NEUROMODULATION IN EPILEPSY - ochsner … · pathways to the cortex • Hypothalamic hamartomas with gelasticseizures • Intracranial recordings of cerebellar dysplastic lesions

NEUROMODULATION IN EPILEPSY

Colin Van Hook, M.D., M.P.H.

Ochsner Medical Center

Department of Neurology

International Center for Epilepsy

WHAT IS NEUROMODULATION???

• “The alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body.” INS definition

• Chronic pain

• Movement disorders

• Psychiatric disorders

• Stroke/Brain injury

• Cardiovascular disease

• Gastrointestinal disease

• Genitourinary or colorectal disorders

• Epilepsy

NEUROMODULATION IN EPILEPSY: WHEN TO CONSIDER IT

• Medically Refractory: In an analysis of 1,098 patients

with newly diagnosed epilepsy at a one center between

1982 and 2006 (Brodie 2012)

• 49% became seizure free on the first medication tried

• 13% became seizure free on the second medication tried

• 3.7% became seizure free on the third medication tried

• 1/3 of patients remain medically refractory

NEUROMODULATION IN EPILEPSY: WHEN TO CONSIDER IT

• Non-Surgical candidates

• Primary generalized epilepsy

• Multiple seizure foci

NEUROMODULATION IN EPILEPSY

• VAGAL NERVE STIMULATOR (VNS)

• RESPONSIVE NEUROSTIMULATOR (RNS/NEUROPACE)

• DEEP BRAIN STIMULATION (DBS)

VAGUS NERVE ANATOMY

• CN X (VAGUS NERVE)

• Exits jugular foramen with CN IX and CN XI then travels in the

carotid sheath with the common carotid artery and the internal

jugular vein

• AFFERENT FIBERS = 80%

• Solitary Nucleus and Spinal Trigeminal Nucleus

• EFFERENT FIBERS = 20%

• Originate in Dorsal Motor Nucleus and Nucleus Ambiguus

• Parasympathetic fibers to the viscera

• Right CNX provides significantly more innervation to heart

compared to left (this is why VNS placed usually on left CN X)

VAGUS NERVE ANATOMY

• Projects to Nucleus Tractus Solitarius

BILATERALLY (Henry, Neurology 2002)

VAGUS NERVE PROJECTIONS

• Vagus nerve works through Nucleus Tractus Solitarus(NTS)

and Pontine Parabrahcial Nucleus (PBN)

• Limbic

• Amygdala: implicated in temporal lobe epilepsy

• Insula: connections to orbitofrontal cortex

• Autonomic

• Connections to hypothalamus and periaqueductal gray (PAG)

• Reticular structures

• Thalamus

Henry 2002.

VAGUS NERVE AND SEIZURES

• 1938 (Bailey and Bremer)

• Stimulation of vagus nerve produced EEG changes in cats

• 1952 (Zanchetti)

• Intermittent vagal nerve stimulation decreased or eliminated chemically induced focal epileptiform discharges

• 1960s

• Repetitive stimulation of vagus nerve led to synchronize or desynchronize cortical electrical activity

• Seizures caused by hypersynchronized cortical activity thus VNS could desynchronize

• 1985 (Zabara)

• Hypothesized that VNS antagonizes hypersynchronous states using animal studies

VAGUS NERVE AND THE CORTEX

• 3HZ spike-wave initiated in thalamus and propagated via

pathways to the cortex

• Hypothalamic hamartomas with gelastic seizures

• Intracranial recordings of cerebellar dysplastic lesions

show discharges originating in that structure

• In several cases of frontal lobe epilepsy, seizures

continued following cortical resection with subsequent

seizure freedom following resection of deep structures

with electrographic discharges originating in the striatum.

VNS: CLINICAL EVIDENCE

Design # patients

radomized

Seizure type Results

E01/2 (1988-1992) Single-blinded 14 Partial 28% reduction in seizure frequency

E03 (1990-1992) Randomized

double-blind

active control

114 Partial Mean 24.5% reduction in frequency

with 31% having >50% reduction

E04 (1991-1995) Open label,

non-blinded

116 Partial or

generalized

Mean 21.5% reduction in frequency

with 29.3% having >50% reduction

E05 (1995-1996) Randomized

double-blind

active control

199 Partial Mean 27.9% reduction in frequency

with 23.4% having >50% reduction

VNS CLINICAL EVIDENCE

• Reduction of seizure frequency > 50% (Morris and Mueller, Neurology 1999)

• 1 year = 36.8% patients

• 2 years = 43.2% patients

• 3 years = 42.7% patients

• Well tolerated

• 75% patients continued therapy

• There is a persistent VNS‐induced anticonvulsant effect and indicate that its

efficacy is dependent on the cumulative stimulus duration (Takaya, Epilepsia 1996).

VNS APPROVAL

• In 1997, the FDA approved the VNS Therapy System for use as an adjunctive therapy in

reducing the frequency of seizures in adults and adolescents over 12 years of age with

partial onset seizures refractory to antiepileptic medications

• In 2017, device was FDA approved for children as young as 4 due after data from Japan

Post‐Approval Study (PAS) in which followed patients implanted between 2010 and

2012.

• As of 2017, >100,000 patients treated with VNS

VNS IN GENERALIZED EPILEPSY

• Labar (Neurology 1999) showed >50% reduction in 11 of 24 patients with medically resistant IGE

• Ng and Devinsky (Seizure 2004) compared seizure frequency reduced by > 50% in partial vs. symptomatic

generalized vs. idiopathic generalized

• Partial (PE)= 47.1% patients (N=138)

• Symptomatic generalized (SGE)= 46.1% patients (N=13)

• Idiopathic generalized (IGE) = 57.1% patients (N=14)

• Furthermore, higher proportion of patients with IGEable to achieve 50% or greater

reduction in seizure frequency and reduced antiepileptic drug

• Partial = 9.4%

• Symptomatic generalized = 7.7%

• Idiopathic generalized = 35.7

VNS AND DEPRESSION

• Reduction in depression scores was noted in E03/5 and two subsequent studies (Harden 2000 and

Elger 2000) showed trend to depression reduction was INDEPENDENT of seizure reduction

• One year trial of VNS for patients with depression (n=185) or bipolar I/II (n=20) refractory to at

least 2 medications showed a significant reduction in symptoms on the 24 item Hamilton Rating

Scale for Depression. (Rush 2005)

• Five year open-label, non-randomized trial of patients with treatment resistant depression showed

reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with VNS (n=494)

versus treatment as usual (n=301). (Aaronson 2017)

• In 2005 FDA approved VNS for adjunct treatment in depression but coverage denied by US

Committee on Medicare and Medicaid Services

VNS AND QUALITY OF LIFE

• PuLsE (Open Prospective Randomized Long-term Effectiveness) trial showed

significant improvement in Quality of Life in Epilepsy Inventory-89 total score

(QOLIE-89) in 61 patients with VNS versus 61 patient with medical therapy only

(Ryvlin 2017)

• VNS patients with autism showed improved alertness, verbal communication,

memory, and school performance (Levy 2010)

VNS OPERATIONS

• Battery powered device

• Leads placed in carotid sheath around left

vagus nerve and connected to

subcutaneous programmable pacemaker

• Typical battery life is 5-10 years based on

settings

VNS OPERATIONS

Pulse width

Signal frequency

Output current Amount of electrical current delivered in a single pulse of

stimulation

Signal frequency Number of pulses per second (measured in Hz)

Pulse width Duration of a single pulse within a stimulation period

VNS OPERATIONS

Parameter Units Range Typical

Output current milliamps 0–3.5 1.25

Signal frequency hertz 1–30 20-30

Pulse width microseconds 130–1000 250-500

ON time seconds 7–60 30

OFF time minutes 0.2–180 5

Magnet Settings

Output current milliamps 0–3.5 1.50

Pulse width microseconds 130–1000 500

ON time seconds 7–60 60

VNS OPERATIONS: CYCLING AND DUTY CYCLE

• Initial settings typically:

• Output current 0.25mA

• Signal frequency 30Hz

• Pulse Width 250-500 microseconds

• “On” 30 seconds

• “Off” 5 minutes

• Several small studies do not support increased efficacy for “Rapid Cycling” typically connotating 7 seconds “on” and 30 seconds “off”

• Not recommended as this will wear down battery faster

• Duty cycle should be <50%

ON time + 4 seconds

ON time + OFF time

VNS MAGNET

• Patient or other swipes magnet on generator for 1 second

which gives additional current/stimulation to stop or

shorten seizure

• Morris. Epilepsy and Behavior 2003.

• Patients in E03 trial with active magnets were more likely to

report improved seizure control than patients with inactive

magnets

• In the E04 trial, 22% of patients using the magnet reported

seizure termination and 31% reported seizure diminution

• Magnet output current should always be higher (usually

0.25mA higher) than parameter output

VNS SAFETY

• Side Effects

• Data from E0S trials

• Voice alteration/hoarseness 66.3 %

• Cough 45.3%

• Pharyngitis 34.7%

• Dyspnea 24.2%

• Most resolved after 1-2 years of continued treatment

• Mild increase in hypopnea and apnea in patients with OSA, may unmask latent OSA

(Marzed, Edwards, Sagher. Epilepsia 2003)

VNS: MANAGING SIDE EFFECTS

• Reduce pulse width from 500 to 250

• Reduce frequency from 30 to 20

• TAPE MAGNET OVER DEVICE TO AVOID VOICE CHANGE

VNS AND MRI

• Safe for brain, lumbar spine, and extremities!

• NOT SAFE for cervical and thoracic spine

• PRIOR to MRI reprogram

• Output current = 0.0

• Magnet current = 0.0

• Autostimulation = 0.0

• AFTER imaging

• Reset to previous parameters

• Perform diagnostic, should show IMPEDENCE = OK

TRANSCUTANEOUS VNS (T-VNS)

• Stimulation applied to auricular branch of CNX at

the tragus

• 5 of 7 patients showed a reduction in seizure

frequency at 9 months (Stefan 2012)

• Randomized, double-blind controlled trial

(cMPsE02) showed no statistical difference in

change in seizure frequency between high and

low stimulation groups at 20 weeks (Bauer 2016).

• NEMOS system is approved in Europe

• LOW THRESHOLD FOR APPROVAL – EFFICACY

NOT NEEDED

PRO

• Option for anyone who is not a candidate for resection

• No cognitive side effects

• Compliance is not an issue

• Improved quality of life

• More alertness

• Less daytime sleepiness

• Improved memory

• Improved mood

• Provides patient/family with sense of control

• Safe in pregnancy

• Surgery required

• Battery replacement 5-10 years

• Still need AEDs

• Rarely seizure-freedom (5%)

• What are best settings?

CON

VNS: WHO TO CONSIDER?

OPEN LOOP STIMULATION:

VNS OR DBS

CLOSED LOOP NEUROSTIMULATION:

RNS

RESPONSIVE NEUROSTIMULTION: AN ALTERNATE APPROACH

CORTICAL STIMULATION

• In the 1950’s Penfield and Jasper noted that cortical

stimulation could disrupt epileptiform activity and lead to

suppression of both normal and epileptiform activity at

distant sites.

• Cooper (1978) noted that closed loop stimulation of the

cerebellum could reduce seizures

• Kinoshita et al (2004, 2005) noted reduction in interictal

spikes in high versus low open-loop stimulation in

patients undergoing intracranial monitoring and

functional mapping.

RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE)


• Allows for significant amounts of electorcortography (ECoG) recording based

on several triggers

• Scheduled storage (up to 4)

• Magnet swipes by the patient

• Long episode: specified duration of time meeting detection parameters

• Saturation: when ECoG amplitude exceeds a designated threshold


• Multi-center, double-blind, randomized controlled trial (Morrell 2011)

• 191 patients with partial onset seizures with ≥3 seizures per month

despite ≥2 medications trials were implanted with RNS after 12

week baseline period between 2005 and 2008

• Patients were randomized 1:1 for stimulation versus sham with

blinded physician gathering outcome data and medications held the

same during 12 week evaluation period


• Mean seizure frequency remained reduced in

stimulation(41.3%) versus sham (9.4%) at three months

(p=0.012)

• 29% of treatment group showed ≥50% reduction in

frequency at the end of the blinded period with increase

to 46% at two years post implant

• 7% were seizure free for the most recent three months at

the end of the 2 year evaluation period.

• Serious adverse events occurred at 12%, less than 15%

noted in patients with intracranial electrode placement for

epilepsy surgery

• In 2013, the FDA approved RNS for the treatment of

medically-refractory partial onset epilepsy


• In an open-label follow, 191 patients were followed for an average of 5.4 years and showed a sustained response rate (≥50% reduction) of >60% at six years post-implant

• Serious adverse events were rare following immediate implantation period.

• Improvement in QUOLIE scores was sustained through year 4 on follow up (p=0.001)

IMPLICATIONS OF LONG TERM RECORDING IN RNS

• In initial RNS trial, 82 patients with bilateral mesial temporal

lobe RNS electrode placement (King-Stephens 2015).

• 71 were presumed to have seizure foci bilaterally based on EEG

• 11 had suspicion of involvement of contralateral temporal lobe

with other diagnostic modality (i.e. bilateral MTS)

• 16% had only unilateral seizures after 4.6 years

• 32% had first contralateral seizure after more than 4 weeks

post-implant

• Of 71 subjects presumed to have bilateral onset, 9 had only

unilateral onset after 5 years.

DEEP BRAIN STIMULATION

• Open loop stimulation (similar to VNS)

• Cerebellum has been studied due to theory that

stimulation of Purkinje cells could intensify inhibitory

output to the thalamus

• Hippocampal stimulation has shown promising

results in small trials

• Centramedian thalamic nucleus stimulation has

shown some effect in generalized epilepsies

• Anterior Thalamic Nucleus with extensive

connections through the limbic system has

shown the most benefit

Lin, Epilepsia 2017

DBS FOR EPILEPSY: SANTE TRIAL

• Multicenter, randomized, double blind study of 110

patients with partial onset seizure (Fisher 2010)

• Patients were followed for a 3 month blinded period

followed by a 2 year open label period


• By the end of the blinded period, there was a

seizure reduction rate of 14.5% in the control

group versus 40.4% in the stimulation group

(p=0.0017)

• No statistically significant change in 50% responder

rates or QUOLIE during blinded phase


• In patients followed long term, median reduction in

seizure frequency was

• 41% at 13 months (n=99),

• 56% at 25 months (n=81),

• 67% at 37 months (n=42).

• 50% responder rate was 54% at 2 years

• QUOLIE score improved significantly at 13 and 25

months (p<0.001)

• No clinical hemorrhages associated with with device


• Salanova (2015): at five years

• Median reduction in seizure frequency increased to

69%

• 50% responder rate increased to 68%

• 16% (17 of 109 patients) reported seizure freedom of at

least the prior 6 months

• Improvements in QUOLIE remained statistically

significant

• Half of patients required battery replacement at 35

months

DBS FOR EPILEPSY

• In 2010, CE (Conformité Européenne) Mark approved DBS of the anterior

thalamic nucleus for treatment of medically refractory partial onset seizures in

Europe.

• In April 2018 the FDA approved DBS of the anterior thalamic nucleus for

treatment of medically refractory partial onset seizures in the United States

EXTERNAL TRIGEMINAL NERVE STIMULATION (E-TNS)

• In 50 patients randomized to control or stimulation, there was a

significant drop in seizure frequency in the stimulation group during a

3 month blinded period (p=0.01) but no difference between groups

p=0.078).

• Follow-up open label period of 35 patients showed sustained reduction in

seizure frequency (Soss 2015)

• NeuroSigma eTNS began multicenter, Phase 3 trial for partial seizures

beginning in 2014

• Approved in Europe ,Canada, Australia for epilepsy, depression,

ADHD

REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (R-TMS)

• FDA approved for depression 2008, headache 2013,

OCD in 2018

• Magnetic field stimulates a small area of cortex

causing depolarization of nearby axons

• Each pulse arrives during late inhibitory phase of last

causing decreased cortical excitability (Reithler 2011)

• 60 patients with partial onset seizures randomized to

either 90% or 20% of resting motor threshold (rMT)

daily for 2 weeks (Sun 2012)

• High stimulation group showed an 80% reduction in

seizure frequency (p<0.01) in comparison to baseline

versus 2.3% in low stimulation group which was

maintained over 10 weeks

• There was significant reduction in the number of

epileptiform discharges on EEG before and after

treatment in the high stimulation group only

TRANSCRANIAL DIRECT CURRENT STIMULATION (T-DCS)

• tDCS hypothesized to change resting membrane potential by influencing

ion concentrations, transmembrane proteins, and synaptic function to

altering cortical excitability

• 28 patients with mesial temporal lobe epilepsy randomized to placebo

stimulation or to 2mA tDCS for either 3 days, or 5 days with TCD 1ch

Stimulator (San-Juan 2017)

• There was a significant reduction in mean in seizure frequency between both

treatment groups and placebo stimulation at 2 months post-treatment (p=0.0001)

• 5 min showed 54.6% reduction

• 3 min showed 43.4% reduction

• Placebo showed 62.5% reduction

THE END!!!

NEUROMODULATION IN EPILEPSY - ochsner … · pathways to the cortex • Hypothalamic hamartomas with gelasticseizures • Intracranial recordings of cerebellar dysplastic lesions

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