]. This high
proportion reflects the lower
overall incidence of acquired childhood epilepsy, the natural tendency
of NMD to cause early seizures, and its resistance to pharmacotherapy
. Thus, a key element to successful pediatric epilepsy surgery is
the ability to carefully define seizure origin and eliminate the entire
epileptogenic region in developmentally abnormal cortex.
Surgery for focal cortical dysplasia (FCD) is performed at many epilepsy
centers, but rates of seizure-freedom remain low. Palmini et al.
[56, 57] reported 26 patients with intractable partial epilepsy and cortical
dysplasia, 24 of whom had adequate follow-up. Although postoperative success
correlated positively with quantitative tissue removal, complete seizure-freedom
occurred in only 2 cases (8%). Hirabashi et al.  and Fish et
al.  encountered similarly low rates of seizure-freedom. Patients
in these series did not undergo invasive EEG recording.
Similarly disappointing rates of postoperative seizure-freedom are encountered
with other neuronal migration disorders. Seizure control occurs in only
a minority of patients with schizencephaly [60, 61] and nodular heterotopias
. Apart from the epileptogenic lip of the schizencephalic cleft, the
temporal lobe is the most frequent epileptogenic region . More widespread
disturbances outside the primary epileptogenic region have been proposed
to explain the high failure rates.
Several technical advances improve post-operative outcome. High-resolution
imaging identifies abnormalities in non-lesional cases, while specific
electrographic features help design surgical strategies. Any analysis
of the investigative findings must balance the likelihood of postoperative
seizures against the feasibility and safety of an extended resection.
Discrete structural lesions such as neoplasms, vascular malformations
and HS help localize the epileptogenic region in cases of acquired epilepsy
[63-65] but the structural abnormality in dysplastic lesions is often
the "tip of the iceberg". Thus, in FCD, imaging marks the approximate
location of the epileptogenic zone, but may not characterize its true
extent [66, 67].
Functional imaging including PET, SPECT or MR spectroscopy are better
suited to characterize the abnormal neural circuits in FCD. FDG-PET regions
of hypometabolism presumably indicate regions of cortical abnormality.
PET data, in conjunction with intraoperative EcoG, may be used to plan
excisions in cases of infantile spasms and anterior temporal foci [6,
68]. Newer PET ligands such as flumazenil are more specific but await
validation . While ictal SPECT studies impose significant technical
constraints, they are particularly useful under specific circumstances
such as extra-temporal or non-lesional epilepsies. Ictal SPECT may correlate
with regions of ictal onset or secondary involvement depending upon the
timing of isotope injection.
Involuntary intense contraction of the facial musculature is generally
regarded to be a symptom of non-epileptic origin such as myoclonus or
dystonia. It is more frequently encountered in adults as a manifestation
of facial nerve irritation due to vascular causes . In contrast, hemifacial
spasms are uncommon in childhood and extremely rare in infancy. Their
clinical presentation is, however, remarkably stereotyped, consisting
of unilateral clonic or tonic contraction of the orbicularis oculi progressing
to lower facial muscular involvement. Episodes are generally brief, and
consciousness is typically preserved. There is variable limb and autonomic
Convincing proof that hemifacial spasms in infancy constitute a form
of subcortical epilepsy was obtained in a six month infant who became
symptomatic shortly after birth and rapidly became medically refractory
. MR imaging revealed a mass in the left middle and superior cerebellar
peduncle that was ultimately shown to be a ganglioglioma. Ictal SPECT,
intracranial ictal and interictal seizure patterns and seizure-freedom
after lesionectomy provided proof of the intrinsic epileptogenicity of
Retrospective reviews of published cases of infants with hemifacial
spasms confirm its striking association with cerebellar mass lesions .
Histopathology in 4 patients who underwent surgery revealed three with
gangliogliomas, and one with a low-grade astrocytoma. A recent case report
of a patient with Goldenhar's syndrome who presented with hemifacial spasms
at age 3 months revealed a mass in the pontomedullary junction displacing
the fourth ventricle . Although absolute proof of the epileptogenic
potential of cerebellar lesions is lacking, their stereotyped clinical
presentation suggests that all produce symptoms through subcortical epileptogenesis.
The association of hemifacial spasms with cerebellar mass lesions has
important theoretical and pragmatic implications. From a theoretical standpoint,
this clinocopathologic syndrome further extends the anatomic concept of
subcortical epileptogenesis. Rather than being strictly cortical in origin,
partial seizures are now believed to originate in one of several locations
and can be symptomatic if they have access and propagate to symptomatogenic
zones. Pragmatically, the syndrome manifests with a recognizable clinical
semiology, and good response to excisional procedures.
The syndrome of "acquired aphasia with convulsive disorder" was first
reported in 5 children in 1957 . All had shown normal early development
before exhibiting profound disturbances of linguistic communication over
a pe-riod of days to months. Children with Landau-Kleffner syndrome (LKS)
display a variety of seizure types including grand mal, petit mal and
myoclonic epilepsy, accompanied by prominent EEG discharges over the temporal
lobes. Multifocal activity is common, usually in a bitemporal or parieto-occipital
distribution, although generalized complexes and centro-temporal spikes
are also observed. Seizure frequency and type are inconsistently related
to the severity of the language disturbance, although more marked EEG
abnormalities are more typical of severely affected patients. The EEG
reveals "subclinical electrical status epilepticus" during sleep that
consists of near-continuous spike-wave discharges (CSWS) in non-REM stages.
LKS is a rare disorder whose exact prevalence is incompletely known.
It is slightly more common in boys, and typically presents between age
3-8 years with a peak at 5-7 years. The language disturbance is usually
severe with some children being absolutely mute and unresponsive to all
verbal and occasionally even non-verbal stimuli. Behavioral problems include
hyperactivity and attention deficit disorder. Significant proportions
of patients exhibit prior abnormal neurological development making it
unclear whether all patients undergo acute language regression.
Seizures are usually well controlled by standard anti-epileptic drugs
although atypical absences and atonic drop attacks may remain refractory.
A wide variety of agents have been used successfully but sodium valproate
and the benzodiazepines continue to be the drugs of choice. Corticosteroids
may induce long-lasting favorable effects.
In 1995, Morrell et al. reported successful surgical treatment
of LKS utilizing the technique of multiple subpial transection . His
patients developed LKS between age 3-6.5 years, and were evaluated up
to 2-6 years after symptom onset. They had no functional linguistic ability
despite age-appropriate language milestones. CSWS was observed in all
cases, and magnetoencephalography revealed an electrical dipole within
the sylvian fissure with a suprasylvian negativity and a positivity at
Seven of 11 children recovered age-appropriate speech post-operatively,
while 4 improved to the point where they could speak and comprehend with
speech therapy. Three unimproved patients continued to have seizure activity.
Substantial improvement did not occur until a minimum of 6 months after
Subsequent studies report somewhat more variable linguistic competence
and seizure control after MST [75-78]. However, the demonstration of focally
increased metabolic activity in the superior temporal region on FDG PET
in patients with CSWS, and MEG localization within sylvian cortex continue
to bolster support for the existence of a restricted region of functional
abnormality . Although more careful assessment is needed, the lack
of significant functional compromise after MST is consistent with experimental
observations that function in the mammalian cortex is organized through
interconnections of vertical columns. In contrast, epileptic synchronization
is believed to involve tangential neuronal connections in neocortical
layers 4 and 5. Further studies of these complex issues are clearly indicated
before MST can be endorsed without reservation.
Pediatric epilepsy surgery has undergone a period of explosive growth.
Along with advances in localizing the seizure focus, it is now possible
to select patients for surgery whom until recently, were considered inoperable.
This trend is likely to continue into the future. Advances in functional
neuroimaging represent a particularly exciting opportunity for greater
selectivity in choosing surgical candidates. Higher resolution MR imaging
and functional imaging are likely to play a critical role in surgical
selection and surgery will more often be performed earlier. The complication
rates do not differ from older patients and the earlier alleviation of
seizure activity is associated with more favorable neurobehavioral status
in later life.