Journal ofNeurology, Neurosurgery, and Psychiatry, 1977, 40, 179-185

Effects of oral amines on the EEGD. F. SCOTT, A. M. MOFFETT, AND M. SWASH

From the Section ofNeurological Sciences, The London Hospital, Whitechapel, London

SUMMARY Oral tyramine activated pre-existing episodic EEG abnormalities-namely, sharpwaves, spike and wave, and localised theta activity-in epileptic patients. Little change was found inthe EEGs of migrainous subjects after chocolate or beta-phenylethylamine. The implications of thefindings with tyramine are discussed.

In our earlier studies on groups of patients withmigraine, dietary migraine, and with migraine andepilepsy, it was shown that the administration of oraltyramine increased pre-existing EEG abnormalities(Scott et al., 1972). This EEG activation was ob-served both in patients whose migraine was appa-rently precipitated by the ingestion of foods con-taining tyramine and in patients who had bothmigraine and epilepsy, but not in those whosemigraine was unrelated to dietary factors. The EEGchanges consisted principally of an increase in theamount of episodic slow activity and sharp com-ponents over the temporal areas. These findings,and the observation that tyramine activated experi-mental epileptic foci in monkeys (Scott et al., 1972),have led us to investigate the effect of oral tyramineon the EEG of patients with epilepsy alone, using asimilar design to that of our previous studies.Preliminary results have been reported elsewhere(Swash et al., 1975).Although patients with migraine frequently report

that chocolate seems to precipitate their headache(Hanington et al., 1970), a double-blind investigationof the effect of chocolate in triggering migraineheadache in susceptible patients did not confirm thiseffect of chocolate (Moffett et al., 1974). In thepresent study EEG recordings were made afteringestion of chocolate and after placebo. In addition,a similar group of patients were given beta-phenyl-ethylamine, the amine present in chocolate andconsidered to be important in migraine (Sandleret al., 1974; Chaytor et al., 1975). Here EEGs werealso performed.

In this report we shall describe the detailed EEGresults in these groups of patients and discuss theimplications of the results.

Accepted 21 September 1976

Cliniical methods

TYRAMINE AND EPILEPSYFifteen patients with epilepsy were studied (Swashet al., 1975). Their ages ranged from 16 to 63 years(mean 36 years). There were eight patients withidiopathic epilepsy and six with temporal lobeepilepsy. The remaining patient had Jacksonianseizures. All had at least one fit every month. Theyhad been attending the neurological clinic at TheLondon Hospital for treatment of their epilepsy formany years. There was no history of migraine or ofany relationship between food substances and theirseizures. The patients continued anticonvulsanttherapy throughout the investigation. They weregiven tyramine hydrochloride 125 mg or its matchinglactose placebo, in capsule form, at an interval of aweek using a balanced, double-blind design. Eachpatient then had an EEG recorded about four tofive hours after ingesting each capsule.

CHOCOLATE AND MIGRAINETen migrainous subjects whose ages ranged from 34to 62 (mean 41) years were studied. These patientswere carefully selected to include only those withdefinite classical migraine, who had excluded cocoa-containing products from their diet because they werecertain that these precipitated their headaches. Theycontinued their regular anti-migraine medication, ifany, throughout the investigation. These patientswere given a bar of chocolate weighing 44 g and itsmatching placebo in a balanced double-blinddesign. The chocolate bars contained approximately18 g of cocoa solids, and were similar to those usedin a previous investigation (Moffett et al., 1974).These, and the placebo bars were administered atintervals of at least a week. Approximately five hoursafter ingestion an EEG was recorded.

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D. F. Scott, A. M. Moffett, and M. Swash

BETA-PHENYLETHYLAMINE AND MIGRAINEA second group of 10 migrainous subjects, whoseages ranged from 42 to 62 years (mean 51 years)all of whom had classical migraine and who hadexcluded cocoa-containing products from their dietbecause they were certain that these precipitatedtheir migraine, were studied. For these patients asimilar design was used but capsules containingbeta-phenylethylamine 3 mg or its matching lactoseplacebo were given. EEG recordings were madeabout five hours after each capsule had been ingested.

EEG methods

The EEGs were recorded on Elema Schbnanderapparatus using a standard technique. As far aspossible the two records on each patient were madeby the same technician using the same apparatusin the same room, at the same of day (Margerison

et al., 1967). The electrodes were placed according tothe international 10/20 system and transverse as wellas average reference montages were employed.Hyperventilation was always carried out, as this hadbeen frequently observed to potentiate abnormalitiesin our earlier studies on the effect of tyramine on theEEG of migrainous subjects (Scott et al., 1972).When the studies had been completed, the pairs of

EEGs from each patient were coded, masked, andrated without reference to whether the active orinactive substance had been administered. Ratingswere carried out by M.S. and D.F.S. according tocriteria established in previous investigations (Scottet al., 1972). Assessment of background activity andof the occurrence of paroxysmal features was madeseparately. The raters were asked to decide which ofeach pair of records was the more abnormal: thiswas subsequently related to ingestion of the activesubstance or its placebo. The occurrence of head-

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Fig. 1 A S9yearoldpatient with intractable temporal lobe epilepsy. TheEEG taken afterplacebo(P)showsirregular slow activity over the right temporalarea but after tyramine (T)sharp wavesandsharp/slow complexesare evident over the right temporalregion.

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Effects oforal amines on the EEG

aches or epileptic attacks related to ingestion of theactive substance or its placebo was also assessedat each visit and subsequently by a questionnaire,returned in a stamped, addressed envelope 48 hourslater, as in previous studies (cf. Moffett et al., 1972).

Results

TYRAMINE AND EPILEPSYAgreement was reached as to which of the pair ofEEGs was the more abnormal in 14 of the 15 epilepticpatients. In the remaining patient no difference couldbe discerned between the records made after tyramineand placebo. In 11 of the 14 pairs of records the moreabnormal EEG was that made after tyramine(p <0.01). In these 11 patients the pre-existing EEGabnormalities were markedly accentuated (Figs. 1, 2,and 3). This effect was more pronounced during andafter hyperventilation (Fig. 4) so that focal sharp

waves and bursts of atypical spike and wave as wellas paroxysms of slow activity became more promi-nent, especially over the temporal areas. There waslittle effect on background activity. No patientexperienced a seizure in the 24 hours after capsuleingestion.

CHOCOLATE AND MIGRAINEIn four of the 10 subjects the EEGs recorded afterchocolate were more abnormal than after placebo;in four there was no change, and in two the recordwas found to be more abnormal after placebo. Thesedifferences did not reach significance. All fourpatients whose EEGs were rated as activated afterchocolate tended to have disorganised backgroundactivity with episodic theta activity, sharply con-toured theta forms, and a few sharp waves (Fig. 5).These abnormalities were mildly accentuated byoverbreathing.

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Fig. 2 A 40year oldpatient with temporal lobe epilepsy. TheEEG taken afterplacebo (P)shows lefttemporalsharp waves but after tyramine (T) there is not only sharp wave activity but a widespreaddisturbance ofslow wave type appears mainly over the left hemisphere.

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D. F. Scott, A. M. Moffett, and M. Swash

BETA-PHENYLETHYLAMINE AND MIGRAINEIn five of the 10 patients the EEG recorded afterbeta-phenylethylamine was assessed as the moreabnormal of the pair (Fig. 6). In three no differencecould be discerned between the two records and intwo the EEG made after placebo was rated as themore abnormal. In each of these patients the differ-ences between the two records was slight, consisting,in three of the five EEGs activated by beta-phenyl-ethylamine, of sharpened theta forms and sharp waveepisodes. There was some accentuation in two ofthesepatients during hyperventilation.

Discussion

Our earlier studies with oral tyramine in variousgroups of migrainous patients showed that pre-existing EEG abnormalities were increased in allbut the non-dietary group (Scott et al., 1972).However, we were unable to demonstrate that

tyramine induced migrainous headache in thesepatients (Moffett et al., 1972). Similarly, we havefound that chocolate failed to induce migrainousheadache, even in apparently susceptible subjects,when investigated in a double-blind study (Moffettet al., 1974). In the present investigation the effectsboth of chocolate and of beta-phenylethylamine onthe EEG in these migrainous subjects have beenexamined, as it has been suggested that beta-phenyl-ethylamine is the active amine in chocolate (Sandleret al., 1974; Chaytor et al., 1975). However, asneither chocolate nor beta-phenylethylamine inducedsignificant activation of pre-existing EEG abnormali-ties it must be concluded that tyramine has a differentand more important effect on the central nervoussystem in migraine (Scott et al., 1972) than doeschocolate or beta-phenylethylamine.

Since we have shown previously that tyramineaccentuated the pre-existing abnormalities in patientssuffering from both dietary migraine and migraine

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Fig. 3 A 25yearoldpatient withgeneralisedfits. The restingEEG (P) taken afterplacebo capsuleshows a mildabnormality consisting ofsharp waves in the left temporalarea. After tyramine (T)hadbeen administereda burst ofpolyspike andwave is seen. This has a markedright-sided,post-centralemphasis.

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with epilepsy (Scott et al., 1972) the next part of thepresent investigation has been concerned with theeffects of tyramine on patients with epilepsy but with-out a history of migraine. In this group we havedemonstrated that tyramine markedly increased ab-normalities found in the resting EEG of a significantproportion of patients. Sharp waves, spikes, and spikeand wave were particularly augmented. These arethe EEG features found in the inter-ictal records ofpatients with frequent fits (Dawson et al., 1961;Rowan et al., 1975).Although none of these patients experienced a

seizure in the 24 hours after tyramine ingestion, oneobvious possible implication of these findings is thattyramine may be an important factor in the bio-chemical changes associated with the induction ofattacks in patients with epilepsy. There are other

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clues which suggest that tyramine or similar aminescould be important in epilepsy-for example,tyramine is a substrate for monoamine oxidase in thecentral nervous system, and seizures can be pre-cipitated in susceptible individuals by the adminis-tration of monoamine oxidase inhibitor drugs(Shepherd et al., 1968). Further, Chadwick et al.(1975) have reported increased monoam.inemetabolite concentrations in the CSF of epilepticpatients, although these changes could have beendue to anticonvulsant drugs. In addition, however,Shohmori et al. (1975) have observed reducedlevels of monoamine oxidase in the circulating bloodplatelets of patients with epilepsy, some of whomwere not receiving anticonvulsant medication.Clearly, further studies along these lines could proveof great interest.ffi>-1- \ .. ,..'

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Fig. 4 A 35year oldpatient withgeneralised convulsions. Immediately after overbreathing, theplaceboEEG (P)shows somepost-centralslow components. These occurred in a moregeneralisedfashion andwith greaterprofusion after tyramine (T)hadbeen administered.

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D. F. Scott, A. M. Moffett, andM. Swash

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Fig. 5 A 54year oldmigrainouspatient whose attacks occurredafter the ingestion ofchocolate.TheEEG afterplacebo (P)shows some irregularity with theta waves in the temporal channels. Aftereating chocolate (C) this was enhancedand was seen also on the opposite side. Some ofthe thetacomponents on both sides hadasharpenedoutline.

We are grateful to the patients who took part in thesestudies; to Miss Sue Virden, the chief technician andthe other technicians of the EEG Department whomade the recordings, and to Mrs Held for secretarialhelp.

References

Chadwick, D., Jenner, P., and Roberts, E. H. (1975).Amines, anticonvulsants and epilepsy. Lancet, 1,1425-1426.

Chaytor, J. P., Crathorne, B., and Saxby, M. J. (1975).The identification and significance of 2-phenylethyl-amine in foods. Journal of Science, Food and Agricul-ture, 26,593-598.

Dawson, J., Anderson, W. McC., and Margerison, J. H.(1961). Water, electrolytes and the EEG in a case offocal cortical epilepsy with diabetes insipidus onvarying drug regimes. Epilepsia (Amsterdam), 2,144-160.

Hanington, E., Horn, M., and Wilkinson, M. (1970).Further observations on the effect of tyramine. InBackground to Migraine. 3rd Migraine Symposium,

1969, pp. 113-119. Edited by A. L. Cochrane. Heine-mann: London.

Margerison, J. H., John Loe, P. St., and Binnie, C. D.(1967). Electroencephalography. In Manual ofPsycho-physiological Methods. Edited by P. H. Venables, andMarten Irene. North Holland: Amsterdam.

Moffett, A., Swash, M., Scott, D. F. (1972). The effect oftyramine in migraine: a double-blind study. Journal ofNeurology, Neurosurgery, and Psychiatry, 35, 496499.

Moffett, A. M., Swash, M., and Scott, D. F. (1974). Theeffect of chocolate in migraine: a double-blind study.Journal ofNeurology, Neurosurgery, and Psychiatry, 37,445-448.

Rowan, A. J., Pippenger, C. E., McGregor, P. H., andFrench, J. H. (1975). Seizure activity and anticonvul-sant drug concentrations. Archives of Neurology(Chic.), 32,281-288.

Sandler, M., Youdin, M. B. H., and Hanington, E. (1974).A phenylethylamine oxidising defect in migraine.Nature, 250, 335.

Scott, D. F., Moffett, A., and Swash, M. (1972). Observa-tions on the relation of migraine and epilepsy. Anelectroencephalographic, psychological and clinicalstudy using oral tyramine. Epilepsia, 13, 365-375.

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Fig. 6 A 5I yearoldmigraine sufferer who hadobservedthat chocolateprecipitatedattacks. TheEEGafterplacebo (P)shows some sharp components in the left temporalregion. These were slightlyaugmentedand vere seen over both temporal regions after the administration ofbeta-phenylethylamine(B).

Shepherd, M., Lader, M., and Rodnight, R. (1968).Clinical Pharmacology. English University Press:London.

Shohmori, T., Kaneyuki, T., Kobayashi, K., Mori, A.,and Kohsaka, M. (1975). Reduced blood plateletmono-amine oxidase activity in epileptic patients.

IRCS. Medical Science, Clinical Pharmizacology andTherapeutics, 3,558.

Swash, M., Moffett, A. M., and Scott, D. F. (1975).Tyramine activates the EEG in epileptic patients.Nature, 258, 749-750.

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