Medical Hypotheses (2003) 61(2), 231234 2003 Elsevier Science Ltd. All rights reserved.

doi:10.1016/S0306-9877(03)00150-6

Intractable epilepsy management: an EEG-oriented approach

Harinder Jaseja
Physiology Department, G.R. Medical College, Gwalior, Madhya Pradesh, India

Summary Intractable epilepsy has always posed a challenge to management; conventional, surgical and alternative techniques available so far (e.g. vagal nerve stimulation, i.e. VNS). The author has attempted to search for a novel alternative (drug-regime) approach to its management to minimise any invasive technique or surgery. The drug-regime is based primarily on EEG-background picture (namely synchronisation and de-synchronisation), which the author claims plays a crucial role in epileptogenesis and/or enhancement of epileptic recruitment. Thus an EEG (both in wake and sleep states) shall be a pre-requisite. The novel drug-regime promises to alter the cortical background-activity in a manner to render it un-favorable for epileptogenesis/enhancement of epileptic recruitment, thereby attempting to produce control over Intractable Epilepsy. The new drug-regime, by virtue of its properties to alter the EEG-background activity, thus could enhance the efficacy of conventional treatment and together, they could form a highly effective management for Intractable Epilepsy, thus minimising the intervention of invasive techniques like VNS and epilepsy brain surgery. 2003 Elsevier Science Ltd. All rights reserved.

INTRODUCTION Epilepsy is prevalent throughout the world. It affects any age and sex. Majority of epileptics are fairly controlled by conventional anti-epileptic drugs, be it monotherapy or polytherapy. But there still remains a considerable number of patients who are refractory to all forms of drug treatment and they fall in the class of Intractable Epilepsy. Epilepsy brain surgery is effective in only a fraction of these patients (success is limited to mainly Mesial Temporal lobe resection); others receive some relief with adjunctive treatment by Vagal Nerve Stimulation (VNS); both are invasive surgical procedures and highly expensive with definite limitations and unpredictable efficacy.

THE HYPOTHESIS Neurophysiological basis The author has worked out a drug combination/regime (for Intractable Epilepsy) based on the underlying principle of Synchrony of cortical neurons leading to epileptogenesis. There is overwhelming evidence that synchronous firing of an abnormally large number of cortical neurons generates epileptic potentials and likewise de-synchronisation is associated with reduction or total abolishment of the epileptic potentials. In fact, so strong is this association that the author claims de-synchronisation may form Natures inherent mechanism of anti-epileptogenesis in the body, as occurs during REM Sleep. If this synchrony among the cortical neurons is disrupted, the epileptic firing can be interrupted or at least decreased in frequency, thereby producing control over Intractable Epilepsy. De-synchronised/low voltage EEG background is totally absent or rare in epileptics (1); whereas high voltage (high amplitude) may be considered epileptic from EEG point of view (2). A very highly convincing evidence follows from a recent study (published in Epilepsia-2002 itself), which

Received 10 September 2002 Accepted 11 November 2002 Correspondence to: Harinder Jaseja MD, 8, C-Block, Near Paliwal Health Club, Harishanker-puram, Lashkar Gwalior, MP 474001, India. Phone: +91-751-2331147; E-mail: dr_jaseja@yahoo.com

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shows that low frequency stimulation of anterior Thalamus leads to EEG synchronisation making cortex more susceptible to seizures; whereas high frequency stimulation leads to EEG de-synchronisation rendering cortex less susceptible to seizures (3). There are established drugs and physiological states which are well documented to produce either synchronisation (cortical susceptibility to seizures) or de-synchronisation(cortical resistance to seizures)(as recorded by EEG). Keeping in view this basis of epileptogenesis, a drugcombination/regime has been put forward by the author in order to exercise control over Intractable Epilepsy. Chronic/repeated suppression of epileptogenesis/ propagation of epileptic potentials (during de-synchronisation) may eventually lead to abolishment/reduction in frequency of seizures.

7. Phenothiazines Produce SWS-EEG (NREM) and are contra-indicated in epilepsy (16). 8. MAOI They are potent REM sleep inhibitors and contra-indicated in epilepsy (17). De-synchronisation: De-synchronisation: inhibits burst activity and recruiting response (therefore prevention of epileptic potential propagation) (18). 1. Alertness Associated with EEG desynchronisation reduces seizure frequency (19). 2. REM sleep.

EEG-oriented basis Synchronisation: 1. Hyperventilation: causes synchrony and precipitates epilepsy (4). It is a Provocative Technique during EEG recording. 2. Sleep: (5,6): It also is a Provocative Technique, a significant number of epileptics reveal inter-ictal epileptiform activity in their EEG only during sleep. Hypersynchrony of sleep facilitates both initiation and propagation of partial seizures. It is well known that NREM sleep causes increased susceptibility to epilepsy. 3. Spiky epileptic discharge means more synchronisation of unit cell populations (7). 4. Spike is caused by synchronisation of population group 1 neurons (8). 5. 5-Hydroxy-tryptamine (serotonin) also has been implicated in epileptogenesis and anti-serotonin are anti-epileptic (9,10). 5-HT 2A receptor activation causes slow depolarisations and enhancement of excitatory signals such as glutamate (11) and cyproheptadine is 5-HT 2A blocker (12), therefore should be anti-epileptic, anti-serotonin (cyproheptadine) has anti-convulsant activity (13). 6. Anti-depressants: They decrease REM sleep and epileptic threshold (14). They increase serotonergic activity (serotonin produces SWS sleep). They increase latency to REM sleep and decrease total REM sleep duration (15).
Medical Hypotheses (2003) 61(2), 231234

Associated with EEG desynchronisation inactivates generalised bursts and all abnormal discharges usually disappear during REM sleep (20). No seizures during REM sleep (21). Generalised events increase in NREM and decrease in REM (22,23). Focus tends to get restricted spatially therefore focal epilepsy with secondary generalisation reveals the occult focus (as the generalisation discharges are abolished) (22). MAOI have very strong selective action on suppression of REM sleep (17,24), therefore contraindicated in epilepsy. p-Chlorophenylalanine (anti-serotonin):  Selectively decreases concentration of serotonin (therefore could suppress NREM sleep).  Produces low voltage fast EEG activity (desynchronisation) therefore should be anti-epileptic. Physostigmine (anti-cholinestrase):  Produces REM sleep, cortical arousal and alertness.  Crosses blood brain barrier and EEG arousal (25), also causes EEG changes similar to that of Amphetamine therefore should be anti-epileptic.  Atropine abolishes EEG de-synchronisation by anti-ChE (26) and produces EEG synchronisation, i.e., high voltage, slow activity (27). Physostigmine is used in treatment of poisoning with phenothiazines and tri-cyclic anti-depressants (28). 3. Amphetamine: Adjunctive treatment in Petit-mal and Grand mal epilepsy (29). Increases alertness (30), therefore should be anti-epileptic by virtue of its alertness effect (de-synchron-

2003 Elsevier Science Ltd. All rights reserved.

Intractable epilepsy management: an EEG-oriented approach 233

ising effect), produces stimulation of RAS (31). Amphetamine has also had following indications (32): (a) May control certain cases of temporal lobe epilepsy. (b) Useful in aborting seizures in certain nocturnal epilepsy. (c) In certain behavioral problems in children with abnormal EEG. Epilepsy during drowsiness (33): AED like phenobarbitone (which produce drowsiness) should be avoided as they increase the frequency of the attacks, therefore Amphetamine adjunction could be effective. Epilepsy during relaxation after work (34): Could be due to relaxation after work being associated with increased a-activity in EEG (a feature of synchronisation), probably a rebound increase in a-activity and build-up of synchrony. YOGA meditation: Produces relaxation and EEG-a synchrony, continued relaxation leads to hyper-synchrony (35,36) and therefore could precipitate an attack in an epilepsy-prone person (in the authors opinion). The mental relaxation which occurs during Meditation could also enhance epileptic recruitment as mentioned in previous section (epilepsy during relaxation after work). Kiloh and Osselton (37) observed decreased a-activity on left side during an arithmetical task, but during Meditation there occurred inter-hemispheric symmetry in a rhythm. This greater inter-hemispheric coherence could aid in propagation and generalisation of epileptic potentials (in the authors opinion). PROPOSED DRUG REGIME A single or a combination of two or more of the following drugs would form the hypothetical drug-regime:
Physostigmine: REM production(de-synchronisation), Cortical arousal and Alertness. Amphetamine: Anti-serotonin: Alertness (de-synchronisation) CNS stimulation, release of nor-epinephrine e.g., p-chlorophenylalanine, cyproheptadine

a frank attack. It is a common observation that many epileptics often have attacks during early sleep and some have attacks only during this period. On the other hand, de-synchrony (spontaneous, as occurs in REM sleep and alertness OR induced esp. druginduced) may be deployed to bring about a significant control over Intractable Epilepsy. It is a common experience that epileptics engaged in attentive work, even like car-driving in crowdy areas (which requires alertness) seldom have attacks, it is mainly while driving on a lonely and vacant road that the driver becomes relaxed (synchronisation of EEG background) and therefore is at a greater risk of sustaining an attack. The de-synchronisation associated with REM sleep and its protective effect on epileptogenesis may be accepted as an indication of Natures inherent mechanism of Anti-epileptogenesis, because the increased synchronisation occurring with deeper stages of sleep [i.e., stages 3 and 4, marked by gradually increasing synchronised h and d activity akin to that seen during hyperventilation (which is well documented provocative measure of epilepsy)] is apt to precipitate an attack in an epileptic and to make a non-epileptic person epilepsyprone. The periodic break (interruption) in this deepening synchronising slow-wave sleep by REM stages may thus be a potent anti-epileptic factor and also may provide (to some extent) an answer to the purpose of REM stage of sleep in humans apart from its memory-consolidating role. As mentioned earlier, neuroscientists have recently achieved relief in epileptic-activity on thalamic-stimulation (3); if the same could be obtained by drug(s) simulating thalamic-de-synchronisation, it could obviously be a miraculous achievement in the management of Intractable epilepsy. The above drugs are not totally novice to the treatment of epilepsy (they have been used in the past to a variable extent). This hypothesis envisages a re-orientation of rational application of the drug-regime as an adjunctive aid to conventional anti-epileptic drugs. REFERENCES
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DISCUSSION From the ongoing documentation and event-related phenomena, it can be appreciated that Synchrony (random or otherwise) of cortical-neuronal-activity is a high risk factor for being favorable to epileptogenesis and/or spread of epileptiform activity, many times precipitating
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