Language, hemispheric epilepsy, and hemispherotomy

The classical paradigm of balancing seizure management and the loss of developmental potential is represented in the hemispheric epilepsies of childhood. Disorders like Rasmussen encephalitis (RE), hemimegalencephaly, and Sturge-Weber syndrome are rare overall but well known in pediatric epilepsy centers, and present disabling and functionally damaging refractory seizures in childhood which have warranted epilepsy surgery in its most extreme form: hemispheric disconnection. This “gold standard” treatment of hemispherotomy puts function associated with the hemisphere at risk of permanent loss but is justified given the risk of functional loss inextricably linked with ongoing seizures. The plasticity of the pediatric brain to compensate for such a comprehensive disconnection, when sustained early in childhood, justifies the invasiveness of the approach. Nevertheless, the long-term consequences of hemispherotomy must be carefully considered.

Multiple single center , and multicenter systematic reviews and metaanalyses , Weil et al. , Harris et al. , show seizure freedom rates in over two-thirds of the patients but significant rates of functional loss and language difficulties when the dominant hemisphere is targeted . Nahum and Liegois performed a systematic review of language outcomes after left or right hemispherectomy in childhood with 1–15 years of follow up and found that for left hemispheric disconnections, all language skills were impaired except those for reading comprehension. Overall, these analyses reveal that the further removed from surgery a child advances, the lower the seizure freedom rate, and the greater the consequences of having lost language and cognitive skills, calling into question the dogma that hemispherotomy is a “gold standard” for pediatric hemispheric epilepsy in all cases. A measured approach taking into account developmental age (under or over 5), contralateral epileptiform irritability, and etiology (e.g., perinatal stroke vs post meningitic epilepsy) allows for a holistic analysis of long-term risk and benefit from hemispherotomy as it concerns language development .

Language, regional epilepsy, and focal disconnection

Where semiology suggests proximity to language, but electroclinical correlation or imaging may not be definitive in guiding resection, a focal disconnective strategy has been employed that has crossover to multiple facets of eloquence, be they language, motor, sensory, memory, or visual function. Multiple subpial transections (MSTs) were first described by Morrel in 1969 , which sever cortico-cortical connections while preserving vertically oriented afferent and efferent neurons that serve functional purposes . As it pertains to language, the clinical scenario of acquired epileptiform aphasia (AEA), also known as Landau–Kleffner syndrome, is the paradigmatic condition where MSTs have been used and probably best studied. In AEA, sudden mutism, deafness, and behavioral changes are accompanied by recognizable seizures arising from language areas in over two-thirds of children .

MSTs applied in identified areas of epileptiform activity may follow a general rule in epilepsy surgery, the more comprehensively the epileptogenic zone is treated, the better the outcome . As described above, the best methods for identification of the epileptogenic zone have involved electrical stimulation mapping, either extraoperatively with subdural grids or stereo electroencephalography (sEEG) depth electrodes, or intraoperatively with awake mapping and in the opinion of some authors, intraoperative spike detection . The technique follows that described by Morrell et al. to create vertically oriented disruptions of the cortex in 4–5 mm increments using a hooked wire that is inserted into the gray matter via a small nick in the avascular pia of the gyrus. The hook is then maintained in a vertical plane at a depth of about 4–5 mm to not undercut the cortex and is drawn to the far side of the gyrus and then back to the entry point, without disturbing the overlying pia. In doing so, the intercortical connections are disturbed but the functional, descending columns and even u-fibers are spared .

Multiple analyses of short- and long-term outcomes and functional preservation through single surgeon experience to systematic reviews and meta-analyses have appeared that demonstrate an overall benefit of this procedure with important caveats and conditions . While temporal lobe targets were associated with better seizure outcomes and combining a resective strategy in combination with MSTs for residual, unresectable epileptogenic zone fared even better, only a little more than half of patients achieved long-term seizure freedom. Complications included transient mono or hemiparesis in about 20% of patients, dysphasia in approximately 12%, and a small but definite risk of permanent weakness or dysphasia with this technique.

In AEA, typically a nonlesional epilepsy centered in the eloquent cortex, two-thirds of patients in a disaggregated review of patient-level data achieved seizure freedom , which is associated with arrest of speech regression and language improvement in most cases. While the sample size of this population is limited, the success rate underscores the utility of MSTs for addressing epilepsy in the relatively limited epileptogenic zone involving perisylvian language areas. In this location and for this indication of AEA, the risk-benefit ratio is still in favor of a focal disconnection technique that MSTs provide.

Language, focal epilepsy, and focal resection

In focal epilepsy where the epileptogenic zone involves language areas in part or in whole, resective, ablative, and functional-sparing disconnective strategies have been employed with reasonable safety and efficacy. Clinico-electrico-anatomical considerations must be taken into context. For example, a seizure semiology that suggests proximity to the language area in the form of speech arrest or word-finding difficulty at onset, coupled with video EEG (vEEG) localization to that region, in the setting of a visualized abnormality on MR such as a migrational disorder, cavernous malformation, or benign intrinsic tumor would warrant a focused, ablative approach. A clinical scenario with similar semiology but less precise electroclinical definition and a nonlesional MR would necessitate a different approach, as discussed below.

If an ablative/resective/disconnective strategy is chosen, adequate localization of cortical and subcortical language function is the cornerstone of safe and effective epilepsy surgery. In general, language localization in the pediatric age group can be difficult, with some preliminary results suggesting that noninvasive resting-state functional magnetic resonance imaging and navigated transcranial magnetic stimulation can be of utility. Where language function is concerned in proximity to the epileptogenic zone, direct stimulation mapping is unparalleled in terms of safety. Subdural electrode placement can be useful to allow extraoperative mapping of the awake pediatric patient in epilepsy monitoring unit setting , and we and others have shown the utility of brain mapping with the less invasive methodology of sEEG electrode placement. These extraoperative modalities provide useful adjuncts for language mapping in children.

However, the most comprehensive methodology for addressing epilepsy involving language areas entails awake mapping during resection to facilitate the safest and most thorough removal of the epileptogenic zone. While this may seem prohibitive in the pediatric age group, awake brain surgery in children is tolerable and reported in children as young as 7 . Individualized assessments of a patient’s capacity for an interactive operation must be weighed by the surgeon, epileptologist, neuropsychologist, and parents, and the patient themselves. Awake mapping is safe, feasible, and well tolerated in children but is underutilized relative to adult patients because of assumptions of greater vulnerability and fragility . In this author’s experience, tolerability factors do not appear age-related above the age of 10, and we have performed awake brain mapping in a child as young as 9 to facilitate maximal tumor resection in the supratentorial space. In the setting of epilepsy, a case example is included here that illustrates the utility of awake mapping in a pediatric patient with refractory epilepsy involving lesional epilepsy in dominant temporal language areas:

• 
  

  Patient 1 : A 14-year-old female presented with a four-year history of refractory epilepsy, and a workup revealed semiology and a discernible lesion on imaging near expressive speech areas. Previously, she had been advised against resective surgery due to operative risk. An assessment of tolerability for awake mapping including weigh-in by the patient’s long-standing epileptologist, neuropsychologist, and mother, and rehearsal with thorough preparation was performed prior to surgery. sEEG leads were placed and seizures were localized to the superior temporal gyrus near the area of the lesion. A left craniotomy was undertaken in the semi-lateral position, positioning the patient awake and avoiding the placement of a Foley catheter out of concern that it would be a distraction to the patient at her request. The clinical neuropsychologist and epileptologist formed the mapping team and given their familiarity with the patient and the rehearsal that had been performed prior to surgery, the patient tolerated the left temporal craniotomy and resection of the epileptogenic zone back to a primary naming area 7 cm from the temporal tip on the superior temporal gyrus, where the patient encountered naming difficulty with bipolar stimulation mapping at 3 mA using a Nicolet Cortical Stimulator (Natus Neurology, Inc., Middleton, WI) and resection in this area ( Fig. 7.1 ). While the patient has remained seizure free for 43 months since surgery, it is worth noting that a major stressor during surgery could have derailed a complete removal of the epileptogenic zone. The patient was distracted by the need to urinate and her difficulty doing so on a bedpan in front of the OR team, illustrating the smallest details that can derail the goals of a maximal resection of the epileptogenic zone.

  
  

  
  

  
  

  

  
  

  
  

  Surgeon’s view during awake craniotomy: Comprehensive removal of the epileptogenic zone was facilitated by awake craniotomy, given the close proximity of the FCD to the language cortex. Abbreviations: MTG : middle temporal gyrus; STG : superior temporal gyrus; FCD : focal cortical dysplasia.

  
  

Language, focal epilepsy, and focal ablation

While laser interstitial thermal therapy (LITT) has become a critical therapeutic tool in the armamentarium to control temporal lobe epilepsy in adults, data demonstrating its safety and efficacy in children are more limited but do exist , reviewed in , Chen et al. . Early experience highlights LITT’s utility in commonly seen pediatric epilepsies where seizure onset zones are deep or networks are complex such as hypothalamic hamartoma, periventricular nodular heterotopia (PVNH), or tuberous sclerosis. In the setting of insular onsets, which are more commonly being recognized in the era of robotic sEEG monitoring, language considerations make LITT a valuable tool if a “lesionectomy” or focal ablation approach is chosen in the dominant hemisphere. Here, following sEEG monitoring, a stereotactic approach is used to place a laser probe in the region targeted for ablation and utilizing magnetic resonance thermography (Mr-T) guided visualization, focal destruction of the epileptogenic cortex is created, obviating the need for open dissection and manipulation of the perisylvian cortex.

Perry et al. reported a series of 20 children who had undergone 24 ablations of the insula, where 50% had seizure free outcomes and neurological deficits including dysphasia was common but transient . Hale et al. made a direct comparison between open surgery and LITT for insular epilepsy in children and found similar control rates and complications between approaches and in line with the results of the Perry study with a mean of 2.4 years follow-up . In a similar series of 27 children treated with LITT, this sEEG to ablation strategy was used to treat eight patients with insular epilepsy, but no detailed outcome data are available in this cohort . The overall concern in such insular ablative cases is the limited duration of follow-up that these studies provide and the uncertainty of long-term efficacy in seizure control . The spread of the ablation zone to the adjacent language pathways, when the dominant hemisphere is involved, as well capsular fibers with risk to sensorimotor function that could be at risk independent of the hemisphere targeted, are real concerns of this technology, despite the lower risk of perforator injury compared to open insular surgery.

Language, epilepsy, and neuromodulation with responsive neurostimulation

The multigenerational mindset that resective surgery is superior in efficacy to neuromodulatory therapy holds true in many cases but must not be viewed as the gold standard alone. The responsive neurostimulation system (RNS system) became FDA-approved in late 2013 after a pivotal trial to treat one or two seizure foci through a neuromodulatory rather than destructive approach, albeit in patients 18 years and older. With respect to the pediatric population, heretofore, the vagus nerve stimulator represented the dominant neuromodulatory treatment that is both FDA-approved and available. Certainly, RNS with leads that could be placed in eloquent areas represented a paradigm shift in the potential to treat epilepsy in areas and for patients that had previously not been considered surgical candidates. We and other groups have applied RNS off-label in children with excellent preliminary safety and seizure control .

Overall, children represent a population that could be prime beneficiaries of a modulatory rather than destructive approach. The finality and irreversibility of disconnections, resections, and ablations do not apply in RNS, where strip or depth electrodes are placed at presumptive epileptogenic zones, and a skull implant is used for both diagnostic and therapeutic purposes in an ambulatory setting. Rather than single therapeutic interventions that apply in cases of ablative epilepsy surgery, RNS provides long-term daily therapeutic input that has typically seen improvement in seizure control with time which is in contradistinction to long-term seizure control rates after resective surgery that drop precipitously with time . Intuitively, parents faced with the difficult decision regarding the surgical management of their child’s epilepsy would more easily accept a strategy that provides safety, reversibility, and modulation with advancements in technology, all the while without threat to the preservation of function. Such promise would most certainly change the utilization rates of epilepsy surgery once medical refractory epilepsy was established.

But while rates of diagnostic epilepsy surgeries have risen in the era of robotic sEEG-guided operations, therapeutic procedures have declined . Given the limited time that this technology has been available, evidence of efficacy superior to or approaching that of resective strategies has yet to be established. Time is of the essence in finding better seizure control outcomes in children, whose developmental window is limited. Thus, paradigm shifts in the therapeutic strategies for epilepsy away from ablation and toward neuromodulation will be slow to develop.

Preliminary experience from our group and others points to positive outcomes when RNS is applied in the setting of seizures involving language cortex . We have applied neuromodulatory strategies to preserve language in children where hemispherotomy was considered prohibitive by parents and practitioners, where MSTs were deemed to be of low yield, and where maximal focal resection failed to completely control seizures. The next three illustrative cases and the clinical scenarios are presented here to illustrate the utility of a neuromodulatory strategy, where an ablative strategy was considered too invasive or had already proved ineffective in the setting of epilepsy associated with language cortex.

Responsive neurostimulation for dominant hemispheric epilepsy

Given the poor language outcomes discussed above after hemispherotomy in the dominant hemisphere, particularly after language lateralization in patients with good baseline function and acquired pathology, we have applied a neuromodulatory strategy in a patient with RE involving the left, dominant hemisphere, after prior failure of epilepsy surgery:

Patient 2: A 17-year-old male had initial seizure onset at age six where an imaging and medical workup revealed the diagnosis of RE in the setting of medically intractable epilepsia partialis continua (EPC). Over a 2-year period, the patient had progressive hemiatrophy of the left hemisphere and evidence of language function lateralized to the left on fMRI. Despite weekly intravenous immunoglobulin (IVIG) therapy and multiple medication trials, the patient’s seizures remained refractory, and he developed a progressive right hemiparesis. In the setting of four antiepileptic drugs (AEDs) (valproic acid, oxcarbazepine, clonazepam, topiramate) at age 8, he underwent MSTs to the left hemisphere, to preserve speech and functional gait. With no additional functional impairment, he experienced resolution of the EPC. Nevertheless, he continued to have intermittent focal seizures of the right leg and arm and two years later underwent VNS placement. While daily seizures reduced in frequency, after puberty his seizures became more severe and occasionally generalized. The patient remained highly functional in his teenage years, mobile with good strength in the right leg, functional dexterity in both upper extremities, and fluent speech. We offered RNS for further control of his epilepsy. Based upon the patient’s seizure semiology, recent EEG, and remote electrocorticography data that preceded the MSTs, four anatomic locations were selected for lead placement. The patient received one superior temporal gyrus electrode, two inferior Rolandic strip electrodes, one middle Rolandic strip electrode, and one superior Rolandic strip electrode. Electrode adjustments were made with intraoperative electrocorticography, which revealed maximal irritability in the left superior Rolandic contacts and the left superior temporal gyrus contacts. These two cortical electrodes were ultimately selected for connection to the RNS device. Currently, at 8 years post-RNS placement, the patient reports an average of 1–3 brief clinical seizures per month. RNS System chronic ECoG, accessed via a secure data repository (Patient Data Management System), shows a 90% reduction in electrographic seizures with a dramatic decrease in prolonged epileptiform discharges. ASMs have been decreased by 25% and IVIG therapy has been halted with favorable results. The patient’s gait and cognitive function have remained stable. There has been no further deterioration of his sensorimotor, speech, or mental functioning. Functionally, the patient can ambulate and feed himself independently, and has completed his special education program.

Responsive neurostimulation for nonlesional regional epilepsy involving language

While the relative efficacy and safety of MSTs for nonlesional epilepsy has been discussed above, the concerns about more widespread regional onsets involving eloquent regions have directed us to use RNS . We first employed this strategy in a child, however, using the RNS off-label and reported this successful approach to the utility of a neuromodulatory rather than ablative/resective approach previously :

Patient 3: A 9-year-old female presented with refractory seizures with MRI evidence of a small left parietal watershed infarct. Her seizures started at 18 months and became intractable by age 5, with a baseline mild right hemiparesis. Seizure semiology was characterized by impaired speech, and parents described debilitating fatigue, frequent falls, and academic regression. Scalp EEG suggested her seizures emanated from her left temporal lobe, away from the MRI lesion. Invasive monitoring with grid and strip electrodes identified an epileptogenic zone in the left posterior frontal and parietal lobes that co-localized to her language and Rolandic cortical regions. Extraoperative stimulation mapping triggered significant discharges in these regions that suppressed with higher amplitude stimulation, suggesting the potential for a favorable therapeutic response to direct cortical stimulation. At the time, our center was using a subdural recording approach to guide resective or ablative surgery, and RNS was not initially planned. However, RNS was presented to the family based on the extraoperative recordings and response to stimulation during brain mapping, rather than an ablative procedure. An RNS neurostimulator was placed with four cortical strips in the angular and supramarginal gyrus regions. Intraoperative ECoG demonstrated rhythmic epileptiform discharges from the most rostral and caudally placed leads, which were connected to the device. Her seizures became milder in frequency, duration, and severity. School attendance improved: prior to treatment with the RNS System, the patient would typically miss one day per week, either because of a seizure at school or because of a difficult postictal recovery after a seizure at home. Since she has been treated with responsive neurostimulation, she has not missed any school days due to epilepsy. Despite lead placement in functional areas of the cortex, the patient is unaware of stimulation, which is subthreshold cortical stimulation when the device is activated.

Responsive neurostimulation after failed lesionectomy in language cortex

The extent of resection of the epileptogenic zone correlates with seizure freedom, and when a migrational disorder or otherwise benign condition abuts or involves an eloquent region, the results may not be satisfactory in the long term. Here a case is presented of an adolescent whose focal cortical dysplasia involved his dominant angular/supramarginal gyrus area, where resective epilepsy surgery was temporarily beneficial, but ultimately inadequate in controlling his epilepsy alone:

Patient 4 : A 15-year-old presented with seizures since age 6 months characterized by nocturnal shaking of the right side of the body. These were treated with monotherapy from age 6 to puberty and then worsened significantly by age 14, with 10–15 events per month of violent focal to bilateral tonic-clonic seizures on three ASMs. We performed an awake craniotomy guided by sEEG monitoring to resect a region of focal cortical dysplasia from the dominant angular gyrus region, and the patient experienced four months of seizure freedom. With epilepsy returning to his preresection baseline in terms of frequency but with lessened severity, we placed an RNS System with strip electrodes at the margins of his resection cavity, and a depth electrode in the left insular cortex that remained capped. Recording and stimulating through the two angular gyrus region strip electrodes has afforded the patient a significant benefit in seizure control with 90%–99% reduction in events dependent upon medication compliance.

While complete seizure freedom has not yet been achieved, the RNS has provided adjunctive daily treatment in a neuromodulatory manner, where a resective approach was limited by proximity to eloquent brain regions, despite maximal awake resection. The case illustrates the necessity to employ all of the tools in the epilepsy surgery armamentarium and understand that none are mutually exclusive.

Sensorimotor function, epilepsy in Rolandic cortex, and hemispherotomy

Given the high short-term rate of seizure control balanced against the global developmental delay and functional loss associated with severe pediatric epilepsies, hemispherotomy is favorably looked upon in most pediatric epilepsy centers. Definitive destruction of sensorimotor pathways due to hemispherotomy in early childhood results in a range of early functional outcomes from complete hemiplegia to no change, depending on preoperative status. Analysis of late outcome experience and novel functional imaging evidence gives us the confidence to be able to predict the ability of a child to be ambulatory and have good proximal contralateral upper extremity strength , with better outcomes when surgery is done earlier in childhood. However, a well-established permanent deficit relates to hand movement: after hemispherotomy, long-term recovery of finger dexterity remains a challenge and is likely to be permanently lost if not already reorganized preoperatively .

Sensorimotor function, epilepsy in Rolandic cortex, and targeted resection

Some of the earliest work in focal or regional resective surgery in the Rolandic area involved children and case series showed a relative preservation of function and mixed results depending upon etiology of epilepsy . More modern series demonstrate the effectiveness and safety of resective surgical management of epilepsies in the central region , and highlight the following conclusions. Kerezoudis summarized this work to show a near 70% seizure freedom rate in the setting of 90% of these cases being lesional epilepsy in the central lobule, with almost half of the patients having temporary or permanent worsening of neurological function beyond their baseline, preexisting hemiparesis . In cases where nonlesional epilepsy involves the rolandic cortex, both resection and MSTs have been used with better rates of control associated with resection combined with MSTs (summarized in ). Taken together, a prediction that two-thirds of the patients will become seizure-free with a substantial risk of deficit, a nonoperative decision is easier to understand despite our concerns about ongoing epilepsy and long-term risk.

Sensorimotor function, epilepsy in Rolandic cortex, and responsive neurostimulation

Experience with neuromodulation in children being treated for epilepsy involving sensorimotor function is limited but promising. In the Kerezoudis summary involving literature up until mid-2021, they found 11 children treated with electrical stimulation (RNS or continuous subthreshold cortical stimulation [CSCS]) to control seizures in the perirolandic region . They reported nearly 80% seizure reduction in this metaanalysis that included children and adults and found no deficits incurred from these modulatory approaches.

To guide decision-making, these authors also summarized and echoed Yan and Ibrahim’s guidance factors when discussing epilepsy surgery in the central region, such as goals of treatment and tolerance for deficit. We know that these are different between children and adults, where development and safety are considered over driving and employment, and parents are less likely to accept a deficit in the context of only partial seizure control. The case presented below highlights this clinical conundrum and a novel approach to hemispheric epilepsy in a child:

Patient 5 : A 7-year-old girl presented with EPC involving the dominant left hand and leg refractory to medical therapy, leading to a brain biopsy and the diagnosis of RE. A hemispherotomy was suggested to the parents who were reluctant to consent given the inevitable loss of dominant hand function. We performed sEEG and found regionalized onsets involving the right rolandic cortex and placed an RNS system with strip electrodes, one covering the leg and foot motor areas and the second in the hand sensorimotor region ( Fig. 7.2 ). The patient has had a 99% reduction in seizures at 4 years of follow up with no deterioration in dexterity of the affected hand, gait, or cognitive function on serial neuropsychological evaluations. She has been maintained on weekly IgG infusions and ASM polytherapy, and seizure control related to RNS recordings show significant improvement with time, suggesting a demonstrable neuroplastic effect of chronic therapy with the device. The natural history of RE in the nondominant hemisphere, with progressive cognitive and sensorimotor decline, has not been seen in this patient.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Evidence in pediatric epilepsy surgery Controversies in the timing of pediatric epilepsy surgery: is earlier better? Lesional epilepsy: lesionectomy versus ECoG-guided resection Insular/perisylvian epilepsy: Open resection versus stereotactic ablation (MR-guided laser ablation/radiofrequency thermocoagulation) versus responsive neurostimulation Temporal lobe epilepsy with preserved function: multiple hippocampal transection versus neuromodulation (deep brain stimulation, responsive neurostimulation) Corpus callosotomy: anterior two-thirds (two-stage) versus complete (one-stage)

Stay updated, free articles. Join our Telegram channel

Join