The Development of a Provincial Pediatric Epilepsy Program

Home , Christianson syndrome

The Development of a Provincial Pediatric Epilepsy Program:

An Analysis of Early Multidimensional Outcomes

Alysa Almojuela

A Thesis submitted to the Faculty of Graduate Studies of

The University of Manitoba

in partial fulfilment of the requirements of the degree of

MASTER OF SCIENCE

Department of Surgery

Rady Faculty of Health Sciences

University of Manitoba

Winnipeg

Abstract iv

Acknowledgements vi

List of Tables vii

List of Figures viii

Chapter I: Introduction & Literature Review 1

Epilepsy Epidemiology and Background 1

Surgical Management of Epilepsy and Seizure Outcomes 4

Pre-operative Work-up 5

Curative Techniques 7

Palliative Techniques 13

Long-Term Outcomes 15

Neuropsychological Outcomes of Epilepsy 16

Patient Quality of Life 20

Caregiver Quality of Life 22

Quality Assessment and Caregiver Satisfaction 23

Economic Evaluation 24

Program Development 25

Study Objectives 27

Chapter II: Methods 28

Design 28

Patient Population 29

Outcome Measures 30

Data Analysis 33

Chapter III: Results 33

Demographics 33

Seizure Outcomes 36

Neuropsychological Outcomes 37

Patient Quality of Life 46

Caregiver Quality of Life 48

Caregiver Satisfaction 50

Chapter IV: Discussion 51

Limitations and Future Directions 58

Conclusions 60

Literature Cited 61

Appendix 68

Appendix A: Data Fields in RedCap Database 68

Appendix B: Systematic Review – Search Strategy 69

Appendix C: EpiTrack Junior 71

Appendix D: Quality of Life in Childhood Epilepsy (QOLCE-55) Questionnaire 77

Appendix E: CarerQol Questionnaire 81

Appendix F: Caregiver Satisfaction – Modified Version of the Parent Questionnaire 82

Appendix G: Bias Assessments Using the RTI Item Bank on Risk of Bias and Precision 84 of Observational Studies

Appendix H: Sample Telephone Script and Mailed Consent Form 85

iii

Abstract

Introduction

Access to epilepsy surgery is improving across Canada, but the province of Manitoba, with a population of approximately 1.37 million, has - until recently - lacked the local infrastructure to deliver surgical epilepsy care. This thesis aims to describe the change in care provided to pediatric epilepsy patients in Manitoba since the formation of a comprehensive Pediatric Epilepsy Program, provide an early analysis of local outcomes, and present a framework for program development.

Methods

Data was collected retrospectively from medical records on patients who previously had

epilepsy surgery in Manitoba, and prospectively on new, incoming patients. Caregivers were asked

to complete questionnaires on quality of life and satisfaction with the Program. An online database

was created to capture demographic information, seizure and neuropsychological outcomes, patient and caregiver quality of life, and caregiver satisfaction. Descriptive statistics were used to describe these outcomes.

Results

Prior to the formation of the Pediatric Epilepsy Program, 16 patients underwent vagal nerve

stimulator (VNS) insertions. Mean time to surgery was 5.5 +/- 2.92 years. At a follow-up of 1-5

years, 1 patient (6.25%) achieved Engel class I outcome, 12 patients (75%) achieved Engel class

III outcome, and 3 patients (12.5%) achieved Engel class IV outcome.

After formation of the Pediatric Epilepsy Program, 14 patients underwent a variety of epilepsy surgeries, including 11 resective procedures and 3 VNS insertions. Mean time to surgery was 5.49 +/- 2.99 years. At a follow-up of 3-12 months, 11 patients (78.6%) achieved Engel class

I outcome, 2 patients (14.3%) achieved Engel class III outcome, and 1 (7.1%) patient achieved

Engel class IV outcome. Neuropsychological testing remained stable in the 2 patients it was completed on. The average QOLCE-55 score measuring patient quality of life was (59.7 +/-

23.2)/100. The average CarerQol-7D score measuring caregiver quality of life was (78.3 +/-

18.6)/100. Caregiver satisfaction was high with an average rating of (9.4 +/- 0.8)/10.

Conclusion

Access to epilepsy surgery has improved for children in Manitoba with favorable multidimensional outcomes. Structural organization, funding and multidisciplinary engagement are necessary for program sustainability. A longitudinal database is recommended for continuous quality assessment and improvement.

Acknowledgements

I would like to thank my primary supervisor, Dr. Demitre Serletis, and my co-supervisors,

Dr. Helen Xu and Dr. Lesley Ritchie, for their invaluable assistance and guidance with this project.

List of Tables

Table 1. Patient Demographic Information 35

Table 2. Studies Examining Outcomes Following a Single Type of Surgical 42 Procedure

Table 3. Studies Examining Outcomes Following Surgery for a Specific Type of 43 Patient Population

vii

List of Figures

Figure 1. Seizure Outcomes 37

Figure 2. Flow Diagram of Study Selection 38

Figure 3. Patient Quality of Life Outcomes 48

Figure 4. Caregiver Quality of Life Outcomes 49

Figure 5. Caregiver Satisfaction Outcomes 50

Figure 6. Program Development Model 57

viii

Chapter I: Introduction and Literature Review

Epilepsy Epidemiology and Background

Epilepsy is a neurological condition characterized by recurrent and persistent seizures. The

worldwide prevalence of epilepsy is high; in North America alone, more than 3 million individuals

have epilepsy at a given time. Canada, in particular, has an overall incidence of 40-70 per 100,000 people; taking Canada’s 2003 population of 31 million, there is an incidence of approximately

15,500 new cases of epilepsy per year(1). Epidemiological studies have demonstrated that the incidence of epilepsy tends to be higher in infants, and decreases with age: in children less than 1 year of age, the incidence is 118 per 100,000; in children aged 1 to 5 years old, the incidence is 48 per 100,000; in children 6 to 10 years of age, the incidence is 43 per 100,000; and in children 11 to 15 years old, the incidence is 21 per 100,000(2). Prevalence has been shown to be higher among populations with lower education levels, lower income levels, and who are unemployed. In

Manitoba specifically, the prevalence of epilepsy is approximately 4.49 per 1,000(3).

In very young children, the common etiologies underlying epileptic seizures include hemispheric syndromes such as Sturge-Weber syndrome, Rasmussen encephalitis and hemimegalencephaly. Malformations of cortical development, vascular malformations or stroke, tuberous sclerosis complex, neoplasms, gliosis, and prior infections are also common causes(4).

Among neonates in particular, hypoxic-ischemic encephalopathy is responsible for 40% of epilepsy cases, with central nervous system infection accounting for 20% of cases and metabolic

abnormalities accounting for 19% of cases(3). Given the diffuse nature of these etiologies, the

most common seizure type in this patient population is generalized tonic-clonic activity, reported in 52-56% of patients, followed by complex partial seizures in 14% of patients(3).

The morbidity of epilepsy extends further than the physical impact of repeated seizures.

Epilepsy is associated with higher rates of accidental trauma, negative side effects from anti-

epileptic drugs (AEDs), and emotional, psychological and social stressors. As adults, persons with

epilepsy (PWE) have lower annual income compared with other common chronic conditions(5).

The diagnosis of epilepsy also carries a profound social stigma such that even with improvements

in overall clinical seizure burden, the effects of social isolation typically persist into adulthood. In

fact, there are many misconceptions regarding the cause or source of epilepsy in some communities

today, including the belief that epilepsy is primarily a mental illness(6). As unimpeded seizure

activity can impact cognitive and behaviour development as well, achieving seizure freedom

earlier may positively impact cognition, psychiatric illness, social integration, and overall lead to

improved quality of life. Early weaning of AEDs can also prevent harmful side effects from

prolonged medication use(7). In adulthood, seizure freedom leads to increased independence with benefits seen in marital/social status, gainful employment outcomes and level of education

attained(8, 9).

The mortality associated with epilepsy, as compared to the general population, may be up

to 8.8 times higher according to a population-based study of pediatric epilepsy in Nova Scotia(10).

In children, the incidence of Sudden Unexplained Death in Epilepsy (i.e. SUDEP) is 0.2 per 1,000

person years(11). Both US and Canadian data suggest that mortality in non-symptomatic epilepsy

is only marginally increased above the general population; however, in patients with symptomatic

epilepsy, mortality is significantly increased. Although studies are plagued by difficulties in distinguishing cause of mortality due to the underlying cause of epilepsy as opposed to symptomatic epilepsy itself, this highlights the importance of achieving improved seizure control so as to minimize the risk of morbidity and/or mortality associated with the condition(3).

Unfortunately, of all patients who are diagnosed with epilepsy, only 47% will attain seizure freedom with just one AED; an additional 13% of PWE will attain seizure freedom with the addition of a second medication; and only 4% with addition of a third medication, underscoring an extremely high risk of failure with further medication trials following the initial agent(12). The

International League Against Epilepsy (ILAE) defines drug resistance, or medically intractable epilepsy, as the failure of adequate trials of two tolerated and appropriately chosen anti-epileptic drug schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom

(13). For those patients who fail medical therapy (i.e. approximately one-third of epilepsy patients), epilepsy surgery may offer the only chance for improved seizure control. As such, national and international guidelines, including the ILAE, now strongly advocate for early surgical referral of patients with medically intractable epilepsy(14).

In Canada, although access to healthcare is theoretically universal, attempts to control cost and allocate resources, as well as geographic and political barriers, lead to variable access to epilepsy therapies(3). Access to AEDs, epilepsy surgery and comprehensive pre-operative work- up is inconsistent from province to province. In 2002, 45 video-EEG beds were available in 22 separate epilepsy centres across the country, as well as 326 CT scanners, 147 MRI scanners, and

14 PET scanners. Though most anti-epileptic medications were available through direct purchase

from pharmacies, coverage of some medications varied according to province and special

application for unlisted medications was (and continues to be) tedious and often unsuccessful.

Long wait times continue to accrue for EEG studies, imaging studies and surgical procedures(3).

Although no comprehensive studies on epilepsy surgery wait times have been done locally or

nationally, one U.S. study has shown that the time from second AED failure to presurgical referral

was greater than 1 year in almost two-thirds of children, with an average time from epilepsy onset

to surgery approximated at 5.4 +/- 3.8 years(15).

In 2006, a joint effort by the Global Campaign against Epilepsy (GCAE), the International

League Against Epilepsy (ILAE), the International Bureau of Epilepsy (IBE), and the World

Health Organization (WHO) published a report emphasizing a need for organizations to focus on

delivering quality epilepsy care, addressing disparities to access, and developing collaborative regional facilities to improve the level of epilepsy care delivered, worldwide(3). These

recommendations are increasingly relevant and arguably necessary not only to global but also to

regional and national programs, given the inconsistent access to epilepsy medications and surgery

itself within Canada.

Surgical Management of Epilepsy and Seizure Outcomes

Epilepsy surgery revolves around the theoretical concept of the ‘epileptogenic zone’ (EZ).

This zone describes the region or networks of the brain responsible for generating and participating

in the early electrophysiological propagation of seizure activity. By definition, resection or

disconnection of the EZ will result in seizure freedom. Within the EZ, the ‘ictal onset zone’ more

specifically defines the region responsible for generating ictal EEG onset of seizure activity. The

‘irritative zone’ refers to the cortical region propagating interictal epileptiform discharges, which may exceed the boundaries of the EZ and therefore may not require complete resection for seizure freedom to be achieved(12).

Pre-operative Work-up

Presurgical evaluation involves, at the minimum, interictal scalp EEG and MR

imaging(16). Interictal scalp EEG should include natural sleep recording, with video-EEG to

capture ictal events(17). Serial studies may be necessary, often times accompanied by temporary

weaning of AEDs during admission to an Epilepsy Monitoring Unit (EMU), to capture these events

and evaluate their pattern so as to characterize the semiology of the seizure events. Structural

imaging in the form of MRI is necessary to evaluate intracranial anatomy and identify a possible

lesion for resection or disconnection. MRI was introduced as a valuable tool in the 1980s for the

neurosurgical work-up of epilepsy, and today, this imaging modality continues to be central to the

pre-operative work-up of epilepsy patients(18). An epilepsy-specific MRI protocol includes high-

resolution T1- and T2-weighted axial and coronal sequences, as well as contrast-enhanced

sequences when a neoplasm is suspected(19). In some cases, the MRI examination may also

include diffusion tensor imaging used in tractography, which allows the visualization of white

matter tracts and can be a useful aid in both surgical planning and the detection of subtle cortical

malformations(19). Unique to pediatric epilepsy is that age will affect the interpretation of radiographic studies; for example, gyral and sulcal pattern development is influenced by age, and

the imaging characteristics of specific entities such as focal cortical dysplasia is influenced by age and brain maturity, according to the maturity of the myelination process(4).

Other pre-surgical investigations may be indicated including functional imaging, such as fluorodeoxyglucose positron emission computed tomography (FDG-PET), which reveals hypometabolism in affected brain regions; and subtraction ictal single photon emission computed tomography (SPECT), which detects regions of hyper-perfusion(18). Magnetoencephalography

(MEG) can also be used to localize interictal discharges; its spatial resolution is superior to scalp

EEG and is reliable for localization when there are anatomic abnormalities present, such as skull defects(19). Unfortunately, the latter is costly and unavailable in most provinces within Canada, apart from Quebec and Ontario. Lastly, but certainly not least, neuropsychological consultation is imperative and plays a significant role in the pre-operative assessment and work-up of patients undergoing evaluation for possible epilepsy surgery.

For patients to qualify as candidates for surgical resection or disconnection, along with demonstrating refractoriness to at least 2 AEDs, they must undergo an extensive pre-operative work-up to identify, as best as possible, the EZ. This requires that recorded epileptic activity on video-EEG should register in agreement with a well-defined and radiographically apparent lesion on MRI; that is, the results of EEG and structural imaging investigations should be concordant(20).

In MRI-negative patients where no abnormality is seen on MR imaging, or when data is discordant, invasive EEG monitoring must be pursued via subdural grids or stereoelectroencephalography, to better characterize the EZ(18, 20, 21).

Stereoelectroencephalography (SEEG) is an approach that involves the use of anatomical,

electrophysiological and clinical information to formulate a hypothesis as to where the

epileptogenic areas of seizure onset and early propagation are located. Based on this hypothesis, intracerebral SEEG electrodes are implanted into the depths of the brain for recording ictal and interictal activity(7). SEEG can access deep cortical structures, including the insula, cingulate

gyrus, orbitofrontal gyrus and mesial temporal lobe, and is especially useful for evaluating possible

multifocal seizure onset and bilateral regions(22). In contrast, placement of subdural electrodes

often involves a relatively large craniotomy, with superficial electrodes placed broadly over the

cortical region of interest. In some circumstances, a combination of subdural and depth electrodes

may be used(19).

Although pediatric epilepsy surgery is being performed worldwide, specific techniques and details surrounding the operations vary by centre(23). According to a global survey of 88 centers

across all continents, variation was found among epilepsy surgeons regarding the use of

intraoperative electrocorticography (55% use intra-operative electrocorticography to guide cortical

resection), drains (44% of centers placed subgaleal drains), and steroid use (40% used steroids post-operatively)(23). Regardless, the following sections will broadly detail commonly employed surgical strategies in managing pediatric epilepsy. Epilepsy surgery can be commonly thought of as either curative – performed with the intent of achieving seizure freedom, or palliative –

performed with the intent of decreasing seizure burden and the negative effects of epilepsy, without

necessarily achieving complete freedom from seizures.

Curative Techniques

Temporal Lobe Resection

While temporal lobe resections comprise more than 50% of epilepsy surgeries in adults, up

to 90% of epilepsy surgeries in infants and toddlers involve extratemporal resections(4). When

performed, temporal lobe resection typically focuses on the removal of mesial structures including the hippocampus, parahippocampal gyrus and basolateral amygdala, with the extent of lateral neocortical resection based on the location of the epileptogenic zone. Multiple approaches exist including the standard anterior temporal lobectomy (ATL) and various forms of selective amygdalohippocampectomy (SAH)(18). Whereas ATL involves en-bloc resection of the amygdala, hippocampus and up to 6 cm of the anterior temporal cortex, SAH involves focusing the resection on mesial structures, and attempting to preserve as much neocortex as possible. SAH can be performed through a transcortical, sub-temporal or trans-Sylvian corridor(20).

For temporal lobe epilepsy (TLE) patients undergoing surgical resection, complete seizure freedom may be achieved in up to 76% of patients, based on a systematic review of pediatric epilepsy patients followed for at least 1 year following surgery(24). Between techniques, standard

ATL conveys an improved chance for seizure freedom over the less invasive selective approaches(25). Post-operatively, patients may suffer a mild visual defect (i.e. a superior, contralateral quadrantanopia) due to damage to Meyer’s loop as it courses through the temporal lobe, although this is generally well-tolerated and not clinically impairing. Some may also experience deficits in verbal learning in the case of dominant side resections, or visual memory deficits in non-dominant resections. Young children are more likely to recover from these deficits as a result of neuroplasticity(20).

Extratemporal Resection

Extratemporal lesions as the cause of epilepsy are seen more often in children than adults

as a result of a higher prevalence of developmental dysplasia and diffuse epileptogenic foci. The

frontal lobe is the most affected region, followed by the parietal and occipital lobes. Epileptogenic lesions may include cortical dysplasias, tumors, ischemic insults and vascular malformations(18),

amongst other conditions.

In such cases, the extent of resection generally depends on whether eloquent brain

structures are involved, in which case only partial resection may be possible to avoid unacceptable

post-operative deficits. This may result in less favorable seizure outcomes as compared to surgical

resections undertaken in non-eloquent areas(18). Seizure outcomes following extratemporal

resections are quite variable and relate to the extent of resection and underlying etiology. Typically, seizure-freedom rates are lower than in temporal resections; a systematic review including 1259 pediatric patients who underwent extratemporal resections reported a seizure-freedom rate of

56%(26).

Posterior Quadrant Resection/Disconnection

The posterior quadrant consists of the parietal, posterior temporal and occipital lobes.

Posterior quadrant resections are reserved for very large epileptogenic zones that are multi-lobar,

unilateral and spare the frontal and Rolandic cortex. The goal of resection in these cases is to

remove or isolate the posterior quadrant except for the post-central gyrus, thereby sparing

somatosensory function(20). Seizure freedom rates following posterior quadrantectomy range

from 50-92%(27-37). While either an anatomical resection or simpler disconnection can be performed (similar to the options in hemispherectomy, discussed below), no formal randomized studies have been conducted to compare surgical outcomes between the techniques(20).

Hemispherectomy

Hemispherectomies (i.e. hemispheric removal) and hemispherotomies (i.e. functional disconnection of the hemisphere) comprise approximately 16% of epilepsy surgeries in children, and almost one third are in patients less than 4 years old(18). Indications for these major neurosurgical procedures include catastrophic epilepsy arising secondary to developmental and congenital pathologies such as cortical dysplasia and hemimegalencephaly, or acquired pathologies such as perinatal ischemia and Rasmussen encephalitis(20).

While anatomical hemispherectomies have been classically described for epilepsy affecting an entire hemisphere, this procedure has been associated with the complications of superficial cerebral hemosiderosis and late-onset hydrocephalus, which may be seen in up to one third of anatomical hemispherectomies(38, 39). Severe blood loss is another major challenge for these procedures(18). An alternative option, functional hemispherotomy, has thus emerged, which is a minimally resective procedure that aims to fully disconnect the affected hemisphere while minimizing such complications. Specifically, hemispherotomy incorporates techniques to disconnect the entire affected hemisphere from the contralateral hemisphere, basal ganglia and brainstem. The temporal lobe is removed, a corpus callosotomy is performed, and there is decortication of the remaining tissue to disconnect the frontal and occipital lobes from the rest of

the cerebrum(19). Ultimately, a large majority of the hemisphere will be left in place and remains

vascularized, but will be functionally disconnected(20).

Following hemispherectomy, seizure freedom rates range from 50-85%, with comparable seizure outcomes between both hemispherectomy and hemispherotomy(18, 40-45). The underlying etiology of epilepsy is the most important prognostic factor, with acquired diseases

having better outcomes compared to developmental malformations such as

hemimegalencephaly(41-45). Post-operatively, almost all patients will have a homonymous

hemianopsia. Many children will already have pre-operative hemiparesis, which may become

worse immediately after surgery. Language outcome depends on language lateralization and the

age of the patient, with greater improvements seen in younger patients(20, 46, 47). In infants, acquired craniosynostosis may also occur due to the loss of drive for cranial growth as a result of the loss in cerebral volume(20).

Minimally Invasive Curative Techniques

Many parents of children with epilepsy initially perceive surgery to be a “scary,” “horrific,” and “risky” “last resort” option(15) despite the superior evidence for surgery in the context of medically refractory epilepsy. Evidently, a barrier for many patient families in pursuing epilepsy surgery is the morbidity associated with open craniotomy, though complications from high-volume epilepsy centers are quite low. Importantly, morbidity associated with surgery is typically concentrated in the immediate peri-operative period, while morbidity from poorly controlled epilepsy persists over a lifetime. To minimize any surgical morbidity, less invasive treatment

options have recently been developed and are currently being evaluated for their seizure

outcomes(48). The more common procedures are discussed below, although additional

innovations are currently underway, including focused ultrasound ablation and Gamma Knife

radiosurgery.

Laser Interstitial Thermal Therapy

Laser interstitial thermal therapy (LITT) involves the minimally invasive laser ablation of epileptogenic tissue. This procedure involves the stereotactic placement of a rod with a laser at its distal end through a burr hole and into the target intended for ablation. Intra-operative MRI is used to confirm placement, and while the patient is still in the MRI scanner, the laser is activated. Its heat signature is monitored to evaluate the extent of damage to the region by the laser’s thermal

energy, and the operator is able to halt the treatment before damage to healthy tissues can occur

(20, 48). This technique offers a great degree of precision due to improved MRI visualization as compared to open resective surgery and faster recovery times(19), although its main hindrance

remains the targeting of only small lesions or brain regions. Its greatest use thus far is in the

treatment of hypothalamic hamartomas(19, 49), which are commonly deep-seated and unamenable

to open resection without at least moderate surgical morbidity; seizure-freedom rates following

LITT for hypothalamic hamartomas have been reported to be 79%(49).

Responsive Neurostimulation

Responsive neurostimulation (RNS) involves the placement of leads into an epileptogenic

target (often in an eloquent, unresectable brain region), which are then attached to an internal pulse

generator implanted in the patient’s skull. The leads are able to detect the onset of ictal activity

using a rudimentary threshold detection paradigm, and allow the delivery of an electric current

from the generator back to the lead and into the target, thereby suppressing or possibly aborting

the seizure(48). RNS has shown some promise in adult epilepsy patients(20, 48); in children, case reports exist(50, 51) but so far studies are lagging.

Deep Brain Stimulation

Deep brain stimulation (DBS) has recently been proposed as a therapeutic option for epilepsy. Targets include the anterior nucleus of the thalamus, centromedian nucleus, subthalamic nucleus and more; at this time, only the anterior nucleus of the thalamus and hippocampus are supported by level 1 evidence(52, 53). Overall, a reduction in seizure frequency achieved by DBS has been reported in 85% of select cases of children with a variety of targets, according to a systematic review(54), although the technique remains quite limited in its scope and utility for treating epilepsy as compared to Parkinson’s disease and other movement disorders.

Palliative Techniques

Vagal Nerve Stimulation

Vagal nerve stimulation (VNS) has been used as a palliative therapy for medically intractable epilepsy for a number of years, and involves placement of a lead onto the vagus nerve in the neck, with attachment to a pulse generator implanted in the subcutaneous tissue of the chest.

The generator is then able to send pulses of electrical energy to the brain via the vagus nerve to suppress ictal activity. Outcome studies show a relatively consistent rate of 30 to 50% reduction in seizure frequency in up to 50% of patients(55). Newer versions of the device use a cardiac

sensing algorithm to detect rapid heart rate changes associated with seizure onset. Newer, smaller- profile pulse generators have also been developed(48). Surgical complications are rare and include

infection (4-6%), hoarseness and/or changes to the voice, which are often well-tolerated. The

complication of asystole occurs rarely, in <0.1% of patients, as a result of stimulation to the

sinoatrial node via the vagus nerve and its branches(55).

Corpus callosotomy

Corpus callosotomy is most commonly indicated to decrease the frequency of “drop attacks,” or sudden, tonic/atonic seizures that can result in significant physical trauma and

debilitation(20). Given the lack of a resectable focus, most commonly in patients with multiple

epileptogenic foci, the aim of this procedure is therefore to alleviate the seizure burden. In this

procedure, anywhere from two-thirds up to the entire corpus callosum is transected to functionally

disconnect the two hemispheres and prevent the spread of epileptogenic activity from one

hemisphere to the other. Unique sequelae to corpus callosotomy have been described, including a

“disconnection syndrome” in which patients are unable to process a stimulus when presented

unilaterally. Hemiparesis, alien limb, supplementary motor area syndrome, ataxia, alexia and mutism may also occur(56-58). Complete seizure freedom following corpus callosotomy is exceedingly low, in some cases reported as low as 18.8%, but freedom from dangerous drop attacks may occur in up to 55.3% of patients undergoing the procedure(59).

Multiple subpial transections

The technique of multiple subpial transections (MST) is based on the idea that functional fibers in the brain run vertically in the cortex, while fibers that propagate seizures are oriented

horizontally. Small transections are thus made below the pia that serve to interrupt the horizontal

fibers, thereby halting the spread of ictal activity, but functional vertical fibers (and their blood supply) are relatively preserved to protect cortical function. This operation is typically performed when the epileptogenic zone encompasses an eloquent area such as the motor or language areas, prohibiting its total resection(60-65). According to a systematic review, MST combined with

resection may achieve a seizure-freedom rate of 55.2%, but only 23.9% when MST is performed

alone(66).

Long-term Outcomes

The ILAE recommends that all outcome measures of epilepsy surgery should be uniformly

applicable, feasible and validated to facilitate multicentre collaboration(67). It is also

recommended that pediatric epilepsy surgery outcomes should include not just seizure frequency

and AED use, but quality of life, development, cognition, behaviour and psychosocial adjustment,

and adverse events should also be documented(67).

Long-term outcomes at least 10 years following pediatric epilepsy surgery are robust. In

one survey of 110 patients who had surgery more than 10 years prior, 76.5% reported an Engel

Class I outcome (i.e. are completely seizure-free, experience auras only, experienced atypical generalized convulsion with AED withdrawal only, or have been seizure free for at least 2 years), and 44.6% were not taking any antiepileptic medications. The best results were obtained by temporal lobectomy. 44.6% of those surveyed also had full-time jobs and 79.5% were satisfied with their treatment outcome(68). Seizure-free adults were more likely to be employed than

epileptic patients still suffering seizures(68). Neuropsychological outcomes will be discussed in the following section.

Previously reported predictors of good outcome following pediatric epilepsy surgery have included unilobar temporal resection; the presence of unifocal lesions on MRI; localizing ictal

EEG findings; complete lesional resection; an active region on EEG; the absence of generalized tonic-clonic seizures on pre-operative assessment; shorter epilepsy duration; and younger age(69).

However, the literature shows great breadth in these reports, often with conflicting results. While comprehensive morbidity and mortality rates are difficult to find, mortality rates in adult epilepsy surgery range from 0.1-0.5% and are higher for extratemporal procedures. Temporary neurological complications occur in about 10% of patients, with permanent neurological complications in 5%.

Other complications include cerebrospinal fluid leaks (8.5%), aseptic meningitis (3.6%) and hemorrhage (2.5%)(70).

Neuropsychological Outcomes of Epilepsy

One of the unique differences in pediatric epilepsy compared to that in adults is that epilepsy may be associated with developmental arrest or regression, particularly in children less than 2 years of age. This is attributed to the idea that seizures pose undesirable negative effects on rapid brain development that occurs during infancy and early childhood. This ultimately can lead to progressive disturbances in cognitive and behavioural functioning(71, 72). While the neurocognitive effects of epilepsy and antiepileptic medications may be reversible, they may become permanent when they negatively interfere with brain development(73).

While cognitive impairment can be the consequence of epilepsy, it can also occur as a

result of the underlying pathology of epilepsy and can precede the development of seizures.

Developmental delay should therefore not be a contraindication to epilepsy surgery(71). Rather,

many clinicians view early surgical intervention to be critical in infants with epileptic

encephalopathy to prevent developmental arrest or further regression(71, 72, 74). Successful

seizure control may facilitate cognitive development, reverse epileptic encephalopathy when

present, and reduce dependence on AEDs, which themselves may pose negative effects on intellectual development (71, 72, 74, 75).

The idea of functional plasticity is key to the recovery of neurological deficits in children, as the developing brain is capable of significant reorganization of function after surgery, a unique phenomenon to consider in surgical planning(71, 74, 75). Presurgical development is often impaired in many children with epilepsy, with more severe developmental delays associated with longer durations of epilepsy (75, 76). Higher intelligence quotient (IQ) and developmental quotient

(DQ) scores before surgery generally correlate with higher IQ/DQ scores after surgery(74, 76),

however, children at the lower end of the this spectrum may have the most to gain after surgery,

as compared to those with a higher presurgical IQ/DQ score(74).

The effect of epilepsy surgery on cognitive outcome can be viewed as the result of an

interplay of two factors: function within the epileptogenic zone, and dysfunction outside the

epileptogenic zone (caused by recurrent epileptic seizures)(72). If the two zones are congruent,

epilepsy surgery is likely to produce no cognitive change. If the dysfunctional zone is outside the

epileptogenic zone, then removal of the epileptogenic zone may actually lead to recovery of the

dysfunctional zone and improved cognition. However, if the dysfunctional zone is within the

epileptogenic zone, and the epileptogenic zone harbours cognitive function, resection may lead to

cognitive decline. In this context, from a neuropsychological perspective, minimally invasive

treatments may be preferable to avoid damage to non-affected functional tissue(71).

Pre-operative neuropsychological assessment is recommended by the ILAE(67), and ensures a baseline evaluation against which to track development throughout the disease course and after surgery(77). This assessment also provides invaluable information regarding a child’s cerebral organization; the site and laterality of the seizure focus; how epilepsy has affected development; and importantly, provides insight into the possible effects of surgery(77). Despite this, however, multiple complex questions remain unanswered regarding neuropsychological development in epilepsy, including the appropriate timing for surgical intervention in order to maximize childhood development. It is also unclear whether timing should be influenced solely by the number of failed medications, or perhaps by a specific location/region of the EZ(77).

Unfortunately, there are several difficulties with measuring cognitive outcome in epilepsy patients(72). Many young children cannot be reliably tested by standardized intelligence scales.

Tests applicable at a younger age may also become invalid at an older age, making long-term comparisons difficult. Acquisition of new abilities may be part of normal development rather than improvement from surgery, and is difficult to differentiate with current tools. There is considerable heterogeneity in age, etiologies, and surgery types within studies in the existing literature; the same surgery for different pathologies may yield widely variable results. Few studies also have

appropriate control groups. In the future, it will be essential that multicenter studies require the

collection of concise demographic and clinical information(77). Lastly, objective changes in

cognitive scores are difficult to translate to meaningful daily living skills relevant to patients and

their families(72).

Despite these shortcomings, according to an ILAE survey of neuropsychological practises

among epilepsy surgeons(77), 69% of responders “almost always” conducted a pre-operative

neuropsychological evaluation, and 22% of responders did so “for 75% of cases.” In regards to

post-operative evaluations, 58% responded “almost always” and 32% did “for 75% of cases.”

However, the time interval between surgery and follow-up was not consistent, with only 22% of respondents conducting their post-surgical evaluation at a pre-specified time. Approximately half of responders conducted a 12 month follow-up, while others conducted follow-up at a shorter or longer time period. 92% of respondents conducted comprehensive evaluations that required at least three hours of testing(77), underscoring the significant amount of effort and resources required to obtain complete testing. Barriers to post-surgical follow-up included a lack of insurance, loss to

follow-up when patients were seizure-free, and clinical demands not allowing adequate time for full testing(77).

In the same survey, there was consistency demonstrated in regard to which specific domains were assessed: intellectual functioning, language, attention/executive function and memory were assessed by more than 90% of respondents. Other areas commonly evaluated were academic achievement (72%), social/emotional (76%) and adaptive behaviour (74%). Only 37%

of respondents conducted quality of life assessments. However, the specific tools used to evaluate these domains were inconsistent and varied according to centre as well as the age of the patient(77).

A few studies evaluating neuropsychological outcomes following surgery report that the majority of children have no change in cognitive scores. In the setting of hemispherectomy, it has been reported that 68% will experience no significant change, 13% will improve cognitively, and

19% will deteriorate(78). Similarly, following temporal lobectomy, two-thirds of patients have no change in verbal IQ or memory; improvement in cognitive scores has been reported in 9-14% of patients(79-83). A pooled analysis of 16 studies including a heterogenous group of surgical patients also showed that 70% of IQ/DQ scores did not change(74). Other studies, however, show improvement in visual memory after left-sided surgery, verbal memory after right-sided surgery, episodic memory with higher residual hippocampal volumes, and semantic memory with the preservation of the temporal poles(79). There may be a transient decline in memory in the short- term, with recovery 1 to 2 years later (79, 84). Overall, these variable results underscore the heterogeneity present in the literature and among patient populations in these studies.

Patient Quality of Life

Quality of life, which encompasses physical, psychological, cultural, social, and economic domains, has become an increasingly important outcome measure in epilepsy surgery. The ILAE has recognized health-related quality of life (HRQOL) as an essential outcome in studies examining the overall impact of epilepsy surgery(85). Children with epilepsy are at increased risk of poor HRQOL due to the potentially long-term impact of epilepsy on behavioural development,

psychological functioning, social integration and academic growth. Children are also heavily

dependent on their caregivers and the family unit, and HRQOL is the result of the interplay

between all of these elements (86). As a result, improvement in seizures alone may not improve

HRQOL due to interactions with other factors, stressing an interdisciplinary and holistic approach to epilepsy care.

The majority of studies examining HRQOL following epilepsy surgery have been performed in adults and have shown post-operative improvement. In contrast, the development of

HRQOL measures for children is lagging(85). There are a number of scales to capture HRQOL in the pediatric population, but many of these tools have not been comprehensively tested for reliability, sensitivity or validity in the literature. Furthermore, self-reported questionnaires, which are often used, may be problematic given the high prevalence of developmental delay and learning disabilities in the pediatric epilepsy population(87).

In one pediatric study of HRQOL following epilepsy surgery, HRQOL was shown to improve by 2 years after surgery, and was associated with better seizure outcome; no improvements were seen at the 6 month mark(88) (85). The number of AEDs, side effects, seizure type, and family functioning have previously been shown to be predictors of HRQOL, as well as internalizing problems(86). Ultimately, further tools that accurately capture changes in HRQOL after epilepsy surgery are required. In general, disease-specific measures as opposed to generic health-related quality of life measures are preferred and need to be developed further, as they are more uniquely sensitive to aspects of a specific disease (epilepsy) and may be more sensitive to detecting change (87).

Caregiver Quality of Life

Epilepsy has a significant impact not only on the patient but on their caregiver as well(85), especially in pediatrics, given the crucial role caregivers play in decision making and providing at-home care. There is a complex relationship between patient factors, such as the severity of epilepsy or developmental delay; contextual factors, such as caregiver socioeconomic status; caregiver psychological factors, such as the presence of mental illness and coping abilities; and available resources(89) -- which all influence overall caregiver quality of life (QOL). Despite this, caregiver QOL is a neglected field of epilepsy research, and there are few studies examining the effect of epilepsy surgery on caregiver QOL (89, 90). One study conducted post-operatively in a heterogenous group of children with epilepsy showed no improvement in caregiver QOL(85).

Another study incorporating a generic health-related QOL and disease burden questionnaire showed improvement in the mental component of QOL scores, with no change in the physical component. In the same study, 75% of caregivers deemed their QOL improved post-surgery, versus 19% who felt there was no change. 94% felt their decision to go through surgery was worthwhile(90). Among caregivers of adults with epilepsy, 31.30% have anxiety symptoms and

33.59% have depressive symptoms(91). Anxiety symptoms have also been reported in up to 58% of caregivers of children with epilepsy, highlighting the emotional and psychological burden of caring for a patient with epilepsy.

Studies are conflicting on whether higher seizure frequency negatively impacts caregiver

QOL. One study has shown that patient HRQOL, caregiver mood and family factors were more

significant predictors of caregiver QOL than seizure severity(89). Properly delineating these

factors is important to further research, as these may be alternative modifiable factors to improve

caregiver QOL. Ultimately, treatment should aim at a collaborative model that incorporates

caregiver wellness into the desired outcome. It has been advocated that caregiver QOL also

become a core quality measure in the evaluation and management of epilepsy(90), and that it be

used as a measure of the effect of patient intervention(92).

Quality Assessment and Caregiver Satisfaction

To date, patient satisfaction has become an indicator of quality of care in many medical

settings, especially in the era of patient- or family-centered care(93-95). For children, caregiver satisfaction takes on increased importance as caregivers are their main advocates and decision- makers. Studies suggest that better caregiver satisfaction leads to increased knowledge of caregivers, higher confidence, and better adherence to treatment plans(96, 97). On the other hand, dissatisfaction with treatment has been suggested as a primary reason that patients may drop out of therapy(98). Satisfaction questionnaires have thus been developed to attempt to measure the impact of patient satisfaction on health attitudes and behaviours.

A systematic review of studies looking at methods for measuring satisfaction with epilepsy care found only 9 studies (36%) that utilized validated instruments, with 74% using non-validated instruments. Overall, 86% of those surveyed were satisfied with their care(93). Patients seen in specialized settings and who received more information had higher satisfaction scores. Overall, patients placed a high value on communication, the type and amount of information they received,

the technical skills of their providers and the presumed knowledge of their providers. Other studies have shown higher caregiver satisfaction with improved physician communication, more parental involvement in care(96), better quality of life, and lower educational level(99).

Any measure of satisfaction should comprise a multi-dimensional scale that accurately

encompasses areas related to the experience of care, and should have avenues to allow for positive

changes to be made in response to the results(94). Such tools can be used in goal-setting programs, can help improve employee performance, and may provide a method of assessing patterns within a health care system(95). Importantly, the development of validated tools would allow for a more meaningful assessment of this important health outcome in epilepsy surgery.

Economic Evaluation

In one U.S. study on the long-term reduction of health care costs after epilepsy

surgery(100), the mean direct medical cost difference between PWE with uncontrolled seizures who underwent surgery versus continued medical management was found to be US$6,806.

Surgical patients also had 0.58 to 1.19 fewer emergency room visits, and 0.92 to 2.64 fewer’

outpatient visits per year. The mean annual cost per person was, on average, US$8,484 lower in

surgical patients than those with continued medical management(100). Comparisons of before and

after surgery also demonstrated significant cost and resource utilization reductions. Following

surgery, subjects had a US$6,841 (95% CI, US$2,241) reduction in annual costs; 0.58 (+/-0.21)

fewer inpatient visits; 2.93 (+/-0.84) fewer outpatient visits; and 1.03 (+/-0.42) fewer emergency

room visits per year, compared to before surgery(100). In Canada, a recent cohort study comparing

children with epilepsy to children without epilepsy matched for age, sex, rurality, socioeconomic status, and comorbidities, also showed significant cost differences (101). Both 1-year and 5-year cumulative costs were higher in children with epilepsy compared to children without epilepsy: $14

776 versus $6 152 at 1 year, and $39 261 versus $15 598 at 5 years, with the highest total costs incurred in the first year of life with epilepsy(101). These numbers help emphasize the economic benefits of epilepsy surgery and improved seizure burden in decreasing the overall costs associated with medically intractable epilepsy.

Program Development

As demonstrated, there is a multitude of evidence supporting a role for epilepsy surgery in treating medically refractory epilepsy, with positive effects that spill over into multiple other domains of life. In addition to decreasing seizure burden and mitigating the physical risks of uncontrolled seizures and medication side effects, epilepsy surgery also has the chance to positively effect and facilitate neuropsychological development. Although studies to date show that most patients remain cognitively stable(74), this is a desirable outcome as progressive deterioration due to uncontrolled seizures is avoided. Epilepsy surgery also may play a significant role in improving patient and caregiver quality of life(85, 90) and helps lessen the enormous economic strain that many families face as a result of associated medical costs(101).

For all these reasons, early evaluation regarding surgical candidacy is warranted.

Capable health care providers share an ethical obligation to help facilitate access to epilepsy surgery and comprehensive work-up for selected patient populations. As outlined by

Ibrahim et al(102), who proposed an ethical framework to address the inequities in access to pediatric epilepsy surgery, certain subgroups of children may face disproportionately larger barriers in access to epilepsy surgery. This population includes children with non-localizable epilepsy who may benefit from palliative procedures; children who are developmentally delayed;

African American patients; children whose parents have less education; older children; children on polytherapy; and children with concurrent psychiatric diagnoses(103). Geographic location also affects a child’s chances of surgical candidacy and seizure freedom, as there may be significant variability in practise patterns and available technologies(103) according to location. At this time, there is no established minimum criteria to define a pediatric epilepsy specialist centre or surgical unit. In an international survey polling various epilepsy centres from 12 countries, there existed a wide range in the availability of dedicated support staff, operating room capabilities and critical care unit infrastructure at each centre. The average number of procedures performed annually was

15, but with extensive variation amongst these centres(67).

In Manitoba, prior to the formation of a comprehensive epilepsy program, a qualitative online survey was delivered to primary care and specialist physicians (including pediatrics, internal medicine, psychiatry, emergency medicine, neurology and family medicine trained physicians) to gauge the state of clinician knowledge and comfort towards the management of epilepsy(104).

Only 33.3% of respondents had heard of ILAE guidelines, with 56.5% unaware of invasive EEG techniques. 78.7% of respondents understood a role for epilepsy surgery, but 11.1% were unaware of surgical therapies beyond vagal nerve stimulation(104). These results ultimately highlighted a gap in provincial epilepsy knowledge and management.

In 2016, the Pediatric Epilepsy Program was established. This included the eventual

development of a 2-bed Pediatric Epilepsy Monitoring Unit (EMU), and the recruitment of epilepsy-trained physicians to total 3 adult and 2 pediatric epileptologists, and 1 fellowship-trained epilepsy neurosurgeon. A bimonthly multidisciplinary Refractory Epilepsy Conference was also instated, with participation from radiology, neurology, neurosurgery, pathology, nuclear medicine and neuropsychology(104). All these efforts have substantially bolstered the referral of pediatric patients with medically intractable epilepsy throughout Manitoba, Nunavut and Northern Ontario

to the Winnipeg Children’s Hospital/Health Sciences Centre in Winnipeg.

Study Objectives

Ultimately, given the complexity of pediatric epilepsy patients, a need has emerged for a

structured, standardized approach to their assessment, work-up and management within our province. A database to permit information tracking and close monitoring of outcomes of epilepsy surgery is key, and the examination of local seizure, neurocognitive, quality of life, and caregiver satisfaction outcomes thus far, will serve as an important benchmark for future quality improvement initiatives. This database will also provide the groundwork for the analysis of patient and clinical factors that may affect these important outcomes, allowing for optimization of our pediatric epilepsy surgery results in the future.

In the face of Manitoba’s rising numbers of surgically-treated pediatric epilepsy patients, the

specific objectives herein were to:

1. Create a provincial-wide database for children undergoing epilepsy surgery in Manitoba.

2. Describe the change in clinical management of children in Manitoba requiring epilepsy

surgery since the formation of the Pediatric Epilepsy Program in 2016, with respect to

surgical wait times, types of surgeries being offered and surgical case volume.

3. Assess seizure outcomes of patients who have undergone epilepsy surgery in Manitoba.

4. Perform a systematic review of the literature on neuropsychological outcomes following

pediatric epilepsy surgery.

5. Assess neuropsychological outcomes of patients who have undergone epilepsy surgery in

Manitoba.

6. Assess the quality of life of patients and their caregivers.

7. Assess caregiver satisfaction with the Epilepsy Program.

Chapter II: Methods

Design

A retrospective review was undertaken of all pediatric patients who had previously undergone epilepsy surgery at the Children’s Hospital in Winnipeg between 1997-2016, prior to the start of the Epilepsy Program in 2016. This review aimed to describe the seizure outcomes of the pre-existing cohort of pediatric epilepsy surgery patients and allowed comparisons to be made with patients treated after 2016.

Next, a formal, electronic database platform was created using RedCap software (i.e. a secure web application for building and managing online databases). This was used to capture and store the demographics and outcomes of all patients who underwent epilepsy surgery since the

creation of the Epilepsy Program in 2016, and whose legal guardians gave consent. For these

patients, a survey assessing caregiver satisfaction was administered to their legal guardian, as well

as quality of life surveys for both the patients and their caregivers.

For all new incoming patients, pre- and post-surgical testing was implemented as much as possible, including a standard 3-month and 6-month post-operative assessment of anti-epileptic medications, seizure frequency and neurocognitive screen when possible.

Medically-treated pediatric epilepsy patients were also identified through the Epilepsy

Clinic and their families were asked to complete the QOLCE-55 and CarerQol questionnaires, to identify differences in scores in comparison to the surgically-managed group. These patients had medically refractory epilepsy and were in the process of a comprehensive work-up for possible surgical candidacy.

Primary data collection was completed and collected either retrospectively (from clinic charts and medical records) or prospectively (on new, incoming patients who met inclusion criteria), beginning at their initial Neurosurgery Clinic visit. All data was entered into a secure database on RedCap; the specific data fields captured are found in Appendix A.

Patient Population

The initial retrospective review included all patients between 3 and 20 years of age who, prior to 2016, underwent a surgical procedure for epilepsy at the Winnipeg Children’s

Hospital/Health Sciences Center in Winnipeg. After 2016, all patients between 3 and 20 years of age who underwent a surgical procedure with at least a 3 month follow-up period were included in the database, and were administered quality of life and caregiver satisfaction questionnaires

during the data collection period. New, incoming patients were assessed pre-operatively, in

addition to post-operative assessments at 3 and 6 months following surgery, when possible.

Patients who underwent previous epilepsy surgery performed elsewhere, i.e. outside Winnipeg, were excluded.

Outcome Measures

Neurocognitive Assessment

Systematic Review

A systematic review using the methodology outlined in the Cochrane Handbook for

Systematic Reviewers(105) was conducted. The specific aim was to address the following question: In pediatric patients with epilepsy, how does epilepsy surgery affect short- and long- term neuropsychological outcomes? Six databases (Medline, BIOSIS, Central, Scopus, Global

Health and Embase) were searched from inception to November 2019. An example search strategy is found in Appendix B. The resulting titles and abstracts were screened for inclusion. Full texts for citations passing the initial screen were then obtained, and inclusion and exclusion criteria were applied to each article to identify a filtered set of final articles for review.

Prospective studies performed after 1995 on patients less than 18 years of age, that reported both pre- and post-operative neuropsychological outcomes after epilepsy surgery, were included.

Exclusion criteria included: non-English studies; animal studies; patients greater than 18 years of age; subjectively reported outcomes; reoperations; retrospective studies; studies only reporting either pre- or post-operative data; studies performed prior to 1995; review articles; conference abstracts; editorials; and case reports (with sample sizes less than 4). The results of studies with

homogenous cohorts (ie. either a single type of surgery or a single type of epilepsy) following

resective surgical procedures will be reported in the Results section.

Each study was evaluated for quality of evidence using the RTI Item Bank on Risk of Bias

and Precision of Observational Studies(106). Applicable to a wide range of observational study

designs, this item bank has been previously validated and is used for evaluating the risk of bias

and internal validity of studies using a comprehensive list of itemized questions.

Local Data Collection

Historically, a full neurocognitive assessment had been performed approximately 1 year

post-operatively, when possible. The results of this full neurocognitive assessment were

documented and collected via chart review. For new, incoming patients, neurocognitive screening

was planned at the pre-operative, 3 month and 6 month post-operative time points. Testing was

performed for patients greater than 6 years of age using EpiTrack Junior(73, 107), a screening tool

that comprises six tests for attention, psychomotor, speed, language and memory function

(Appendix C). Epitrack Junior is recommended for the rapid detection of problems in attention and

executive functions in children and adolescents with epilepsy, and was originally developed for the assessment of cognitive side effects of AED treatment. To qualify for assessment using this tool, children must be 6 years of age or older, be able to read aloud ‘1’ and ‘2’, and be able to count from 1-20. Overall, the screening tool takes approximately 12-15 minutes to complete.

The EpiTrack Junior tool has demonstrated satisfactory concurrent validity and discriminant validity with respect to comprehensive neuropsychological battery testing(107).

Sensitivity and specificity have also been evaluated and found to be satisfactory in validation

studies(107). Overall, it is a time-efficient screening mechanism and may be employed when

comprehensive testing is limited by resources; it does not, however, replace a comprehensive

neuropsychological battery of tests, and impaired scores are followed up with comprehensive

testing(107).

Quality of Life Assessment

Patient quality of life was assessed using the ‘Quality of Life in Childhood Epilepsy

Questionnaire’ (QOLCE-55) which assesses parent-reported health-related quality of life of

children with epilepsy between 4 to 18 years of age (Appendix D). The QOLCE-55 tool has been

shown to be a valid, reliable measure of health-related quality of life in children with epilepsy(108-

110). This tool takes approximately 12-14 minutes to complete, and evaluates functioning in four

domains: cognitive, emotional, social and physical. It has demonstrated satisfactory measurement

equivalence, internal consistency, reliability and convergent and divergent validity in the

literature(108-110).

Caregiver Quality of Life Assessment

The impact of caregiving on caregiver quality of life was assessed using CarerQol-7D, which measures subjective burden via five negative dimensions (relational problems, mental health problems, problems combining daily activities with care-tasks, financial problems and physical problems) and two positive dimensions (fulfilment from caregiving and social/family support when needed) associated with providing care (Appendix E). Utility scores have been developed based on relative weighted utility weights; possible scores range from 0 to 100, with higher numbers indicating reduced caregiver burden. Country-specific tariffs have been developed

for use in economic evaluations, including one from the U.S.(92), which was used here. The

CarerQol tool also measures overall caregiver happiness on a scale of 0 to 10, with 10 being a state

of complete happiness, and has been shown to have good convergent and divergent validity(89).

Caregiver Satisfaction Assessment

Ygge et al(96) developed a parent version of an existing adult patient satisfaction questionnaire that assesses satisfaction with: information about the illness; information about the

routines; accessibility; medical treatment; care processes; staff attitudes; participation; and staff

work environment. Caregiver satisfaction was assessed in our population using this tool (Appendix

F), which has shown good internal content and construct validity, as well as internal reliability(96).

Data Analysis

Descriptive statistics were used. Demographic, clinical and outcome numerical data were

summarized using means, standard deviations and ranges. Categorical variables were presented as frequencies and percentages. In comparing surgically-treated groups versus medically-treated

groups, unpaired t-tests for sample sizes with unequal variances were used. Given inherent small sample sizes, meaningful multivariate models could not be utilized to identify factors affecting seizure outcome, neurocognitive outcome or quality of life.

Chapter III: Results

Demographics

Prior to Formation of the Pediatric Epilepsy Program

Prior to 2016, 16 children, including 9 females and 7 males, underwent epilepsy surgery in

Manitoba. All had a vagal nerve stimulator insertion for medically refractory epilepsy. Etiologies

of epilepsy included pachygyria in 2 (12.5%) patients, grey matter heterotopia in 1 (6.25%) patient, cortical dysplasia in 1 (6.25%) patient, ceroid lipofuscinosis in 1 (6.25%) patient, prior trauma in

1 (6.25%) patient, lissencephaly in 1 (6.25%) patient, perinatal stroke in 1 (6.25%) patient,

Aicardi-Goutieres syndrome in 1 (6.25%) patient, Dravet syndrome in 1 (6.25%) patient, mosaic trisomy 13 in 1 (6.25%)patient, Q10 deletion syndrome in 1 (6.25%) patient, and an unknown cause in 4 (25%) patients.

Seizure frequency among patients was high, ranging from 60 seizures per day to clusters

of seizures every 2 weeks. 11 out of 16 (68.75%) patients experienced multiple seizures per day.

The average number of AEDs that patients were on pre-operatively was 3.12 +/- 0.75. The mean

age at surgery was 9.69 +/- 3.48 years, and the mean time to surgery from seizure onset was 5.5

+/- 2.92 years (range 2-11 years). There were no complications documented related to surgery.

After Formation of the Pediatric Epilepsy Program

After 2016, 14 children underwent epilepsy surgery, including 6 females and 8 males. The etiology of epilepsy was quite heterogenous, with 5 patients (35.71%) having epilepsy due to low grade tumors, 2 (14.29%) due to cortical dysplasia, 2 (14.29%) due to unknown etiologies, 1

(7.14%) due to mesial temporal sclerosis, 1 (7.14%) due to cavernoma, 1 (7.14%) due to arachnoid cyst, 1 (7.14%) due to remote traumatic brain injury and 1 (7.14%) with West syndrome.

Seizure frequency varied from greater than 100 per day in 1 patient, to clusters of seizures

every 2 months. 6 out of 14 (42.86%) patients experienced multiple seizures per day. The average

number of AEDs that patients were on pre-operatively was 2.29 +/- 1.20. The mean age at surgery was 11.21 +/- 5.1 years, and the mean time to surgery from seizure onset was 5.49 +/- 2.99 years

(range 4 months to 10 years).

Surgeries performed included: 5 anterior temporal lobectomy and

amygdalohippocampectomy procedures (35.7.1%); 1 hemispherectomy (7.14%); 1 frontal

lobectomy (7.14%); 2 non-temporal tumor resections (14.29%); 1 cavernoma resection (7.14%);

1 arachnoid cyst resection (7.14%); and 3 vagal nerve stimulator insertions (21.43%).

In terms of peri-operative complications, 1 patient had temporary increased seizure

frequency following resection of a frontopolar arachnoid cyst and required a load of an AED; 1

patient had transient right-handed weakness following a left frontal lesionectomy, which was not

unexpected and improved within 1 month; and 1 patient developed transient diabetes insipidus

following hemispherectomy requiring treatment with vasopressin. 2 patients had placement of an

extraventricular drain intra-operatively (discontinued at 4 days and 9 days post-operatively). The

average length of hospital stay was 4.64 +/- 3.30 days; all patients were discharged home.

Table 1. Patient Demographic Information

Prior to Pediatric Epilepsy Program After Pediatric Epilepsy Program n (M:F) 16 (7:9) 14 (8:6) Number of pre-op AEDs 3.12 +/- 0.75 2.29 +/- 1.20 Mean age at surgery 9.69 +/- 3.48 11.21 +/- 5.10 (years) Mean time to surgery from 5.5 +/- 2.92 5.49 +/- 2.99 seizure onset (years) Etiology of epilepsy Unknown (4) Low grade tumor (5) Pachygyria (2) Cortical dysplasia (2) Grey matter heterotopia (1) Unknown (2) Cortical dysplasia (1) Mesial temporal sclerosis (1) Ceroid lipofuscinosis (1) Cavernoma (1) Trauma (1) Arachnoid cyst (1)

Lissencephaly (1) Trauma (1) Perinatal stroke (1) West syndrome (1) Aicardi-Goutieres syndrome (1) Dravet syndrome (1) Mosaic trisomy 13 (1) Q10 deletion syndrome (1) Surgery type Vagal nerve stimulator insertion (16) Anterior temporal lobectomy and amygdalohippocampectomy (5) Hemispherectomy (1) Frontal lobectomy (1) Non-temporal tumor resection (2) Cavernoma resection (1) Arachnoid cyst resection (1) Vagal nerve stimulator insertion (3)

Seizure Outcomes

Prior to Formation of the Pediatric Epilepsy Program

Of the 16 patients who had surgery prior to 2016, follow-up ranged from 1 to 5 years. At last follow-up, 1 patient (6.25%) was seizure-free (Engel class I). 12 patients (75%) had a worthwhile improvement in seizures (Engel class III), and 3 patients (12.5%) experienced no worthwhile improvement in seizures (Engel class IV). All patients remained on AEDs at the last follow-up.

After Formation of the Pediatric Epilepsy Program

Of the 14 patients who had surgery after 2016, follow-up ranged from 3 to 12 months. At last follow-up, 11 patients (78.6%) were seizure-free (Engel class I). 2 patients (14.3%) had worthwhile improvement with at least a 50% reduction in seizure burden (Engel class III), and 1 patient (7.1%) had no worthwhile improvement (Engel class IV) following vagal nerve stimulator placement. 1 patient was off his AEDs at the last-follow-up.

Figure 1. Seizure Outcomes

Seizure Outcome at Last Follow-up 14

6 Number of Patients Number

0 Engel Class I Engel Class II Engel Class III Engel Class IV

Prior to Pediatric Epilepsy Program After Pediatric Epilepsy Program

Neuropsychological Outcomes

Systematic Review

An initial search identified 7,563 citations. Figure 2 shows a flow diagram used for study selection. Of 214 studies selected for full-text review, 7 studies had a homogenous cohort of patients who underwent one type of surgery (for various etiologies of epilepsy)(111-117), and 6 studies had a cohort of patients with a single form of epilepsy (where patients underwent various types of surgical procedures)(118-123).

Figure 2. Flow Diagram of Study Selection

Pediatric Epilepsy Surgery Neuropsychological Outcomes

Databases: Medline, BIOSIS, Central, Scopus, Global Health, Embase

Titles and Abstracts Excluded studies: 7349 (n= 7563) • Greater than 18 years of age (205) • Case report (776) • Conference/comment/editorial (252) • Review (660) • Prior to 1995 (475) • Retrospective (136) • Missing data (94) • Non-English (42) • Animals (5) • Irrelevant/Other (4704) Full-text Articles

(n= 214)

Excluded studies: 201 • Greater than 18 years of age (70) • Case report (2) • Prior to 1995 (43)

• Retrospective (40) • Missing data (10) • Other: o Psych/behaviour outcomes only (3) o Mixed cohort of Total Articles surgeries and epilepsy

(n= 13) types (22) o Non-resective surgery (8) Single surgery type (7) Duplicate cohort (1) Single epilepsy type (6) o Other (2) o

Of the 7 studies that focused on a single surgical procedure (Table 2), 3 studies included

only temporal lobectomies(112, 113, 116), 1 study included only occipitoparietal resections(117),

2 studies included hemispherectomies/hemispherotomies(114, 115), and 1 study included only

anterior corpus callosotomies(111). Neuropsychological evaluations were performed and the

results were reportedly variable and mixed.

Of the 3 studies on temporal lobectomies, Williams et al(112) utilized the full scale IQ

score, which improved non-significantly at 1 year following surgery. In this study, delayed verbal

memory also significantly decreased 1 year after surgery, and there were no significant changes in

verbal IQ, receptive vocabulary, verbal memory index, or executive function. Jambaque et al(116)

also found non-significant improvements in IQ at 1 year following surgery, but in contrast,

reported significant improvements in tests of episodic memory (including verbal memory,

immediate story and list recall, sentence recognition, naming, coding, digit span, and the Corsi

block test). At 2 years following surgery, De Koning et al(113) examined language development,

and found no significant change in receptive syntax; a decrease in receptive lexicon at 1 year that

then stabilized by 2 years; and a progressive linear decrease in productive lexicon.

Of the 2 hemispherectomy studies, all reported on left-sided surgeries. Boatman et al(114)

evaluated patients at 9-13 months following surgery and reported nonsignificant changes in full

scale IQ, receptive language and expressive language testing. Bulteau et al(115) evaluated patients later, at 3-6 years following surgery, and reported decreases in the performance reasoning index and in an oral speech battery.

Battaglia et al(117) evaluated a mixed cohort of left and right occipitoparietal resections at

2-9 years following surgery, and found an increase in performance IQ and memory testing, but no

significant changes in verbal IQ, visuomotor, visuoperceptual or visuospatial attention, or language testing. Lastly, Liang et al(111) reported on anterior corpus callosotomy for patients with

Lenox-Gastuat 2 years following surgery, and found no significant change in Full Scale IQ, Verbal

IQ or Performance IQ.

Of the 6 studies reporting neuropsychological outcomes following surgery for a specific

type of epilepsy (Table 3), patient populations included those with infantile spasms(119), patients

with lesional Lennox Gastaut syndrome (LGS)(123), patients with childhood onset epileptic

encephalopathy (EEOC)(121), patients with temporal lobe epilepsy (TLE)(122), patients with

frontal lobe epilepsy(120), and patients with tuberous sclerosis(118). Again, the

neuropsychological outcomes reported were quite heterogenous and inconclusive , though this is

not unexpected given the variation in etiology.

Caplan et al(119) evaluated patients with infantile spams at 2 years following either multi-

lobar resection or hemispherectomy, and found that overall, scores on the Early Social

Communication Scales improved, but were significant only for the subcategory of social

interaction. Ding et al(123) evaluated patients with lesional LGS between 3 to 5 years following

surgery and found significant improvements in full scale IQ; in this study, patients had undergone

various single or multi-lobar resections, along with corpus callosotomies. In patients with EEOC,

Lee at al(121) found a significant change in full scale IQ as well as non-significant improvements

in DQ at 2 years following surgery (which included single or multi-lobar resections,

hemispherotomies and corpus callosotomies).

Following lesionectomy or anterior temporal lobectomy, Gleissner et al(122) reported

outcomes of verbal memory (including learning capacity, recognition performance and loss after

delay) at 1 year following surgery. This study showed a significant decrease in learning capacity

at 3 months, which then recovered at 1 year in left-sided resections only; a significant decrease in recognition at 3 months, which then recovered at 1 year in right-sided resections only; and a significant decline in loss after delay in left-sided resections only. In frontal lobe epilepsy at 1 year after surgery, Lendt et al(120) showed significant improvements in attention, short-term and long- term memory, but no significant changes in executive function or language. Lastly, Zaroff et al(118) found no significant change in DQ or IQ following frontal, temporal, or posterior tuber resections in patients with tuberous sclerosis.

The quality of evidence within each study was evaluated using the RTI Item Bank on Risk of Bias and Precision of Observational Studies(106). Appendix G demonstrates the tabulated

results of these bias assessments. Overall, there was a low risk of bias among the included studies;

however, some general weaknesses were identified, including a wide range of follow-up periods in three studies, and unclear blinding procedures within studies that involved separate outcome groups.

Table 2. Studies Examining Outcomes Following a Single Type of Surgical Procedure

Surgery Author, N, Length of Outcomes studied Change year ages follow-up

Temporal Williams, 9, 8-15 1 year Full scale IQ Improved (nonsignificant) lobectomy 1998 years Delayed verbal memory Worsened (significant)

Verbal IQ, receptive No change vocabulary, verbal memory index, executive function

Temporal Jambaque, 20, 7- 1 year Full scale IQ Improved (nonsignificant) lobectomy 2007 14 years Episodic memory Improved (significant) (verbal memory, story and list recall, naming, coding, digit span, Corsi block test)

Temporal De Koning, 24, 5- 2 years Receptive syntax No change lobectomy 2009 15 years Receptive lexicon Worsened, then stabilized

Productive lexicon Progressive decrease

Occipitoparieta Battaglia, 12, 5- 2-9 years Performance IQ Improvement (significant) l resection 2012 13 years Memory Improvement

Verbal IQ, language No change testing No change Visuomotor, visuoperceptual, visuospatial attention

Hemispherecto Boatman, 6, 7-14 9-13 months Full scale IQ No change my 1999 years Receptive and No change expressive language

Hemispherecto Bulteau, 6, 4-8 3-6 years Performance reasoning Worsened my 2015 years index Worsened Oral speech battery

Anterior corpus Liang, 2014 60, 6- 2 years Full scale IQ No change callosotomy 12 years Verbal IQ No change

Performance IQ No change

Table 3. Studies Examining Outcomes Following Surgery for a Specific Type of Patient Population

Patient Author, N, ages Length Outcomes studied Change population year of follow- up Infantile Caplan, 29, 18 2 years Early Social Improved – significant only spasms 1999 months Communication Scales for Social Interaction +/- 11.54 subcategory

Lennox Ding, 43, 4-18 3-5 Full Scale IQ Improved (significant) Gastaut 2016 years years

Childhood Lee, 2014 95, 8 2 years Full Scale IQ Improved (significant) onset epileptic months – encephalopathy 17 years Developmental Improved (nonsignificant) (EEOC) Quotient Temporal lobe Gleissner, 55, 6-17 1 year Learning capacity No change overall epilepsy 2002 years Recognition No change overall

Loss after delay Worsened (significant) Frontal lobe Lendt, 24, 6-15 1 year Attention Improved (significant) epilepsy 2002 years Short and long-term Improved (significant) memory

Executive function No change

Language No change Tuberous Zaroff, 7, 2-21 6-15 Developmental No change sclerosis 2005 years months Quotient No change Intelligence Quotient

Comprehensive Local Assessment

In the project described herein, the results of pre- and post-operative comprehensive neuropsychological testing were available for 2 patients.

Patient 1 underwent a left anterior temporal lobectomy plus amygdalohippocampectomy for mesial temporal sclerosis and achieved complete seizure freedom. This patient’s 3 AEDs were

weaned to 2 AEDs by the time of the second neuropsychological assessment. Overall cognitive

performance assessed by the Wechsler Adult Intelligence Scale (WAIS-IV) changed from the 19th

percentile to the 32nd percentile. Verbal comprehension scores changed from the very low range to the impaired to average range. Working memory remained stable at very low. Visual perceptual reasoning changed from the average range (55th percentile) to above average range (82nd

percentile). Processing speed decreased slightly from the high average range (79th percentile) to

average (73rd percentile) range. Executive functioning assessment revealed poor phonemic

fluency, but performance on the remaining measures of executive functioning fell within or above

normal limits post-operatively. On the pre-operative memory and learning assessment, visual

memory performance was average to high average, though verbal memory was more variable, with

deficits in working memory and rote verbal learning; this was suggestive of variable impairments

in encoding verbal information and retrieval. Post-operatively, a retrieval deficit was noted on a measure of structured auditory memory; visual memory and unstructured auditory memory were within normal limits. Tests of receptive and expressive language were scored average prior to surgery and impaired to low-average at follow-up, with deficits in expressive language identified.

Overall, the patient’s post-operative neuropsychological results were commensurate with

pre-operative testing. There was a significant discrepancy between verbal and nonverbal skills,

with a clinically meaningful deficit in verbal comprehension skills. She also demonstrated deficits

in passive auditory attention, expressive vocabulary, confrontation naming, phonemic fluency and

retrieval on verbal memory. The remainder of her testing fell within or above normal limits.

Overall, her post-operative results were not suggestive of a marked decline in functioning.

Patient 2 underwent a right anterior temporal lobectomy plus amygdalohippocampectomy

for low grade glioma and achieved complete seizure freedom. This patient had no change in his

AEDs between neuropsychological assessments, remaining on 2 medications. Overall cognitive

function score assessed via the Wechsler Intelligence Scale for Children (WISC-V) was in the 16th

percentile pre-operatively and 8th percentile post-operatively. Processing speed (13% percentile)

and working memory (9th percentile) did not change after surgery, remaining low average. Verbal

comprehension changed from the 13th percentile to the 5th percentile. Visual spatial skills were stable and in the 37th percentile pre-operatively, and the 50% percentile post-operatively.

Nonverbal reasoning skills were also stable and in the 34th percentile pre-operatively, and the 27th

percentile post-operatively. Visual motor integration (VMI) improved from the 14th percentile to

the 73rd percentile. Academic achievement was stable, with reading and spelling skills very low,

and math skills average. Learning and memory were assessed with the Children’s Memory Scale

(CMS). Immediate and delayed verbal memory remained stable at extremely low to average.

Learning and memory for spatial information improved from the 9-25th percentile to the 37-50th

percentile.

Overall, the patient’s post-operative cognitive functioning fell within the very low to

average range, compared to the low-average range pre-operatively, and appeared to be due to weakness in verbal skills. Rote memory and literacy skills were areas of weakness, and memory for stories decreased significantly. As in the pre-operative assessment, non-verbal skills including visual spatial skills, fluid reasoning abilities, and math skills were more consistent and generally within the average range. Visual motor integration also improved significantly.

EpiTrack Junior

One patient underwent pre-operative and 6 month post-operative EpiTrack screening

following a left anterior temporal lobectomy plus amygdalohippocampectomy procedure for

epilepsy, in the context of a brain tumour. This patient was free from seizures at the last follow-

up. The overall pre-operative EpiTrack Score was 27, corresponding to a performance of

‘significantly impaired’ following age correction. At the 6 month post-operative follow-up, the

overall EpiTrack Score was 30, corresponding to a performance of ‘mildly impaired’ following

age correction. The evaluation of significant change according to the EpiTrack tool was

‘improved.’ This patient was seizure-free at follow-up, and had no change in his AEDs, remaining

on 2 medications. The reasons for this significant change are likely multifactorial – while

medication effect is unlikely to have contributed, improvement in seizure control may have played

a role. As well, the effects of age and test repetition are difficult to discern within this one patient

and would require further assessments to better study.

Patient Quality of Life

Surgically Treated Group, Post-2016

Eleven out of 14 patient caregivers completed the QOLCE-55. Two patients were excluded from the questionnaire due to age, and 1 patient caregiver did not complete the questionnaire.

The average composite QOLCE-55 score was (59.69 +/- 23.22)/100, with higher scores in emotional ([69.38 +/- 16.69]/100) and social functioning ([66.56 +/- 29.83]/100). The lowest score was in cognitive functioning ([51.05 +/- 32.42]/100). Scores were higher following resective surgeries ([63.70 +/- 22.29]/100) compared to non-resective surgeries ([49.00 +/- 26.85]/100), but this result was not statistically significant (p=0.5).

Two patient caregivers had both pre- and post-operative QOLCE-55 scores completed. In

1 patient, the total score increased from 70.83/100 to 82.95/100, with increases in cognitive and

emotional functioning, but decreases in social and physical functioning. In the second patient, the

total score decreased from 72.15/100 to 60.83/100, with increases in cognitive functioning, and

decreases in emotional, social and physical functioning.

Medically Treated Group

Caregivers for a group of medically treated epilepsy patients currently undergoing

comprehensive work-up (n=3) completed the QOLCE-55. The average QOLCE-55 score for this group was (46.25 +/- 22.78)/100 compared to (59.69 +/- 23.22/100 in the surgically treated group, although this difference was not statistically significant (p=0.4).

Figure 3. Patient Quality of Life Outcomes

QOLCE-55 Results 80

40 Score

0 Cognitive Functioning Emotional Functioning Social Functioning Physical Functioning Total

Surgically Treated Patients Medically Treated Patients

Caregiver Quality of Life

Surgically Treated Group, Post-2016

Fourteen patient caregivers completed the CarerQol-7D. The average composite CarerQol-

7D score was (78.31 +/- 18.64)/100. Scores were similar in resective ([78.21 +/- 16.46]/100) and

non-resective surgeries ([78.73 +/- 31.30]/100), with no significant difference. The average global

happiness score was (7.23 +/- 1.68)/10.

Two patient caregivers had both pre- and post-operative CarerQol scores completed. In 1

patient, there was no change in the CarerQol-7D score, but an increase in global happiness score

from 8/10 to 10/10. In the second patient, there was an increase in CarerQol-7D score from

76.3/100 to 89.2/100. The caregiver did not complete the global happiness score.

Medically Treated Group

Caregivers for a group of medically treated epilepsy patients currently undergoing comprehensive work-up (n=2) completed the CarerQol-7D. The average CarerQol-7D score for this group was (73.75 +/- 3.89)/100 compared to (78.31 +/- 18.64/100 in the surgically treated group, although this difference was not statistically significant (p=0.4). The average global happiness score in the medically treated group was (7 +/- 0)/10.

Figure 4. Caregiver Quality of Life Outcomes

CarerQol-7D Results

72 Score 70

64 Total Global Happiness

Surgically Treated Patients Medically Treated Patients

Caregiver Satisfaction

Surgically Treated Group, Post-2016

Twelve patient caregivers completed the Parent Questionnaire. Satisfaction with the

Pediatric Epilepsy Program was high with an average rating of (9.38 +/- 0.77)/10, with the highest

subcategory scores in staff attitudes ([96.18 +/- 8.23]/100) and participation ([92.36 +/-

10.93]/100). The lowest subcategory score was in staff work environment ([70.00 +/- 23.20]/100).

Intermediate subcategory scores were as follows: Information – illness (mean [91.67 +/-

13.30]/100); Information – routines (mean [86.81 +/- 15.67]/100); Accessibility (mean [86.11 +/-

17.81]/100); Medical treatment (mean [90.28 +/- 12.73]/100); and Caring process (mean [90.63

+/- 11.11]/100).

Figure 5. Caregiver Satisfaction Outcomes

Parent Questionnaire Results 120

100

60 Score

Information - Illness Information - Routines Accessibility Medical Treatment Caring Processes Staff Attitudes Participation Staff Work Environment

Chapter IV: Discussion

Epilepsy surgery can significantly decrease the seizure burden in medically intractable

patients, with seizure-free success rates reported as high as 70% in the literature (124). Moreover, given that epileptic seizures affect quality of life, psychosocial and neuropsychological functioning, and multiple domains in the lives of caregivers of PWE as well, epilepsy surgery is also thought to deliver widespread improvements in these outcomes(74, 125). In pediatrics, specifically, the goal of epilepsy surgery is not only to halt seizure activity, but to maximize the developmental and functional capacity of the child, improve quality of life, and mitigate caregiver burden.

Unfortunately, there is a scarcity of literature studying the effect of early epilepsy surgery on both neuropsychological and quality of life outcomes. However, early epilepsy surgery leading to seizure freedom is likely to maximize the capacity or potential for a young child’s brain to develop, by minimizing harmful exposure to repeated seizure activity. Information gleaned in this area is invaluable in counseling patients and determining what patient and clinical factors may play a role in their neurocognitive outcomes. The same sentiment applies to quality of life outcomes for both patients and their caregivers, as there may be potential modifiable factors that can further improve HRQOL in this complex population.

In the cohort presented here, following the establishment of a formal Pediatric Epilepsy

Program in 2016, the mean time to surgery from seizure onset for pediatric epilepsy patients in

Manitoba has remained relatively stable, from 5.5 +/- 2.92 years (range 2-11 years) to 5.49 +/-

2.99 years (range 4 months to 10 years). However, the various types of surgeries offered in- province and now successfully performed have vastly increased in number. Satisfactory seizure

outcomes were achieved with numbers of patients achieving complete seizure freedom (78.6%),

consistent with the literature and similarly published results from high volume centers in North

America. Patient quality of life scores in epilepsy cohorts typically range from 30-60% pre-

operatively and 30-80% post-operatively (8, 89, 126, 127), which is also consistent with the results

shown here of an overall mean QOLCE-55 score of 57.69%. Similarly, the mean CarerQol-7D

score of 78.31 and mean global happiness score of 7.23 are in agreement with CarerQol-7D scores

in the literature, which range from 70-80; and global happiness scores, which range from 6-8

among both caregivers of epilepsy patients and mixed cohorts of caregivers (89, 128).

Neurocognitive development in pediatric epilepsy patients is a complex process, and the

tools required to measure outcomes in neuropsychological performance vary from centre to centre,

as previously discussed. As illustrated herein, the systematic review of neuropsychological

outcomes following pediatric epilepsy surgery underscores the extreme heterogeneity of studies

present in the literature. The majority of studies to date have been performed retrospectively,

lacking comprehensive pre- and post-operative comparisons, and are limited by small sample sizes

and/or mixed populations encompassing varying pathologies or types of surgical procedures.

Evidently, any single surgical procedure can produce vastly different outcomes when performed for different etiologies, making it increasingly difficult to confidently delineate the effects of surgical intervention. Furthermore, the neuropsychological evaluations performed and reported in the literature vary from study to study, making the synthesis of data through meta-analysis unachievable. Overall, most studies seem to show a lack of significant change in many outcome measures over the short-term (1 to 2 years following surgery), which may reflect the heterogenous samples and use of varied neuropsychological tests. Ultimately, longer-term studies with homogenous cohorts employing consistent outcome measures are required to better evaluate this.

Despite the ILAE recommendation that a pre-operative neuropsychological assessment be performed prior to epilepsy surgery(67), only 69% of clinicians consistently perform this as part

of their pre-operative work-up(77). In the cohort presented here, only 2 patients had both

comprehensive pre- and post-operative neuropsychological assessments performed, with the

reduced numbers likely owing to local logistical barriers and resource constraints in Manitoba.

While one patient remained relatively stable on neuropsychological testing, the other showed some

decline in verbal skills; however, drawing conclusions regarding the effects of surgery would be

premature based on this small dataset. EpiTrack Junior has been recommended as a time-efficient screening tool for neurocognitive performance, although it is important to note that screening tools should not be considered replacements for comprehensive neuropsychological evaluations, as

screening measures such as EpiTrack may fail to detect subtle impairments in higher functioning

individuals. In our study, though this tool was introduced prospectively for testing in new patients,

interruptions in surgical slating and clinic appointments for procedures such as epilepsy surgery were haltingly introduced by the COVID-19 pandemic. This ultimately prohibited more extensive

data collection during this project and serves as a primary limitation of the results presented herein

(discussed below). Nevertheless, the EpiTrack Junior assessment remains a potentially useful tool

for identifying changes in neurocognitive performance, particularly in underserved regions such

as Manitoba, with financial and resource constraints that preclude comprehensive testing for these

patients. In all patients however, cognitive screening using EpiTrack Junior should be followed by comprehensive testing when able to ensure accuracy of the initial assessment. Prospectively, it is hoped that this screening tool will continue to be applied when indicated, and initially should be implemented in concert with comprehensive neuropsychological testing to evaluate the accuracy and utility of this tool. Based on the preliminary results presented herein, this remains an area for

further study and improvement, as more robust data is required to support a confident evaluation of this integral aspect of pediatric epilepsy care at our centre.

Experiences with epilepsy program development have rarely been published, aside from those in developing countries or severe low-resource settings. In this context, high complexity surgical care such as that required of epilepsy surgery has been shown to require a multidisciplinary team and innovative solutions to overcome limitations in equipment and facilities(129). Telecollaboration tools have also been suggested for long-distance training in low- resource settings, as well as visiting professorships(129). Within our own centre, we consider several aspects fundamental to the establishment and continued growth of the Pediatric Epilepsy

Program, namely structural organization, funding, multidisciplinary engagement and ancillary support.

First, structural organization is necessary from early on, and involves securing physical resources and supplies. An example includes the early creation of the Pediatric EMU and procurement of all required components for its appropriate functioning: hospital beds, nursing staff, EEG technologists, rescue AEDs, video monitoring, and more. The creation of the Pediatric

EMU also created incentives for the hiring of two dedicated fellowship-trained pediatric epileptologists, which was instrumental in moving the program forwards. Additionally, structural organization also includes the development of a streamlined path for each patient on their course to epilepsy surgery, from initial neurologist referral, pre-operative work-up (including imaging and neuropsychological consultation), neurosurgical referral, and post-operative care. This type of organizational structure requires planning and input from providers and stakeholders at each stage, in order to run efficiently. A longitudinal database such as the one created herein is necessary to

monitor each patient’s progression through the system, and essential to allowing multiple providers

to monitor patient progress and eventual outcomes.

Second, funding is a well-recognized component of program development, as adequate

funding allows for proper structural organization and continued growth of any program. Local

epilepsy research, academic credibility, fundraising efforts and public promotion of the relevance

of epilepsy surgery have all been helpful in attracting the funding and resources that are necessary

for continued expansion of the program(103).

Finally, both multidisciplinary engagement and ancillary support are fundamental in

developing an epilepsy surgery program. Competent nursing staff, EEG technicians, neurologists, neurosurgeons, radiologists, pathologists, and neuropsychologists are just some examples of the diversity of staff required to run a sustainable epilepsy program. Multidisciplinary Epilepsy

Rounds have been essential in providing an avenue for interdisciplinary discussion and collaboration on patient management and program development issues.

Kolb’s adult learning cycle for experiential learning may be applied to the development of

surgical education programs(103), and consists of four key components: experience, assessment,

goals and change. The Pediatric Epilepsy Program has now experienced the initial stages of

program development, with an early cohort of epilepsy patients having dramatically benefited from

surgical intervention and post-operative care. This thesis has thus been instrumental in capturing

an early (albeit comprehensive) assessment of multidimensional clinical and patient outcomes,

including seizure, neuropsychological, patient quality of life, and caregiver quality of life

outcomes, and has further solicited feedback by way of Caregiver Satisfaction questionnaires.

Moving forwards, in accordance with Kolb’s cycle, the next steps would include improved data collection methods (expectantly facilitated in a post-pandemic era), the setting of goals for improvement, and the implementation of changes to achieve those goals and thereby improve overall performance.

Figure 6. Program Development Model

Funding

Structural Multidisciplinary Organization Engagement

Pediatric Epilepsy Program

Experience

Change Assessment

Goals

Limitations and Future Directions

Primary limitations to evaluating pediatric epilepsy surgery outcomes in this cohort relate

to the small sample size and short duration of follow-up, the majority of which is accounted for by

the early stages of this program coinciding with the clinical upheaval incurred by the COVID-19

pandemic. The latter put a significant halt on elective procedures, including epilepsy surgery, and

any in-patient appointments including testing. It is anticipated that more extensive data would have been collected under more normal circumstances, which would have further elucidated the trends in the data presented here. Additionally, although evaluating outcome measures at 6 months post- surgery or even later is ideal to capture significant long-term effects, the initial results presented herein are nevertheless important in the early evaluation of this developing program. They serve as proof-of-concept for the downstream effects of the Pediatric (and eventually, the Adult)

Epilepsy Programs at Winnipeg Children’s Hospital/Health Sciences Centre. At this time, the interim outcome results reported here are consistent with results from high volume centers, and

these patients will continue to be monitored clinically in a prospective fashion as outpatients.

As previously discussed, another limitation to data collection in this project may be

explained by access to neuropsychological testing in Manitoba, which is lower than the Canadian

average, given financial and resource constraints, including understaffing. With increased

provincial awareness towards the proposals for developing the Pediatric and Adult Epilepsy

Programs, this issue has gained a new focus with increased advocacy for additional supports,

hopefully in the coming years. As mentioned, the implementation of initial cognitive screening

through tools such as EpiTrack Junior as well as comprehensive pre- and post-operative

assessments performed in tandem will be necessary to fully assess this key component of epilepsy

surgery.

Despite offering a wider variety of surgeries since the implementation of our Epilepsy

Program, the time from epilepsy onset to epilepsy surgery has remained stable. This persistent wait

time may be due to a variety of contributing factors. Depending on the complexity of patient

pathology, some may require a lengthier pre-operative work-up and/or a higher number of

investigations prior to surgery. Certain pre-operative investigations such as MEG and invasive

EEG monitoring are also unavailable in Manitoba at this time; as such, patients who require these investigations prior to surgery may first need to travel to neighboring provinces, such as Ontario, that offer them. Each of these steps will undoubtedly add to the time from epilepsy onset to epilepsy surgery. In addition, delayed referral to neurosurgery from general practitioners and/or neurologists, as well as variable operative wait-times may also contribute. In this regard, increased advocacy for epilepsy patients and increased exposure of our program among the general pediatric community through medical conferences, educational lectures, and social media, will all help raise awareness around early epilepsy surgery and its beneficial effects.

Given the small sample size herein, it was not possible to compute statistically relevant analyses on factors that may influence seizure, neuropsychological and quality of life outcomes, both pre- versus post-operatively, and in surgically treated versus medically treated patients. It is

hoped that these analyses may be pursued in the future, conditional on increased data capture of more patients and possible multi-centre collaboration to acquire a more robust and homogenous study population. Our established database will be a key component in allowing such multi-centre collaboration and data sharing. The results of these analyses will help practitioners provide

informative patient counseling and will provide insight on modifiable factors that may be potentially adjusted, in an effort to maximize the positive effects of pediatric epilepsy surgery.

Conclusions

Until recently, children with epilepsy in Manitoba were referred out-of-province for

surgical treatment, making access to care difficult and imposing significant socioeconomic

stressors on their families. With the instatement of the newly-created Pediatric Epilepsy Program

in 2016, access to epilepsy surgery has dramatically improved for children in Manitoba, with a

wide variety of procedures now being safely offered and available. This project has introduced a

provincial-wide database for data collection, in addition to identifying favorable multi-

dimensional outcomes following epilepsy surgery in pediatric patients with intractable epilepsy,

including: improved seizure outcomes, patient quality of life outcomes, caregiver quality of life

outcomes, and caregiver satisfaction outcomes. These preliminary findings will allow for

improved counselling of patients and families with respect to complex epilepsy management.

Structural organization, funding, multidisciplinary engagement and ancillary support have

been necessary for program sustainability and expansion. A longitudinal, ongoing database is

recommended for continuous quality assessment and improvement, to allow for ongoing

surveillance of trends and post-operative outcomes. This will ultimately facilitate the future

development and sustained growth of the Pediatric Epilepsy Program, to provide improved and

more cost-effective care for this previously underserved patient population in Manitoba.

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Appendix A: Data Fields in the RedCap Database

a. Gender b. Age of epilepsy onset and age at surgery (i.e. Duration of epilepsy) c. Patient comorbidities, including known learning or developmental delay d. Frequency of seizures e. Etiology of seizures f. Key imaging findings (MRI, PET, and functional imaging studies if performed) g. Key EEG findings (scalp or invasive) h. Type, laterality and length of operation i. Length of hospital stay, including length of intensive care unit stay j. Post-operative complications, including infection, hemorrhage requiring transfusion of blood products and hydrocephalus k. Pre-surgery, 3 month, 6 month and 1 year post-surgery antiepileptic medications l. Pre-surgery, 3 month, 6 month and 1 year post-surgery seizure frequency m. Pre-surgery, 3 month, 6 month and 1 year post-surgery neurocognitive assessment n. Patient quality of life outcome (QOLCE-55 questionnaire results) o. Caregiver quality of life outcome (CarerQol questionnaire results) p. Caregiver satisfaction questionnaire results

Appendix B: Systematic Review – Search Strategy exp infant/ or exp child/ or adolescent/ child health/ or infant health/ or adolescent health/ exp child health services/ or adolescent health services/ or exp pediatrics/ or adolescent medicine/ (p?ediatric*).ti,ab,kf (infant* or infancy or baby* or babies or neonat* or newborn* or new-born*).ti,ab,kf (child* or kid or kids).ti,ab,kf (schoolchild* or school age* or schoolage* or primary school* or elementary school* or secondary school* or high school* or highschool*).ti,ab,kf (preschool or pre-school or toddler* or kindergar* or nursery).ti,ab,kf (adolescen* or teen* or youth or youths or young people or young person* or young adult* or pre-teen* or preteen*).ti,ab,kf (boy* or girl*).ti,ab,kf or/1-10 exp epilepsy/ (epileps* or epileptic* or seizure disorder* or seizure syndrome* or convulsi* disorder* or convulsi* syndrome*).ti,ab,kf (adcme or adeaf or adlte or adnfle or adpeaf or aerrps or aicardi or akinectic attack* or "alice in wonderland" or alpers or angelman or astatic fit* or bafme or battaglia-neri or batten or bcects or becrs or bects or bfie or bfis or bfnis or bfls or bfns or bimse or boec or borjeson- forssman-lehmann or brec or cae or cdfe or cdfes or cects or christianson syndrome* or csws or dacrystic or dend syndrome* or dentatorubral-pallidoluysian atroph* or desc syndrome* or doose* or dravet* or east syndrome* or efmr or egtcs or eiee or emas or epm? or fcd or feigenbaum-bergeron-richardson or ffevf or fimes or flexor spasm* or fmtle or focal cortical dysplasia or focal clonic or focal tonic or focal seizure* or fukuhara or gefs or gelastic or geloleps* or gepd or grand mal or gurrieri-sammito or haut mal or haw river or icee or idend or infantile spasm* or ((infantile or neonatal) adj2 (seizure* or convulsion*)) or jack knife attack* or jackknife attack* or jack knife seizure* or jackknife seizure* or jae or jankovic- rivera or janz or jeavon* or jme or juberg-hellman or kcnq2 or kohlschutter-tonz or kojevniko* or kojewnijo* or kosherniko* or kozhevniko* or kuzniecky or lafora or landau-kleffner or lennox-gastaut or lennox syndrome* or lgs or lightning attack* or lks or ltle or lundborg or mae or may-white or meak or mehmo or merrf or micropsia or mmpei or mmpsi or moynahan or mpei or mpsi or mscae or mtle or myoclonia or myoclonus or naito-oyanagi or negrete or neuronal ceroid lipofuscinos* or neuronal ceroidosis or neuronopathic gaucher or nodding spasm* or nodding syndrome* or ohtahara or panayiotopoulos or paramyoclonus or petit mal or pmei or (progressive adj2 poliodystrophy) or pyknoleps* or ragged red or rasmussen or salaam attack* or salaam seizure* or scae or sesame syndrome* or sensory seizure* or shokeir or smei or spasmus nutans or spax5 or spemr or spielmeyer or spprs or tle or uld or uncinate or partial seizure* or unverricht or versive or west* syndrome* or ((trauma* or posttrauma* or impact or concuss*) adj2 (seizure* or convulsion*))).ti,ab,kf or/12-14 exp epilepsy/su or laser therapy/ or exp brain/su or deep brain stimulation/ or vagus nerve stimulation/ or exp neurosurgical procedures/

(epilep* adj2 (surgery or surgical or neurosurg* or operati* or resect*)).ti,ab,kf (focal resect* or topectom* or amygmalotom* or amygdalohippocampectom* or hippocampectom* or parahippocampectom* or lobectom* or atl resect* or lobe resect* or temporal resect* or extratemporal resect* or frontal resect* or parietal resect* or occipital resect* or resecti* surger* or lesionectom* or subpial transect* or litt or thermal ablation* or laser ablation* or thermal therap* or hemispherectom* or hemispherotom* or callosum transect* or callostom* or radiosurgery or neurostimulation or vns or vagus nerve stimulation or rns or dbs or deep brain stimulation).ti,ab,kf or/16-18 exp outcome assessment, health care/ or adolescent development/ or exp child development/ or exp cognitive dysfunction/ or exp psychological tests/ or exp mental processes/ ((neuropsychologic* or neurologic* or psychologic* or developmental* or cogniti* or neurocogniti* or neurodevelopmental* or behavio* or psychosocial*) adj5 (test* or assess* or outcome*)).ti,ab,kf ((achievement or aphasia or attenti* or comprehension or decisionmaking or decision-making or judgment or judgement or dexterity or coordination or executive function or intellect* or intelligence or language or linguistic* or psycholinguistic* or neurolinguistic* or learning or memory or motor function or gross motor or fine motor or perception or performance or problem-solving or problemsolving or retention or recall or verbal or auditory or communicati* or vigilance or visual or spatial or visuospatial or mental navigation) adj5 (test* or assess* or outcome*)).ti,ab,kf or/20-22 11 and 15 and 19 and 23 exp animals/ not humans.sh 24 not 25

Appendix C: EpiTrack Junior

Appendix D: Quality of Life in Childhood Epilepsy (QOLCE-55) Questionnaire

Appendix E: CarerQol Questionnaire

Appendix F: Caregiver Satisfaction - Modified Version of the Parent Questionnaire

No, not No, not Yes, to a Yes to a at all especially certain great degree degree Information-illness - Have you received sufficient information concerning: Your child’s illness/course of illness? Tests/examinations/treatments to be done? Information-routines - Have you received sufficient information concerning: Ward/clinic routines? To whom you should direct your questions? Which physician was responsible for your child’s care? Which nurse was responsible for your child’s care? Accessibility - Have you experienced problems: Contacting the hospital by telephone? Contacting your child’s physician by telephone? Contacting a nurse by telephone? Medical treatment Do you think that your child received satisfactory pain treatment? Do you think that your child received satisfactory pain treatment within a reasonable period of time? Do you have confidence in staff competence? Do you have confidence in staff skill? Caring processes Did you feel that staff had time for you? Did you feel that staff had time for your child? Have staff introduced themselves to you? Have staff introduced themselves to your child? Did staff offer support when you needed it? Did staff offer support to you child when he/she needed it? Were staff responsible to your needs/requests? Were staff responsive to your child’s needs/requests? Staff attitudes Were you treated kindly in your contact with staff at the hospital? Was your child treated kindly in contact with staff at the hospital? Were you well taken care of when you first came to the ward/clinic? Was your child well taken care of when you first came to the ward/clinic?

Did staff take you seriously? Did staff take your child seriously? Have you been treated with respect? Has your child been treated with respect? Participation Did you have the possibility to ask questions about your child’s illness? Have you understood the information you received about your child’s illness? Did you have the opportunity to participate in discussions concerning your child’s examinations/treatments? Have you had the opportunity to discuss the goals of your child’s treatment with the child’s physician? Staff work environment - Do you think that: There is a positive work climate among staff? Staff work under stress? Staff find their work stimulating? Staff have a heavy workload? Staff assume responsibility and are engaged in their work? Staff have a positive attitude toward their work? The care is characterized by good cooperation among staff? The care is efficient? All staff work towards the same goal – good care for the patient?

Appendix G: Bias Assessments Using the RTI Item Bank on Risk of Bias and Precision of Observational Studies

Citation Inclusions Interventions Outcomes Creation of Blinding Soundness Follow-up Analysis Analysis Interpretation Presentation & & Exposures Treatment of Comparability Outcome and Exclusion Groups Information Reporting Criteria

Williams, L L L N/A N/A L U L L L L 1998 (2-4 years)

Jambaque, L L L N/A N/A L L L L L L 2007

De Koning, L L L N/A N/A L L L L L L 2009

Battaglia, L L L N/A N/A L H U L L L 2012 (2-9 years)

Boatman, L L L L U L L L L L L 1999

Bulteau, L L L N/A N/A L U L L L L 2015 (3-8 years)

Liang, L L L U U L L L L L L 2014

Caplan, L L L N/A N/A L L L L L L 1999

Ding, 2016 L L L L U L L U L L L

Lee, 2014 L L L N/A N/A L L L L L L

Gleissner, L L L N/A N/A L L L L L L 2002

Lendt, L L L L U L L L L L L 2002

Zaroff, L L L N/A N/A L L H U L L 2005

H = high risk, L = low risk, U = unclear

Appendix H: Sample Telephone Script and Mailed Consent Form