Transcript Stimulating The Brain In Epilepsy

Stimulating the Brain in Epilepsy
Anli Liu MD MA
Assistant Professor of Neurology
NYU FACES 2013 Epilepsy Conference
May 5, 2013
Background: An Unmet Need
• About 2/3 of patients with epilepsy will achieve seizure
control with medications
• Despite the introduction of 14 new anti-epileptic medications
since 1993, there is still a huge need for patients with drugresistant epilepsy (DRE)
• Seizure surgery is the best option for DRE patients and offers
the best chance for seizure freedom.
• However, some patients are not eligible for seizure surgery
Bergey, 2013
Background: Neurostimulation
Recent completion of
well-designed large clinical
Trials
Advances in brain
stimulation and
hardware technology
Neurostimulation options for patients with
poorly controlled partial-onset epilepsy
Background: Neurostimulation
While counterintuitive, delivering an excitatory stimulation during a seizure can
Disrupt the seizure and prevent its spread. Mechanism not understood.
Background: Neurostimulation
Potential benefits:
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Absent or minimal side effect profile
No teratogenicity
Distinct mechanism of action
Can occur automatically and as a supplementary treatment
Background: Partial vs. Generalized Epilepsy
Partial Epilepsy
• Seizure starts from one side
• Most adult-onset epilepsy
• 50% have seizure control with
medications
Generalized Epilepsy
• Seizure starts from both sides
• Most childhood and adolescent onset
• Primary generalized w 80% seizure
control
Background: Neurostimulation
While stimulating the brain in epilepsy seems
counterintuitive, these therapies could
potentially be an excellent treatment option
for patients with partial onset seizures who
are not candidates for surgery.
Neurostimulation
Invasive
• Vagal Nerve Stimulation (FDA 1997)
• Deep Brain Stimulation (Thalamus)
(Appr. Europe and Canada 2012)
Non-invasive
• Transcranial Magnetic
Stimulation (TMS)
• Transcranial Current Stimulation
(TCS)
• Responsive Neurostimulation (RNS)
(FDA approval pending)
Larger, multicenter controlled trials
FDA approval granted or pending
Smaller, pilot studies
Applications in epilepsy, cognition,
Psychiatry, and many other neuro
Logic disorders.
Invasive Neurostimulation
• Vagal Nerve
Stimulation (VNS)
• Deep Brain
Stimulation
(thalamus)
• Responsive
Neurostimulation
(RNS)
A vagal nerve stimulator
Vagal Nerve Stimulation
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First FDA approved device for
epilepsy and treatment refractory
depression (1997)
The most prevalent
neurostimulation method (60,000
patients in US)
Programmed to have constant
modulation, and a magnet rescue
setting
Trials demonstrate between 25-50%
of patients had a reduction of >50%
of seizure frequency; few become
seizure free.*
Very safe. Side effects of hoarseness
and cough.
Vagus Nerve Stimulation
Leads are wrapped around the vagus nerve in the neck. Through an unknown
Mechanism, can decrease the frequency of seizures in partial onset epilepsy.
Fridley Neurosurg Focus 2012
Deep Brain Stimulation (DBS)
Deep Brain Stimulation (DBS) has been FDA approved for Parkinson’s
Disease and Esssential Tremor and is now investigated for epilepsy
Deep Brain
Stimulation (DBS) of
the Anterior
Thalamus
DBS delivers continuous
low-level stimulation
The anterior thalamus has
widespread connections
And is an attractive
target.
Patients can have
multiple seizure onset
zones
DBS Thalamus
• A multicenter controlled trial (SANTE, Fisher 2010) of
patients with poorly controlled partial epilepsy*
40% decrease in seizure frequency after 3 months
44% decrease for temporal lobe epilepsy
56% decrease by 2 years
13% were seizure free for at least 6 months
• Safe: no significant bleeding or death.
• Side effects: Sensory changes (18%), transient
memory impairment and depression
• Approved in Europe and Canada, but not in US.
Responsive
Neuro
Stimulation
(RNS, Neuropace)
• Depth electrodes
Are placed into or near
The seizure focus and
Connected to a
Neurostimulator
Implanted into the
Patient’s skull.
• Continuous EEG
Is recorded by implanted
computer
Fridley Neurosurg Focus 2012
• When a seizure is
Detected, electrical
Stimulation is delivered
And stops the seizure from
spreading
Responsive Nerve
Stimulation (RNS)
A patient with
temporal lobe
epilepsy
and RNS device.
Bergey 2013
• Large controlled trial
(Morell,2011) with drug resistant
partial onset epilepsy showed a
38% seizure reduction
• Progressive improvement over
time: 50% reduction at 2 years.
• Improvement in quality of life,
Verbal ability, and memory
• Retention 90% at 3 years,
reflecting good side effect profile
• Major risks: infection and
bleeding
• Waiting FDA approval
Summary: Invasive Neurostimulation
PROS
CONS
•
Could be an excellent therapy for
patients with partial onset seizures
who are not candidates for surgery.
•
Range from slightly invasive (VNS)
to invasive (anterior thalamic and
RNS) neurosurgical procedures
•
Good efficacy (25-40% seizure
Reduction) with improved benefit
over time
•
Risks are bleeding and infection
•
Optimal stimulation parameters
not proven
•
Number of seizure free patients is
very low, partly because of patients
enrolled in studies
•
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Good safety profile
May spare from side effects from
epilepsy medications
Non-invasive stimulation
Transcranial Magnetic
Stimulation (TMS)
Transcranial Current
Stimulation (TCS)
Why the excitement?
We can stimulate a superficial area to activate
Deeper and widespread networks
To produce temporary and long-lasting effects
Many Treatment Applications in
Neuropsychiatric Disorders
• Depression (FDA cleared)
• Parkinsons Disease
• Stroke
• Pain
• Epilepsy
• Schizophrenia
• Autism
• Tinnitus
• Alzheimer’s Disease
• Tourette’s syndrome
• Ataxia
Research with noninvasive stimulation
is rapidly growing (71)
Transcranial Magnetic
Stimulation (TMS)
TMS uses an alternating magnetic field to produce a
secondary current in the underlying brain tissue
TMS-guidance with MRI Brain
Co-registration of the TMS wand with the patient’s MRI Brain increases precision.
Useful for presurgical planning.
TMS for Epilepsy
• As seizures arise from areas of hyperexcitability, we apply low-frequency
TMS to suppress this activity
• Since 2002, a few controlled trials published showing mixed results:
No significant effect
Theodore (2002)*
Joo (2007)
Cantello (2007)
Significant Decrease in Sz frequency
Fregni (2005)
Fregni (2006)*
Santiago (2008)
Sun (2012)
• Mix of findings due to mixed patients and protocols
• Meta-analysis of low-frequency rTMS (Hsu 2011) shows modest reduction
in seizure frequency
Seizure Reduction after rTMS (Bae 2007)
Suggestion of TMS benefit persisting between 2 to 8 weeks after stimulation.
TMS Batwing (H) Coil:
Stimulating Deep Targets
• Batwing Coil increases
Depth of Penetration,
up to 6 cm
• Currently a Pilot Study
of Deep TMS in Patients
with Temporal Lobe
Epilepsy (Rotenberg)
TMS Safety
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Rare reports of seizure (1.4%) Bae 2007
Most seizures typical in character and duration
No reported instances of status epilepticus
Safety guidelines are now published
Transcranial Direct Current Stimulation
(tDCS)
• Application of a weak direct
current (1-2 mA) to scalp
• Modulation of brain activity,
can enhance or suppress
tCS advantages
• Easy to use
• Low cost
• Non-invasive
• Painless
• Long lasting effects
• Few mild side effects
(itching, tingling, headache, burning
sensation and discomfort limited to
the scalp site)
• Safe: no reports of
seizures
Safety in tDCS
Brunoni 2011
tDCS for Epilepsy
Fregni (2006): RCT of single 20 minute session of
over cortical malformation showed trend toward
reduction in seizure frequency
Potentially good for patients with partial
onset epilepsy with a seizure focus that is
near the surface
HD-tDCS for Ongoing Focal Seizures
(Alex Rotenberg, MD PhD, CHB/Harvard)
•Targeted direct current stimulation may produce a more potent effect.
Summary: Non-Invasive Neurostimulation
PROS
CONS
•
•
Current research is early with
mixed results
•
Treatments will likely need to be
repeated
•
Optimal stimulation parameters
not proven
Could be an excellent therapy for
patients with partial onset seizures
where seizure focus is superficial.
•
Noninvasive
•
Safe
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May spare from side effects from
epilepsy medications
•
May eventually be a portable,
inexpensive office or home
treatment
Research at NYU Comprehensive
Epilepsy Center
• Efficacy of TDCS for Working Memory
Dysfunction and Depression in Patients with
Temporal Lobe Epilepsy (now recruiting)
• TCS during Sleep to Improve Cognition in
Epilepsy
Research Question
In patients with temporal lobe epilepsy (TLE),
what is the efficacy of transcranial direct current
stimulation (tDCS) on:
•Working Memory Dysfunction?
•Depression?
•Seizure Frequency?
•Interictal Discharges/EEG?
Study Design
A double-blinded, randomized, sham-controlled
trial of tDCS on patients diagnosed with temporal
lobe epilepsy
Outcomes:
• Verbal and visuospatial working memory tests
• Mood questionnaires
• Seizure frequency
• Interictal discharge frequency
Study Design
• Participation involves 8 visits (1-3 hrs)
• Subjects undergo memory and mood testing,
20 minutes of EEG at baseline
• Five (5) sessions of real of sham tDCS
• Repeat testing and EEG
• Followup at 2 and 4 weeks
Compensated $50 a visit.
Summary: Neurostimulation
Invasive
• Vagal Nerve Stimulation (FDA 1997)
• Anterior Thalamic Stimulation
(Appr. Europe and Canada 2012)
Non-invasive
• Transcranial Magnetic
Stimulation (TMS)
• Transcranial Current Stimulation
(TCS)
• Responsive Neurostimulation (RNS)
(FDA approval pending)
Larger, multicenter controlled trials
FDA approval granted or pending
Smaller, pilot studies
Applications in epilepsy, cognition,
Psychiatry, and many other neuro
Logic disorders.
Summary: Neurostimulation
While stimulating the brain in epilepsy seems
counterintuitive, these therapies could
potentially be an excellent treatment option
for patients with partial onset seizures who
are not candidates for surgery.
Summary: Neurostimulation
Discuss your eligibility for neurostimulation with
your epilepsy doctor.
Supporting research is important:
Find out how you can get involved!
References
Bergey G., Neurostimulation in the Treatment of Epilepsy, Experimental
Neurology, epub 2013
Fridley et al. Brain Stimulation for the Treatment of Epilepsy, Neurosurg Focus
32 (3) E 13, 2012.
Morrell MJ. Responsive Cortical Stimulation for the Treatment of Medically
Intractable Partial Epilepsy, Neurology 2011.