neurostimulation in epilepsy some (provocative) thoughts · lc-lp 1 2 3 stn 1 stn 2 stn 3...
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Neurostimulation in epilepsy
Some (provocative) thoughts
P. Kahane, MD, PhDNeurology Department & GIN INSERM U1216, Grenoble
LYON, MAY 26-28, 2019
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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
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NS of remote control systems NS of seizure generators
Neurostimulation in epilepsy
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Outline
o DBS : (every) where ?
o CS : an efficient paradox ?
o DBS, CS or VNS : are they similar ?
o Back to non invasive methods ?
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Outline
o DBS : (every) where ?
o CS : an efficient paradox ?
o DBS, CS or VNS : are they similar ?
o Back to non invasive methods ?
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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.
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In search of a magic target...
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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
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Fisher et al. Epilepsia 2010
N=110
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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
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Salanova et al. Neurology 2015
5 yrs F-up
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Bien et al. 2009
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Epilepsy is not Parkinson’s disease
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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
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P47. Pizzo et al. The role of subcortical structures during
seizures: evidence from SEEG recordings
12th International Epilepsy Colloquium, Lyon, May 26-28, 2019
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Stimulation parameters are empirical
Al-Otaibi et al. Neurosurgery 2011
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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 ?
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Outline
o DBS : (every) where ?
o CS : an efficient paradox ?
o DBS, CS or VNS : are they similar ?
o Back to non invasive methods ?
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2016; 127(1): 31-39
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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
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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
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Is the hippocampus the best target ?
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Responsive stimulation
Nagel & Najm 2009
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Morrell et al. Neurology 2011
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Heck et al. Epilepsia 2014
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The ictal generator is rarely focal
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Tem
po
ral
neo
cx
Fz-Cz
EKG
TpNAECaHcpHcPHcGFG
Insu
la
FbiFbe
CopPopT-PPCG
We only see what we look at
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Cortical stimulation has a widely extended effect
O. David - ERC F-TRACT
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Feddersen et al. 2007 Saillet et al. 2012
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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
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Outline
o DBS : (every) where ?
o CS : an efficient paradox ?
o DBS, CS or VNS : are they similar ?
o Back to non invasive methods ?
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VNS
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Wheeless 2002
VNS
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VNS
From Schulze-Bonhage. Seizure 2017
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DBS vs RNS
From Schulze-Bonhage. Seizure 2017
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Rolston et al. Neurosurg Focus 2012; 32(3): 14
The 50%-50% rule ?
VNS vs DBS vs RNS
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May 2, 2019 : end of inclusions (n=62)
PI : S. Chabardès
VA DBS in patients whom VNS failed
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Outline
o DBS : (every) where ?
o CS : an efficient paradox ?
o DBS, CS or VNS : are they similar ?
o Back to non invasive methods ?
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Transcutaneous stimulation of the cranial nerves
Transcutaneous trigeminal nerve stimulation (tTNS) Transcutaneous vagus nerve stimulation (tVNS)
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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 .
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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
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Transcutaneous stimulation of the cranial nerves
From Schulze-Bonhage. Seizure 2017
Effects on median seizure rate
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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.
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Cathode
+
Anode -
Cathode +
Anode
-
Anodal
stimulation
Excitatory
Effect
Cathodal
Stimulation
Inhibitory
effect
Transcranial direct current stimulation (tDCS)
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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)
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Don’t loose your head over tDCS
Buzsaki 2016
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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
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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)
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Conclusion
Non invasive
Neocx – MCD
rTMS / tDCS
Other
tVNS
Invasive
Clear
‘Focus’
RNS
Limbic
VA-DBS
Other
VNS
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Bien et al. 2009
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«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.
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After becoming intractable, 20.5% subsequently entered remission
and 13.3% were seizure free at last contact.