Aims of workshop · initially every 2--3 months, than 13 months, than 1--2 seizures/month2 seizures/month Unable to attend school for 2--3 days following sei3 days following seizure

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What to do if AED’s are not What to do if AED’s are not

working?working?

‘‘Managing Intractability’Managing Intractability’

Christin EltzeChristin EltzeConsultant Paediatric Neurologist,Consultant Paediatric Neurologist,

Great Ormond Street Hospital for Children, LondonGreat Ormond Street Hospital for Children, London

Aims of workshopAims of workshop

�� Recognising / Predicting ‘Intractability’Recognising / Predicting ‘Intractability’

�� Setting ‘Goals’ of therapeutic interventionsSetting ‘Goals’ of therapeutic interventions

�� Management beyond seizuresManagement beyond seizures

�� NonNon--pharmacologic approaches and when to pharmacologic approaches and when to

consider theseconsider these

KateKate

�� Pregnancy and Birth: uncomplicatedPregnancy and Birth: uncomplicated�� Early development: Early development:

�� age appropriate mile stones, no concerns age appropriate mile stones, no concerns

�� First seizure at 5 y: Generalised tonic First seizure at 5 y: Generalised tonic –– clonic (< 5min)clonic (< 5min)

�� EEG:EEG:�� after hyperventilation burst of generalised S/W discharges associated after hyperventilation burst of generalised S/W discharges associated

with staring and mouthing movements, some evidence of with staring and mouthing movements, some evidence of photosensitivityphotosensitivity

�� Seizure free for 2 years without AEDsSeizure free for 2 years without AEDs�� Age 7y: Age 7y:

�� paroxysmal headachesparoxysmal headaches

�� episodes of facial twitching (bilateral involvement), later associated episodes of facial twitching (bilateral involvement), later associated with vocalising noise, with vocalising noise,

�� EEG: single spikes over central and occipital regions EEG: single spikes over central and occipital regions

→ Motor and vocal tics

KateKate

�� Age 13 Age 13 –– 14.5 y: 14.5 y: �� seizure in the morning in shower seizure in the morning in shower

�� (found half sitting, unresponsive, jerking all over, < 5 min)(found half sitting, unresponsive, jerking all over, < 5 min)

�� Further similar seizures, often early morning after wakingFurther similar seizures, often early morning after wakinginitially every 2initially every 2--3 months, than 13 months, than 1--2 seizures/month2 seizures/month

�� Unable to attend school for 2Unable to attend school for 2--3 days following seizure 3 days following seizure

�� AEDs:AEDs:1.1. Carbamazepine: episodes of starring + abnormal mouth movementsCarbamazepine: episodes of starring + abnormal mouth movements

2.2. Topiramate: numbness in both legs, tiredness, headachesTopiramate: numbness in both legs, tiredness, headaches

3.3. LamotrigineLamotrigine: increased jerks : increased jerks –– both arms + vocalisationboth arms + vocalisation

4.4. LevetiracetamLevetiracetam: no improvement: no improvement

5.5. Valproate: jerks improved and seizures less frequent (6 weeks seizure free, Valproate: jerks improved and seizures less frequent (6 weeks seizure free, school attendance improved)school attendance improved)

�� EEGEEG: no epileptiform activities, no photosensitivity : no epileptiform activities, no photosensitivity �� MRI (age 13.5 y) MRI (age 13.5 y) –– reported normalreported normal

QuestionsQuestions

�� Mother: Mother:

⇒⇒ Which type of epilepsy has she got ?Which type of epilepsy has she got ?

⇒⇒ Will she always have to take AEDs ?Will she always have to take AEDs ?

�� What is intractability ?What is intractability ?

Intractable epilepsyIntractable epilepsyHow common is it ?How common is it ?

�� Adults (>15 y): 16% approx 1:1000Adults (>15 y): 16% approx 1:1000Picolet et al, 2008Picolet et al, 2008

�� Childhood epilepsy cohorts:Childhood epilepsy cohorts:�� Netherlands: DSEC: Netherlands: DSEC: 8.5 %8.5 % (Geerts et al 2010)(Geerts et al 2010)

�� USA: Connecticut cohort USA: Connecticut cohort 14%14% (Berg AT et al, 2006)(Berg AT et al, 2006)

23% failed at least 2 AEDs23% failed at least 2 AEDs

�� Temporal lobe epilepsy: Temporal lobe epilepsy:

�� 37 % (Dlugos et al, 2001)37 % (Dlugos et al, 2001)

�� 69% (Spooner et al 2006)69% (Spooner et al 2006)

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PredictorsPredictors

�� Symptomatic aetiology Symptomatic aetiology

�� Neuroimaging abnormalityNeuroimaging abnormality

�� Abnormal NeurologyAbnormal Neurology

�� Early age at onset Early age at onset

�� History of neonatal seizures and status History of neonatal seizures and status

epilepticusepilepticus

�� ⇒⇒ Epilepsy Syndrome Epilepsy Syndrome Berg et al 2001Berg et al 2001

Supporting information Table A. Significant variables for active epilepsy (TRE < 5 year) and final intractability, and odds ratios for intractability (OR) for each value as compared with the reference value of that variable.

NumberActive

epilepsyIntractable

in final year

OR for intractability

(95% CI)

Overall 413 120 [29.1%]

35 [8.5%]

Type of epilepsy *** *** **

- generalized idiopathic 176 (42.6%) 41 [23.3%] 5 [2.8%] ref

- generalized symptomatic 29 (7.0%) 8 [27.6%] 2 [6.9%] 2.5 (0.5, 13.7)

- generalized cryptogenic or symptomatic (incl. LGS, West Synd)

32 (7.7%) 15 [53.1%] 10 [31.2%] 15.5 (4.9, 49.7)

- localization-related idiopathic 23 (5.6%) 0 0 .00

- localization-related symptomatic 59 (14.3%) 27 [45.8%] 8 [13.6%] 5.4 (1.7, 17.1)

- localization-related cryptogenic 78 (18.9%) 26 [33.3%] 10 [12.8%] 5.0 (1.7, 15.3)

- unclassifiable 16 (3.9%) 1 [6.2%] 0 .00

Aetiology at enrolment *** *** ***

- idiopathic 210 (50.8%) 43 [20.5%] 6 [2.9%] ref

- remote symptomatic 115 (27.8%) 48 [41.7%] 17 [14.8%] 5.9 (2.3, 15.4)

- cryptogenic 88 (21.3%) 29 [33.0%] 12 [13.6%] 5.4 (1.9, 14.8)

From Geerts et al Epilepsia 2010, 51(7): 1189-1197

15 year follow up Dutch Study of Epilepsy in Childhood

Spooner, C. G. et al. Neurology 2006;67:2147-2153

New-onset temporal lobe epilepsy in children Connecticut childhood epilepsy cohort

Berg AT et al, 2006:n=613, median follow up 9.7 y

• ~14% intractable (stringent criterium)~ 23% failure of 2 AEDs

• 1/3 reached these criteria after > 3 years• Mean duration of preceding remission:2 years (range 1-8years)

•after becoming intractable (17/83) 20% experienced periods of remission

and of these 11 (13%) in remission after last contact

Relapsing – remitting course

•• Drug resistant epilepsy Drug resistant epilepsy may be defined as failure of may be defined as failure of adequate trials of two tolerated and appropriately adequate trials of two tolerated and appropriately

chosen and used AED schedules (whether as chosen and used AED schedules (whether as monotherapiesmonotherapies or in combination) to achieve or in combination) to achieve

sustained seizure freedomsustained seizure freedom..�� Drug responsiveness:Drug responsiveness:

seizureseizure--free free for a for a minimum of minimum of three times the longest three times the longest pretreatmentpretreatment interseizureinterseizure interval, or interval, or 12 months, whichever is 12 months, whichever is

longer.longer.

KateKate

�� Age 15:Age 15:

�� Nocturnal seizures 1Nocturnal seizures 1--3 per month3 per month

�� Parents alerted by noise Parents alerted by noise –– find her in bed unresponsive find her in bed unresponsive neck hyperextended neck hyperextended –– body jerking, usually < 5 minutes, body jerking, usually < 5 minutes,

�� 11--2 days unwell after seizure, tired “feels washed 2 days unwell after seizure, tired “feels washed

out”, unable to attend schoolout”, unable to attend school

�� Mainstream school Mainstream school –– academically keeping up with academically keeping up with

difficultiesdifficulties

�� Waking and sleep EEG Waking and sleep EEG –– reported no reported no unequivocal epileptiform activities unequivocal epileptiform activities

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Question Question

�� Should other differential diagnoses be Should other differential diagnoses be

considered ?considered ?

�� How can school attendance be improved ?How can school attendance be improved ?

�� Next steps in management Next steps in management

Home videoHome video

�� Several events:Several events:

�� In bed head extended backwards into pillow, appears In bed head extended backwards into pillow, appears

unresponsive, body appears stiff with generalised unresponsive, body appears stiff with generalised

rhythmic jerking movements 3rhythmic jerking movements 3--4 minutes4 minutes

�� VideoVideo--telemetry age 15.5 ytelemetry age 15.5 y

�� 2 nights2 nights

Interictal discharges stage 1 sleep

Video clip

Nocturnal seizure 1

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Nocturnal seizure 2

Conclusion: ictal onset – no consistent lateralisation,

seizures appear to have frontal lobe origin

KateKate

�� Age 16 y:Age 16 y:�� 4 months seizure free on VAL + LEV4 months seizure free on VAL + LEV

�� Worsening of paroxysmal headaches, tiredness Worsening of paroxysmal headaches, tiredness during day time (AEDs adjusted) during day time (AEDs adjusted)

�� Investigations:Investigations:�� Optimised MR imaging (Epilepsy protocol, 3T MRI)Optimised MR imaging (Epilepsy protocol, 3T MRI)

�� No cortical abnormalitiesNo cortical abnormalities

�� Age 16.5 yAge 16.5 y�� Worsening of seizures, now 2Worsening of seizures, now 2--3 per months, 3 per months,

nocturnal incontinencenocturnal incontinence

QuestionQuestion

�� Parents:Parents:

�� What is the chance that her seizures respond to the What is the chance that her seizures respond to the

next AED (Zonisamide suggested) ?next AED (Zonisamide suggested) ?

Quantifying the response to AEDs: Effect of past treatment historySchiller, Y. et al. Neurology 2008;70:54-65

• Information from 429 consecutive

patients> 12 years

• maximal sz free ~ 62%

•For every 1.5 failed AED

decrease of sz free rate by 50%•After 2-5 AEDs – 16.6% sz free

• > 50% sz reduction max 85%

Decrease by 50% for every 2 AEDs tried• After 6-7 AEDs .>50% sz reduction in

1/3

•No effect on response of any

specific AED or EEG findings

Remission on medical treatmentRemission on medical treatment

�� 67% that started on AEDs > 5 y 67% that started on AEDs > 5 y szsz remissionremissionGreets et al, Epilepsia 2010, 51(7):1189 -1197

�� Success of AED’s in 470 “untreated“ patients Success of AED’s in 470 “untreated“ patients

(9(9--93y) 93y) [Kwan P, [Kwan P, BrodieBrodie M, NEJM, 2000M, NEJM, 2000]]

�� 47 % response to 1rst drug47 % response to 1rst drug

�� 13% response to 213% response to 2ndnd drug drug

⇒⇒ 9% seizure9% seizure--free on monofree on mono--therapy with 2therapy with 2ndnd drugdrug

�� 4% response to 3rd or multiple drugs 4% response to 3rd or multiple drugs

⇒⇒ 1 % seizure1 % seizure--free on free on monotherapymonotherapy with 3with 3rdrd drugdrug

⇒⇒ 3% seizure3% seizure--free on 2 drugsfree on 2 drugs

Cumulative probability of being seizureCumulative probability of being seizure--free by time from start of treatment free by time from start of treatment

and number of antiepileptic drug regimensand number of antiepileptic drug regimensBrodie M et al. Neurology 2012;78:1548-1554

Chance of seizure freedom declines with successivedrug regimes

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QuestionQuestion

�� Parents:Parents:

⇒⇒ Are there any other treatment options ?Are there any other treatment options ?

Epilepsy surgery Epilepsy surgery

�� LongLong--term sz outcome after epilepsy surgery term sz outcome after epilepsy surgery TéllezTéllez--Zenteno et al 2005, Brain: 128:1188Zenteno et al 2005, Brain: 128:1188--11981198

�� Systematic literature review (>= 5 years follow up, 40 Systematic literature review (>= 5 years follow up, 40

studies, children and adults)studies, children and adults)

�� Seizure free outcomeSeizure free outcome

⇒⇒Temporal lobe surgery: 66%Temporal lobe surgery: 66%

⇒⇒Temporal lobe and extra temporal surgery: 48%Temporal lobe and extra temporal surgery: 48%

Epilepsy surgery in ChildrenEpilepsy surgery in Children

Seizure outcomesSeizure outcomes

�� UK (London): UK (London): D’ArgenzioD’Argenzio et al, 2012:et al, 2012:�� n=80, 3 mn=80, 3 m--18 y, median 9.1 y18 y, median 9.1 y

�� ExtraExtra--temporal lobe epilepsy temporal lobe epilepsy

�� Follow up: 8mFollow up: 8m--10years, median 3 y10years, median 3 y

�� 50% 50% szsz freefree

�� USA (Los Angeles)Hauptman et al 2012USA (Los Angeles)Hauptman et al 2012�� n=257/338 (76%), 5 year follow up data, n=257/338 (76%), 5 year follow up data,

�� 53% continuously 53% continuously szsz free free

�� 18% late 18% late szsz recurrencerecurrence

�� 25% never 25% never szsz freefree

Epilepsy surgery Epilepsy surgery ? Worth exploring if MRI lesion negative? Worth exploring if MRI lesion negative

Téllez-Zenteno et al 2010, Epilepsy Res 89, 310-318

systematic literature review: 40 papers, 697 patients non-lesional, 2860 patients lesional >= 1 year follow up

Paediatric subgroup:

Meta analysis of extra-temporal epilepsy surgery 13 studies – adults and children – n= 350 lesional epilepsy, n=156 non lesional

Lesion present vs no lesion (MRI or pathology) ⇒ Odds of seizure freedom 2.5 higher in lesional epilepsy

(OR 2.9, 95% CI 1.6-5.1, p < 0.001)

Presurgical EvaluationPresurgical Evaluation

Identification of epileptogenic zone

→generation of focal seizures

→removal necessary for seizure freedom

Presurgical EvaluationPresurgical Evaluation

Eloquent cortex

(cortical stimulation, fMRI)

Functional deficit zone (FDG-PET)

Lesion (MRI)

Ictal onset zone

(video telemetry, SPECT)

Irritative zone

(interictal EEG)

Slide Courtesy of Ronit Pressler

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MultiMulti--modality premodality pre--surgical work upsurgical work up

�� Core investigations:Core investigations:�� Scalp video EEG (videoScalp video EEG (video--telemetry)telemetry)

�� Optimised MRIOptimised MRI

�� Neuropsychology + NeuropsychiatryNeuropsychology + Neuropsychiatry

�� Extended work up step1Extended work up step1::�� Radioisotope imaging FDGRadioisotope imaging FDG--PET, ictal SPECTPET, ictal SPECT

�� FMRI FMRI �� language, motor (eloquent cortex)language, motor (eloquent cortex)�� spike activated (spike activated (irritativeirritative zone)zone)

�� MEG MEG

�� Specialised MRI (DTI)Specialised MRI (DTI)

�� Extended work up step 2Extended work up step 2�� Invasive EEG recording Invasive EEG recording

�� Subdural grids, depth electrodesSubdural grids, depth electrodes

�� Stereo tactic EEG (stereotactic depth electrode implantation)Stereo tactic EEG (stereotactic depth electrode implantation)

Question Question

�� Is timing of referral and epilepsy surgery Is timing of referral and epilepsy surgery

important ?important ?

Full-scale IQ (FSIQ) changes from baseline to long-term follow-up (A) FSIQ distribution of the surgical group at baseline (white bars) and at long-term follow-up (black bars).

©2011 by Lippincott Williams & Wilkins

Long-term intellectual outcome after temporal lobe surgery in

childhoodSkirrow C et al. Neurology 2011;76:1330-1337

• Surgical group:

• N=42• Follow up 5-15 years

(mean 9 years)

• Seizure free 86%, off AEDs 57%

• Control group:• N=11• Underwent pre-

surgical evaluation

• At follow upseizure free 36%, off AEDs 27%

Longitudinal profile of IQ changes Preoperative to postoperative full-scale IQ

changes across time after surgery, shown for subsequent 2-year periods (positive values denote IQ gains).

Skirrow C et al. Neurology 2011;76:1330-

1337

©2011 by Lippincott Williams & Wilkins

DifficultiesDifficulties

�� Potential delay in entering prePotential delay in entering pre--surgical surgical

evaluation at time care is transitioned to adult evaluation at time care is transitioned to adult

servicesservices

�� Clear transition of care arrangements are Clear transition of care arrangements are

important important –– which service can carry out which which service can carry out which

elements of work upelements of work up

�� Joint paediatric/adult multidisciplinary team Joint paediatric/adult multidisciplinary team

meetings meetings

Question:Question:

�� Are there alternatives ?Are there alternatives ?

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Ketogenic DietHigh fat , low carbohydrates (Glucose)

Hartman et al, Ped Neurol, 2007

MCT Ketogenic Diet

Modified Atkins Diet (1:1 ratio)

Classical Ketogenic Diet 4:1 ratio (LCT)

Normal Diet

E. Neal, 2012

Dietary Treatment of Epilepsy, Wiley-Blackell

Types of the KDTypes of the KD�� Classical Diet:Classical Diet:

�� Composition of meals :Composition of meals :3:1 or 4:1 fat : (carbohydrate + protein ratio)3:1 or 4:1 fat : (carbohydrate + protein ratio)

�� 90% of total calories from fat90% of total calories from fat

�� Strict meal/snack recipes, all in correct ratioStrict meal/snack recipes, all in correct ratio

�� MCT Diet:MCT Diet:�� 4040--60% of daily calorie intake as MCT oil / MCT liquigen (overall 60% of daily calorie intake as MCT oil / MCT liquigen (overall

75% fat)75% fat)

�� Greater choice of foods Greater choice of foods –– less carbohydrate restricted (15less carbohydrate restricted (15--20% of 20% of total calories)total calories)

�� Modified Atkins Diet:Modified Atkins Diet:�� High fat, carbohydrate restricted (10High fat, carbohydrate restricted (10--30gm/d), unlimited protein30gm/d), unlimited protein

IndicationsIndications

�� Drug resistant epilepsy Drug resistant epilepsy

�� ? Poor tolerance to AEDs? Poor tolerance to AEDs

�� (Rare) metabolic disorders affecting (Rare) metabolic disorders affecting

�� transport of glucose from blood into brain transport of glucose from blood into brain

�� Glut 1 transporter deficiency syndromeGlut 1 transporter deficiency syndrome

�� Metabolism of glucoseMetabolism of glucose

�� Pyruvate dehydrogenase deficiencyPyruvate dehydrogenase deficiency

When would be the KD be When would be the KD be

contraindicated ?contraindicated ?�� Metabolic conditionsMetabolic conditions

�� BetaBeta--Fatty oxidation defects Fatty oxidation defects

�� Familial hyperlipidaemiaFamilial hyperlipidaemia

�� Organic Organic aciduriasacidurias

�� Pyruvate carboxylase deficiency (lactic acidosis)Pyruvate carboxylase deficiency (lactic acidosis)

�� Relative contraindicationsRelative contraindications

�� Feeding difficulties (food refusal)Feeding difficulties (food refusal)

�� Dysphagia (alternative feeding route: NG tube or Dysphagia (alternative feeding route: NG tube or

PEG)PEG)

�� Severe Severe gastrogastro--oesophageal reflux (frequent vomiting)oesophageal reflux (frequent vomiting)

Adverse Adverse effects?effects?

Keene D, Pediatr Neurology, 2006; 35, 1-5

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Side EffectsSide Effects

�� GastroGastro--intestianintestian symptoms (nausea, vomiting, constipation)symptoms (nausea, vomiting, constipation)

�� HypoglycamiaHypoglycamia (initiation phase)(initiation phase)

�� Excess ketosis Excess ketosis –– acidosis (initiation phase)acidosis (initiation phase)

�� PancreatitisPancreatitis

�� Renal stones (3Renal stones (3--6%)6%)�� Risk factors: young age, Risk factors: young age, hypercalciuriahypercalciuria, (, (txtx with carbonic anhydrase with carbonic anhydrase

inhibitors: inhibitors: TopiramateTopiramate, , ZonisamideZonisamide))

�� Prevention Prevention –– potassium citrate (alkalinisation of urine)potassium citrate (alkalinisation of urine)reduction from 6.7 to 0.9 % (McNally et al, reduction from 6.7 to 0.9 % (McNally et al, PediatricsPediatrics, 2009), 2009)

�� Bruising easilyBruising easily

�� Hyperlipidaemia Hyperlipidaemia

�� Weight loss, Inadequate growthWeight loss, Inadequate growth

�� Decreased bone density Decreased bone density –– fractures (Longfractures (Long--term treatment) term treatment)

�� Cardiomyopathy, cardiac arrhythmiasCardiomyopathy, cardiac arrhythmias

EfficacyEfficacyD Keene Ped Neurol 2006;35:1D Keene Ped Neurol 2006;35:1--55

�� Systematic reviewSystematic review

�� 26 studies; 14 met criteria for inclusion26 studies; 14 met criteria for inclusion

�� Total collective population N=972Total collective population N=972

�� After 6 months on the diet After 6 months on the diet

�� 16 % (CI 10 16 % (CI 10 -- 21) seizure free21) seizure free

�� 33 % (CI 2433 % (CI 24--42) >50% reduction 42) >50% reduction


Response rates – percentages based on initial sample size


Efficacy Efficacy -- longtermlongtermFreeman et al 1998, Hemingway et al 2001Freeman et al 1998, Hemingway et al 2001

Seizure improvement continued after coming off the diet

? KD disease modifying effect or

? Natural progress of epilepsy (relapsing and remitting)

�� RCT RCT �� seizure control in children (2seizure control in children (2--16 years) on the KD against 16 years) on the KD against

control group control group (delayed start on (delayed start on diet )diet )�� the classical type and MCT the classical type and MCT typetype

�� Results:Results:�� After 3 months: After 3 months:

�� significantly lower seizures in diet group than control (75% significantly lower seizures in diet group than control (75% decrease , 95%CI 42decrease , 95%CI 42--104%) 104%)

�� > 50% > 50% szsz reduction 38% diet group reduction 38% diet group vsvs 6% in control (p < 6% in control (p < 0.0001)0.0001)

�� MCT and classical diet comparable in efficiency and MCT and classical diet comparable in efficiency and tolerability (Neal et al, Epilepsia 50 (5): 1109tolerability (Neal et al, Epilepsia 50 (5): 1109--1117, 2009)1117, 2009)

Lancet Neurology, 2008;7(6): pp 500-506

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Mechanisms Mechanisms –– hypotheseshypothesesBough &Rho Epilepsia 48 (1):43Bough &Rho Epilepsia 48 (1):43--58, 200758, 2007

Rho & Stafstrom Epilepsy Research 2011Rho & Stafstrom Epilepsy Research 2011

�� AntiAnti--epileptic effect not only mediated by epileptic effect not only mediated by

ketone bodies ketone bodies –– but by adaptive metabolic but by adaptive metabolic

processes induced by ketosisprocesses induced by ketosis

�� Effects mediated by polyunsaturated fatty acidsEffects mediated by polyunsaturated fatty acids

�� Ketosis induces shifts in brain amino acid Ketosis induces shifts in brain amino acid

handling favouring GABA productionhandling favouring GABA production

�� Suppression of seizures mediated by adenosine Suppression of seizures mediated by adenosine

acting on adenosine A1 receptorsacting on adenosine A1 receptors

NeuroprotectiveNeuroprotective effects of KD effects of KD MaaloufMaalouf et al 2009 , Brain Research Reviewset al 2009 , Brain Research Reviews

�� Improvement of Improvement of mitochondrial functionmitochondrial function

�� Decrease of reactive oxygen Decrease of reactive oxygen species species –– reduction of reduction of oxidative stressoxidative stress

�� Increased ATP productionIncreased ATP production

�� Inhibition of apoptosisInhibition of apoptosis

�� AntiAnti--inflammatory effectsinflammatory effects

Potential role of KD

following brain trauma and

in neurodegenerative

conditions

Efficacy MADEfficacy MAD

�� Miranda et al, Miranda et al, Seizure 20:151Seizure 20:151--155, 2011155, 2011

�� Prospective, n=33, 1.1 Prospective, n=33, 1.1 --15.6 y (mean 8 y) 15.6 y (mean 8 y)

Efficacy MADEfficacy MAD

�� Chen, Chen, KossoffKossoff; ; J Child J Child NeurolNeurol 2012, 27(6):7542012, 27(6):754--758758

�� follow up data on 56/87 patientsfollow up data on 56/87 patients

54 on MAD > 6 months (mean age 8.1 y, SD 4.2)54 on MAD > 6 months (mean age 8.1 y, SD 4.2)

34/87 (39%) on MAD at 12 months34/87 (39%) on MAD at 12 months

�� At 6 months (n=54)At 6 months (n=54)

�� 36 (64%) > 50% 36 (64%) > 50% szsz reduction, reduction, inclincl 24 (43%) > 90 24 (43%) > 90 reductionreduction

�� 12 months (n=35)12 months (n=35)

�� 28 (50%) > 50% 28 (50%) > 50% szsz reduction, reduction, inclincl 22 (44%) > 90 22 (44%) > 90 szszreductionreduction

KD in adolescents/adultsKD in adolescents/adults

�� Lack of data in the literatureLack of data in the literature

�� High attrition rate in some studiesHigh attrition rate in some studies

�� Open label studies suggestive of response in Open label studies suggestive of response in proportion of patients proportion of patients

�� Lack of service provision in adult servicesLack of service provision in adult servicespossible exception Glut1 transporter possible exception Glut1 transporter defciencydefciency

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VNS Therapy VNS Therapy

�� Pulse generator device is Pulse generator device is implanted surgically in the left implanted surgically in the left chest/axillachest/axilla

�� Electrodes are tunneled Electrodes are tunneled beneath the skin from the beneath the skin from the

pulse generator to the left pulse generator to the left vagus nerve in the neck.vagus nerve in the neck.

�� The vagus nerve is stimulated The vagus nerve is stimulated periodically at the site of the periodically at the site of the

neck. neck.

�� Surgical scars left axilla and Surgical scars left axilla and

left neckleft neck

VNS Therapy: the componentsVNS Therapy: the components

LeadPulse generator

Electrodes

Slide courtesy of Sophia Varadkar

Programming System Components Programming System Components

Handheld Computer

• Platform for Programming

Software

Programming Wand

• Accessory to programming

handheld computer

• Communication tool between

Programming Software and

Pulse Generator


Vagus Nerve Stimulation Vagus Nerve Stimulation

TherapyTherapy�� NonNon--pharmacological pharmacological

therapy for epilepsytherapy for epilepsy

�� Repeated Repeated electricalelectrical

stimulation of the left stimulation of the left

vagus nerve by the pvagus nerve by the pulse ulse

generator devicegenerator device

�� 3 areas of benefit for 3 areas of benefit for

seizuresseizures

�� Acute abortiveAcute abortive

�� Acute prophylacticAcute prophylactic

�� Chronic progressiveChronic progressive

�� Other benefits?Other benefits?

�� Quality of lifeQuality of life

�� Mood, behaviour, Mood, behaviour, alertness, memory, schoolalertness, memory, school

Potential mechanisms of actionPotential mechanisms of action

�� Animal modelsAnimal models

�� Early neurophysiological studies indicated Early neurophysiological studies indicated

desynchronisation in catsdesynchronisation in cats

�� Locus Locus coeruleuscoeruleus mediates antimediates anti--seizure effect of VNSseizure effect of VNS

�� Human studiesHuman studies

�� Changes in cerebral blood flow; Changes in cerebral blood flow;

�� Changes in CSF neurotransmittersChanges in CSF neurotransmitters


UCL - Institute of Child Health

Average VNS Therapy Response:Real-World 1

1. De Herdt V, et al. Eur J Paediatr Neurol 2007;11:261-9. 2. Labar DR. Seizure 2004;13:392-8.

3. Renfroe JB and Wheless JW. Neurology 2002;59(suppl 4):S26-S30. 4. Vonck K, et al. J

Clin Neurophysiol 2004;21:283-9. 5. Elliot RE et al.Epilepsia BeBehavior 2011: 20(1):57-63

Post-approval Responder Rate

% P

ati

en

ts


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VNS Effectiveness Over Time

Morris GL, Mueller WM. Neurology. 1999;53(7):1731-1735.



VNS Therapy Seizure-Free Rates

1. Renfroe JB and Wheless JW. Neurology 2002;59(suppl 4):S26-S30. 2. Helmers SL, et al. Neurologist

2003;9:160-4. 3. De Herdt V, et al. Eur J Paediatr Neurol 2007;11:261-9. 4. Amar AP, et al. Neurosurgery2004;55:1086-93. 5. Labar DR, et al. Neurology 2002;59:S38-43. 6. Labar DR. Seizure 2004;13:392-8. 7. Amar

AP, et al. Stereotact Funct Neurosurg 1999;73:104-8. 8.Ghaemi K et al. Seizure,2010;19:264-268(6.9%).


EfficacyEfficacy

�� MetaMeta--analysis: analysis: EnglotEnglot et al et al J J NeurosurgNeurosurg 20112011

�� 74 clinical studies, 3321 patients,74 clinical studies, 3321 patients,

�� inclincl 3 blinded RCT , 2 non blinded RCT, 10 prospective 3 blinded RCT , 2 non blinded RCT, 10 prospective studiesstudies

�� > 1 year after implant 51% > 1 year after implant 51% szsz reduction, at last follow up reduction, at last follow up seizure reduction of at least 50% in 50%seizure reduction of at least 50% in 50%

�� Predictors of favorable outcome Predictors of favorable outcome -- post traumatic epilepsy and post traumatic epilepsy and TS TS

VNS in ChildrenVNS in Children

�� Elliot et al 2011Elliot et al 2011J Neurosurg PediatricsJ Neurosurg Pediatrics

�� N =141, mean follow up 5.3 years (25 daysN =141, mean follow up 5.3 years (25 days--11.4 11.4

years)years)

�� Mean reduction of sz 59%, > 50 sz reduction in Mean reduction of sz 59%, > 50 sz reduction in

64%64%

Consider VNS Therapy ifConsider VNS Therapy if

�� drug resistant epilepsy and drug resistant epilepsy and resectiveresective surgery not surgery not

an optionan option

�� multifocal seizuresmultifocal seizures

�� generalised seizures in epilepsy with bilateral generalised seizures in epilepsy with bilateral

structural/ metabolic or genetic aetiologystructural/ metabolic or genetic aetiology

�� idiopathic generalised epilepsies idiopathic generalised epilepsies

Deep Brain Stimulation

(Not evaluated in children !)

� SANTE study, Fisher et al Epilepsia 2010

� Bilateral anterior thalamic nucleus stimulation for

medically refractory epilepsy in adults

� 3 months blinded phase stimulation vs no stimulation,

followed by unblended phase

� At end of 3 months blinded phase median sz reduction

control group 14 % vs 40 % in stimulated group, by 2 years

56% reduction in sz frequency,

� Adverse events: 5 haemorrhages (incidentally identified), 2

transient stimulation related sz exacerbations, depression

and memory problems

19/07/2013

12

Trigeminal Nerve StimulationTrigeminal Nerve StimulationDDeGiorgioeGiorgio et al Neurology 2013et al Neurology 2013

�� DoubleDouble--blind randomised blind randomised active control trialactive control trial

�� n=50 (adults)n=50 (adults)

�� High stimulation (120Hz) High stimulation (120Hz) vsvs low stimulation (2 Hz)low stimulation (2 Hz)

�� Baseline 6 weeks, Baseline 6 weeks, evaluation at 6,12, 18 evaluation at 6,12, 18 weeksweeks

�� At 18 weeks : At 18 weeks : �� > 50% > 50% szsz reductionreduction

�� 30% 30% txtx group group vsvs 21% 21% control (p=0.31)control (p=0.31)

Applied for a minimum of 12 hours

per day

Trigeminal Nerve StimulationTrigeminal Nerve StimulationDeGiorgioDeGiorgio et al, Neurology 2013et al, Neurology 2013

Potential role: response to peripheral nerve neurostimulation

prior to implantation of VNS device

ConclusionConclusion

�� Intractability Intractability –– can be difficult to recognisecan be difficult to recognise

(relapsing and remitting course)(relapsing and remitting course)

�� Consider nonConsider non--pharmacological treatment pharmacological treatment

options early in the course and set goals options early in the course and set goals

appropriatelyappropriately

�� Clear transition of care arrangements are Clear transition of care arrangements are

important important to avoid delays in provision of care to avoid delays in provision of care

and negative impact on outcomesand negative impact on outcomes

Documents

Aims of workshop · initially every 2--3 months, than 13 months, than 1--2 seizures/month2 seizures/month Unable to attend school for 2--3 days following sei3 days following seizure