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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.