Challenges and solutions

Stephanie Garcia-Tarodo, MD

02/07/2019

I have no actual or potential conflict of interest in relation to this presentation

1. Introduction

Epilepsy surgery: current trends

Particularities in infant population

2. Clinical application of MEG in infants

Technical perspective

Role in surgical decision process

3. Clinical outcome after surgery

Results of retrospective analysis

30% children with epilepsy develop drug refractory epilepsy (DRE)

Repercussions on development and cognition

DRE children are potential surgery candidates

Early surgery = longer period for developmental plasticity

Single-center RCT in children aged 10 mo – 17 yrs :

77% seizure free in surgery group compared to 7% in medical group

And yet, only 1% receive epilepsy surgery

(NEJM, 2017; 377(17): 1639-1647)

Obstacles vs Incentives for epilepsy surgery

Obstacles/disadvantages Incentives/advantages

Subtle/non-localizing semiology Preliminary epilepsy network

Generalized EEG pattern Developmental plasticity

Multiple etiologies Costs in the long-term

Supplementary investigations:

- Sedation

- Technical difficulties (head size…)

Improvement of QoL

- Motor

- Cognition

Limitation of intracranial EEG recording

Parental fear/opposition

Independency

Categorical predictors :

Age at seizure onset

Pathology

Identified lesion on MRI

Localized ictal EEG finding

Conditional predictors :

Timing of surgery

Surgery type‘Children 4 years or less were more likely to undergo

large resective operations (hemispherectomy and

multilobar procedures)’ ILAE Pediatric Epilepsy Surgery Survey Taskforce, 2008

Epilepsia 2008; 49(1): 146-155

Seizure

semiology

Infancy Childhood

Noninvasive presurgical evaluation

Scalp EEGMRI

SPECT

PET

MEG

Phase II

Surgery

Subdural grids SEEG

Detecting the origin of seizure activity

Sensitivity of 70% (Stefan et al, Brain 2003)

Non-redundant information in 33-35% of cases (Stefan et al, 2003; Sutherling et al, 2008)

Complimentary MEG-EEG data : tangential vs radial orientations of spikes

Concordance with the epileptogenic zone (Englot et al, Epilepsia 2015)

0

20

40

60

80

100

MEG + lobe ofresection

MEG + ECoG MEG + MRI

%

1. Presurgical evaluation 2. Postsurgical evaluation

Ages 5-79 years

Ages 3-68 years

Detecting the origin of seizure activity : sensitivity = 100% interictal, 55% ictal

Concordance with the epileptogenic zone

2 infants / 9 subjects 1 infant / 13 subjects

- MEG identified 1 clear focus with generalized EEG

findings in all 3 cases

- 62-67% concordance with MRI and/or ictal EEG

- No data on post-surgical outcome

Past reservations for use of MEG in infants

Head size and increased head to sensor distance

(1) Alternate head-side position (L/R hemisphere)

(2) ‘Reference’ or ‘neutral’ head position

Head movement and artifact

(1) Pre-recording : preparation procedures (allocation of time, parental accompaniment)

(2) Peri-recording : continuous head position monitoring (+/- 5 cm)

(3) Post-recording : temporally extended signal space separation (tSSS)

Effect of one anesthetic exposure on long-term behavioral changes in children Chemaly et al, J Clin Anesth 2014

DiMaggio et al, Anesth Analg 2011

MEG technologists : pediatric-trained, familiar to parents/child (PEMU)

Recording during natural sleep Sleep pattern, sleep deprivation

Time adaptation to feeding routine

Comfort/T°(heated blanket wrapping)

Time allocation : ‘Being on their schedule′o Preparation/installation : 1-2 hours

o Recording time : 60-80 minutes

Calming techniques o Parental presence during electrode placement

o Acknowledging specific anxiety/agitation trigger factors

o Technician remaining in the magnetically shielded room

o Maintains eye/physical contact

o Rapid to address signs of distress (sing a song, tell a story, calming voice)

Use of sedatives since 2013 :

0 infants

Technical adequacy : Non-sedative, non-invasive study

Head size and signal attenuation

tSSS and movement compensation

Localization of seizure focus : Concordance with the epileptogenic zone

Effect of MEG results on surgical management in infants : Additional information to the work-up

Surgical outcome

Inclusion criteria

- Children aged < 2 years (infants)

- Refractory epilepsy

- MEG in pre-surgical work-up between 01/2007 and 7/2017

Data collection

- Seizure history : semiology, age at onset, etiology

- Work-up : continuous vEEG, brain MRI, additional imagery (PET…)

- Phase II : SEEG, subdural grids

- If surgery :

Type of surgery

Follow-up (short/long term)

Total study population = 31 infants

Total pediatric MEG (2007-2017)

N = 407

Total number of patients : 341

Children (2-18 yrs)

n = 310 (91%)

Surgery

n= 126 (40.6%)

No surgery

n= 184 (59.4%)

Infant (< 2yrs)

n = 31 (9%)

Surgery

n = 18 (58%)

No surgery

n = 13 (42%)

0 10 20 30 40 50 60 70 80

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

Total MEG pediatric cases Infant cases Infant surgery cases

A

B

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Age at seizure onset Age at MEG Time MEG to surgery

< 1 month 1-6 months 7-12 months 13-24 months

3.5 mo 12 mo 3.5 mo

Age at seizure onset, MEG and surgery (with mean)

Seizure classification at onset

Generalized Focal Unknown

45.1%51.6%

Seizure etiology

TSC

FCD

Hemimegalencephaly

Vascular

Genetic

Unknown7

7

Supine position, magnetically shielded room

(248-) or 306-channel whole-head neuromagnetometer(Elekta, Helsinki; MAGNUS, San Diego)

5 head position indicator coils, continuous head position monitoring

Simultaneous EEG : 22- or 32-channels

Acquisition parameters :- Sampling rate : 1000 Hz

- Band-pass filter : 0.1 to 330 Hz

tSSS method

Source analysis : multiple ECD model

Dipole fitting Reduced Chi square, ~2.0

Goodness to fit > 80%

Positive interictal spikes on MEG recordings : sensitivity

MEG findings 1st exam Total exams

Positive (interictal +/- ictal) 28 33

Negative (normal or inconclusive) 3 4

90% 89%

0 2 4 6 8 10 12 14 16 18

MRI

EEG

MEG

MEG, EEG and MRI localizing results

Multifocal, bilateral Multifocal, unilateral Focal Negative

- Interictal foci : MEG = 14, EEG = 6

- MRI negative group = 9/31 infants

- 4/9 focal localization on MEG

- 8/9 multifocal discharges on EEG

18/31 infants subsequently had surgery within 12 months of MEG recordings

2 infants had subdural grid placement

1 with bilateral EEG but unilateral MEG findings focal resection, Engel I (46 mo)

0 2 4 6 8 10 12 14

Surgey outcome

Type of surgery

Focal resection

Partial disconnection

Hemispherectomy

Engel I

Engel II

Engel III-IVFollow-up period:

- Mean 20.6 mo

- Range 4-55 mo

Influence of MEG results on surgery type :

Focal resection (total = 9)

5/9 focal findings on EEG + MEG Engel I

2/9 focal findings on MEG + bifocal on EEG + normal/multifocal on MRI Engel I and II

Partial disconnection or corpus callosotomy (total = 5): multiple lesions and seizure types

1/5 multifocal findings EEG + focal on MEG Engel I

Hemispherotomy : extensive lesions to one hemisphere

3/4 multifocal and lateralizing on EEG + MEG Engel I

MRI negative

4/9 focal on MEG (8/9 multifocal on EEG) : 3/4 surgery Engel I (1), Engel II (1)

GroupPatients with good post-surgery outcome/patients with surgery

Both MEG and MRI identify focal 7/8 (correct prediction)

Neither MEG and MRI identify focal 0/1 (wrong prediction)

Negative MRI but MEG identifies focal 2/3 (correct prediction by MEG)

Positive MRI but multifocal MEG 5/7 (correct prediction by MRI)

Correlation between MEG and MRI

and effect on outcome prediction

Seizure free

(Engel I)

Non seizure free

(Engel II-IV)

Sensitivity/PPV

Positive likelihood ratio

Focal MEG 8 2 61.5%/80%

1.53Multifocal MEG 5 3

Positive MRI 12 3 92%/80%

1.53Negative MRI 1 2

Focal EEG 5 0 36%/100%

Multifocal EEG 9 4

Sensitivity :

MRI > MEG > EEG

Positive predictive value :

EEG > MRI = MEG

Well established protocols for MEG recording in infants

Counteract technical issues with head size and movement

Non invasive and non-sedative method of data retrieval

MEG has a good sensitivity in depicting epileptiform activity in infants

MEG provides additional information to EEG/MRI

Generalized EEG pattern

Negative MRI

MEG has a predictive role in surgical outcome

80% of infants with a focal MEG became seizure free after surgery

Widespread use in all age groups

Valid

Complementary

Broaden surgical candidacy in infants

Applicability of MEG to infants = earlier surgery interventions, better outcomes

Michael Funke, MD, PhD – Director of MEG

Gretchen Von Allmen, MD – Director UT Pediatric Epilepsy Program

Michael Watkins, MD – Pediatric Epileptologist

Jeremy Lankford, MD – Pediatric Epileptologist

Manish Shah, MD – Pediatric Epilepsy Neurosurgeon

Nitin Tandon, MD –Epilepsy Neurosurgeon

Lisa Caballero and Wayne Mead – MEG Technicians

Bagic A, Funke ME, Ebersole J. American Clinical MEG Society (ACMEGS) position statement: the value of magnetoencephalography (MEG)/magnetic source imaging (MSI) in noninvasive presurgical evaluation of patients with medically intractable localization-related epilepsy. J Clin Neurophysiol 2009; 25: 1-4

Stefan H, Hummel C, Scheler G et al. Magnetic brain source imaging of focal epileptic activity: a synopsis of 455 cases.Brain 2003; 126: 2396-2405.

Englot DJ, Nagarajan SS, Imber BS et al. Epileptogenic zone localization using magnetoencephalography predicts seizure freedom in epileptic surgery. Epilepsia 2015; 56: 949-958.

Albert GW, Ibrahim GM, Otsubo H et al. Magnetoencephalography-guided resection of epileptogenic foci in children. J Neurosurg Pediatrics 2014; 14: 532-537.

Shibata S, Mosher JC, Kotagal P et al. Magnetoencephalographic recordings (MEG) in infants using a standard-sized array: technical adequacy and diagnostic yield. J Clin Neurophysiol 2017; 34: 461-468.

Shukla G, Kazutaka J, Gupta A et al. Magnetoencephalographic identification of epileptic focus in children with generalized electrographic (EEG) features but focal imaging abnormalities. J Child Neurol 2017; 32: 981-995.

Harvey AS, Cross JH, Shinnar S, Mathern GW, ILAE Pediatric Epilepsy Surgery Survey Taskforce. Defining the spectrum of international practice in pediatric epilepsy surgery patients. Epilepsia 2013; 49(1): 146-155

Chemaly M, El-Rajab MA, Ziade FM, Naja ZM. Effect of one anesthetic exposure on long-term behavioral changes in children. J Clin Anesth 2014; 26(7): 551-556

Englot DJ, Han SJ, Rolston JD et al. Epilepsy surgery faliure in children: a quantitative and qualitative analysis. J Neurosurg Pediatrics 2014; 14: 386-395