Neurostimulation in epilepsy

Some (provocative) thoughts

P. Kahane, MD, PhDNeurology Department & GIN INSERM U1216, Grenoble

LYON, MAY 26-28, 2019

EpilepsyEurope - 740 M ha

Forsgren et al. 2005

Prevalence : 4.5-7 / 1000

Incidence : 30-100 / 100000

DR Epilepsy : 30%

Kwan & Brodie 2000

Surgery candidates : 12.5-25%

Jallon 2004

75-225,000

DR Focal Epilepsy : 60% 0.6-0.9 M

The spectrum of drug-resistant epilepsy

1-1.5 M Alternative

treatments

NS of remote control systems NS of seizure generators

Neurostimulation in epilepsy

Outline

o DBS : (every) where ?

o CS : an efficient paradox ?

o DBS, CS or VNS : are they similar ?

o Back to non invasive methods ?

Outline

o DBS : (every) where ?

o CS : an efficient paradox ?

o DBS, CS or VNS : are they similar ?

o Back to non invasive methods ?

Cooper IS. Effect of chronic stimulation of anterior cerebellum on

neurological disease. Lancet. 1973 Jan 27; 1(7796): 206.

Cooper IS. Effect of stimulation of posterior cerebellum on

neurological disease. Lancet. 1973 Jun 9; 1(7815): 1321.

Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar

stimulation upon epilepsy in man. Trans Am Neurol Assoc.

1973;98:192-6.

In search of a magic target...

Target

Cerebellum

CM

AN

Authors

Van Buren (1978)

Wright (1984)

Velasco (2005)

Fischer (1992)

Velasco (2000)

Fisher (2010)

Study protocol

Double-blind crossover (6-19 mo)

Double-blind crossover (6 mo)

Double-blind crossover (24 mo)

Double-blind crossover (9 mo)

Double-blind crossover (>12 mo)

Double-blind randomized (>13 mo)

Outcome

No improvement

No improvement

> 50% Sz reduction in 80% of pts

> 50% Sz reduction in 3/6 pts

(open-label phase)

> 50% Sz reduction in 90% of pts

40.4% median sz reduction

n°

5

12

5

7

13

110

From Al-Otaibi et al. Neurosurgery 2011

A few controlled studies

Fisher et al. Epilepsia 2010

N=110

100Hz AT stimulation increases 2,5 fold the number of

chronic seizures in kainate-treated rats (Lado et al. 2006)

?

From baseline to 25 months of stimulation

Fisher et al. Epilepsia 2010

Salanova et al. Neurology 2015

5 yrs F-up

Bien et al. 2009

Epilepsy is not Parkinson’s disease

LF-LC

LC-LP

12

3

STN 1

STN 2

STN 3

Subthalamic nucleus (Chabardès et al. 2002)

Pulvinar nucleus (Guye et al. 2006)

Seizures may invade many subcortical circuits

P47. Pizzo et al. The role of subcortical structures during

seizures: evidence from SEEG recordings

12th International Epilepsy Colloquium, Lyon, May 26-28, 2019

Stimulation parameters are empirical

Al-Otaibi et al. Neurosurgery 2011

The best candidates are not known

Target

Cerebellum 1

AN Thal 2-6

CM Thal 7,8

STN/SNR 9-15

(1) Velasco et al. 2005; (2) Hodaie et al. 2002; (3) Kerrigan et al. 2004; (4) Lim et al. 2007; (5) Osorio et al. 2007; (6)

Fisher et al. 2010; (7) Velasco et al. 1993, 1995, 2001, 2002, 2006; (8) Cukiert et al. 2009; (9) Alaraj et al. 2001; (10)

Loddenkember et al. 2001; (11) Neme et al. 2001; (12) Chabardès et al. 2002; (13) Shon et al. 2005; (14) Vesper et

al. 2007; (15) STIMEP study in prep;

Pts N

4

93

13

18

Best indication

tonic / tonic-clonic seizures ?

limbic seizures ?

LGS (GTCS – atypical A) ?

central seizures ?

Outline

o DBS : (every) where ?

o CS : an efficient paradox ?

o DBS, CS or VNS : are they similar ?

o Back to non invasive methods ?

2016; 127(1): 31-39

2 pilot studies :

Velasco et al. Epilepsia 2000.

7 / 10 patients :

abolishment of clinical seizures

reduction of interictal spikes

Vonck et al. Ann Neurol 2002.

3 patients : 50-90% sz reduction

2 controlled studies :

contradictory results

Continuous stimulation of the hippocampus

Continuous stimulation of the hippocampus

Tellez-Zenteno et al. Neurology 2006; 66: 1490-1494.

• 4 patients

• double blind, multiple cross-over, randomized treatment

• mean reduction in seizures of 15% (ns)

• no adverse events

Velasco et al. Epilepsia 2007; 48: 1895-1903

• 9 patients

• double blind multiple cross-over, randomized treatment

• MRI- group (n=5): reduction in seizures of > 95%

• HcS group (n=4): reduction in seizures of 50-70%

• no neuropsychological deterioration

Is the hippocampus the best target ?

Responsive stimulation

Nagel & Najm 2009

Morrell et al. Neurology 2011

Heck et al. Epilepsia 2014

The ictal generator is rarely focal

Tem

po

ral

neo

cx

Fz-Cz

EKG

TpNAECaHcpHcPHcGFG

Insu

la

FbiFbe

CopPopT-PPCG

We only see what we look at

Cortical stimulation has a widely extended effect

O. David - ERC F-TRACT

Feddersen et al. 2007 Saillet et al. 2012

P42. Hajnal et al. The neocortical neural correlates of electrically

evoked cortical potential un humans

12th International Epilepsy Colloquium, Lyon, May 26-28, 2019

N1-P2 amplitude of evoked potential detected

Sum of single unit activity from all channels of multielectrodes

Outline

o DBS : (every) where ?

o CS : an efficient paradox ?

o DBS, CS or VNS : are they similar ?

o Back to non invasive methods ?

VNS

Wheeless 2002

VNS

VNS

From Schulze-Bonhage. Seizure 2017

DBS vs RNS

From Schulze-Bonhage. Seizure 2017

Rolston et al. Neurosurg Focus 2012; 32(3): 14

The 50%-50% rule ?

VNS vs DBS vs RNS

May 2, 2019 : end of inclusions (n=62)

PI : S. Chabardès

VA DBS in patients whom VNS failed

Outline

o DBS : (every) where ?

o CS : an efficient paradox ?

o DBS, CS or VNS : are they similar ?

o Back to non invasive methods ?

Transcutaneous stimulation of the cranial nerves

Transcutaneous trigeminal nerve stimulation (tTNS) Transcutaneous vagus nerve stimulation (tVNS)

Transcutaneous stimulation of the cranial nerves

5 uncontrolled studies 1-5

1 phase II randomized trial 6

responders rate: 30.2% vs 21.1% (ns)

Long-term outcome 7

(1) DeGiorgio et al. 2003; (2) DeGiorgio et al. 2006; (2) DeGiorgio et al. 2009; (4) Pop et al. 2011; (5) Zare et

al. 2014; (6) DeGiorgio et al. 2013; (7) Soss et al. 2015 .

Transcutaneous stimulation of the cranial nerves

2 pilot studies

Stephan et al. 2012 : Adults (n=12)

He et al. 2014 : Children (n=14)

1 randomized controlled trial

Rong et al. 2014 : at 8 weeks :

Sz by 42.6% in tVNS group (n=98)

Sz by 11.5% in sham group (n=46)

p<0.05

Transcutaneous stimulation of the cranial nerves

From Schulze-Bonhage. Seizure 2017

Effects on median seizure rate

Repetitive transcranial magnetic stimulation (rTMS)

38.6% sz reduction in 8/9 patients 1

3 controlled studies

- 2 proved negative 2,3

- 1 proved positive (MCD) 4

Uncontrolled studies & case reports 5

- more efficient if neocortical lesion

- frequent reduction of IEDs

(1) Tergau et al. 1999; (2) Theodore et al. 2002; (3) Cantello et al. 2007; (4) Fregni et al. 2006; (5) Nitsche &

Paulus 2009.

Cathode

+

Anode -

Cathode +

Anode

-

Anodal

stimulation

Excitatory

Effect

Cathodal

Stimulation

Inhibitory

effect

Transcranial direct current stimulation (tDCS)

19 patients with MCDs 1

tDCS IEDs seizures

Active - 64.3%* - 44%** *p<0.01, **p=0.06

Sham - 5.8% - 11.1%

Case report tDCS (11yr, MCD) 2

Dramatic seizure reduction

Controlled, tDCS for CSWS 3

N = 5 - No effect

(1) Fregni et al. 2006; (2) Yook et al. 2011; (3) Varga et al. 2011.

Transcranial direct current stimulation (tDCS)

Don’t loose your head over tDCS

Buzsaki 2016

65 papers, including only 10 original clinical studies and 147 patients.

5 sham-controlled studies with crossover or parallel-arm design included 12–37 patients

(Fregni et al., 2006; Auvichayapat et al., 2013; Liu et al., 2016; San-Juan et al., 2016; Tekturk et al., 2016).

-> No recommendation for cathodal tDCS of the epileptic focus or anodal tDCS of the L DLPFC

Placebo-controlled, double-blinded, 3 arms of tDCS

* Mean reduction of SZ frequency at 2 months in both active groups

significantly higher than placebo (−48% vs. −6.25%, p < 0.008).

p = 0.001

p = 0.001

3 sessions (n=12)

5 sessions (n=8)

Placebo (n=8)

tDCS in mTLE with HS (San Juan et al. 2017)

Conclusion

Non invasive

Neocx – MCD

rTMS / tDCS

Other

tVNS

Invasive

Clear

‘Focus’

RNS

Limbic

VA-DBS

Other

VNS

Bien et al. 2009

«A surprisingly large number of patients we surveyed, with

refractory partial epilepsy not eligible for surgical

management, reported reduced seizure frequency at follow-up,

and 21% were seizure free. Our findings suggest that the long-

term prognosis in patients with refractory partial epilepsy who

are not surgical candidates may be more positive than might

be generally expected».

Epilepsia 2003; 44: 1568-1572.

After becoming intractable, 20.5% subsequently entered remission

and 13.3% were seizure free at last contact.