Furosemide and Mannitol Suppression of Epileptic Activity in the
Michael M. Haglund1and Daryl W. Hochman2
1Departments of Surgery (Neurosurgery) and Neurobiology and2Surgery (Experimental) and Pharmacology and Cancer Biology,
Duke University Medical Center, Durham, North Carolina
Submitted 10 September 2004; accepted in final form 17 February 2005
Haglund, Michael M. and Daryl W. Hochman. Furosemide and
mannitol suppression of epileptic activity in the human brain. J
Neurophysiol 94: 907–918, 2005. First published February 23, 2005;
doi:10.1152/jn.00944.2004. Most research on basic mechanisms of
epilepsy and the design of new antiepileptic drugs has focused on
synaptic transmission or action potential generation. However, a
number of laboratory studies have suggested that nonsynaptic mech-
anisms, such as modulation of electric field interactions via the
extracellular space (ECS), might also contribute to neuronal hyper-
synchrony and epileptogenicity. To date, a role for nonsynaptic
modulation of epileptic activity in the human brain has not been
investigated. Here we studied the effects of molecules that modulate
the volume and water content of the ECS on epileptic activity in
patients suffering from neocortical and mesial temporal lobe epilepsy.
Electrophysiological and optical imaging data were acquired from the
exposed cortices of anesthetized patients undergoing surgical treat-
ment for intractable epilepsy. Patients were given a single intravenous
injection containing either 20 mg furosemide (a cation-chloride co-
transporter antagonist) or 50 g mannitol (an osmolyte). Furosemide
and mannitol both significantly suppressed spontaneous epileptic
spikes and electrical stimulation-evoked epileptiform discharges in all
subjects, completely blocking all epileptic activity in some patients
without suppressing normal electroencephalographic activity. Optical
imaging suggested that the spread of electrical stimulation-evoked
activity over the cortex was significantly reduced by these treatments,
but the magnitude of neuronal activation near the stimulating elec-
trode was not diminished. These results suggest that nonsynaptic
mechanisms play a critical role in modulating the epileptogenicity of
the human brain. Furosemide and other drugs that modulate the ECS
might possess clinically useful antiepileptic properties, while avoiding
the side effects associated with the suppression of neuronal
I N T R O D U C T I O N
Approximately 1% of the population suffers from epilepsy,
and 20–30% of epilepsy patients have seizures that are intrac-
table to control with existing antiepileptic drugs (AEDs) (Ben-
badis et al. 2000; Hauser 1998). Available antiepileptic thera-
pies are considered to be inadequate since they do not provide
sufficient seizure-control in a significant proportion of epilepsy
patients and are often accompanied by adverse side effects
(Loscher 2002). Currently prescribed AEDs are thought to
mediate their antiseizure effects by reducing neuronal excit-
ability, either by directly affecting synaptic interactions or by
reducing the likelihood of action potential generation(LaRoche
and Helmers 2004). Persistent adverse effects, such as sedation
and cognitive impairment, are commonly associated with
AEDs because neuronal excitability is reduced indiscrimi-
nately in both epileptogenic and normal areas in the brain
(Aldenkamp et al. 2003; Brodie 2001).
Previous studies on hippocampal slices suggested that an-
tagonism of the cation-chloride cotransport system, with furo-
semide (Lasix) or reduced extracellular chloride, potently
blocked epileptiform activity without suppressing neuronal
excitability (Hochman and Schwartzkroin 2000; Hochman et
al. 1995, 1999). In those studies, it was proposed that the
antiepileptic action of chloride cotransport antagonism was
mediated through nonsynaptic mechanisms involving the
Na?,K?,2Cl?cotransporter and hence potentially represented
a novel approach to seizure control. The furosemide-sensitive
Na?,K?,2Cl?cotransporter is thought to mediate activity-
evoked cell volume changes in glial cells and to play a significant
role in the redistribution of potassium from the extracellular space
and Hertz 1984; Walz and Hinks 1985).
It has long been hypothesized that alterations of the ECS
could modulate neuronal synchrony by affecting nonsynaptic
mechanisms such as the electrical resistance of brain tissue,
extracellular ionic concentrations, local ephaptic interactions,
and long-range electric field effects among neuronal popula-
tions (Dudek et al. 1986; Faber and Korn 1989; Jefferys 1995).
Numerous clinical and experimental studies have shown that
changes in the osmolarity of the ECS, which presumably
modulates the volume fraction of the ECS by directly affecting
cell volume, can significantly affect epileptogenicity (Andrew
1991). In vivo studies in rats demonstrated that systemically
injected hyperosmotic solutions significantly increase electro-
shock seizure thresholds (Reed and Woodbury 1964) and
prevent the development of kainic acid-induced seizures (Ba-
ran et al. 1987). In vitro studies on the role of nonsynaptic
mechanisms in epilepsy began with the observation that syn-
chronized discharges could occur in hippocampal slices in
which chemical synaptic transmission had been eliminated by
the reduction of calcium in the bathing medium (Jefferys and
Hass 1982; Taylor and Dudek 1982, 1984a,b). Increasing
osmolarity in this preparation with mannitol or sucrose reduced
Address for reprint requests and other correspondence: D. W. Hochman,
Dept of Surgery, Duke University Medical Center, Box 3807, Durham, NC
27710 (E-mail: email@example.com).
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of page charges. The article must therefore be hereby marked “advertisement”
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J Neurophysiol 94: 907–918, 2005.
First published February 23, 2005; doi:10.1152/jn.00944.2004.
9070022-3077/05 $8.00 Copyright © 2005 The American Physiological Society www.jn.org
or blocked synchronized discharges, whereas decreasing os-
molarity had the opposite effect (Dudek et al. 1990; Roper et
al. 1992). A study on hippocampal slices bathed in high-
potassium medium suggested that alteration of the size of the
ECS is a critical component in the generation of epileptiform
activity (Traynelis and Dingledine 1989).
Both furosemide and mannitol are known to affect the size
of the ECS but through different mechanisms. Furosemide
blocks activity-evoked cell swelling through antagonism of
cation-chloride cotransporters, whereas mannitol removes wa-
ter from intracellular compartments through osmotic forces
(Geck et al. 1980; Hochman et al. 1995; Kimelberg and
Frangakis 1985; Paczynski 1997; Traynelis and Dingledine
1989). Two considerations of particular clinical interest moti-
vated the studies reported here. First, furosemide more potently
blocks epileptiform activity in in vitro studies than many of the
commonly prescribed AEDs (Hochman et al. 1995). Second,
both furosemide and mannitol have been observed to suppress
epileptiform activity in laboratory models of seizure without
reducing excitatory synaptic transmission or the ability of
neurons to fire action potentials (Dudek et al. 1990; Hochman
and Schwartzkroin 2000; Hochman et al. 1995; Traynelis and
Dingledine 1989), suggesting that the neurological side effects
associated with currently prescribed AEDs might be avoided.
Because the role of ECS modulation in human epileptogenicity
has not yet been experimentally investigated, we studied the
effects of furosemide and mannitol on patients suffering from
medically intractable epilepsy.
M E T H O D S
Intraoperative studies were performed on 27 patients, 11 of whom
received no experimental treatments (control) and 16 of whom re-
ceived either furosemide or mannitol during the recording sessions
(experimental group). All patients were suffering from medically
intractable epilepsy and had given informed consent; studies adhered
to a protocol that was approved by the Duke Human Subject Com-
mittee (Institutional Review Board Protocol 2082). The control group,
whose ages varied from 14 to 57 yr, consisted of 5 males and 6
females. The ages of the patients in the experimental group varied
from 12 to 56 yr, consisting of 4 males and 12 females. All patients
were suffering from seizure conditions that could not be adequately
controlled with existing AEDs. Patients were classified as having
either mesial temporal epilepsy (MTE, control group, n ? 7; exper-
imental group, n ? 13) or neocortical epilepsy (NE, control group,
n ? 4; experimental group, n ? 3), depending on where the sites of
seizure onset had been identified in the mesial structures with video
electroencephalographic (EEG) monitoring, concordant hypometabo-
lism on PET in the mesial temporal lobe, and hippocampal atrophy on
high-resolution MRI or implanted subdural electrode array monitoring
for neocortical seizures. Some patients were involved in more than
one experiment (i.e., both spontaneous spiking and stimulation-
evoked afterdischarge activity were studied on the same patient).
Patients remained on their preoperative AEDs and were anesthe-
tized with the inhalational agent isoflurane (0.2 MAC) and intrave-
nous remifentanil and propofol. Propofol was administered up until 10
min prior to the EEG recording session at which point propofol
administration was stopped and not re-administered until the record-
ing session had ended. Additionally, a local field block was adminis-
tered consisting of 1.0% lidocaine with 1:200,000 epinephrine and
0.25% marcaine with 1:200,000 epinephrine mixed 1:1. The lido-
caine/marcaine/epinephrine solution (9 ml) was mixed with a
NaHCO3solution (1 ml) for the field block. Vital signs were moni-
tored so that variables, such as blood pressure, blood oxygen satura-
tion, and arterial CO2(paCO2? 35–39) and PO2were as close as
possible between experiments. No changes in vital signs were ob-
served during experimental treatments; importantly, neither the furo-
semide nor mannitol treatments caused changes in blood pressure.
The furosemide (Lasix) solution was composed of 4-chloro-N-
furfuryl-5- sulfamoylanthranilic acid, sodium chloride for isotonicity
and sodium hydroxide to adjust pH. The furosemide injection solution
was a sterile, nonpyogenic solution with a concentration of 10 mg/ml
and 2 ml were injected as a single bolus (20 mg). Mannitol I.V.
(Mannitol injection, USP) was a sterile, nonpyogenic solution of
mannitol dissolved in water for injection at a concentration of 20%. A
50-g intravenous bolus of mannitol was administered over 5–10 min.
After the cortex was exposed, electrophysiological recordings were
acquired from an array of subdural EEG electrodes placed directly on
the cortical surface. The electrode array (Ad-Tech Medical Instru-
ment, WI) was recorded by an analog EEG machine equipped with
signal amplifiers and noise filters (Grass, RI), and passed to an A/D
converter and recorded as a digital signal on VCR tape cassettes
(VR-100-B-8 A/D, Instrutech). Each surface EEG electrode was 5
mm in diameter with the inter-electrode distances of 10 mm. Record-
ings were acquired from at least seven electrodes in an array covering
?5 ? 5 cm of the cortical surface. An eighth input to the amplifier
received impulses from the camera used for optical imaging experi-
ments so that images could be accurately correlated to the electro-
physiological activity in time. A silver-ball reference electrode was
placed on the contralateral mastoid process. All eight channels were
digitized at 14-bit resolution, 11.8 k samples/s per channel. The mean
voltage of the EEG recording from the interictal focus was calculated
over a 20-min duration just prior to administration of either the
furosemide or mannitol treatment. Only those EEG events that were at
least ?3 SD from this mean were counted as spikes. This “3-sigma”
criterion was chosen because it had been empirically determined to
avoid overcounting ambiguous events based on waveform morphol-
ogy, while still counting enough events for statistical analysis.
Electrical stimulation of cortex
For electrical stimulation during afterdischarge studies, a bipolar
stimulating electrode (5 mm interelectrode distance), powered by a
constant-current source (Ojemann Cortical Stimulator, Integra Life-
Sciences), was placed on the neocortex at sites distant from the
interictal focus. The minimal stimulation current (4 s at 60 Hz, 1-ms
biphasic pulse) required to elicit ?5 s of afterdischarge activity was
determined. A recording electrode was placed between the stimulating
electrodes for recording afterdischarge activity (see gray-scale image
in Fig. 2, bottom middle, for the electrode configuration). The duration
of afterdischarge activity was defined to be the time during which a
train of spikes followed the cessation of the 4-s stimulus.
The intraoperative optical imaging technique used in these studies
was similar to what has previously been reported, where it was
demonstrated that changes in the activity-evoked optical spectro-
scopic properties of the cortex can be used to provide high-resolution
maps of epileptiform activity in humans (Haglund et al. 1992). A 4 ?
908 M. M. HAGLUND AND D. W. HOCHMAN
J Neurophysiol • VOL 94 • AUGUST 2005 • www.jn.org
on the epileptogenicity of the tissue. It is known that furo-
semide blocks activity-evoked volume change in brain tissue
(Holthoff and Witte 1996; MacVicar and Hochman 1991;
Sykova et al. 2003), and mannitol reduces activity-evoked
changes in the electrical resistivity of hippocampal slices (Fox
et al. 2004).
Interpretation of the optical-imaging data
Our interpretation of the optical-imaging data relies on the
following assumption: changes in the in vivo intrinsic optical
signal (IOS) are positively correlated to changes in neuronal
activity. Even though a complete understanding of the mech-
anisms underlying the generation of IOS is lacking, this cor-
relation is generally consistent throughout the literature (Grin-
vald et al. 1988; Haglund et al. 1992; Seth et al. 2003; Ts’o et
al. 1990). There are at least three components that contribute to
the changes of IOS: changes in blood volume, changes in blood
oxygenation, and blood-independent changes involving ion
fluxes and cell volume changes (Grinvald et al. 1988;
MacVicar and Hochman 1991). It is believed that the intrinsic
signal in vivo is dominated by hemodynamic components
(Grinvald et al. 1988). In our study, we used 535-nm light for
illumination, which has been shown to be highly selective for
blood volume changes in vivo (Haglund and Hochman 2004)
and minimizes the blood-independent component of the IOS
(MacVicar and Hochman 1991). Because blood volume
changes are thought to be tightly correlated to neuronal activity
(Ngai et al. 1988), we believe the IOS recorded in our studies
does indeed represent changes in neuronal activity. Given this
interpretation, our data suggest that mannitol and furosemide
treatment result in a decrease in the spatial extent of cortex
activated by 60-Hz electrical stimulation of the cortical sur-
face. Presumably, this type of stimulation elicits a synchronous
discharging of a population of neurons. Hence, the optical-
imaging data suggest that furosemide and mannitol reduce the
spatial extent through which a synchronous drive can activate
neurons in the neocortex. Because the IOS showed no dimi-
nution in its amplitude in the area between the two poles of the
bipolar stimulating electrode, it is suggested that furosemide
and mannitol treatment did not result in a reduction in action
potential firing evoked by direct electrical stimulation. These
interpretations would be consistent with in vitro studies on
hippocampal slices showing that chloride cotransport antago-
nism desynchronized the timing of synaptically evoked action
potentials, but did not affect the ability of neurons to generate
action potentials (Hochman and Schwartzkroin 2000).
Because large quantities (50-g boluses) of mannitol were
used in these studies to suppress epileptiform activity, this
compound would not be a practical chronic antiepileptic treat-
ment. However, relative to laboratory studies that required
?40 mg/kg of furosemide to block kainic acid-induced epilep-
tiform activity in rats (Hochman et al. 1995), surprisingly small
doses of furosemide (0.18–0.45 mg/kg, depending on the
weight of the patient) were highly effective in suppressing
epileptic activity in human patients. Because doses of furo-
semide that are 50- to 200-fold greater than what was used in
this study have been given chronically to patients with man-
ageable side effects, this compound is worthy of further inves-
tigation as a treatment for epilepsy (Cotter et al. 1997; Ferrara
et al. 1997). It may also be important to test other loop diuretics
for their anti-epileptic properties in human subjects. In partic-
ular, bumetanide has been shown to be at least an order of
magnitude more potent than furosemide in blocking kainic
acid-induced seizures in rats (Schwartzkroin et al. 1998). Also,
torasemide has been shown to have even fewer side effects
than furosemide with chronic use in high doses in patients
(Ferrara et al. 1997), although its antiepileptic effects have yet
to be investigated.
Although it was demonstrated that furosemide suppresses
epileptiform activity in patients who are intractable to existing
AEDs, significant further study is required before it, or related
molecules, can be used as a practical clinical treatment. The
limitations of the studies presented here include: the effects of
furosemide were monitored for only 40 min after administra-
tion, giving no information about the time course over which
furosemide suppresses epileptiform activity, and even though
spontaneous interictal and stimulation-evoked epileptic activ-
ity was suppressed, it still is not known whether furosemide
would reduce the number of spontaneously occurring seizures
in patients. However, the results presented here strongly sug-
gest that furosemide, a safe and widely used diuretic, has the
potential to be a treatment for epilepsy in some patients. The
notion that furosemide may have use as an antiepileptic drug is
further supported by evidence from an epidemiological study
suggesting that past or present use of furosemide was protec-
tive for the development of a first unprovoked seizure in older
adults (Hesdorffer et al. 2001).
These results support the notion that nonsynaptic mecha-
nisms, involving the water content and volume of the ECS,
may play an essential role in modulating the epileptogenicity of
the human brain. Molecules that modulate the extracellular
space, either directly or through antagonism of the cation-
chloride cotransport system, might provide a potent means to
control seizure activity while avoiding the side effects associ-
ated with current therapies that suppress neuronal excitability.
In particular, furosemide and other loop diuretics might have
clinical value in treating patients suffering from medically
A C K N O W L E D G M E N T S
We thank P. A. Schwartzkroin and J. O. McNamara for valuable comments
on this manuscript; M. Bikson for suggestions regarding the analysis of tissue
electrical resistance changes; the Duke Epilepsy Center for generous help,
particularly the epileptologists R. A. Radtke, K. E. van Landingham, and A. M.
Husain; anesthesiologist D. Warner, and EEG Technicians J. Brame, M. Ellis,
B. Durrance, and L. McFadden; A. Kvanvig and F. Boschini for technical
assistance; and J. Lucas and M. Levine of the Duke University Statistical
Consulting Center for advice on statistical analysis.
G R A N T S
This work was supported by a Junior Investigator Research Grant from the
Epilepsy Foundation of America and National Institute of Neurological Dis-
oders and Stroke Grants R21NS-042341 to D. W. Hochman and K08NS-01828
to M. M. Haglund.
D I S C L O S U R E
Daryl W. Hochman has an equity interest in Cytoscan Sciences LLC, a
private company engaged in the design and commercialization of novel
molecules that are structurally related to furosemide for the treatment of CNS
917 FUROSEMIDE SUPPRESSION OF EPILEPTIC ACTIVITY
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