Epilepsy Research (2008) 78, 235—239

journal homepage: www.elsevier.com/locate/epilepsyres

SHORT COMMUNICATION

Effects of subdural application of lidocaine in
patients with focal epilepsy
Deepak Madhavan a,∗, Piotr Mirowski a, Nandor Ludvig a, Chad Carlson a,
Werner Doyle a,b, Orrin Devinsky a, Ruben Kuzniecky a
a

New York University Comprehensive Epilepsy Center, 403 East 34th Street, 4th Floor,
New York, NY 10016, United States
b
New York University Department of Neurosurgery, New York, NY 10016, United States
Received 19 September 2007; received in revised form 30 October 2007; accepted 18 November 2007
Available online 4 January 2008

KEYWORDS
Lidocaine;
Transmeningeal;
Focal;
Epilepsy

Summary Antiepileptic drug (AED) delivery directly into the neocortex has recently been
shown to be able to both prevent and terminate focal seizures in rats. The present clinical
experiment aimed to test the local effects of lidocaine delivered onto the pia mater adjacent
to epileptogenic zones in human patients. Administration of lidocaine resulted in a marked
diminishment of spike counts on all patients, with a decremental effect of lidocaine on the
faster frequency elements of individual spikes and overall testing epochs. The direct cortical
application of lidocaine appears to affect local epileptogenic activity in human patients with
intractable focal epilepsy.
© 2007 Elsevier B.V. All rights reserved.

1. Introduction
The transmeningeal application of antiepileptic drug (AED)
directly to the brain neocortex has recently begun to be
explored for the treatment of refractory partial epilepsies
(Ludvig et al., 2006; John et al., 2007). Drug delivery through
the meninges has been shown to both prevent and terminate
focal seizures in rats, as demonstrated by the epidural application of diazepam (DZP) markedly reducing the amount of
electroencephalographic (EEG) spiking in rat models (Eder
et al., 1997), and intracortically infused GABA by reducing motor seizures in amygdala kindled rats (Fukuda et al.,

∗ Corresponding author. Tel.: +1 212 263 8327;

fax: +1 212 263 8341.
E-mail address: dpak01@yahoo.com (D. Madhavan).

1987). Based on these observations, and on recent histological evidence that water-soluble small molecules diffuse
into the neocortex through the cerebral meninges (Ludvig
et al., 2008), the delivery of AEDs transmeningeally in situ
to terminate or prevent seizures in humans appears to be a
feasible concept.
Specifically, this experiment aimed to test the hypothesis that focal administration of a channel blocker in
humans can have similar effects to those observed in animals. During these experiments, we tested the local effects
of lidocaine delivered onto the pia mater overlying EEG
spiking activity. Lidocaine is a local anesthetic with a
number of distinct cellular effects, including inhibition of
the calcium-activated potassium channel and voltage-gated
sodium channel. It has been demonstrated to have multiple inhibitory effects in the central nervous system (CNS)
in animal models, with lidocaine administration increas-

0920-1211/$ — see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2007.11.007

236
ing the current threshold to depolarization and decreasing
action potential amplitude in single pyramidal cells isolated from rat hippocampus (Butterworth et al., 1993).
We have also shown that intrahippocampal microdialysis
with lidocaine suppresses hippocampal neuronal firing in
freely moving rats (Ludvig et al., 1994). In addition, there
appeared to be a concentration-dependent effect on current threshold in the above study, which was also found in
sciatic nerve experiments in the frog and rat (Bokesch et al.,
1986). Lidocaine also produces severe impairment of auditory brain-stem responses (ABR) in rat models (Schmidt et
al., 1990), thereby demonstrating its inhibitory effects on
neuronal transmission. As it is water soluble, it was technically feasible to directly infuse lidocaine solutions onto the
pial surface. The following study is an initial demonstration
of the effects of direct lidocaine application on local spiking characteristics in humans, intended as a proof of concept

D. Madhavan et al.
for future experiments related to transmeningeal focal AED
administration.

2. Methods
2.1. EEG recordings
Consent from the IRB was obtained for the intraoperative use of
lidocaine. Three patients undergoing resection for intractable focal
epilepsy were examined using intraoperative electrocorticography
(ECoG, sampled at 256 Hz, using a band-pass of 0.1—70 Hz and application of a 60 Hz notch filter), recorded using a Nicolet Biomedical
EEG system (Viasys Healthcare, Inc.). Either a 4 × 4 electrode grid
or multiple four contact electrode strips (5 mm electrode diameter)
were placed directly over the region of the resection zone, which
was determined by previous intracranial EEG recordings. After the
recording of a 5 min baseline ECoG control epoch, a Gelfoam®

Figure 1 Patient spike counts (left) and corresponding FFT plots determined over 5-min epochs prior to lidocaine application (red),
and with application of 0.2% (green) and 0.4% (violet) solutions, in patients 1—3. Lidocaine administration appeared to diminish
spike numbers at both concentrations in each patient, with a markedly pronounced spike reduction noted in patient 1. The FFT
frequency scale is expressed on the x-axis, and the total power at a given frequency expressed as a percentage is visualized on
the y-axis. Note the decrement of power after lidocaine administration in patients 1 and 2. Please note the difference in scale in
the spike count of patient 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web
version of the article.)

Subdural lidocaine in focal epilepsy

237

Figure 2 Wavelet analysis of averaged spikes from patient 1, prior to lidocaine administration (a), after 0.2% solution application
(b), and after 0.4% solution application (c). Spikes were isolated, and aligned according to their amplitude maxima. The maximal
frequency can be seen as the region of highest power on the spectrogram, and also expressed numerically on the figure.
square (1 cm × 1 cm) was immersed in 0.2% lidocaine solution (1 cc
of 2% lidocaine dissolved in 9 cc saline) for 30 s, and applied to the
maximal area of spiking by placing the Gelfoam underneath and
between the electrodes followed by 5 min of recording. Following
the first recording, we increased the dose to 0.4% lidocaine solution
using an identical protocol as above with 5 min recording period.
Finally, the Gelfoam was removed and the area of cortex irrigated
with 38 C saline for 1 min followed by a 5 min of EEG recording using
the same electrodes.

2.2. Patients
Patient 1 is a 30-year-old right-handed male with a history of refractory seizures originating from the right frontal region, without an
appreciable lesion noted. Frequent epileptiform spikes and sharp

waves were noted during intracranial monitoring with subdural electrodes, and the patient underwent corticography-assisted resection
of this region.
Patient 2 is a 26-year-old left-handed male with a history of
developmental delay and seizures starting at 1 month of age. He
continued to have refractory seizures despite corpus callosotomy
at age 14. Intracranial monitoring revealed very frequent spike and
wave discharges occurring in 10 s runs and partial seizures originating from the left frontal lobe.
Patient 3 is a 38-year-old right-handed female with a history
of a right temporo-parietal arteriovenous malformation (AVM), who
developed seizures 2 years following a hemorrhage of her AVM with
subsequent resection. Intracranial monitoring revealed a persistent
spiking focus in the superior parietal lobe, around the region of postoperative encephalomalacia. During monitoring, she developed a

238
complex partial seizure which evolved into status epilepticus, originating from the temporal lobe border of encephalomalacia.

2.3. EEG and spike analysis
A single EEG channel was identified from each patient to represent the areas of most active spiking. Spikes from each epoch were
identified based on morphology and temporal features (<50 ms spike
duration), and counted for each patient. Wavelet analysis (Mallat,
1989; Torrence and Compo, 1998) was employed to perform spike
signal analysis. As opposed to Fourier analysis, which separates frequent bands within a defined epoch, the wavelet transform (WT)
decomposes the signal in both frequency and time. This can provide additional instantaneous frequency information at the peak of
each spike, and not only during a longer fixed time interval. Morlet wavelets were chosen for the analysis of individual spike curves,
between the frequencies of 2—50 Hz, sampled every 0.5 Hz. Wavelet
analysis was performed on 10 randomly selected spikes from each
epoch of patient 1 (who was the only patient who had a sufficient
number of spikes for analysis), and averaged. Average wavelet spectrograms were obtained by superimposing the wavelet frequency
decompositions in spectrogram form for individual spikes, with their
temporal location aligned at their maxima. Local maxima on the
cross-section of the spectrogram at the time of the spike were used
to identify the dominant instantaneous frequency of each spike, and
these maxima were averaged. Fast Fourier Transforms (FFTs) were
then performed on each 5 min epoch from each patient to identify
changes in power among frequency bands between 0 and 50 Hz.

3. Results
Administration of lidocaine resulted in a gradual diminishment of spike counts on all patients, with an almost 20-fold
decrement for patient 1 (Fig. 1). FFT analysis revealed a
decrease of power over frequencies between 5 and 20 Hz
after lidocaine administration in patients 1 and 2, with relative increases in the frequencies under 5 Hz (Fig. 2). FFT
analysis on patient 3 did not yield similar results, which
may have been related to increased electrical noise present
on this recording. In patient 1, averaged wavelet analysis
revealed a decrement of the maximal frequency peak after
each lidocaine administration (7.3 Hz prior to lidocaine,
6.1 Hz with 0.2% solution, and 5.7 Hz with 0.4% solution),
again suggesting a decremental effect of lidocaine on the
faster frequency elements of individual spikes (Fig. 2).

4. Discussion
The above experiments demonstrate that lidocaine, delivered directly on the pia mater adherent to underlying
epileptogenic cortex, suppresses cortical EEG spiking. This
phenomenon was observed in all examined patients. As
the generation of an interictal spike on ECoG appears to
be correlated with the synchronized production of action
potentials from multiple neuronal generators within the
epileptogenic cortex, lidocaine may be interfering with this
synchronization process by raising depolarization thresholds
in these cell populations. The attenuation of spiking may
be a direct reflection of the pharmacological effects of
lidocaine; for instance, the resultant sodium channel blockade on pyramidal cell dendrites can reduce the excitatory
post-synaptic potentials (EPSP) and paroxysmal depolarizing
shifts (PDS) necessary for the production of action poten-

D. Madhavan et al.
tial trains that underlie spike production. These effects,
possibly in combination with sodium channel blockades on
subcortical and cortical axons carrying excitatory inputs to
pyramidal cells, may result in disordered and temporally
spread out action potentials, which could potentially cause
spikes with diminished amplitude or complete absence of
spikes on ECoG. The suppression of faster frequencies with
increased lidocaine concentration as displayed by FFT may
be due to dendritic and axonal sodium channel inhibition in
pyramidal cells, resulting in a diminished capacity of neuronal populations to produce synchronized high frequency
activity. Lidocaine may also have an inhibitory effect on
GABAergic interneurons, which appear to be related to the
production of gamma-frequency cortical activity (Buzsaki et
al., 1995; Fisahn et al., 1998; Ylinen et al., 1995), and high
frequency field oscillations (Buzsaki et al., 1992). This may
play a further role in interfering with neuronal synchronization.
These preliminary experiments appear to demonstrate
the effectiveness of pial administration of AED, namely lidocaine, on spiking activity within the human epileptogenic
zone. These results suggest that transmeningeal application
of a current channel blocker such as lidocaine or similar
drugs could be effective in the reduction of epileptogenic
activity, and perhaps seizures in human subjects. These
initial protocols did not accurately control for specific lidocaine concentrations, as the Gelfoam® was immersed in
lidocaine solution and placed on the cortical surface without accurate control of how much drug is delivered into
the cortex. However, these shortcomings are limited by the
observation of a direct correlation between spiking rate
reductions and lidocaine concentrations, by the use of a
consistent lidocaine concentration and by incorporating an
internal control via the washout period. Future experiments
are currently underway to confirm this effect using more
stringent controls for lidocaine concentration, and washout
periods following each lidocaine solution administration.
These results suggest that localized cortical infusion of drugs
should be further explored for treatment of focal seizures.

Acknowledgements
All authors confirm that we have read the Journal’s position
on issues involved in ethical publication and affirm that this
report is consistent with those guidelines. No conflicts of
interest related to this project were reported by any of the
contributing authors, and all authors are aware and approve
of the contents of this submission.

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