Magnetic Field Therapy for Epilepsy

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Epilepsy & Behavior 2, S81–S87 (2001)doi:10.1006/ebeh.2001.0210, available online at http://www.idealibrary.com on

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Magnetic Field Therapy for Epilepsy

Michael McLean, M.D., Ph.D.,1 Stefan Engstrom, Ph.D.,nd Robert Holcomb, M.D., Ph.D.

Department of Neurology, Vanderbilt University Medical Center,Nashville, Tennessee 37212

Received May 11, 2001; accepted for publication May 14, 2001

Unlabeled/investigational or unapproved use of products will be presented in this article.

Attempts to control seizures in animal models and in humans with magnetic fields are in early stagesof development. Devices that produce fields ranging from static to high frequency and with fluxdensities from well below geomagnetic intensities (nano-Tesla) to several Tesla have been tested withvariable results. Fundamental cellular mechanisms of interaction and transduction of magnetic fieldshave not been adequately elucidated for systematic hypothesis-driven experimentation. However,indications of efficacy are sufficient to warrant further investigation at the basic and clinical levels.© 2001 Academic Press

Key Words: magnetic fields; epilepsy; therapeutic magnetic fields; cellular actions of static mag-netic fields; animal seizure models; static (time-invariant) magnetic fields; alternating (time-varying)magnetic fields; electromagnets.

INTRODUCTION

Alternating (time varying) and static (time invariant)magnetic fields have been used in experimental efforts tomodify seizure activity. Field characteristics studied bydifferent research groups vary greatly and can be di-vided into four categories based on the flux density. Atthe high field end, transcranial magnetic stimulation(TMS) represents the most readily understood andmechanistically accepted exposure modality. Large-flux-density (1–2 T), time-varying fields (1–25 Hz) have beenused to treat clinical depression and are under study forepilepsy as detailed elsewhere in this supplement. Ex-periments with static magnetic fields in the range 100 to300 mT have demonstrated variable effects in differentanimal models, and static fields with significant gradi-ents (changes in flux density over distance) may haveneuroprotective properties. Concerns for adverse effectsof environmental and occupational types of magneticfields prompted investigations of power line and otherextremely low-frequency (1- to 100-Hz) magnetic fields

1 To whom correspondence should be addressed at Departmentof Neurology, Vanderbilt University Medical Center, 2100 PierceAvenue, 351 MCS, Nashville, TN 37212. Fax: (615) 936-0223. E-mail:[email protected].

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of moderate magnitudes (0.1–1 mT). A range of obser-vations is available in this class of field exposures, but atthis point the physical transduction mechanisms areunknown.

Humans with epilepsy and animals with seizures trig-gered by a number of mechanisms have been exposed tofields at the lowest end of the spectrum reviewed here, inthe range 100 pT to 1 mT, using time-varying fields.Treatment benefits have been claimed. Once again, nocompelling evidence for physical transduction mecha-nisms has been adduced. For the most part, the studiesare not hypothesis-driven and tend to be phenomeno-logic. In the absence of clearly identified mechanisms ofinteraction with biological systems due to a paucity ofbasic research, methods of investigation are open to chal-lenge. Nonetheless, the increasing number of reports ofsignificant effects suggests that magnetic therapy forepilepsy should be seriously considered.

TRANSCRANIAL MAGNETICSTIMULATION (TMS): FIELDSWITH HIGH FLUX DENSITY

This technique employs a capacity discharge devicewith a copper coil that is placed in close proximity to

S82 McLean, Engstrom, and Holcomb

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the tissue to be stimulated. Comparatively large mag-netic fields (.2 T) occur with each pulse applied to thecoil. Rapid changes in the magnetic field have theeffect of stimulating tissue beneath the coil by induc-ing electric currents. Smaller currents are induced atgreater distances from the coils. Because the magneticfield decays rapidly over distance, effective inducedelectric field-stimulation does not occur beyond about2 cm (1). Devices capable of rapid stimulation rates ofup to 50 Hz for short periods (limited by heating)became available about 1989. Availability of such de-vices has facilitated clinical studies.

The use of repetitive transcranial magnetic stimula-tion (rTMS) has led to the observation of seizure-likephenomena in depressed patients (2). This hasprompted concern about the safety of rTMS and con-sequently recommendations for stimulation parame-ters have been made (3). While some studies havesuggested that rTMS can provoke seizures (4, 5), itwould appear that adverse effects of rTMS are uncom-mon (6–8). Interestingly, the transient surge of prolac-tin and luteinizing hormone that follows seizures ofseveral different types occurred in only one of sixpatients who had a complex partial seizure after rTMS(5). This suggests that the stimulation-induced eventsmay differ neurophysiologically from epileptic events.

The effects of rTMS depend in large part on the rateof stimulation. Low-frequency (#1-Hz) rTMS seems todecrease motor cortex excitability (9). Low-frequencyelectrical stimulation can also inhibit the developmentof amygdala-kindled seizures (10). On the other hand,higher-frequency rTMS (5–25 Hz) tends to be excita-tory and in some patients with epilepsy may be moreeffective in activating the epileptic focus (11). In somecases of medication-resistant epilepsy, even high-fre-quency rTMS is capable of decreasing spike frequency(12). Characterization of fields, stimulation rates, andthe place of stimulation are important issues that mustbe investigated further to design informative clinicaltrials of magnetic fields for the treatment of epilepsy.

Meanwhile, there is some evidence that TMS maybe a useful therapeutic modality. Nineteen patientswith mesiotemporal epileptogenic foci were treatedwith 0.1- to 0.3-Hz TMS to determine its safety andpotential benefits. None of the patients had significantspike activation, and several had bilateral reduction ofepileptiform activity (13). Nine patients participated ina pilot study of TMS for refractory partial epilepsiesby the same group. The stimulation protocol involvedtwo trains of 500 pulses at 0.33 Hz per day for 5consecutive days. Seizure frequency was followed for4 weeks before and 4 weeks after the treatment. Two

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patients had no change, one showed a 20% decrease,three experienced a 20 to 50% decline, and three hadmore than a 50% reduction of seizures throughout the4-week period after TMS (14). A larger clinical trial isin progress by the same group, and another study oflow-frequency rTMS is in progress at the NationalInstitutes of Health (Theodore, W. Personal commu-nication). The mechanism(s) by which intermittentTMS could reduce seizures over this long period afterstimulation is not understood.

STATIC MAGNETIC FIELDS OFINTERMEDIATE FLUX DENSITY

Enhanced static fields in the range 0.9 to 1.8 mTevoked epileptiform spikes in the EEGs of six epilepticpatients undergoing presurgical evaluation (15). Ad-ditional data from the same group were mixed. Twopatients with mesial temporal lobe seizure foci hadincreased frequency of interictal epileptiform activityduring long exposure to DC magnetic fields of 0.9-and 1.8-mT flux density. The third patient had a com-plete cessation of interictal spike waves (16). So far, thehope of using magnetic stimulation as a diagnosticand localizing tool in epilepsy has not been realized.The possibility of using static magnetic fields for treat-ment of epilepsy has not been explored systematically.

GEOMAGNETIC AND SYNTHETICLOW-LEVEL FIELDS

Fluctuations in the earth’s geomagnetic field andsynthetic magnet fields in the environment have beenreported to cause paroxysmal abnormalities of thenervous system. Increasing geomagnetic activity cor-relates with decreased threshold for convulsive sei-zures in humans with epilepsy (17). Reduction of sei-zure frequency by pico-Tesla fields also has been re-ported (18), but no controlled studies exist and thefield dosimetry is questionable for these exposures.

Although changes in geomagnetic activity havebeen tentatively linked to increased seizure frequency,there is no apparent correlation with sudden unex-pected death in human subjects with epilepsy (19).Others reported increased bereavement hallucinations(20) and complex partial seizure–like experiences dur-ing premenstrual syndrome (21) when daily geomag-netic activities either changed abruptly or were greaterthan 40 nT per day.

S83Magnetic Fields and Epilepsy

A range of effects of magnetic fields on seizures alsohas been observed in animal models of epilepsy. Inrats with audiogenic seizures, 100-Hz fields with fluxdensities in the range of 1.3 mT, but not 10- or 28-Hzfields simulating synthetic atmospheric frequencies,increased seizure latency by about 13% (P , 0.02; seeTable 1) (22). Fields of a constant intensity (700 nT)decreased seizure frequency in chronic epileptic malerats, whereas fluctuating fields were associated withincreased seizure frequency (23). The lethality of lith-ium/pilocarpine seizures increased when geomag-netic indices exceeded 20 nT for more than 1 to 2 daysprior to injection of the convulsant drugs (see Table 1)(24).

These results suggest that mammalian brains aresensitive to very low-level imposed magnetic fields.Crucial factors involved in producing proconvulsantand anticonvulsant effects of naturally occurring mag-netic fields, or their simulated counterparts, must beelucidated to establish mechanisms of physical inter-action with biological systems. Variations of flux den-sity with time, field strength, and frequency, if notstatic, are potential contributors.

TABLE 1

Effects of Magnetic Fields on Animal and Cell Models of Epilepsy

Study population Activity Magnetic

Juutilainen et al., 1988(22)

Female adult rats Audiogenic seizures 100 Hz, 1sound s

Ossenkopp and Cain,1988 (34)

Male adult rats Amygdala kindling 60 Hz, 0.1stimula

Ossenkopp and Cain,1991 (38)

Male adult rats Pentylenetetrazole-inducedseizures

60 Hz, 0.0prior to

Keskil et al., 2001 (39) Female mice Pentylenetetrazol-inducedseizures

50 Hz, 0.2injection

Bureau andPersinger, 1992 (24)

Male adult rats Lithium pilocarpine-induced seizures

Geomagn

Bawin et al., 1996 (40) Rat hippocampalslices

Carbachol-induced thetaactivity

1 Hz; 5.6,10 minambien

Jenrow et al., 1998(41)

Urethane-anesthetized rats

Hippocampal theta 60 Hz, 28

Potschka et al., 1998(35)

Female adult rats Amygdala kindling 50 Hz, 0.1before s

Lai and Carino, 1999(42)

Male adult rats Cholinergic activity 60 Hz, 0.5

Wieraszko, 2000 (43) Mouse hippocampalslices

Population spike dc 2–3 mT

DO MAGNETIC FIELDS ANDMELATONIN INTERACT?

Several lines of evidence suggest that magneticfields can alter melatonin, an endogenous antiepilepticcompound. The intraventricular injection of antimela-tonin antibodies elicited transitory epileptiform ab-normalities on the side of the injection only (25). Noc-turnal application of experimental magnetic fields en-hanced seizures in rats, presumably by suppressingmelatonin synthesis or release (20). Mongolian gerbilshave spontaneously occurring seizures. Pinealectomycaused a marked increase in seizure frequency thatdecreased to nearly normal range after subcutaneousadministration of melatonin (26). Pinealectomy alsoresulted in increased high-affinity GABA binding andloss of diurnal variation in binding that normalizedafter administration of melatonin (27).

In at least one reported case, high-dose melatonin(7.5 mg/kg) in addition to phenobarbital led to sus-tained control of previously refractory myoclonic ep-ilepsy in a child (28). Prolonged exposure of rats to;0.1-mT, 50-Hz magnetic fields depressed the synthe-

osure system Findings Comments

1 h prior ton

Prolonged seizure latency(13%, P , 0.02)

10 and 28 Hz simulated atmosphericsineffective

1 h prior to Abbreviation of afterdischarge(P 5 0.019)

Powerline frequency used; possibleeffect on Ca21 channels, G proteins

T for 1 h LD50 increased from 65.9 to88.3 mg/kg (P , 0.0005;seizures abbreviated(P , 0.05)

Possible effect on Ca21 channels

1 h prior to No effect No effect

(GMEs) Death increased with GMF.20 nT for several daysbefore injections

GMF suppression of pineal functioncould increase seizure susceptibility

0 mTrms forosed on

s

Destabilized interburstintervals

Nitric oxide implicated; 60-Hz fieldsless effective

for 1 h Rhythmic slow activitychanged to large, irregularactivity for ;90 min

Resonance mechanism forsynchronization hypothesized

r 1–2 hn

Kindling acquisitionunchanged, after dischargeduration decreased, higherthreshold for generalizedseizures

Weak (subtle) effects on some seizureparameters, signal transductionmechanisms likely

Decreased high-affinity cholineuptake in 2-mT field for 60min, 1-mT field for 90 min

Time-dependent increase in fieldefficacy

in Decreased amplitude duringexposure, increased afterremoval

Inhibition by dantrolene implicateseffect on intracellular Ca21 release

field exp

A/m fortimulatiomT for

tion5–0.185 minjection

mT for

etic fields

56, or 56superimpt dc field.9 mTrms

mTrms fotimulatio

–2 mT

for 20 m

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sis of melatonin (29–31). Melatonin also had anticon-vulsant effects in the kindling model of seizures in rats(32), a model system that is sensitive to magneticstimulation (see below). Melatonin also may have neu-roprotective effects (33).

IN VIVO AND IN VITRO STUDIES

The fundamental basis for effects of magnetic fieldson seizures is not well established. A small number ofstudies have shown effects of externally applied mag-netic fields on animal and cell models of epilepsy(Table 1). Effective alternating fields are generallylarger than geomagnetic fields at frequencies in therange of atmospheric fields generated by industry andpower lines. Some of the effects are subtle and requiresophisticated measurements for detection. For exam-ple, Juutilainen et al. (22) found prolonged seizurelatency in audiogenic rats as mentioned above. Inamygdala-kindled rats, power-line frequencies abbre-viated after discharges (34, 35). Kindling acquisitionwas unchanged, but, in fully kindled rats, the thresh-old for generalized seizures was elevated (35). Al-though the mechanism(s) of these subtle effects wasnot studied in these papers, possibilities cited in-cluded interaction with signal transduction (36), cal-cium mobilization (36), endogenous opioids (37), andmelatonin (as described above).

Exposure to weak (0.1- to 0.185-mT), 60-Hz fieldsalso decreased the frequency of seizures and mortalityproduced by pentylenetetrazole in rats (38). Pentyl-enetetrazole increases influx of calcium into neuronsof rat hippocampal slices, implicating calcium chan-nels as a target for magnetic fields. Another groupfailed to show magnetic field effects (0.2 mT, 50 Hz, 1hour prior to injection) on pentylenetetrazole-inducedseizures (39). Carbachol-induced beta activity in rathippocampal slices (40) and endogenous hippocampaltheta activity in urethane-anesthetized rats (41) be-came irregular during exposure to alternating fields of1 and 60 Hz, respectively. Inhibitors of nitric oxidesynthetase prevented alteration of carbachol-inducedtheta activity in vitro (40). Jenrow et al. (41) implicatedesonance mechanisms for synchronization as a targetor the magnetic fields. Effective field strengths dif-ered for the two frequencies, but this may have beenelated to the conditions of the experiment and 60-Hzelds were less effective. Exposure to 60-Hz fieldsith flux densities in the low milli-Tesla range de-

reased high-affinity choline uptake in a time-depen-


ent manner (42), but the authors did not speculatebout the mechanisms of the field effect.Little information has been published about effects

f static magnetic fields on epileptiform activity. Pop-lation spikes detected in mouse hippocampal slicesecreased in amplitude during exposure to DC fieldsf 2- to 3-mT flux density and then increased afteremoval of the field. These effects were inhibited byantrolene, suggesting effects on intracellular calciumelease (43). In cultured mouse spinal cord neurons,ntracellularly recorded responses to N-methyl-d-as-artate (NMDA) were reversibly reduced slowly byxposure to 10-mT gradient fields produced by anrray of four permanent magnets with alternating po-arity (Fig. 1) (44). The characteristics of fields pro-uced by this array of magnets are discussed else-here in this issue. The molecular mechanism(s) for

his and other cellular effects observed by our group isnder investigation. Placing mice in the maximallyffective regions of the field produced by this arrayltered the threshold for sound-induced seizures inring’s mice, ameliorated AMPA-induced status epi-

epticus and hippocampal neuronal death in mice, andeduced the percentage of mice demonstrating syn-hronous clonic limb jerking after intracerebroventric-lar injection of NMDA (45). Preliminary results inenetically epilepsy-prone rats revealed a decrease inhe ED50 for phenytoin (McLean et al. Unpublishedata).

DISCUSSION

The use of magnetic fields to treat epilepsy is in itsinfancy. There are clinical reports of reduced seizureactivity after intermittent treatment with trains ofpulsed magnetic fields of a stimulatory nature (rTMS)and by application of very weak magnetic fields. Inthe absence of clearly demonstrated mechanisms ofphysical interaction of the fields with brain elements,it is difficult to understand how intermittent treat-ments could have prolonged efficacy. No controlledstudies of pulsed magnetic therapy have been per-formed. Laboratory research, particularly in animalmodels, suggests that there is an underlying funda-mental basis for continuing to develop this new mo-dality for the treatment of epilepsy.

Interestingly, fields produced by capacity dischargedevices and arrays of permanent magnets have lim-ited depths of penetration because field strength de-clines rapidly with distance from the devices. Bothtypes of devices produce effect-field components at

sddfiwtaadbsood

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distances equivalent to the depth of the cortical sur-face (1) (see McLean et al., this issue), and their fieldshould be able to reach the cortical surface when theevices are positioned near or placed on the scalp. Inorsal root ganglion neurons, effective portions of theeld produced by the array of permanent magnetsith alternating polarity reversibly blocked action po-

ential firing and responses to capsaicin (see McLean etl., this issue). As shown here, the static fields may beble to reduce responses to NMDA. Some antiepilepticrugs reduce action potential firing frequency andlock NMDA receptors to produce their anticonvul-ant effects (46), and here the magnetic fields mayverlap with pharmaceutical agents. In this context,ne might think of the magnetic fields as acting likerugs from a distance.

FIG. 1. Effects of exposure to a static magnetic field produced byo 5 3 1024 M NMDA applied by pressure ejection from a blunt-tiptudy. The neuron was positioned above the array of magnets in aifferent membrane potentials (Em) to show effects on action potentiaction potentials (280 mV). PRE: Control traces in response to 10-s

MAG-4A: Responses were elicited at three different times (10, 15, anwith time at both Em. POST: After removal of the array of magneompletely (280 mV, 3 minutes after removal). Lines below traces iight apply throughout.

CONCLUSION

Much work remains to elucidate molecular mecha-nisms of action of magnetic fields with the many targetsthat could produce anticonvulsant effects. Mechanisticunderstanding will undoubtedly influence the design ofclinical studies. Finally, only convincing data from well-controlled clinical studies will allow magnetic therapy tobe considered a potentially viable treatment option.

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Magnetic Field Therapy for Epilepsy

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