John Libbey Eurotext

Pediatric epilepsy surgery: the widening spectrum of surgical candidacy Volume 1, numéro 3, Septembre 1999

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 [3]. Further advances in imaging and monitoring hold promise for even wider patient selection.

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

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 subcortical dysfunction.

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 [4]. Similar observations were subsequently confirmed in a larger series [5], 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 [6]. Localized cerebral hypoperfusion may also be demonstrated by SPECT [7]. 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[6]. 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. [8] 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 [9]. Asymmetric spasms and partial seizures can coexist as the principal seizure pattern, or occur concurrently [10]. Partial seizures trigger spasms in some patients [11].

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 [14].

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 [15]. 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 outcome [15].

Catastrophic partial seizures in infancy

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 [16], 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 [17], 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 [18]. 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 [19]. 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 [20]. Wyllie et al. [21] 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 [22], 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 [23].

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 [24]. There is a significant incidence of infantile spasms, although partial seizures affect a much higher proportion of patients [25]. 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 [26].

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 [27] and to lateralize apparent bilaterally synchronous discharges [28].

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 [29]. More recently, alpha methyl ­l-tryptophan PET studies have revealed regions of increased isotope corresponding to single tubers associated with ictally-confirmed seizure origin [30]. 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 [36]. The persistence of multifocal abnormalities in some patients [33] 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 [39] including an unusual, stereotyped hindbrain malformation consisting of dentato-olivary dysplasia [40]. 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 [41]. 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 [42]. 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 [39]. 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 [43]. Patients go on to manifest complex partial seizures or motor convulsions in the form of tonic, atonic or clonic movements [44]. 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 [46].

Both surgical excision [48, 49] and radiofrequency lesioning [46] 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 [48].

In contrast, focal resection of epileptogenic cortical regions in this group of patients is rarely beneficial [50]. 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 [51], 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 [52] (figure 2).

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 ectopia [53].

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 [55]. 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. [58] and Fish et al. [59] 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 [62]. Apart from the epileptogenic lip of the schizencephalic cleft, the temporal lobe is the most frequent epileptogenic region [60]. 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 [69]. 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.

Hemifacial spasms

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 [70]. 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 involvement.

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 [71]. 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 the lesion.

Retrospective reviews of published cases of infants with hemifacial spasms confirm its striking association with cerebellar mass lesions [71]. 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 [72]. 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.

Landau-Kleffner syndrome

The syndrome of "acquired aphasia with convulsive disorder" was first reported in 5 children in 1957 [73]. 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 [74]. 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 temporal sites.

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 surgery.

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 [79]. 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.

The future

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.