Selecting the right paediatric patient for epilepsy surgery

Selecting the right paediatric patient for epilepsy surgery

SYMPOSIUM: NEUROLOGY Selecting the right paediatric patient for epilepsy surgery Goals Drug resistant childhood epilepsy is a debilitating condition...

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SYMPOSIUM: NEUROLOGY

Selecting the right paediatric patient for epilepsy surgery

Goals Drug resistant childhood epilepsy is a debilitating condition. A high seizure burden has a significant impact on quality of life, as well as considerable social stigma, a risk of injury and even of sudden death in epilepsy (SUDEP). AEDs can have considerable side effects especially as these patients usually take multiple AEDs and in high doses. Furthermore childhood epilepsy is often accompanied by comorbidities such as neurodevelopmental delay and behavioural problems. The goal of epilepsy surgery is first and foremost seizure freedom, ideally with no functional deficit. As seizures in early childhood can be associated with developmental arrest it would appear to follow that an early reduction of seizure burden with subsequent reduction of AED intake would improve quality of life with the likely added benefit of improved cognitive and behavioural outcome from epilepsy surgery. However this cannot be guaranteed based on current available literature. Early surgery is advocated in children to give them the best chance of optimised neurodevelopmental and behavioural outcome not least by utilizing the functional plasticity of infant and young children’s brain important to the recovery of linguistic and motor competences after epilepsy surgery. The most important predictor for seizure freedom after epilepsy surgery is the complete resection of the epileptogenic zone. Comprehensive pre-surgical assessment is important in order to first identify with certainty the area responsible for the patient’s seizures, to secondly define its extent and to thirdly assess any possible functional consequences of removing it so that this may be avoided. This information is prerequisite to counsel families, help them carefully weigh the pro or cons of surgery and create realistic expectations.

J Helen Cross Katharina Vezyroglou

Abstract Even though epilepsy is commonly referred to as one disease it would be much more accurate to refer to the epilepsies, as the term describes a wide group of conditions with the common characteristic of recurrent epileptic seizures, but many different underlying causes and consequently differing underlying pathophysiologies. One group within these conditions are the structural epilepsies, epilepsies in which there is a structural brain abnormality responsible for the seizures. Even though this again is a heterogeneous group, structural epilepsies do share some common characteristics not least that they very often prove drug resistant, failing two or more appropriately chosen and dosed antiepileptic drugs as defined by the International League Against Epilepsy (ILAE). We know that patients failing the first two antiepileptic drugs (AEDs) have fewer than 5% chances of responding to a third or fourth medication. Unilateral structural lesions however may be amenable to resection giving these patients a chance of cure. Thus it is crucial that this treatment is considered.

Keywords childhood epilepsy; drug resistant epilepsy; epilepsy; epilepsy surgery

Criteria for patient referral Epilepsy surgery

Guidelines (NICE/ILAE) The UK National Institute for Health and Care Excellence (NICE) guidelines for epilepsy in children and young people state that a referral to tertiary services should be considered when one or more of the following criteria are present:  The epilepsy is not controlled with medication within 2 years of onset.  Management is unsuccessful after two drugs.  The child is under 2 years of age.  The child or young person experiences, or is at risk of, unacceptable side effects from medication.  There is a unilateral structural lesion.  There is psychological or psychiatric comorbidity.  There is diagnostic doubt as to the nature of the seizures or the seizure syndrome. If epilepsy is confirmed the possibility of epilepsy surgery as an effective treatment for the patient should be considered at this point in time. In 2006 the International League against Epilepsy (ILAE) also published proposed criteria for referral and evaluation of children for epilepsy surgery. They state that children with seizures that are uncontrolled by medical treatment (i.e. failure of two or three appropriate drugs) or are disabling (including medication side effects) are possible surgical candidates. In addition, childhood epilepsy that cannot be classified as a clearly defined

History Contrary to its reputation as a relatively new form of epilepsy treatment, epilepsy surgery has a history spanning over more than 100 years with its beginnings dating back to 1886 when Sir Victor Horsley operated successfully on three patients with focal Jacksonian epilepsy. Being a physiologist as well as a surgeon he utilized bipolar electrodes in later operations in order to intraoperatively map the motor cortex. Other surgeons followed his example extending the field of epilepsy surgery beyond the motor cortex and leading to a better understanding and mapping of the brain. Today technological advances especially in the field of neuroimaging and electrophysiology allow a much more tailored utilization of epilepsy surgery techniques in our individual patients.

J Helen Cross OBE MB ChB PhD FRCP FRCPCH holds The Prince of Wales’s Chair of Childhood Epilepsy and is Head of the Developmental Neurosciences Programme at UCL-Institute of Child Health, London, UK. Conflict of interest: none declared. Katharina Vezyroglou MD is a Clinical Research Fellow at the UCL-Institute of Child Health, London, UK. Conflict of interest: none declared.

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Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Cross J Helen, Vezyroglou K, Selecting the right paediatric patient for epilepsy surgery, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/j.paed.2017.03.003

SYMPOSIUM: NEUROLOGY

electroclinical epilepsy syndrome (ILAE classification) should be evaluated by a paediatric specialty centre. This includes patients with stereotyped or lateralized seizures or other evidence of focality (that cannot be definitely attributed to idiopathic focal epilepsies) or in whom the MRI reveals a lesion amenable to surgical removal. They further recognize the following surgical syndromes in childhood for which epilepsy surgery should be considered with diagnosis:

4. Hemispheric syndromes Focal drug resistant epilepsy in childhood can result from pathologic conditions affecting an entire hemisphere such as hemimegalencephaly, hemispheric dysplasia or an extended perinatal stroke. In these patients hemispherectomy or hemispherotomy techniques will be used to treat the epilepsy. As these patients often are hemiplegic and hemianoptic prior to surgery due to the dysfunctional hemisphere the functional deficit actually resulting from epilepsy surgery is not as high as may be anticipated. 5. Polymicrogyria Compared to other hemispheric syndromes polymicrogyria may result in a milder epilepsy and sometimes even spontaneous remission. The typically involved perirolandic and perisylvian areas might retain critical function thus making a decision for resection difficult. Also, even in patients where MRI suggests unilateral involvement, there can commonly be bilateral abnormality. For these reasons polymicrogyria patients are not optimal surgery candidates and detailed expert pre-surgical assessment is important. 6. SturgeeWeber syndrome (SWS ) SWS is a condition characterized by vascular malformation affecting skin, brain and eyes. Affected patients have a facial port wine stain typically around their forehead and/or scalp as well as pial angioma of the brain and choroid angioma of the eye. The pial angioma can be lobar or hemispheric and even bilateral in rare cases. Due to this structural brain abnormality patients with SWS can develop troublesome epilepsy that is difficult to treat with medication. They are prone to prolonged seizures resulting in initially transient and then permanent hemiplegia. As they are potential candidates for focal or hemispheric resections if the angioma is unilateral, they should be assessed at a specialist epilepsy surgery centre early in the course of their epilepsy. Resection can be risky due to the vascular pathology of SWS and should be performed by experienced paediatric epilepsy surgeons. 7. Rasmussen syndrome Rasmussen encephalitis is a rare acquired presumed autoimmune condition that presents in the majority in childhood. It is characterized by the progressive inflammation of one cerebral hemisphere resulting in drug resistant focal epilepsy as well as progressive neurological (as hemiplegia) and cognitive deterioration. Epilepsy surgery and more specifically hemidisconnection remains the only available cure to halt disease progression, but inevitably comes with functional deficit especially if the dominant hemisphere is involved. Experienced risk-benefit assessment is crucial to determine the best timing for surgical intervention.

Specific paediatric syndromes to consider epilepsy surgery 1. Focal malformations of cortical development Focal cortical dysplasia and other focal/hemispheric malformations of cortical development are the most common pathologies seen in children coming to epilepsy surgery. Contrary to adults who will present with focal semiology respective to the area of abnormality in the brain, children and especially infants with focal cortical dysplasia may present with generalized seizures such as infantile spasms. These can, but do not have to be asymmetric or accompanied by focal seizures. Equally the interictal scalp EEG might not always display focal features, but can be i.e. hypsarrhythmic. Early neuroimaging is extremely important in infants with catastrophic epilepsy. As lesions can be very subtle this should be high-resolution MRI and sometimes further imaging techniques like i.e. FDG-PET will be needed to identify the dysplastic area. These patients are likely to be drug resistant and early surgical intervention represents their best chance for seizure freedom and best possible neurodevelopmental outcome. Complete resection of the lesion is associated with the best epilepsy control. Early referral of these difficult to diagnose patients to an advanced speciality service is paramount. Focal cortical dysplasia can be associated with somatic DEPDC5 mutations; the relevance of this to suitability for surgery and the ultimate outcome currently is unclear. 2. Tuberous sclerosis complex (TSC ) Patients with TSC usually have multiple dysplastic brain areas (tubers), so usually are not clear epilepsy surgery patients. Nevertheless, if these patients have one predominant seizure type it is possible that they have a single epileptogenic tuber that might be suitable for resection. Of course postsurgical prognosis is more guarded in these patients as other tubers may prove epileptogenic in their future. Still resecting an epileptogenic tuber might still significantly decrease seizure burden in patients that otherwise prove drug resistant. Reported series of children carefully selected for surgery report short term outcomes similar to series of children undergoing surgery for focal cortical dysplasia. 3. Hypothalamic hamartoma Patients with hypothalamic hamartoma often present with gelastic (laughing) seizures that are difficult to treat. Behavioural and developmental difficulties often emerge with other seizure types. Referral to a specialist centre is important as surgery in these patients even though possibly curative might not be straightforward due to the difficult location of the tumour and possible endocrine and cognitive sequelae.

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Pre-surgical evaluation As already mentioned a thorough pre-surgical assessment in a specialist epilepsy surgery centre is a main prerequisite for successful epilepsy surgery. The goal is to correctly define the epileptogenic lesion and its extent as well as to separate it from eloquent/functional regions and if not possible to define the functional deficits anticipated from its removal. This means

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Please cite this article in press as: Cross J Helen, Vezyroglou K, Selecting the right paediatric patient for epilepsy surgery, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/j.paed.2017.03.003

SYMPOSIUM: NEUROLOGY

be obtained ictally and thus its utilization is more difficult while sensitivity in identifying the epileptogenic zone seems comparable. FDG-PET identifies regions of cerebral hypometabolism that are believed to correlate well with the epileptogenic zone. It is particularly useful in lateralizing the seizure origin and has been successfully used to identify the epileptogenic zone in MRI lesion negative patients with apparent generalized seizures (i.e. infantile spasms). AMT-PET has been useful in identifying the most epileptogenic tuber in patients with TSC and multiple tubers but has limited availability. Magnetoencephalogram (MEG) is another electrophysiologic tool that uses interictal discharges to localize the epileptogenic zone with better spatial resolution than scalp EEG. It has proven more reliable than scalp EEG in patients with anatomical abnormalities, such as scull defects or large cysts. Imaging modalities are not only useful in identifying the structural substrate, but also in defining eloquent cortex. Functional MRI is widely used in children cognitively able to participate in order to identify motor and language localization/ lateralization.

employing a variety of investigations, including a minimum required for every patient (Video-EEG including ictal recording, MRI, neuropsychology and neuropsychiatry assessment) that can be extended as appropriate to meet the needs of each individual case. EEG In the ILAE recommendations interictal scalp EEG including natural sleep is mandatory for the pre-surgical evaluation and video-EEG for ictal events was strongly recommended in all children. Interictal scalp EEG has limited spatial resolution, but it’s wide availability makes it a valuable tool. Localization is better for convexity foci as compared to basal, mesio-temporal and intrahemispheric foci. Also, especially in very young children with a lesion, it is sometimes possible to see multifocal or even seemingly generalized interictal discharges. This should not, as an isolated finding, exclude them from candidacy for epilepsy surgery. Ictal video-EEG is a very valuable tool not only to localize the area of seizure onset, but also to delineate seizure semiology and confirm epileptic origin of suspicious events, as parent and even medical reports can often be inaccurate. Multiple recordings might be necessary to record all seizure types and rule whether one consistent epileptic focus can be identified for the patient as a surgical target. As with interictal EEG ictal onset from a deep focus may be missed on scalp EEG with following propagated discharges being the first feature seen. Simultaneous video proves helpful in identifying the time of seizure onset.

Neuropsychology/neuropsychiatry It is important to recognize that paediatric epilepsy surgery candidates have a high risk of neurodevelopmental and mental health disorders. Thus it is important to perform preoperative neurodevelopmental and neuropsychiatric assessment in order to establish a baseline to which postoperative course can be compared. Neurocognitive evaluation preoperatively might further be useful in order to assist lateralization/localization of function, inform the expected postoperative deficit and help postoperative educational and rehabilitation planning. Unfortunately serial neurodevelopmental assessment of children remains difficult due to the lack of standardized tests spanning all age groups.

Structural imaging Magnetic Resonance Imaging (MRI) is mandatory as the primary imaging modality in the assessment for epilepsy surgery. A CT might only be used additionally in specific situations (i.e. assessing the possible presence of calcification). A specific epilepsy protocol should be followed including T1 and T2 weighted imaging, as well as DTI and appropriate thin slicing for a 3D data set. High-resolution 3T MRI is superior to 1.5T MRI in detecting subtle abnormalities and should be favoured when available. Success in detecting the lesion is important as it allows tailoring the resection and avoiding large disconnections. Further patients with lesions evident on MRI preoperatively have better seizure outcomes following surgery. Lesion negative MRIs should always be reviewed with an experienced paediatric neuroradiologist also to assess whether the available scan is of sufficient quality before labelling the patient as MRI lesion negative. Focal cortical dysplasias (FCDs) can be missed on MRI in children aged 6 months e2 years due to incomplete myelination. Scans obtained in this time frame should be repeated if suspicion of a structural lesion persists.

Invasive EEG monitoring In MRI lesion negative cases, in cases where EEG and MRI data are disconcordant as well as in cases where the epileptogenic zone is adjacent to or even overlaps with eloquent cortex intracranial EEG monitoring should be performed. This consists of either subdural electrodes being placed over the area of interest, sometimes combined with depth electrodes if a deep lesion is suspected, or stereo EEG recording which involves stereotactically placed single electrodes around the area of interest. Both, the subdural and depth electrodes can be used to more precisely localize seizure onset, as well as for stimulation to either provoke a typical seizure thus proving an area to be the epileptogenic zone or to perform functional mapping of the eloquent cortex. This way a detailed map is produced allowing the surgeon to perform a tailored resection including the epileptogenic zone, but sparing eloquent cortex as best possible.

Further imaging techniques In MRI lesion negative patients highly suspected of having a structural substrate to their epilepsy further imaging techniques should be employed to identify the epileptogenic zone. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are the two most commonly used modalities. While PET is obtained interictally, SPECT has to

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Epilepsy surgery procedures The ideal outcome of evaluation for epilepsy surgery is the identification of one restricted epileptogenic zone located in non-

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Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Cross J Helen, Vezyroglou K, Selecting the right paediatric patient for epilepsy surgery, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/j.paed.2017.03.003

SYMPOSIUM: NEUROLOGY

eloquent cortex facilitating easy removal and subsequent seizure freedom. The resultant procedure will depend on the result of investigation and multidisciplinary discussion.

Most patients with large hemispheric lesions have some grade of hemiplegia and hemianopia prior to surgery. The majority of patients with a normal contralateral hemisphere will still be able to walk unaided postoperatively if they reach this developmental level. Fine finger function might be lost if present prior to surgery. It seems that better recovery is achieved after early surgery utilizing the functional plasticity of the brain allowing for reorganization of motor and language skills.

Lesionectomy/lobectomy In patients in whom a defined lesion can be identified as the epileptogenic zone a lesionectomy can be performed. If the lesion is mono-lobar, but extensive and/or the borders of the lesion are ill defined a lobectomy might be favoured to secure better chances of postoperative seizure freedom. The neuropathologic substrate of these lesions varies widely with FCDs being the commonest, but including much other aetiology such as hippocampal sclerosis, arteriovenous malformations (AVMs), developmental tumours (i.e. dysembryoplastic neuroepithelial tumors (DNETs) or gangliogliomas), regions of cortical gliosis and infarction. It has been shown that the primary indicator of good seizure outcome is the complete resection of the epileptogenic zone irrespective of the underlying pathology. Outcome in patients with developmental tumours is better than in FCDs with a rate of 80% of seizure freedom after resection compared to 60%, but this might reflect the fact that these tumours are better-defined lesions allowing complete resection more likely. Similarly, outcomes following resection for FCD type 2 are better than for FCD type 1. The location of the lesion also seems to play a role, as higher rates of seizure freedom have been achieved in patients after temporal as compared to extratemporal lesions. As expected the outcome is inferior after resections in lesion negative patients.

Corpus Callosotomy Unlike the previously discussed procedures Corpus Callosotomy is a palliative rather than curative procedure that does not aim to achieve seizure freedom. It consists of dividing the Corpus Callosum thus disconnecting the two hemispheres and preventing rapid spread of epileptic activity. As a result it is useful in order to control ‘drop’ seizures whether atonic or tonic seizures. As these are very disabling seizure types often resulting in injury and seriously impacting on quality of life the procedure should be considered for patients with a high burden of these particular events. Rarely it might lateralize the EEG showing unilateral activity and allowing the patient to later proceed to respective curative surgery.

Conclusion Epilepsy surgery should be considered early in the treatment of children with drug resistant epilepsy as it can be a curative option for patients otherwise committed to lifelong seizures and antiepileptic medication, with the inevitable impact on quality of life, neurodevelopment and mental health. Even if seizure freedom cannot be achieved there might be a surgical option to significantly reduce seizure burden (i.e. by resecting the most active tuber in TSC patients) or to stop especially troublesome seizures (i.e. Corpus Callosotomy in LennoxeGastaut syndrome where patients experience drop attacks). In order to correctly understand the underlying pathophysiology in each patient and decide upon the best individual surgical option a comprehensive pre-surgical evaluation in a specialist centre employing an experienced team of paediatric neurologists, paediatric neurosurgeons, paediatric neuroradiologists and paediatric neurophysiologists is paramount. A

Hemispherectomy In drug resistant epilepsy patients with widespread unilateral hemispheric abnormality hemispheric disconnection may be the only option for surgical seizure control. Historically this meant an anatomical hemispherectomy with removal of the temporal, frontal, parietal, and occipital lobes, sparing the thalamus, basal ganglia, and insular cortex first attempted in the 1920s. Today the trend has moved more towards disconnective procedures in which the affected hemisphere is disconnected rather than anatomically removed in order to reduce postoperative complications. Aetiologies warranting a hemispherectomy are variable and other than in the lesionectomies here seem to be the primary predictive factor for seizure outcome. They include developmental lesions (primarily hemimegalencephaly and hemispheric dysplasia) and acquired lesions (primarily perinatal stroke). As previously discussed patients with SturgeeWeber syndrome and Rasmussen syndrome also are potential candidates for hemidisconnection. Following hemispherectomy most patients have improvement in seizure frequency with a seizure freedom rate of 60 e70% in most studies. Seizure freedom is more often achieved in patients with acquired as opposed to developmental lesions. The risk of seizure recurrence is highest in the first 6 months after surgery. Bilateral interictal EEG findings do not predict postsurgical seizure recurrence and should not exclude patients from surgery.

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FURTHER READING 1 Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery. Epilepsia 2006; 47: 952e9. 2 Ryvlin P, Cross JH, Rheims S. Epilepsy surgery in adults and children. Lancet Neurol 2014; 13: 1114e26. 3 Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005e2009. Epilepsia 2010; 51: 676e85. 4 Jayakar P, Gaillard WD, Tripathi M, Libenson MH, Mathern GW, Cross JH. Diagnostic test utilization in evaluation for respective epilepsy surgery in children. Epilepsia 2014; 55: 507e18.

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Please cite this article in press as: Cross J Helen, Vezyroglou K, Selecting the right paediatric patient for epilepsy surgery, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/j.paed.2017.03.003

SYMPOSIUM: NEUROLOGY

5 Jayakar A, Bolton J. Pediatric epilepsy surgery. Curr Neurol Neurosci Rep 2015; 15: 31. 6 Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 2007; 69: 389e97. 7 Pestana Knight EM, Gonzalez-Martinez J, Gupta A. Pre-operative evaluation in pediatric patients with cortical dysplasia. Childs Nerv Syst 2015; 31: 2225e33. 8 Lega B, Mullin J, Wyllie E, Bingaman W. Hemispheric malformations of cortical development: surgical indications and approach. Childs Nerv Syst 2014; 30: 1831e7. 9 Van Schooneveld MM, Braun KP. Cognitive outcome after epilepsy surgery in children. Brain Dev 2013; 35: 721e9. 10 Kellermann TS, Wagner JL, Smith G, Karia S, Eskandari R. Surgical management of pediatric epilepsy: decision-making and outcomes. Pediatr Neurol 2016; 64: 21e31.

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11 Guan J, Karsy M, Ducis K, Bollo R J. Surgical strategies for pediatric epilepsy. Transl Pediatr 2016; 5: 55e66.

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In contrast to adults, young children with epilepsies amenable to surgical treatment often present with intractable generalised seizures Very careful pre-surgical assessment at a specialist centre is necessary to identify children likely to benefit from surgery for epilepsy When undertaken, early surgery is advocated in children to give them the best chance of optimised neurodevelopmental and behavioural outcome

Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Cross J Helen, Vezyroglou K, Selecting the right paediatric patient for epilepsy surgery, Paediatrics and Child Health (2017), http://dx.doi.org/10.1016/j.paed.2017.03.003