Epilepsy; a Review of Basic and Clinical Research

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DOCUMENT RESUME ED 026 761 EC 002 478 By- Robb, Preston Epilepsy; A Review of Basic and Clinical Research. NINDB Monograph Number 1. National Inst. of Neurological Diseases and Blindness (DHEW),Washington, D.C. Repor t No- PHS -PUB -1357 Pub Date 65 Note- 79p. Available from-Superintendent of Documents, U.S. GovernmentPrinting Office, Washington, D.C. 20402 ($0.45). EDRS Price MF-$0.50 HC Not Available from EDRS. Descriptors-Biochemistry, Classification, Clinical Diagnosis, *Epilepsy,Etiology, *Exceptional Child Research, Genetics, Incidence, Infectious Diseases, Medical Research, MedicalTreatment, Neurologically Handicapped, Pathology, Research Reviews (Publications), Seizures, *Special Health Problems A discussion of the incidence of epilepsy isfollowed by a discussion of etiology including the following causes: genetic and birthfactors, infectious diseases, toxic factors, trauma or physical agents, heredofamilial anddegenerative disorders, circulatory disturbances, metabolic and nutritionaldisturbances, and neoplasms. Epilepticseizuresare classified by symptoms,duration,precipitatingfactors, postictal phenomena, behavioral disorders associatedwith epilepsy, and related paraxysmal disorders; patterns of attack aredescribed. Diagnosis and pathology are considered along with treatment by anticonvulsantdrugs (available drugs are listed), dietary and surgical treatment, indications andresults of surgery, and prognosis. References follow each chapter. (JM)

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uNADREB MONOGRAPH No. 1

U.S. DEPARTMENT OF HEALTH, EDUCATION &WNEI

OFFICE OF EDUCATION

THIS DOCUMENT HAS BEEN REPRODUCED EXACTLY AS RECEIVEDFROM THF.

PERSON OR ORGANIZATION ORIGINATING IT.POINTS OF VIEW OR OPINIONS

STATED DO NOT NECESSARILY REPRESENT OFFICIAL OFFICE OFEDUCATION ,41 POSITION OR POLICY. EPILEPSY

, i. areview of basic andclinical research

Prepared for the National Instituteof Neurological Diseases and Blindnessby Preston Robb, M.D., VisitingScientist, Office of Program Analysis,National Institute of NeurologicalDiseases and Blindness,Bethesda, Maryland, 20014

U.S. DEPARTMENT OF HEALTH,EDUCATION, AND WELFARE Public HealthService,NationalInstitutesof Health National Institute of NeurologicalDiseases and Blindness

1965 :,

Public Health ServicePublication No. 1357

Office Fior sale by the Superintendent of Documents,U.S. Government Printing Washington, D.C., 20402 -Price 45 cents PREFACE

General recognition of the magnitude of the problems associated with the epilepsies stimulated this comprehensive study into the history, basic pathophysiology, and the programs of treatment focused on epilepsy.It is hoped that the information in this review will provide guidelines for areas needing special attention. This review has been prepared under the sponsorship of the National Institute of Neurological Diseases and Blindness, which has been active in conducting and supporting epilepsy research since the establishment of the Institute in 1950.Appre- ciation is expressed to its Director, Dr. Richard L. Masland, for his stimulation and encouragement in the development of this report.

P. R.

Hi TABLE OF CONTENTS

Page Introduction General Review of Epilepsy Epidemiology Etiology 4 Classification of the Epilepsies 27 Diagnosis 37 Pathology 43 Treatment 46 Prognosis 67 VS,M.

INTRODUCTION

Epilepsy has been defined as a group of conditions characterized by recurring convulsions.From the time that records have been made on the illnesses of man, epilepsy has formed a prominent part.The early history of "The Falling Sickness," as recorded by Temkin (1945), Lennox(1960) and others, is an interesting story, but contributed little to an understanding of the true nature of the disorder.The theories of its origin were a mixture of magic and religious fantasy, and according to Thomas Willis (1684), the early approaches to treatment :frequently did more harm than good. In the Hippocratic (1849) collection of medical papers, written about 400 B.C., a physician hinted at the truth when he wroteof epilepsy, "Its origin is hereditary like that of other diseases."(Hippocrates, Adams translation 1849, vol. 2, p. 843 from Lennox.)He recognized that the seat of the trouble was in the brain and expressed the opinion that the precipitating factors of the attack were cold, sun, and windswhich changed the consistency of the brain.These cosmic phenomena he considered divine and since they influenced all diseases, all diseases were divine.At the same time they were human because of their physiologicalsubstratum.Epilepsy, therefore, should not be treated by magic, he suggested, but rather by diet and drugs. The first ray of hope for the patient came in 1857 when Sir Charles Locock reported the successful use of bromides in the treatment of hystero-epilepsy.It was not until 1912 when Alfred Hauptmann published "Die Behandlung bei Epilepsiemit Luminal," that seizures were first treated with any degree of success and safety.In 1937, Merritt and Putnam, while testing the ability of drugs to prevent electrically induced convulsions in cats, discovered diphenylhydantoin.The drug was effective without seritus side effects, and the following year these investigators reported its successful use in humans.Phenobarbital and diphenylhydantoin continue to be the core of treatment for most patients having epilepsy.Nevertheless, many more drugs have been developed, and some are remarkably effective.Outstanding among them are trimethadione and ethylmethyl succinamideused in the treatment of petit mal, and primidone and mesantoin, used in the more generalized convulsive disorders. About the same time these advances in drug therapy were occurring, and following the leadership of Hans Berger (1933) , the electroencephalogram was being developed, and a new era of understanding and hope opened for the person with epilepsy. The words of St. Mark of the young man who, since childhood had "adumb spirit," which "taketh him, it clasheth him down, and he foarneth and grindethhis teeth and pineth away" and "cast him both into the fires and into the waters tode- stroy him," describe very well the seizure and many ofthe problems of the victim. Although the convulsive seizure represents the popular conception of epilepsy, it is only a part of the problem.The epilepsies compose a group of disorders in which the common factor is a paroxysmal, excessive, neuronal discharge withinthe brain. It is accompanied by a sudden disturbance offunction of the body or mind.The disturbance, whether it is loss of consciousness,disturbance of the mind, excess or Joss of muscle tone or movement, disorders of sensation orspecial senses or disturbances of the autonomic functions of the body is subservient tothe part of the brain involved. The basic disorder of the epileptic neurone lies inthe instability of the cell membrane.It results in an excess've or prolongedneuronal discharge due to excessive depolarization and, possibly, lapses in repolarizingand hyperpolarizing mechanisms. Membrane stability and polarization are intimatelyrelated to ionic balances across the membrane and to mechanisms of oxidativemetabolism.In addition to intrinsic mechanisms, extrinsic factors contribute to theepileptogenic neurone or neurones ; namely, excessive bombardment of cells byimpulses arriving over fiber pathways from a distance, andalterations in the chemical environment ofcells due to systemic metabolic changes or disorders. A study of the epi epsies involves the basicneurophysiological events taking place within the neurone or groups of neurones andtheir dendrites, as well as the extra neuronal abnormal factors contributing tothe activities and life of the cell which lead to the epileptic discharge.It also involves the study of incidences, causes, methods of diagnosis, pathology, treatment,prognosis, and generally, the natural histnry of the disorders. Epilepsy constitutes a serious social and publichealth problem.It has been reported that 1 person in 200 suffers fromepilepsy.Actually, accurate figures for the number of people who have had a convulsion orepileptic seizure at some time during their lives is unknown.There is no accurate figure, either, of thenumber of people with brain damage and epileptic seizures who areunable to advance through a normal course of education, begainfully employed, and adjust normally insociety.It is clear that the incidence of epilepsy is increasing.One reason is that formerly many patients with epilepsy would have died ofbirth injuries or other abnormalities acquired early in life.The effective use of antibiotics and generalmedical care now are saving manychildren with meningitis, brain abscesses,encephalitis, severe head injuries, and brain tumors, thus contributing tothe increase of disabling disorders. Any illness or disorder which is capable ofaffecting the structure or function of the brain may cause seizures.This is why they are better referred to as"the epilepsies."Etiological factors may include congenitalanomalies, disorders during intrauterine life, brain injury acquired aroundthe time of birth, infections, trauma, vascular disturbances, metabolic and nutritionaldisturbances, tumors, degenerative diseases or other genetic disorders. There are many different types of seizures.However, as yet, no classification has been universally accepted.The attack may be a tonic-clonic typeof seizure with loss of consciousness and a postictal confusion statemuch like that described by St. Mark. This is generally referred to as a grandmal attack.On the other hand, the attack may be a transitory pause,"absence," or loss of consciousness, lastingonly a few seconds.This is called a petit mal seizure.The attack may originate in any one part of the brain, and begin with a motor or sensory aura.It may manifest itself with automations, delusions, or hallucinations.One could say that there is adifferent type of attack for every regionof the brain involved.In addition to the actual seizure itself, there are behavioral disordersassociated with epilepsy which frequently are more disablingthan the attacks themselves. A careful history and physical examinationstill constitute a most important aspect in the diagnosis and evaluation of epilepsy;however, modern techniques of X-ray and electroencephalography, biochemistry, psychologyand others, have done much to elucidate our understanding of the epilepsies. viii Anticonvulsant drugs provide the basis of treatment;however, they leave much to be desired and bettermedications are urgently needed.Some patients with a focal type of epilepsy can behelped with surgical therapy.In addition to medical and surgical therapy, however, all patients requirekind and thoughtful consideration to help them take their places in society. Research studies are being conducted on thephylogenesis and ontogenesis of seizures, the genetics of epilepsy, and thechemistry and physiological background of the epileptic seizure.Studies of experimental epilepsy have done much toimprove our understanding ofthe actual epileptic discharge.Also, new techniques are being developed continuously to advance our knowledgeof these disorders. A broad survey indicates thatthere are many areas in the basic sciences inwhich further research is urgently needed, particularly in the studyof the mode of action of anticonvulsants on the nervous system.There is a particular need to develop newanticonvulsants and to provide the means of testingthese compounds safely and carefully. There are still many questions relating to thenatural histories of the disorders which await answers.Many problems at a clinical level remain tobe solved by single or collaborative studies.Finally, there is a need to find ways of makihg the best in medical therapy available to all patients.

Bibliography Berger, H., Ober das Elektrenkephalograrnm desmenschen.Arch. Psychiat. 100: 301, 1933. Hauptmann, A., Lumina! bei Epilepsie.München.Med. Wchnschr.59: 1907, 1912. Hippocrates, The Genuine Works of Hippocrates.Vol. I and II, Francis Adams Translation, London, The Sydenham Society, 1849. Lennox, W. G., Epilepsy and Related Disorders.Boston, Little, Brownand Co., 1960. Merritt, H. H., Putnam, T. J., Sodiumdiphenylhydanioinate in the treatment of convulsive disorders.J.A.M.A. 111: 1068, 1938. Putnam, T. J., Merritt, H. H., Experimental determinationof anticonvulsant properties of some phenyl derivatives.Science, 85: 525, 1937. Temkin, 0., The Falling Sickness.The Johns Hopkins Press, Baltimore, 1945. Willis, T., Practice of Physick.London, H. Clark, T. Dring, C. Harper and F. Leigh, 1684.

ix General Review of Epilepsy -

EPIDEMIOLOGY

The accurate incidence of epilepsy is not known. (Lessell, Torres and Kurland, 1962) where the rate The difficulties involved in diagnosis (e.g., whether was 3 per 1,000.All such studies are open to criticism the patient with one or two seizures may be considered from one approach or another. In the Rochester study, an epileptic, whether the seizures resulting from a Kurland is probably correct when he suggests that the known brain disease, such as phenylketonuria or brain rates are minimal since patients who had only one tumors, constitute epilepsy), as well as the reluctance "known" convulsive attack were not included.Fur- on the part of doctors and patients to report the dis- thermore, despite the unusual nature of the commu- order, complicate the problem of determining the true nity, the possibility of patients being "undeclared" or incidence. being treated elsewhere also must be considered. Kurland (1959, 1960) conducted a study over a ten There were 101 children who had convulsions dur- year period to determine the incidence and prevalence ing febrile episodes.This means only 10 a year. For of convulsive disorders in a small urban community a city with a 30,000 population this seems to be an (Rochester, Minn.). Although he believed that a large incredibly small number.Lessell, Torres and Kur- majority, if not all, of the local residents with diagnosed land's (1962) studies, on Guam, of febrile convulsions convulsive disorders were included in the survey, the would tend to substantiate this criticism.The inci- computed rates must be considered as minimal values. dence was 5 per 1,000. Lennox suggests (1960) that Recurrent convulsive disorders were classified as grand something like 2 percent of children in the community mal, petit mal, focal, including temporal lobe and psy- have one or more febrile convulsions in their first 5 chomotor; and miscellaneous seizures.Febrile con- years, or perhaps 2.3 percent at any age. The evidence vulsions were considered separately. For the recurrent for this figure is not very sound. disorders the average annual incidence rate, age-ad- Taknaka and Aramitsu (1962) studied 626 patients justed to the U.S. population, is about 31 per 100,000 with epilepsy at the Hiroshima University Hospital and per year. The incidence rates are higher among males concluded that the incidence of epilepsy in infancy than among females for all types of seizures combined, and childhood was increasing.It was interesting that and for most individual categories. The incidence rate 15.5 percent had past histories of febrile convulsions. for primary grand mal seizures is highest in infancy Ueki and Sato found the incidence of epilepsy in and early childhood and decreases rapidly after adoles- Niigata City to be 17.3 per 100,000 population. They cence; the same is noted for petit mal cases.For the estimated that if the ages were limited from birth to secondary grand mal and focal seizure groups, the 14, the incidence would be 32 per 100,000 population. highest incidence rates appear at the extremes of the The highest incidence was from 10 to 14 years. Grand age scale.Abnormalities relating to birth and development in infancy presumably were responsible for the mal seizures were most common in all age groups. high rate in childhood, whereas toxicity (alcoholic), Psychomotor seizures rapidly increased between ages vascular disease, and brain tumors were important pre- 10 and 14.These investigators reported that seizures cipitating factors in the older age group.The preva- could be controlled in 34 percent of all cases. lence rates for all types of epilepsy, age adjusted to the For a review of the statistical background of epilepsy, U.S. population, is 3.7 per 1,000 population.This reference should be made to Lennox, chapter 15 is comparable to that found in the study on Guam (1960).

1 54 As part of a genetic study,Metrakos and Metrakos Menigiornata (Supratentorial) Neurochirugie (1960) found that the prevalence ofchildren with a DeVet, A. C. and Ponuen, H. irrespective of cause, 8: 363, 1962 history of at least one convulsion, Phenylketonuria 36 was 11.50-1-.1.01 percent among1,000 serial admis- Partington, M. W., Pediatrics 27: 465,1961 sions to the Montreal Children'sHospital.If children Phenylketonuria 26 who were admitted to the hospitalbecause of their Paine, R., Pediatrics 20: 290, 1957 convulsions were omitted from thestudy, the preva- Supratentorial tumor in children 25 lence would be reduced to8.76±9.91 percent. The Backus, R.E.,Millichap,J.G.,Pediatrics prevalence would be reduced stillfurther, to 6.55± 29: 978, 1962 12 0.80 percent, if children whohad convulsions as an Infratentorial tumor in children Backus, R.E.,Millichap,J.G.,Pediatrics associated symptom of their diseases werealso omitted. 29: 978, 1962 It is clear that any condition thataffects the brain, either physically or chemicallypredisposes the patient Although only approximate figures on theincidence to seizures of one kind oranother. The likelihood of are known, thereis no question that the epilepsies con- the patient's developing seizures isdependent upon the stitute a grave problem.It may cause complete dis- nature and severity of theinsult, the age of the patient, ability and inability to work.It may be related to genetic background, andchanges in the metabolic cerebral palsy, mental retardation orbehavior disor- getting or keep- state.In no one case can an accurateprediction be ders which prevent the patient from made. The following table suggeststhe relative fre- ing a job. The economic loss to the countryis great. quency of seizuresin some disorders. The associated social stigma, fear andsuperstition cause great unhappinessfor the patient and concern TABLE IRelative Frequency ofEpilepsy in Spe- for the family. reveal cific Disorders Further study of its incidence is not likely to its causes or method of prevention;however, it will Percent clearly bring to the attention of thepublic at large 44 Porencephaly and legislators in particular, theseriousness of the Arch.Neurol.andPsychiat. Naef,R.W., problem of epilepsy.It will enable them to realize the 80: 133, 1958 5. 6 great cost of caring forthe disabled patient having Closed brain trauma well as Dereux, J. and Dereux, J. F., Rev.Oto-Neuro- epilepsy, with or without allied conditions, as Ophth. 30:48, 1958 the need for further research intothe causes, methods Hypertensive encephalopathy 20 of prevention and treatment. Hudson, A. J. and Hyland, H. H.,Ann. Int. Med. 49: 1049, 1958 Carotid insufficiency 20 Bibliography Keirns, M. M. and Whiteleather,J. E., Amer. J. Roentg. 81: 929, 1959 Backus, R. E., Millichap, J. G., Theseizure as a manifesta- Spontaneous intracerebral hematoma 55 tion of intracranial tumor inchildhood.Pediatrics 29: Silverman, D., Groff, R. A., Sagen, W.,Neu- 978, 1962. rology 9: 75, 1959 Copeland, G. D., von Capeller,D., Stern, T. N., Systemic 18. 2 lupus erythematosus: A clinical reportof 47 cases with Systemic lupus erythematosis Amer. J. Med. Sc. 236: 318, Copeland, G. D., von Kapeller, D., Stern, T.N., pathologic findings in 18. 1958. Amer. J. Med. Sc. 236: 318, 1958 centrales des trauma- 22 Dereux, J., Dereux, J. F., Les siquelles Cerebral cysticercosis tismes craniens fermis: les siquellesneurologiques.Rev. Lombardo, L., Mateos, J. H., Neurology 11: 825 Oto-Neuro-Ophth.30 : 48, 1958. 1961 37 Drake, W. E., Macrae, D., Epilepsyin multiple sclerosis. Cerebral cysticercosis Neurology 11: 810, 1961. Stepien, L. J., J. Neurosurg. 19: 505, 1962 Gonzales, D., Elvidge, A. R., Onthe occurrence of epilepsy Multiple sclerosis 4. 5 caused by astrocytoma of thecerebral hemispheres.J Drake, W. E., Macrae, D., Neurology, 11:810 Neurosurg. 19: 470, 1962. 1961 Hudson, A. J., Hyland, H. H., Hypertensivecerebrovascular Bacterial meningitis 4 disease: A clinical and pathologicreview of 100 cases. Kresky, B., et aL, Arch Pediat. 79: 63, 1962 Ann. Int. Med. 49: 1049, 1958. 48 Keirns, M. M.,, Whiteleather, J. E., Theangiographic study Cerebral astrocytomas ischemia.Am. J. Gonzales, D. and Elvidge, A. R., J. Neurosurg. of carotid insufficiency and cerebral 19: 470, 1962 Roentg. 81: 929, 1959.

2 Kersky, B., Buchbinder, S., Greenberg, I. M., The incidence Partington, M. W., The early of neurologic residua in symptoms of phenylketonuria. children afterrecovery from bac- Pediatrics 27: 465, 1961. terial meningitis.Arch. Pediat. 79: 63, 1962. Silverman, D., Groff, R. A., Kurland, L. T., IncidenceanJ prevalence of convulsive Sagen, W., Clinical and EEG studies and spontaneous disorders in a small urbancommunity.Epilepsia 1: 143- intracerebral hematoma.Neu- 161, Dec. 1959. rology 9: 75, 1959. Stepien, L. J. Lessen, S., Torres, J., Kurland,L. T., Seizure disorders ina cerebral cysticercosis inPolandclinical Guamanian village.Arch. of Neurol. 7: 37-44, 1962, symptoms and operative results in 132cases.J. Neuro- Lombardo, L., Mateos, J. H.,Cerebral cysticercosis in Mexico. surg. 19: 505, 1962. Neurology 11 : 825, 1961. Taknaka, H., Aramitsu, Y.,A survey of epilepsy in Naef, R. W., Clinical infancy features of porencephaly: Areview of and childhood.Psychiat. Neurol. Paed. Jap. 2:303, 1962. 32 cases.Arch. Neurol. & Psychiat. 80: 133, 1958. Ueki, K., Sato, S., Anepidemiological study of epilepsyin in- Paine, R. S., The variabilityin manifestations of untreated fancy and childhood in patients with phenylketonuria. Niigata City.Psychiat. Neural. Pediatrics 20: 290, 1957. Paed. Jap. 3: 3, 1963.

3 ETIOLOGY

The causes of epilepstare multiple.The seizure it- Perinatal jaundice self, is a symptom of an underlyingdisorler of the Prematurity brain which may be structural,chemical, physiologi- Infectious Disorders cal or a combination of all three.The basic physico- Meningitis chemical phenomena that take place maybe common Purulent to all seizures, but the causevaries from patient to Tuberculous patient.It is preferable to refer to them as"the epilep. Virus sies."Today, after a careful history andexamina- Parasitic and fungus tion; a cause can usually be found. A strongfamily Epidural or subdural abscess history may indicate that it is truly agenetic disorder. Brain abscess and granuloma There may be a history of a difficultbirth, postnatal Metastatic head trauma, a nutritional or toxicdisorder, tumor Direct spread and so on.Frequently, one has to consider the possi- Encephalitis bility of many causes that lower thethreshold and in- Virus duce seizures. Other (including parasites) The following etiological classificationis meant as Fever (febrile convulsions) a guide.It has been useful as a reminder thatthere epilepsy. More important, it serves Toxic Factors are many causes of monoxide) especially for storing and retrieving case Inorganic substance (e.g. carbon as an index, mercury) records of patients with epilepsy due tospecific causes. Metallic substance (e.g. lead, It has also proven useful as a partof the "information Organic substance retrieval key word dictionary" atthe National Insti- Alcohol tute of Neurological Diseasesand Blindness, for stor- Other age of literaturerelated to the etiology, pathology and Drugs treatment of these specificdisorders as related to Allergic disorder Ingestion of foreign protein epilepsy. Vaccination or injection of foreignprotein Epilepsy due to: Pregnancy medical conditions) Genetic and Birth Factors Other (uremia or other toxic Genetic influence (idiopathic,cryptogenic, essen- Trauma or Physical Agents tial) Acute craniocerebral injuries Congenital abnormalities (includingchromosome Subdural or epidural hematomaand effusion abnormalities) Post-traumatic meningo-cerebralcicatrix Antenatal factors (infections, drugs,anoxia, etc.) Anoxia or hyperoxia (includingdrowning) Perinatal factors Circulatory Disturbances Birth trauma Asphyxia neonatorum Subarachnoid hemorrhage Perinatal infections Sinus thrombosis

4 Encephalomalacia due to Minsk and Birth Factors Thrombosis Embolus The Role of Genetics in the Epilepsies Hemorrhage Early in the century epilepsy was divided into two Hypertensive encephalopathy Arteriosclerosis and arterial occlusive disease, intra- types, idiopathic and symptomatic.The term "idio- cranial and extracranial pathic" inferred that the cause was not known, the Vasospasm (e.g. migraine) bruin was structurally intact, and heredity was an important contributing factor. Other termsmeaning the Syncope "essential," and Changes in blood (anemia, hemorrhagic diathesis) same thing, such as "cryptogenic," "genetic" were used. "Symptomatic" inferred a type of Metabolic and Nutritional Disturbances epilepsy where the cause was known. The attitude to- Electrolyte and water imbalance day, in the light of the most recent genetic studies,is Sodium that a genetic or hereditary factor is present in allof Calcium the epilepsies. The greater this factor the morelikely Hydration or dehydration are seizures to occur in aspecific cerebral disorder. Other It was William Lennox who started the postwar Carbohydrate metabolism interest in the genetics of epilepsy when in 1951, he Hypoglycemia published the results of a genetic study on 4,231 epilep- Diabetes tics, and 20,000 near relatives. He showed that there Glycogen storage disease was a significantly higherincidence of seizures in fam- Protein metabolism ilies of patients with "essential' epilepsy than in families By "essen- Phenylketonuria of patients with "symptomatic" epilepsy. tial," he meant that no cause could be demoristrated, Porphyria and by "symptomatic" he meant those with an ante- Other cedent history of brain injury. This was really the first Fat metabolism significant work since it was first suggested by Hippoc- Lipoid storage diseases rates centuries before, proving that there was anheredi- Other tary factor in epilepsy. A subsequentstudy by Lennox Vitamin deficiency and Jolly (1954) on 173 twin pairs tended to support Pyridoxine deficiency the previous findings; however, there were thosewho Other continued to criticize their conclusions. Endocrine disorders In 1950, Alstr6m reported on a study of the near rela- Menstruation tives of 897 patients with epilepsy. He found the prev- Other alence of epilepsy was no higher in these relatives than Neoplasms the prevalence in the same control group usedby Primary intracranial Lennox.This work was not generally accepted and Metastatic subsequent work by Metrakos end others have most Lymphoma and leukemia certainly disproved Alström's conclusions. Blood vessel tumors and vascular malformations In 1940 Lennox, Gibbs and Gibbs first suggested (e.g. arteriovenous malformation, Sturge-Weber that cortical dysrhythmia underlying the epileptic di- syndrome) athesis was inherited as a Mendelian dominant factor. Harvald (1954) divided his index cases according to Heredofamilial and Degenerative Diseases their electroencephalograms and studied the relatives Multiple sclerosis of 203 "cryptogenic" and 34 "symptomatic" epileptics. Leucoencephalopathy He estimated the morbidity risk for parents, siblings Tuberose sclerosis and offspring to be between 4.2 and 5.1 percent for the Cerebellar degeneration with convulsions cryptogenic group, and 1 percent for the symptomatic Other group. The morbidity risk in thewhole group (2.65 Psychogenic Causes to 3.2 percent) was significantlyhigher than in the gen- Cause Unknown eral Danish population (0.46 percent) .Harvald con- 5 eluded that epilepsy WC Li not asingle genetic entity group had acentrencephalic type of EEG abnormality, had such an and that its inheritance wasprobably polygenic. whereas only 2 of the 84 control parents difference between Ounsted (1955), working with 1,000children who abnormality in their EEG's. The 2.4 percent, is statistically had "any sort of fit," concludedthat genetic factors the 2 percentages, 7.7 and were important in all typesof seizures. On the other significant. Livingston inter- The EEG data for 223 siblings ofpatients with cen- hand, in 1960, Eisner, Pauli, and siblings of controls viewed members of families of 669epileptic patients, trencephalic epilepsy and 103 In the centrencephalic including 3,361 close relatives, and of 460control pa- showed a striking difference. approximately twice as many siblings tients, including 2,858 close relatives.They concluded group there were percent) as in the control that hereditary transmission ofepilepsy could not be with abnormal EEG's (53.4 demonstrated nor could it be ruled out.They sug- group (28.2 percent) .When only epileptiform dys- of idiopathic major rhythmias were considered, theprevalence among the gested that familial aggregation (46.2 percent) motor epilepsy may be due tofamilial aggregation of siblings of the centrencephalic group high as the control group (15.5 per- perinatal brain injury, to inheritance, or to acombina- was three times as cent).It is of great significancethat this difference tion of these factors. higher number of siblings The most comprehensive study onthe genetic as- is due ahnost entirely to the carried out by Metrakos with centrencephalic EEGabnormalities in the cen- pects of epilepsy is that being than in the control and Metrakos. At the time of their last reportthey had trencephalic group (36.8 percent) studied approximately 1,200 familiesof epileptics and group (8.7 percent) . than 3,000 electro- In order to analyze the effect of age onthe presence 400 control families, as well as more EEG ob- encephalograms on patients, parents andsiblings. or absenceof the centrencephalic type of findings in cen- normality, the EEG's of the parentsand siblings were They first reported (1960) on their individual at the trencephalic epilepsy, which, by definition,has a char- grouped according to the age of the obtained.Their findings acteristic electroencephalogram, a paroxysmalbilater- time that the record was important bearing on ally synchronous 3 per secondwave-and-spike or a clearly reveal that age has an since there is a slight variant of this. They compared211 typical and whether the EEG trait will be present definite peak for age 41/2 to 16/2 years.For this age atypical centrencephalic patients,with 112 controls, 45 percent of siblings tested had drawn from hospital patients whohad no history of group, approximately convulsion and whose electroencephalograms were the centrencephalic EEG trait. if due allowance is within normal or borderline normallimits. It would appear, therefore, that, of the centrence- Their findings clearly demonstrated afamilial dis- given for the variability of age at onset also for its tend- tribution of convulsions. As the geneticdistance be- phalic type of EEG abnormality and these the patient increases, ency to disappearin later years, the data which tween the relative studied and the hypoth- the prevalence of affected individualsdecreases ( from investigators collected is compatible with is responsible approximately 13 percent in the parents andsiblings to esis that an autosomal dominant gene More recently, Metra- approximately 2 percent in the grandparentsand cou- for the centrencephalic EEG. On the kos and Metrakos have testedoffsprings and nephews sins) in the cise of the centrencephalic group. patients, and the domi- other hand, it tends to fluctuate within narrowerlimits, and nieces of centrencephalic be holding true. around 2 percent, for each class ofrelatives in the con- nant hypothesis appears to autosomal trol group. When all the relatives wereconsidered to- Because of the strong evidence that an centrencephalic gether, prevalence for the centrencephalic group was dominant gene was responsible for the Metrakos studied 2.2 times greater and significantlyhigher than for the EEG abnormality, Metrakos and patients with "symptomatic" .epilepsyresulting from control group. reduce, as much In view of the fact that thepatients selected for definite neuropathology. In order to tremendous heterogeneity of "sympto- this study were ascertained primarily onthe basis of a as possible, the in their electro- matic" epilepsy they chose to comparethe prevalence highly specific type of abnormality dysrhythmias among the encephalograms, the EEG findings of195 parents of of convulsions and/or cerebral hemiplegics having convulsions with centrencephalic and 84 parents of controlprobands near relatives of without convul- compared. On the whole, no startlingdif- that of near relatives of hemiplegics were also that the prevalence ferences were found; for both groupsthe total number sions. Their results clearly showed of individuals with convulsions washigher among all of EEG abnormalities wasapproximately 14 percent. with convulsions However, 15 of the 195 parents of thecentrencephalic classes of relatives of the hemiplegics

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than among similar classes of relatives of the hemi- lepsy was more common in veterans with apositive plegics without convulsions.(The overall difference family history of convulsions, and that there is a is highly significant for P=0.001) .Furthermore, the genetic factor in this disorder. prevalence of epileptiform dysrhythmias among the Rodin and Whelan (1960) found, in EEG studies, parents and siblings of hemiplegics withconvulsions that there is a pronounced tendency to familialin- was higher than among the parents andsiblings of cidence of temporal abnormalities.More recently, the hemiplegics without convulsions.It is interest- Barslund and Danielsen (1963) reported on the occur- ing that in another study, Glenting (1963) found that rence of abnormalelectroencephalograms in three in patients with congenital spastic hemiplegia, genetic families of monozygotic twins suffering from "cryp- factors had some influence on the presence of intel- togenic" temporal epilepsy. In all three families, spike lectual retardation and seizures. foci were found in the temporal region in near rela- As part of their overall study, Metrakos and Metra- tives of the twins, in the ascending and descending line, kos also investigated the genetic aspects of febrile con- or there were reports ofepileptic seizures.In all the vulsions. A prospective longitudinal study has been cases studied, exogenous factors seem tohave been made of 106 children whose first convulsion was labeled less important than hereditary factors.In particular, "febrile."Sixty-three percent of these have had ad- there was nothing to suggest that birth trauma played ditional convulsions since entering the group.Most any role. From these studies oneis forced to conclude of them have had their second convulsive episode that genetic factors contribute to other types of epi- within a year of their first.Of those with additional lepsy besides that with a bilaterally synchronous elec- Convulsions, 36 percent had convulsions other than troencephalographic abnormality. febrile.Such a high percentage had subsequent con- Dr. Julius Metrakos summarized the findings of vulsions not associated with fever that they wondered Dr. Katherine Metrakos and himself on the results of whether there actually is such a thing as a "simple their genetic studies in epilepsy. In looking for genetic febrile convulsion."Approximately 10 percent of factors in "the epilepsies" their search led them to a the siblings of children whose first convulsion was consideration of three major categories of genes, each febrile also had convulsions. The study of the elec- of which might contribute to an individual's resistance troencephalograms of children with febrile convulsions or susceptibility to convulsions.The three categories and of their siblings revealed that approximately 60 were :(1) cerebral disease genes or genes which pro- percent of the patients and 60 percent of theirsiblings duce such hereditary disorders as tuberose sclerosis, had some form of EEG abnormality. This prevalence phenylketonuria, etc.; (2) threshold genes, the genes is at least twice that found in a control group. which enable one man to have a lower threshold for In contradistinction to the work of Colver and Ker- convulsion than another; therefore, one man will have ridge (1962) these investigators did not find that convulsions associated with a specific disease, whereas birth order was a significant factor in the prevalence the other will not; (3) epilepsy "per se" genes, or genes of epilepsy. which may be etiologically linked with well-defined The work of Metrakos and Metrakos clearly indicate forms of epilepsy. They felt that one such gene had that there is an autosomal dominant gene responsible been isolated for centrencephalic epilepsy. for the centrencephalic EEG abnormality. They also The parents of an epileptic child want to know the suggest that genetic factors are partlyresponsible for chances of the child's brother's or sister's developing "symptomatic" or "acquired" epilepsy.Bray and epilepsy.Based on a study of the siblings of a con- Wiser (1962), after a study of children and their fami- vulsant group and a control group, Metrakos and lies, believe that the common form of focal epilepsy Metrakos believed that the following statements could in children is transmitted as an autosomal dominant be made: trait, and is not sex linked.The EEG trait and the (1) A sibling of a nonepileptic child has at least a associated seizure disorder express themselves with 3 percent chance of having some type of convulsion. greatest frequency between the ages of 5 and 12 years. (2) Siblings belonging to a heterogenous group of Rodin (1963) has recently pointed out the familial convulsors have approximately a 10 percent chance of occurrence of 14 and 6 persecond positive spike phe- experiencing at least one convulsion. nomena. Schwartz (1962)has recorded the familial (3) A sibling of a child with a dominaht cerebral occurrence of photosensitivity.Evans (1962) and disease has a modified 50 percent chance of having Caveness (1963) suggested that post-traumaticepi- convulsions. (4) A sibling of a child with arecessive cerebral known to cause severe multiple congenitalmalforma- disease has a modified 25 percent chanceof having tions.Wolf and Cowan (1959) pointed out the role disease, convulsions. of syphilis, toxoplasmosis, cytomegalic inclusion (5) The siblings of hemiplegics withconvulsions bacterial meningitides and meningoencephalitis,and have approximately a 6 percent chance ofhaving some other infections in the prenatal and perinatalperiods type of convulsion.(This risk is probably applicable as causes of damage tothe central nervous system. to various forms of cerebralpalsy or of "acquired" Improper implantation of the placenta may affect Trauma epilepsy.) the growth and development of the foetus. been (6) The siblings of children whose firstconvulsions from a blow to the lower abdominal region has were febrile have a10 percent chance of having con- reported as a cause of cerebral damage andintrauterine Severe tox- vulsions.This risk is at least twice that of the control convulsions (Ozan and Gonzalez, 1963). the group. emia or anoxia, regardless of the cause may affect (7) The siblings of a child withcentrencephalic brain of the foetus and cause subsequentseizures. epilepsy have (a) a 50 percent chance ofinheriting Lilienfeld (1954), in a study of 564 epilepticchildren, the dominant pathological gene and being, atleast, a was able to demonstratethe important role that the carrier; (b) approximately a 40 percent chanceof hav- complications of pregnancy and delivery played inthe ing a demonstrable centrencephalic EEG pattern;(c) subsequent development of seizures. approximately a 15 percent chance of having atleast one convulsion irrespectiveof etiology; and (d) ap- Perinatal Factors proximately a 10 percent chance of having centrence- Birth trauma and asphyxia neonatorum are twoof phalic epilepsy. the most important causes of brain damagewith sub- It is apparent that much more work,unfortunately retardation, and cerebral elucidate the sequent epilepsy, mental long and tedious, needs to be done to Although these disorders are mentioned sepa- dem- palsy. role of hereditary factors in focal epilepsy, as rately, it is frequently impossible to separate onefrom onstrated in the EEG, and epilepsy secondary todis- the other.Extensive reviews by Ford (1960) , Mas- tinct pathological lesions of the brain at all ages. land (1958), Dekaban (1959) and others areavail- able.In the bibliography at the end of thissection Congenital Abnormalities are listed some of the moresignificant studies of the The literature is replete with references tocongeni- roles of perinatal factors as causes of epilepsy. tal abnormalities associated withconvulsions.The The clinical findings and the cerebralpathology were seizure is a symptom, and may occur with any struc- presented, in a very careful review byCraig (1960), tural abnormality of the brain.Seizures are common of newborn babies who had convulsionscommencing in children with porencephalic cysts,microcephaly, within 10 days of birth.Three hundred seventy-four Arnold-Chiarri malformation and so on.The tera- newborn babies were included in thestudy, of whom togenic effects of drugs and radiation havecaused an 158 died and came to autopsy. Craigpointed out how upsurge of interest inthis field and may do much to rarely a precise diagnosis could be madeduring life. unconsciousness, and prevent the related congenitalabnormalities.Mental Convulsions in the presence of retardation and epilepsy are frequently a partof the of deepening cyanosis not responding to oxygen total abnormality seen in childrenwith chromosomal therapy suggest pressure on the mid-brain orbrain abnormalities. The most common, of course,is mon- stem caused by hemorrhagearising from a dural tear. punc- golism or Down's Syndrome.Whether convulsions An uncontrollable encephalopathicpicture, will occur in these disorders depends onthe extent tuated by convulsive seizures,following difficult de- of the abnormality and the activity ofwhat Metrakos livery of a large or postmature infant issuggestive of calls "threshold genes." intracerebral and/or intracerebellarmultiple peri- vascular hemorrhages. The dramaticallysudden ap- Antenatal Factors pearance in a prematurechild of violent, generalized and an agonizingly of certain convulsions, a bulging fontanelle, Reference has been made to the effect intraventricular hemor- and their piercing cry is in keeping with drugs taken in the early months of pregnancy Otherwise, there is no clinicalpicture char- roles in the production ofcongenital abnormalities. rhage. al. 1956), notably acteristic of intracranialpathology of a particular Some virus infections (Adams, et Ter- rubella (German measles), early in pregnancyare kind or with a particularanatomical location. incidence (19.6 per- of their pathological ex- Churchill (1959) found a high rninal convulsions irrespective with 3.4 percent of thegeneral popu- planation and of the maturityof the infant tend to cent compared lation who are born by breechbirth) of breech birth be violent and general.In other circumstances con- babies are in patients who hadepilepsy of the type associated vulsions encountered in small premature spike-and-wave EEG dis- generally of a subdued character. with bilaterally synchronous turbances. His studies suggestthat breech delivery is Lubcheno and colleagues (1963)reported on 63 pre- an importantfactor in the pathogenesis ofthis disorder. mature infants of lowbirth weights at 10 years of age. be an important mal seizures, one had Breech delivery did not seem to They found that one had petit focal cerebral seizures. had "convulsions." factor, however, in the origin of temporal lobe seizures and six and strains associ- colleagues has led to a This would suggest that the stresses The work of Wind le and his tend to damage the dien- further understanding of the roleof asphyxia in the ated with breech delivery cephalic region of the brainrather than the cortex newborn as a cause of cerebraldamage (Wind le, 1958; region. Ranck and Wind le, 1959; Baileyand Wind le, 1959), or hippocampal of The role of birth order as a causeof cerebral in- and the role that asphyxiaplays in the production of epilepsy, has They induced jury at birth, and subsequent cause kernicterus (Lucey, et al.,1964). Colver and Kerridge monkeys near term for 11 to been a controversial subject. asphyxia neonatorum in (1962) studied 174 cases ofcentral (21), focal (45), 16 minutes, followed byresuscitation. A common pat- 10 or in the or undifferentiatedepileptics who had suffered tern of structuralalteration was encountered "it has Nuclei more "convulsiondays" and concluded that, nervous systemof the asphyxiatedmonkeys. reasonable doubt that epi- affected; those most severelydam- been established beyond a were symmetrically lepsy as defined above is morefrequent in first than aged were the nucleus ofthe inferior colliculus, grac- nuclei, roof nuclei of the cere- in second born children." ile and median cuneate The findings of Metrakosand Metrakos (1963), bellum, ventral posterior groupof thalamic nuclei and The parity of and vestibular nuclei. however, do not substantiatethis. the globus pallidus, putamen considered from two vascular distribution was not 1,279 patients with epilepsy was The relation of lesions to (pregnancies resulting in apparent. Hemorrhages wereseldom encountered. points of view, birth order order (all pregnan- Wind le (1963) found thatnewborn monkeys need live infants only) and pregnancy On the basis of the not be asphyxiated tothe point of terminal apnoea cies irrespective of outcome). the elec- in order to suffer structuralbrain damage. Asphyxia presence orabsence of convulsions, as well as neonatorum requiringresuscitation of the offspring, troencephalograms, the pregnancyorder of nine groups which otherwise would die, wasassociated with a re- of convulsant patients and two groupsof nonconvul- markably constant syndromeof bilaterally symmetri- sant probands wasanalyzed.In none of these 11 cal, nonhemorrhagiclesions in thalamic andbrain groups was pregnancyorder found to be otherthan The stem nuclei, mainlythose of afferent systems. randomly distributed.When live births only were clearly retarded monkeys in this second category were considered, an analysis ofthe various convulsantand associated postpartum mentally, and demonstrated control groups failed toreveal any birth ordereffect. atrophy, often of complications leading to neo-cortical These investigators, failing todemonstrate one, sug- considerable magnitude.They were not only remark- conclusions based on theassumed often palsied, epileptic, andin gested that profound ably retarded, but also association of birth orderwith epilepsy be withheld some instances evencomatosed. Wind le alsofound until such an associationhas been demonstrated. that increased intrauterine pressurein the monkey during prolonged laborled to fetal and post-partum Infectious Diseases depression.In this connection,cerebral cortical injury occurred in the absenceof typical asphyxiallesions. Infectious diseases of the nervoussystem and their It is significant thatasphyxia neonatorum, uncom- relationships to epilepsy havebeen extremely well re- plicated by trauma, causesdiffuse symmetrical lesions. viewed by Dekaban (1959)and Ford (1960).Con- that birth trauma causes a Ford (1960) points out vulsions may accompany anyacute infection ofthe localized cerebrallesion, with asymmetricalparalysis result from the damage done the nervous system or may and focal epilepticattacks usually beginning on inflammatory process. Thedam- found that the onset ofconvulsions to the brain by the affected side. He localized, as seen in a brainabscess, or delayed until 10 or more yearsafter age may be was sometimes diffuse as in a virusencephalitis. birth. manifestation of an recently reviewed Seizures are frequently the first Nyhan and Richardson (1963) Increased intracranial pressure, meningitis.Convulsions may acute brain abscess. the complications of lead one to the correct herald the onset of meningitis or may appearyears fever, a running ear, etc. may However, apart from the signsof an ex- after the illness.The seizure during the onsetand diagmosis. panding intracranial lesion there maybe nothing to acute course of thedisease may be due to localized it may be due to lead one to suspect an abscess.Many a surgeon has cortical, venous, or arterial occlusion; what he thought was a the "toxic" state or thefever alone may precipitate been surprised to find that localized abscess. the attack.Seizures of late onset aresecondary to tumor, was, instead, a They are often diffi- Tuberculomas of the brain arerelatively uncommon the meningo-cerebral cicatrix. in which the nutrition is cult to treat medically, and thediffuse nature of the in this country, but in races incidence of tuberculosis is high,and the scar makes it unlikelythat they will be amenable to poor, the natural immunity is low, calcifiedlesions of the brain surgery. meningitispar- are frequentlyfound, indicating healed orhealing tu- Any child who has had bacterial Tiberin ticularly influenzalwho fails torespond to antibi- berculosis.(Armstrong and Edwards, 1963; and convulsions, should and Beller, 1963.)Trichinosis has been shown to be otics, and has a persistent fever seizures (Perot, et al., 1963) .Stepien be suspected of having a subduraleffusion.Investi- a cause of be contemplated. (1962) reported on 132 cases ofcerebral cysticercosis, gation of the subdural space should Twenty-two An infant or young child who startshaving convul- 37 percent of whom hadconvulsions. with cysticercosis studied by sions, has a square looking head andsigns of increased percent of the patients convulsions. intmcranial pressure, should besuspected of having Lombardo and Mateos (1961) had study of Western and subdural effusion. The mechanismby which Zeifert, et al. (1962) , in a a chronic show a consistent collections of subdural fluid occur in acertain number St. Louis encephalitides, failed to clear.Gitlin (1955) correlation between followupelectroencephalographic of patients with meningitis is not patient either determined immunochemically theconcentrations of findings and the clinical status of the patients with sub- during or after the acute illness.They suggested that albumin and gamma globulin in necessarily reflect dural accumulations of fluid inbacterial meningitis, the electroencephalogram did not and following the effects of a viral encephalitis.Finley (In Smadel, following pneumoencephalography, the sequelae in viral encephali- In all three conditions the levels werequite et al., 1958) found that trauma. behavioral disorders, similar, and in each, the ratio ofalbumin to gamma tis consists of motor impairment, In children with globulin in the subdural fluid wasconsiderably higher mental retardation, and convulsions. all types of sequelae occur.In the than in the serum. The data suggestedthat the basic severe damage, in all of these less severely damaged, oneimpairment may appear mechanism by which fluid accumulates Children under 10 have a better conditions is an effusion of fluidthrough damaged or without the others. chance of surviving the acute illness,but are more inflamed capillary walls. residuals. The most common sequelaeof viral encephalitides likely to have severe disabling are disturbancesof movement, sleep, behavior, orin- telligence, but seizures are not uncommon.The type Febrile Convulsions of seizure depends somewhat onthe degree of matu- Febrile convulsions present a specialproblem in Myoclonic massive spasms, focal ration of the brain. epilepsy.There are children who haveconvulsions motor attacks, petit mal, orgeneralized convulsions associated with fever only. They havenormal electro- have all been described. encephalograms between seizures, and appearnormal Aguilar, and Rasmussen (1960)showed that focal examination. The attacks disappear adults who on neurological cerebral seizures in children, and young rs the child growsolder. This is what may be called be symptomatic show evidence of deterioration, may true "febrile convulsions."Unfortunately, many chil- pathological changes in- of chronic encephalitis. The dren who have their first seizureassociated with a clude widespread perivascularcuffing, microglial ac- related to an inflammation, vascular fever may have subsequent seizures not tivity, chronic leptomeningeal elevated temperature, or they mayhave demonstrable changes, gliosis, neuronaldepopulation and, rarely, in- cerebral abnormalities and fever tends toprecipitate an tranuclear inclusion bodies inneuroglial cells.The found that of 106 chil- changes most likely represent asmoldering viral infec- attack. Metrakos and Metrakos dren whose first convulsion waslabeled "febrile," 63 tion.Ultimate proof must rest uponserological and convulsions.Of those with virus isolation studies. percent had additional

10 lr

additional convulsions, 36 percent had convulsions produces focal or diffuse cerebral anoxia and irreversi- other than febrile.They also showed that there was ble brain damage (Fowler, 1957; Schmidt, 1958) . a strong genetic factor in "febrile convulsions."Ap- proximately 10 percent of the siblings of children whose Toxic Factors first convulsion was febrile themselves had convulsions. One is led to agree that "threshold genes" play There are specific drugs known to affect the polari- a significant role in the occurrence of febrile convul- zation of cell membranes sufficiently to produce con- Pentylenetetrazol (metrazol) is the outstand- sions. vulsions. A great deal of significant work has been done in ing example.This is used as a means of activating this area (Lennox, M., 1947, 1949; Peterman, 1952; electroencephalograms and provides a useful means of testing the anticonvulsant properties of certain drugs. Fridericksen and Melchior, 1954; Schmidt and Ward, 1955; Millichap, 1959, 1960; Jennings, 1959; Milli- There are many toxic substances that affect the brain sufficiently to produce convulsions.The mechanism chap, Madson and Aledort, 1960). Problems still remain, however, which continue to be debated actively. varies with different groups of compounds or conditions. Some have a direct effect on the metabolic ac- How should one define "febrile convulsions"?Are they due to fever alone, in a patient with low thresh- tivity of the neurone and its conducting apparatus. Others have a with- old, or is there a toxic factor?In this connection the Strychnine is an example of this. finding of Kowlesser and Forbes (1958) is significant drawal effect.This is seen in alcoholism or certain Others exert an indirect ef- that 42 percent of patients with shigellosis had a con- types of drug addiction. vulsion when their temperature reached 104.2° F., but fect, by causing an impairment of circulation as in. only 11 percent had convulsions with a fever of 100.6° lead poisoning. to 102.2° F. Fischler (1963) also found an in- Lyon, Dodge, and Adams (1961) describe a com- creased incidence of convulsions in children with mon neurological syndrome of children known as acute idiopathic or toxic encephalopathy ; it consists of fever, shigellosis.Prichard and McGreal ( 1958) suggest that it is the rate at which the body temperature rises, convulsion, stupor or coma, decorticate or decerebrate These in- and not the infecting organism, which seems to be im- postures, and respiratory embarrassment. In all except portant in causing convulsions.Wegman (1939) vestigators reported on 16 fatal cases. two cases, the syndrome was ingrafted on an evident working with kittens found that convulsions frequently febrile illness of variable type, the cause of which was occurred if the temperature was elevated rapidly, but Generalized convulsions were the rarely if the temperature rose slowly. seldom identified. The manner in which the febrile convulsion is dominant symptom, often ushering in the neurologic disorder and recurring throughout the acute phase of treated is also a very contentious problem. Some authors recommend no treatment for the first attack. the illness.Lyon, Dodge, and Adams concluded that this was an acute encephalopathy, separable from a Others use the EEG to help make a decision.Some treat the child with anticonvulsants and/or antipyretics primary systemic electrolyte or fluid abnormality, arte- whenever there is a fever.Others start regular anti- rial or venous thrombosis, meningitis, and encephalitis. convulsant therapy and continue it for a year or more. In all probability it was closely related to febrile con- There is no doubt that the attitude of the family physi- vulsions and febrile delirium. The fatal issue or per- cian or pediatrician, who sees many children with manent disability appeared to be determined by hy- febrile convulsions, is different from that of the neurol- poxia or anemia of brain tissue.In other words, among ogist who sees only the patients with severe seizures several factors there are at least two operating in all which may have left a residual defect.Like so many the fatal cases: a primary one which is unidentified, problems in medicine, each case must be decided on its possibly toxic ; another which seems to be secondary own merit. and is hypoxic. The role that febrile convulsions, associated with excessively high fever may play in producing mental Inorganic SubstancesCarbon Monoxide retardation, hemiplegia, or persistent epileptogenic foci warrants further study.Insufficient attention has been The toxicity of carbon monoxide is due mainly to paid to the brain damage that excessive, prolonged its much greater affinity for hemoglobin than oxygen. fever and convulsions can cause. A temperature over The carbon monoxide displaces the oxygen and forms 107° F. probably causes the convulsion. The combina- a relatively stable compound, carboxy-hemoglobin, tion of excessive temperature and convulsions, in turn, thus producing an anemic type of cerebral anoxia.

11 than in the gen- The pathology, well described byMeyer (1958) , de- drinking was no heavier in epileptics patient who has some pends on the degree and length of exposure.In cases eral population. However, the of mild exposure, recovery may becomplete.In se- type of epilepsy, is morelikely to have a seizure follow- death, extensive changes are seen ing even a modest amount ofalcohol.The seizures vere cases leading to the in the cortex and basal ganglia.Infants are much occur, not duringthe period of ingestion, but in of drinking.Seiz- more susceptible thanadults. During the acute stage, firbi 48 hours following the cessation likely to occur in patients who havebeen coma may be precededby vomiting, convulsions, and ures are more They may abnormal breathing.A considerable proportion of drinking excessively for a number of years. seizures. The seizures survivors have permanent neurologicalsequelae, in- have a single seizure or bursts of generalized tonic-clonic type. If they cluding mental retardation, behavioraldisturbances, are usually of the than disorders of locomotion, and epilepsy. are focalseizures, some focal brain disease other alcoholism should be suspected. of delirium Metallic SubstancesLead Seizures frequently occur at the onset tremens. Victor andAdams (1953) found 30 patients Lead poisoning is one of the most seriousthings that with seizures among 101 consecutivepatients with de- can happen to a child.It is most common between lirium tremens.Isbell, et al., (1955 ) showedthat the ages of 1 and 3. Residual defects includeepilepsy, symptoms such as nausea,vomiting, tremor, halluci- mental retardation and behavioral disorders.Smith nations, and delirium tremens areprecipitated by a (1964) reported that 40 percent of hispatients who reduction in the blood alcohol level. The symptomsof had encephalopathy developed focal,generalized, or delirium tremens and convulsions areclosely related, a combinationof convulsive seizures as a sequelae. and the severityrdepends on thelength of time and the Most cases today are due to theinhalation of lead amount of alcohol takenbefore withdrawal. Many oxide from improper ventilation during the processof authors state that the withdrawal symptoms aredue to burning.Epidemics have occurred from the burning malnutrition and vitamin deficiency.It has been of battery boxes, and old wooden freight cars,broken shown (Victor and Adams (1953)),however, that up to be used asfuel.Ingestion of old lead paint the symptoms occur despite theingestion of an ade- is still a cause of lead poisoning. In the acute type con- quate diet and supplementalvitamins throughout the vulsions, delirium and coma are oftenaccompanied period of intoxication and withdrawal.Pluvinage by papilledema and other signsof increased intra- and Lelus (1962) demonstrated apyridoxine defi- cranial pressure.Popoff and his colleagues (1963) ciency in 113 cases of alcoholism,although there was point out that the major effect of leadintoxication is no correlationbetween this and the severityof the the alteration of the small vessels producingcerebral clinical picture.It has also been shown (Oura, etal., swelling and oedema. The vessels ofthe cortex are 1963) that alcohol administered to rats causes anin- affected in a similar fashion and to what maybe a creased excretion of pyridoxine,thiamine, and several similar degree. The vascular changes are notlimited other vitamins.For the present, it must bestated to the small vessels but affectthe larger veins as that the exact biochemical phenomenaassociated with well. The venous walls are greatlythitkened and are the alcoholic withdrawal syndromeis not known. composed largely of fibroblasts andcoll?gen fibers, arranged in a disorganized fashion. Thepathological Drugs appearance suggests thatvascular damage .:c the major which have a stim- factor in the cerebral disorde,., There are groups of compounds ulating effect and others that have adepressant effect Given in sufficient dosages, Alcohol on the nervous system. CNS stimulants will produceconvulsions.Goodman Alcohol, or the withdrawal from it, is oneof the and Gilman (1955) have reviewedthe action of such convulsions after the age of most common causes of drugs as picrotoxin, pentylenetetrazol(metrazol) nik- incidence of 30. Rheinhart (1961) found a 10 percent ethamide, strychnine and camphor.In proper dosages from a reView "rum fits" in an alcoholic popuhtion these drugs are used as stimulants or as a meansof mental of 200 consecutive patients admitted to a state Experimentally, actually is activating the electroencephalogram. hospital.He believed that the incidence animals, and are thus (1941) studied they can produce convulsions in higher. On the other hand, Lennox The CNS depres- the alcoholic histories of a largenumber of adult used for testing anticonvulsants. generally raise the convul- patients with epilepsy and found theincidence of heavy sants in therapeutic doses

k t tive children are likely to beborn.In view of the sive threshold.In massive "suicidal" doses,convul- 1938,Baptisti reviewed sions may occur, but these may be asecondary effect obscurity in the literature, in from anoxia rather than a direct effectof the drug. the problem and reported on astudy of 37 patients. Withdrawal symptoms occur followingprolonged use He concluded that epilepsyhas no appreciable effect in of the CNS depressants, especially inthe withdrawals on the course ortermination of a pregnancy, and did not of barbiturates, the majority of the patients, the pregnancy it has been suggested that convulsantdrugs act by affect the epilepsy.Convulsions do occur during inhibiting the production, or blocking theaction, of pregnancy and inthe postpartum period.There an inhibitorysubstanceperhaps related to gamma may be an increase ordecrease in frequency ofseizures sodium amino-butyric acidand, in turn, affecting in an established epileptic.The pregnancy and the sodium ratio, across neu- transport, by decreasing the associated metabolic disturbances mayinitiate seizures work in an ronal membranes. CNS depressants may in a latent epileptic, orseizures may result from an- convulsions may oc- opposite fashion and withdrawal other complication of the pregnancy,such as eclampsia, cur in the periodof adjustment until a normalhyper- brain tumor, or postpartumcortical venous throm- polarized state of the neuronal membranescould be The possibility of pseudoeclampsiashould be reestablished. A greater undtrstandingof the mode bosis. (1955)cites a case of a woman of action of these compoundsshould be sought. born in mind. Robb admitted as an emergency patientbecause of contin- had the marked Allergic Reactions uing convulsions. She was near term, facial changes of advanced pregnancy,and seemed child receives It is not an uncommon story that a confused. A tentative diagnosis ofeclampsia was a "booster shot"for typhoid, poliomyelitis,diphtheria, made; however, her urine wasnormal and there was shortly there- pertussis, etc., (Byers & Moll, 1948) and no oedema.Ftelher questioning revealed thatshe after has a convulsion that may leave aresidual hemi- was severelyretarded mentally with seizures.She This may be transient or permanent.It is paresis. was treated withanticonvulsant medication and de- highly probable that there is a vascularocclusion associated with the hemiparesis. Someof these have been livered spontaneously. Huhmar and Jarvinen (1961) areof the opinion demonstrated by arteriography;however, more fre- epileptic state may be ag- quently than not, nothingabnormal is seen.It has that, during pregnancy, an retention and other been postulated that there is some type ofallergic re- gravated by the physiologic water 96 women with epi- action, causing localized vascular spasm orocclusion, metabolic changes. They studied that accounts for the hemiparesis,and the convulsion lepsy during pregnancy orduring the puerperium. is secondary to the encephalomalacia.Another sug- Epilepsy preceded gestation in59 cases, and 10 women gestion is that the hemiparesis is apost-ictal Todd's had initial symptoms of epilepsyduring intervals be- paralysis, due to "exhaustion" ofthe involved area of tween pregnancies.Epilepsy unrelated to toxemia the cortex.Regardless of the pathogenesis, suchphe- became manifest in18women during pregnancyor nomena do occurand constitute a calculated riskin any delivery. Symptoms originatedduring the puerperium program of massimmunization (Miller and Stanton, in nine cases, and possibly werecaused by thrombosis 1954;Park and Richardson,1953). Acute allergic of the cerebral veins. Obviousworsening was observed encephalopathies, with convulsionsand coma, have in 70 percent of the womenwith serious epilepsy; 42 been known to occur followingthe ingestion of anti- percent in those withmoderate disease, and 17 percent biotics, including sulpha drugsand penicillin.Not in slight cases. These findings are notuniversal. infrequently, a similar state is seenfollowing certain Many patients with epilepsyhave been free of seizures good of the exanthemata.It has been called encephalitis, duringpregnancy.Others who have been under but actually is more likely tobe an allergic encephalop- control have continued control,provided they have athy.The response to steroids maybe very dramatic. continued to take theirmedications.Occasionally, a patient may stop hermedication for fear of affecting Pregnancy the foetus, but anticonvulsantsused today do not have effect. Over the years the mythhas evolved that the patient a teratogenic It is clear that therelationship between epilepsy with epilepsy has moreseizures during pregnancy, and pregnancy requiresfurther clarification. and that pregnancyshould be avoided becausedefec- 13 Trauma or Physical Agents men 7 to 8 years after theirinjuries and found the overall incidence of post-traumatic epilepsy, based on one or more attacks, was 28 percent.Caveness (1963) Trauma followed 356 veterans of the Korean War for a period Acute craniocerebral injuries constitute a prime of 8 to 11 years.Of these, 197 received missile and cause of symptomatic epilepsy.Seizures may occur 159 nonmissile injuries. Of the total, 109 men had one in the acute phase of the injury due to direct cerebral or more seizures that wereclassified as focal, focal and trauma.They may occur in a convalescent or late general, or general in pattern.The initiation of at- stage due to a meningo-cerebral cicatrix, orthey may tacks ranged from the first day until the ninth year. result as a secondary effect as, for example, seizures Half of the men with seizure had their first attack secondary to a subdural hematoma. within 6 months of injury, and four-fifths within 2 The wars in Europe and Korea have provided an years.Early attacks occurred in an equal propor- opportunity to study post-traumatic epilepsy due to tion of men irrespective of mode of injury, but after penetrating and non-penetrating injuries.In a 5-year the first month the significantly greater proclivityfor followup of 820 brain-wounded patients, Russell and the missile-injured to have fits became apparent.The Whitty (1952) found 43 percent were affected by incidence for the missile-injured was 42.1 percent as seizures.In a series of 286 patients followed by Wat- compared with 16.4 percent for the nonmissile-injured son (1952) , 36 percent hadseizures within 2 years of men. The greater thebrain damage, with or without receiving the wound and 41.6 percent within 3 years. penetration of the dura, the greater the incidenceof In 1930, Credner presented his findings on 1990 seizures.If the site of impact was in the parietal re- German cases of war injuries with head trauma. Over gion, the susceptibility to attack was greater than ifthe half had been followed continuously for 5 years or injury was elsewhere.Although the character of the more. Of the total cases,post-traumatic epilepsy was injury played a significant part in the onset of attacks, reported in 38.2 percent.Ascroft, in 1941, reviewed, there was no correlation between the cessation of at- from the records of the British Ministry of Pensions, tacks and the mode, site, or severity of the injury. The 317 cases of gunshot wounds of the head.After a 7- frequency of attacks was higher in those with persistent to 20-year followup, post-traumaticepilepsy, as ad- attacks.Caveness found little correlation between judged by one or more seizures, was reported in 34 the use of the anticonvulsants and the cessationof percent. seizures. Quadfasel and Walker (1947) reported, from 246 As part of the Korean Study, Gaveness (1961) re- cases of penetrating woundsof the head, that patients ported on the sequelae of cerebral concussion.Pa- with infected, penetrating wounds of the parietal region tients included were those who had a delayed lossof were more prone to develop epilepticseizures. Walker consciousness or profund confusion, a loss in con- (1957) followed 244 men of this group for a 10-year sciousness of under 1 hour, or a loss in consciousness period. During that time, 19 died. Of the surviving of more than an hour but less than 6 hours. The as- group, 46 percent had no attack for 2 years,and 36 sumption of complete recovery depended on the clini- percent had no seizure for 5 years.The number with cal course and laboratory findings in the acutephase major attacks fell from 78 in the first year to 18 in the of injury.For practical reasons transient, minimal, 10th year. Walker also showed that the mental status neurological signs were permitted, such as nystagmus of 213 patients correlated closely with their work sta- or bilateral pyramidal tractsigns of short duration. tus.The employed numbered 14 percent if the LQ. Cerebral concussion as defined occurred in 29.7 per- was below 90; 53 percent if it was from90 to 110, cent of 407 men.It was followed by a neurological and 84 percent if it exceeded 110. Many of the un- deficit of 2.9 percent, post-traumatic epilepsy in 11.9 employed were seizure-free and were not neurologically percent, post-traumatic syndrome in 35.9 percent,and impaired.They suffered from a much more com- social and economic failure in 21.9 percent. plex disability than hemiplegia or epilepsy;i.e., a Paillas and his colleagues (1962) studied 216 cases chronic post-traumatic syndrome of insufficient drive, of post-traumatic epilepsy, 50 of which followed open intellectual or physical, which prevents an adequate head injuries and 166, closed head injuries. The inci- adjustment to their disabilities. dence of epilepsy in open head injury could reach37 Walker and Jablon (1959) reported on a study of percent and in closed injuries, 9.4 percent.They U.S. veterans who were head injury casualties from found post-traumatic epilepsy more frequently in men World War II.These investigators examined 739 than in women, and stressed the possibility that alcohol

14 abnormal but nonepileptic With carefully con- (8 ) A normal, or an could be an aggravating factor. time after injury inpatients trolled medical therapy, clinical curecould be expected EEG is common at any who develop late epilepsy,and is, therefore, of nohelp in 50 percent.Surgical therapy was carried out on30 in predicting thelikelihood of this complication. selected patients with satisfactoryresults. the development of post- Jennett (1962) reviewed in greatdetail epilepsy as The factors that determine traumatic epilepsy are outlinedby Walker (1962) .Of it develops in patients afterblunt head injuries. The the intrin "c factors he suggests:( 1 ) hereditary predis- incidence of early epilepsy wasstudied in 1,000 con- position (2) prenatal, nataland post-natal conditions secutive admissions for headinjury to the Accident causing brain damage,(3) childhood neurologicaf- Service in Oxford. To studythe character of early flictions; and (4) systemicdisorders.Extrinsic factors epilepsy, further cases were addedfrom Oxford, as well may include:(1) location of cerebralinjury, (2) as cases fromManchester and Cardiff.The incidence the selected severity of brain damage,(3) complications of of late epilepsy wasdetermined by following a It is clear that there areother number (315) of patients seenin the acute stageof wound and healing. factors besides the braininjury that contribute to post- injury.This group consisted of 75patients in the in- traumatic epilepsy.There are backgroundfactors, clusive series with earlyepilepsy, plus 240 fromthe such as heredity or otherillnesses, and precipitating 1,000 series who did not haveearly epilepsy.This factors, such astelevision,alcohol, or emotional yielded 58 cases of traumaticepilepsy of late onset. disturbances. The total number ofpatients with post-traumatic the brain can 40 of these had seizuresin Other forms of physical trauma to epilepsy studied was 381, but Mawdsley and Ferguson( 1963) re- the study and, therefore, ap- cause epilepsy. the early and late stages of along with other neurologicaldis- Jennett's careful analysis was sum- port that epilepsy, peared twice. orders, occurs in boxers.Subdural hematomas present marized as follows: problem. Cole and Spatz( 1961) reviewed (1) Epilepsy in the first weekafter injury occurs in a special 50 patients and found that42 percent of themhad less than 5 percent ofpatients admitted to hospital;its seizures. The occurrenceof seizures was not related to importance is that it presages lateepilepsy. age, pasthistory of convulsive disorders, orprognosis. (2) Late traumatic epilepsy(after the first week) When the seizure wasunilateral, it almost always was occurs in about 5 percentof all blunt injuries followed They considered it the risk varies widely indif- contralateral to the hematoma. for more than 4 years, but significant that seizures did not appearto offer evi- ferent types of cases. dence against the diagnosisof chronic subduralhema- (3) Between a quarter and athird of patients who hema- of toma. The first symptomsof infantile subdural have had early epilepsy,and a similar proportion convulsions, and vomiting(Ingra- intracranial hematoma,developlate toma are irritability, thosewith ham and Matson, 1944;Christensen and Husby, epilepsy. . The mechanism of seizureproduction could increases the risk of epilepsy 1963) ( 4) Depressed fracture be due to localized cerebralischemia, as suggested by only in adults in whom thedura is penetrated, or who Penfield and Jasper, or todirect cortical damagewhich in whom the post-traumatic subdural have had early epilepsy, or isfrequentlyanaccompanimentof amnesia (PTA) has exceeded24 hours. The risk in hematoma. such cases is over 50 percent,but the risk in the remaining fractures is only 3 percent. Anoxia and Hyperthermia about 1 percent for all (5) The risk of epilepsy is should be considered as injuries uncomplicated by earlyepilepsy, hematoma, Two other physical agents causes ofepilepsy :excessive heat and severeanoxia. or depressedfra ture, even when the PTAis of more It is probable that they areboth indirectly relatedin than 24 hours' duration. brain damage. It hasalso been half the patients with late their abilities to cause (6 ) Although just over justification, that hyperthermia epilepsy have the first seizurewithin a year of injury, suggested, with some in the remarkable braindestruction the onset is delayed beyondthe fourth year in more may play a role seen after severeconvulsions in infants andin children. than a q arter of the cases. reviewing 12 cases often severe and persist- Gorin and his confreres(1963), (7) Traumatic epilepsy is of "heat stroke," the kind of injury it follows orthe who showed signs and symptoms ent, regardless of of serious neurological se- length of the intervalbetween injury and onset of warned against the dangers quelae. The hyperthermiais secondary to excessive seizure. 15 environmental temperature and dehydration, and it pressure, or localized cerebralischemia secondary to compounds the cerebral anoxia that accompanies spasm or occlusion of a cerebral artery, maylead to an severe and prolonged convulsions. epileptic seizure.Whether cerebral ischemia, either Other forms of anoxia, such as occurs in cardiac generalized or localized, will precipitate a stizure de- arrest or near drowning, cause cerebraldestruction pends on the severity of the ischemia on the one hand, which may or may not be followed by recurring and the susceptibility of the brain to seizure activity on seizures. the other.Seizures are frequently due to the localized The changes in the brain metabolites in anoxia are cerebral ischemia related to migraine. They are seen very similar to those occurringduring convulsions: in the patient who faints on the "sight of blood." They There is a decrease in the brain glucose, glycogen and are frequently the first signof a cerebral hemorrhage. high energy phosphate bonds and an increase in lactic It is not uncommon for a patient who has had a cere- acid, adenosine diphosphate (ADP), and inorganic bral vascular occlusion from an emboltis or thrombosis phosphate.There is also a decrease in the acetyl- subsequently to develop convulsions. Probably local or choline content, a liberation of ammonia, and a redis- diffuse anoxia affects the stability of the neuronal tribution of sodium and potassium in the nerve cells membrane and causes excessive depolarization aswell and extracellular fluid (Richter, 1960) .Convulsions as a disturbance in the ionicbalances across the neu- are commonly accompanied byanoxemia dug to im- ronal membrane. The end result is a focal or gen- pairment of the respiration, and the observed changes eralized epileptic discharge and a seizure. in brain metabolites during convulsions might, there- Cerebral arteriosclerosis frequently is stated to be fore, be attributed to the incidental lowering of the the cause of epilepsy (Kehrer, 1963) .This is not too oxygen tension in the blood.From the observations difficult to comprehend ifthe patient has had a of Gurdjian and his colleagues (1947), it appears known vascular infarct sufficient to cause symptoms. that moderate anoxia increases the irritability of the In the patient over 50 years of age with a lowered brain, whereas severe anoxia decreases it, and that an threshold for seizures, because of alcoholism, genetic adequate oxygen level is one of the necessary conditions factors, or other reasons, the small unrecognized cere- for convulsive activity to take place.Further evi- bral infarct may be sufficient to cause epilepsy. White dence suggests that acute anoxia causes convulsions and his associates (1953) studied 107 patients who had by releasing the lower centers from cortical inhibition, an onset of seizuresafter the age of 50.They con- whereas severe anoxia inhibits convulsions by depress- cluded that cerebrovascular disease was the cause of ing the activity of the lower, as well as the higher, seizures in the majority of instances.Furthermore, centers of the brain.It has been shown also that the their followup studies supported the concept that tu- oxygen consumption of the brain varieswith changes mors were present in only asmall group.Woodcock in temperature.Increasing the temperature of the and Cosgrove (1964) studied 93 patients whosesei- body up to 43° C. increases the oxygen consumption. zures started after the ageof 50, and were able to fol- The effects of temperature on convulsive activity are low up 80 of them.Of these 80, 29 had intracran- clearly complex; they may be expected to depend in ial tumors.Of the 51 remaining, 20 were reported as part on the release of the lower centers throughim- being atherosclerotic,10 had a variety of known pairment of cortical control, and partly on the com- diseases, and 21 had no obvious cause for the seizures. bination of an increased oxygen demand by the neu- The possibilitystill remained that some of the last rone at a rising temperature with theincreased oxygen group could have hadatherosclerosis or a Very slowly requirement for convulsive activity. griming tumor. From the days of Gowers, "Faints or Fits" hasbeen Circulatory Dissturbances a subject that has intriguedthe experts, and has led to Vascular disorders are seldom mentioned as a cause a voluminous, ifsomewhat inconclusive, literature. of epilepsy, and yet it is well known that anything that Gastaut and his conferees recently have done much to interferes with cerebral circulation and causes neuronal elucidate this difficult problem. Penfield has suggested anoxia will cause seizures.Indeed, many thoughtful that seizures may result from fluctuating ischemia at clinicians have attempted to explain all seizures on the the margin of a focal cerebral cicatrix.The whole basis of a circulatory disturbance. problem of anoxia at a neuronal level, and its ability Impairment of cerebral circulation, either of a gen- to cause a synchronousepilepic discharge, warrants eralized nature as seen in syncopy due to a fall in blood further study.

16 al, 1960; Sugar, Mtabolic and Nutritional Disorders mentia (Bronsky, 1958; Melchior, et 1953; Tiberin and Beller, 1963) . The importance of metabolic and nutritionaldis- Magnesium is known to be an importantintracellu- orders as a cause of epilepsy has been knownfor a long lar cation, and magnesium deficiencyin man is asso- time.It is only recently, however, that any realknowl- ciited with muscular weakness andhyperirritability. edge of the role they might play has beendemonstrated. Efforts have been made to relate epilepsy to adefi- A good example is pyridoxine or vitamin136 deficiency ciency of magnesium, but to date, therelationship re- or dependency.It has been shown that pyridoxine mains obscure. plays an important role in the productionof gamma Back, Montgomery and Ward (1962)described five aminobutyric acid, GABA, an inhibitorysubstance, the infants with gastroenteritis who had tremor,muscular lack of which interferes with the sodiumratio, and rigidity, twitches, and convulsionsassociated with low permits seizures to take place.Disorders of electrolyte levels of serum magnesium. Three of thechildren were and water balance are closely related toseizures in in- frankly malnourished.Serum calcium levels were fancy during periods of hydration anddehydration, normal in all and parental calcium waswithout thera- and are undoubtedly related to theshift of sodium peutic effect in three cases. On the otherhand, mag- and potassium across cell membranes.One is re- nesium administration in all five casesinduced remis- minded of the hydration test to bring outabnormali- sion of the neurological disorder. ties in the EEG or to precipitate aconvulsion, as a means of studying theseizure pattern.Physicians con- Disorders of Carbohydrate Metabolism tinue to advise patients againstdrinking too much frequently water.The roles or' acid-base equilibria,and water Newborn children having seizures are Brown and Wallis and salt balance have been reviewedby Tower (1960) found to have a low blood sugar. infants, that Wolfe and Elliott (1962) .Electrolyte disturbances (1963) reported, in a series of newborn birth weight and are not the prime causeof epilepsy. In mild forms they the babies were below expected They postulated may help precipitate anattack in a predisposed indi- nearly all showed gross malnutrition. vidual, whereas in severe forms, asshown by Dodge that intrauterine malnutrition predisposes toneonatal depleted of and his colleagues (1960), actualbrain damage may hypoglycemia because the baby has been take place and be a furthercontributing factor. fat and glycogen stores which arereadily exhausted. inadequately either It is not uncommon for newborn childrenwith sei- Those babies who were treated Those who were zures to have a low serumcalcium.The seizures may died or suffered from brain damage. intravenous glucose stop with the administrationof calcium in one way or treated early and vigorously with completely.Ha- another.These children may subsequently befound and a high calorie diet recovered reported on six infants to be retarded mentally, butit is never known whether worth and his colleagues (1963) the hypocalcemia was primary orsecondary. who appeared normal at birth butwho developed Epilepsy frequently occurs in chronichypocalcemia, apnea, irritability,lethargy, and muscular twitchings and the seizures frequently showfeatures of tetany, between 24 and 72 hours of age.Blood sugar levels The condition was as seen inhypioparathyroidism and pseudo-hypopara- were 10 mg. per100 ml. or less. showed evidence thyroidism.Glaser and Levy (1960) point out that in self-limited in all cases, although two hypoparathyroidism the seizure states usually are as- of permanent brain damage.It is possibly significant sociated with paroxysmal abnormalities in theEEG that four of the mothers had atoxemia, and three characterized by slow theta and delta waves,spike dis- babies were premature.The recognition and treat- charges varying in frequency from 1 IA to 4 persecond, ment of hypoglycemiain the underweight newborn damage in the new- and single and multiple spiking.Usually the treatment baby is one'way of preventing brain of the underlying disorder by theadministration of born.It is probable that in someinstances the pro- calcium salts, vitamin D, and otherphosphaturic longed intrauterine malnutrition hasalready caused agents, relieves the seizure stateand improves the elec- irreversible cerebral changes. Etheridge and Millichap (1963) studiedthe role of troencephalogram.However, the time sequences of cerebral lesions. return of the serum calciumlevel to normal, and the hypoglycemia in children with primary large percentage of disappearance of seizures and EEGabnormalities, are They concluded that in a relatively seizures asso- not always parallel.Others have pointed out the role patients with cryptogenic hypoglycemia, be caused of hypoparathyroidism in theproduction of seizures, ciated with low levels of blood sugar may other lesion of the intracranial calcification, and slow butprogressive de- primarily by a maldevelopment or 17' brain. There was a surprising lack ofcorrelation be- Brain damage may result, in turn, and causefurther tween the occurrence of seizuresand the degree of seizures.Improvement in both behavior and control hypoglycemia, which suggested that the seizures were of the diabetes may result from theaddition of anti- (Fabrykart and not due to the hypoglycemia,but were related more to convulsants to the diabetic regime The incidence a arteriosclerosis is the brain defect. Pacella, 1948). Hypoglycemia may be a familial condition.Deka- high in diabetes.This, combined with fluctuating ban, et al. (1962), reported on five siblingswith this blood sugar, may be the cause of seizuresin the elderly. disorder.They pointed out that the age of onset is usually during early infancy, and mentalretardation Disorders of Protein Metabolism perspiration, frequently results.Epileptic attacks, Each year new diseases are discovered inwhich there find- limpness, and coma are the most common clinical is an inborn error of protein metabolism,usually as- hypoglycemia. ings during the episodes of marked sociated with progressive cerebral deterioration,mental Treatment of this variety of familial idiopathichypo- retardation, convulsions, and frequentlyleading to feedings, glycemia consists of frequent carbohydrate death. The most common is phenylketonuria;others glucocorticoste- and in severe cases, administration of include alkaptonuria, albinism, Hartnupdisease, and roids or corticotropin for a prolonged periodof time. maple-syrup-urine disease, cystinuria, Fanconi syn- In general, there is a tendency towards spontaneousim- drome, etc.(See Watts, 1962.) provement after 5 to 6 years of age.If early and ade- Phenylketonuria has been most carefully studied not quate control of thehypoglycemia is not established, only because it is more common thanthe others, but certainly occur. permanent cerebral changes will most also because the progressive mentaldeterioration can first shown The essential amino acid 1-leucine, was be prevented with proper diet.This disorder is char- in pro- by Cochrane (1960), to be a causative agent acterized by the excretion of phenylpyruvicacid in the voking hypoglycemia in infants.His studies suggested urine, and is due to a metabolic errorcontingent on that the cause was primarily extrapancreatic. the recessive inheritance of a defect in an enzymethat due Some authors have suggested that the effect was converts phenylalanine totyrosine.Pathologically, insulin, and others be- to an increased production of there is, according to Alvord and hiscolleagues (1950) , lieved that inhibition of hepatic glucose output was a marked lack ofmyelinization of the nervous system 1961; Mc- the mode of action (Wohltmann, et al., involving principally the optic,cortico-ponto-cerebel- etal., Kendrick,1962; Pensuwan,1963; Floyd, lar, and perhaps other tracts in the centraland peri- 1963). pheral nervous systems.Other abnormalities such as children Islet cell tumors of the pancreas, found in gliosis and increased fat about the bloodvessels may be and adults, may be a baffling cause of syncopalattacks, present.The findings vary somewhat with the ageof convulsions and weakness. A careful history, defining the patient.Poser and van Bogaert (1959) suggest the relationship of the attacks to meals, isfrequently that the disease, neuropathologically, shouldbe classi- the most important factor in making the diagnosis; fied with the leukodystrophies and thecerebral lipoi= help however, provocative tests, such as starving, may doses in the general group of demyelinatingdiseases. clarify the nature of the problem (Hardy, 1963) . Young children with phenylketonuriafrequently Hypoglycemia is also seen in hypopituitarism and have seizures, usually in the formof infantile spasms. hypoadrenalism (Dunlop, 1963) , and may contribute Paine (1957) found a 26 percentincidence of seizures to the production of seizures.A "hereditary intoler- Epilepsy was more com- hypo- in the patients he surveyed. ance" of the ingestion of fructase, resulting in mon in the mostseverely retarded patients, but fre- Froesch, et al. (1963) , glycemia, has been reported. quently ceased with advancing age.In the majority, which inhibits the release suggest an enzymatic defect, the age of onset was under 18 months.Low and his hypoglycemia. of hepatic glucose, as the cause of the colleagues (1957) , in studies of the young age group, Not all cases reported were associated withseizures. found hypsarhythmia and multipleseizure foci on elec- Hypoglycemia may also follow sudden withdrawalof As the children grow older, sei- alcohol in the chronic alcoholic, or following an alco- troencephalography. change from the myoclonic type ofin- holic debauch, and may be a contributing factorin the zures tend to convulsions, and their "withdrawal seizures." fantile spasms to tonic-clonic generalized spike dis- Convulsions may occur in diabetes, particularlyin EEG's tend to show focal or spike-and-wave the labile diabetic.This is seen in infantile diabetes charges.Of 23 patients, seven had in petit mal epilepsy. where there are wide oscillations in blood sugarlevels. complexes similar to those found

18 Eight of the patients had EEG examinations while un- whom petit mal attacks preceded any other symptoms dergoing treatment with a phenylalanine restricted by many months. diet.There was a beneficial effect on the seizures as The relationship of epilepsy to amauroticfamily well as on the electroencephalograms. idiocy and other lipoidoses has been reviewedrecently Acute intermittent porphyria is another inborn error by Edgar and Post (1963) .Reference should also be of metabolism in which there is a genetic defectin made to the "studies in Tay-Sachs disease" byGomez enzymatic biosynthesis of porphyrins. The disorderis and his colleagues (1963) . characterized by excretion in the urine, both during the Recent studies by Andermann, Fawcett and Owen acute attack and often duringremission, of large have demonstrated usefulness of rectal biopsies as a amounts of porphobilinogen.Prominent signs and means of establishing thediagnosis.Carefully done as symptoms are abdominal pains, polyneuritis,mental a major procedure,this technique has been known to cerebral disturbances,convulsions, and excretion of dark be safe, effective, and much easier than a brownish-red urine.Attacks may be precipitated or biopsy. made worse with barbiturates, and other drugs must be used to control seizures. The mental changesin this Pyridoxine (Vitamin Bo) Dependency disorder may be vcry baffling, and many patients are Following an epidemic of convulsions in children the true suspected of malingering for some time before which was found to be due to a milk preparationdefi- nature of the disorder isdiscovered.If the condition it became fashionable to ad- should cient in pyridoxine, is suspected, repeated examinations of the urine minister pyridoxine in all cases of infantileconvul%, be made. This led to the description of Hunt andhis spread- sions. An acute attack may be accompanied by a colleagues, in 1954, of a case of pyridoxine dependency. lain-Barré ing and complete paralysis, similar to a Guil Since then, many more isolated cases ofpyridoxine Indeed, in all cases of syndrome, and lead to death. dependency have been reported, and recently the con- for Gull lain-Barré syndrome, the urine should be tested dition has been described in siblings (Scriver,1960; (Watson, 1954; Aldrich, et al., 1955; Sun- porphrins. and Waldinger and Berg, 1963) .It is apparent that 1957). derman and Sunderman, 1955; Waldenstrom, seizures may occur in infants from a deficiencyof pyri- The EEG changes in intermittent porphyria are non- doxine in the diet, resulting from either (1) an inborn specific with high voltage and show activityduring the error of metabolism, (2) adependency developed acute exacerbations of the disease.Pathologically the from a high intake of pyridoxine by the motherbe- most common finding is ademyelinating peripheral fore the birth of the child. Using the tryptophanload- neuropathy, with diffuse neurone changes mainly inthe ing test, abnormalities in tryptophanmetabolism, anterior horn cells.Other nonspecific parenchem- which is dependent on vitamin Bg may be detectedby atous changes are describedthroughout the nervous studying the urinary excretion products. system (Dow, 1961) .Convulsive seizures and gross The excretion of Xanthurenic acid after tryptophan EEG changes are a common accompaniment of many loading reflects impairment of a vitamin Bo-depend- biochemical defects in nerve cell metabolism, including ent enzyme which is distributedin liver and kidney acute intermittent porphyria. (Neister, 1957) and is used as a test of vitamin Bg co- enzyme deficiency.(Bessey, et al., 1957; Coursin, Disorders of Fat Metabolism 1964). It has been shown that gamma-aminobutyricacid, Among the inborn errors of fat metabolism, amau- an inhibitory substance, canbe derived from glutamate rotic family idiocy (Tay-Sachs disease)is the most by a pyridoxine-dependent decarboxylase.Reduction common. Seirures may occurin the course of any of of gamma-aminobutyric acid (GABA) in thebrain the lipid storage diseases, but they seem particularly increases its irritability, and the seizure thresholdis prominent in amaurotic idiocy.The type of seizure lowered. varies with the age of the patient. Because of the early More convincing evidence for a relationshipbetween onset, infantile myoclonic seizures are most common, glutamic acid metabolism and seizure activity is pro- but if the age of onset is later, then typical petitmal vided by studies of the convulsant hydrazides.The seizures may occur with a characteristic wave-and- most potent convulsant istheocarbohydrazide.Sei- spike type of EEG abnormality.Andermann, et al., zures produced by this canbe controlled by the admin- have recently had a patient with the juvenile type in istration of pyridoxine.It has been suggested that 19 the action of these convulsants is limited to the meta- parathyroidism on calcium metabolism which, in turn, bolic reactions of pyridoxine.It has also been sug- produces cerebral excitability and seizures. gested that the convulsant action of topically applied Although seizures are more common in disorders of penicillin is related to a local pyridoxine deficiency due the pituitary-thyroid-adrenal axis, the main interest to a release of penicillamine and subsequent reaction is the effect of hormonal changes on excitation and in- with pyridoxine. The evidence for a defect of glutamic hibition of neurones and their abilities to produce acid metabolism in pyridoxine deficiency, whether nu- seizures. A better understanding of the roles these tritional or antimetabolic, is convincing.However, hormones play in the developing brain, and its day- the connection of this kind of defect and decreased to-day and month-to-month metabolism, would be very GABA levels wini neuronal excitability is not clear valuable to the improvement of the treatment of epi- cut ( Wolfe and Elliott, 1962) . lepsy, particularly epilepsy of infancy and childhood. These problems tend to stress the need for a better Convulsions are a fairly common occurrence in Ad- understanding of the chemical reactions of the brain dison's disease (Storrie, 1953; Dunlop, 1963) .Experi- which predispose and lead to convulsions. mental animals, as well as humans, with adrenocortical insufficiency exhibit spontaneous seizures during crises. Endocrine Disorders The seizures have been attributed to a reactive hypoglycemia; however, some studies suggest that there The role of the endocrines in the epilepsies is essen- are other factors involved and that theproblem should tially one of modifying the seizure threshold of the be studied further. The brain of the adrenalectomized brain.Some hormones are capable of activating sei- animal exhibits an increased concentration of intra- zures, and others, of suppressing them. Adrenocortico- cellular sodium, a decreased ratio of extracellular to tropic hormone and cortisone have been shown to ar- intracellular sodium concentration, and a decreased rest myoclonic seizures in the infant.Woolley and turnover of sodium. The total brain potassium con- Timiras (1962) demonstrated, in animals, that testos- centration is unchanged, but the ratio of intracellular terone could have either a convulsant or an anticon- to extracellular potassium is decreased, and the turn- vulsant effect on brain function, depending upon sev- over is unquestionably increased (Woodbury, 1958). eral factors, such as the dose of the hormone or the age In the adrenalectomized animals, the inability of the of the animal.As one would expect, these hormones brain actively to pump sodium resulti in brain elec- play definite roles in the maturing brain.Lennox trolyte changes associated with increase in brain ex- ( 1960) demonstrated the importance of puberty and citability.Additionally, Woodbury and Vernadakis the first menstruation in the development of epilepsy. (1958) found that adrenalectomy caused a marked It is well known that young women are more prone to decrease in certain amino acids of the brain, particu- seizures during the premenstrual period (Laidlaw, larly gamma-aminobutyric acid (GABA ) .This is of interest because of the role GABA seems to play in 1956; Logothetis, et al., 1959). The sexual .cycle of the mature human female involves interactions among inhibition. the pituitary gonadotropins, follicle-stimulating and The relationship of the endocrine glands to the nerv- reviewed in an article luteinizing hormone, and the ovarian steroid hor- ous system recently has been by Reichlin (1961) , which has an extensive bibliog- The mones, principally estradiol and progesterone. raphy. The Association for Research in Nervous and lowered threshold for seizures during the premen- Mental Disease (1963) soon will publish more infor- strual period has been attributed to the decrease in mation regarding this relationship.Reference should progesterone levels following atrophy of the corpus also be made to the reviews by Woodbury, 1958, on luteum. The exact roles of these hormones at a neu- the relationship of the adrenal cortex to the central ronal level are not known, but it is suspected that they nervous system, and by Way andSutherland (1963) on may be related to a change in the sodium ratio in favor pharmacologically active brain substances and their of intracellular sodium. relationships to endocrine effects. In some endocrine disorders, the change in seizure threshold is due, not to the increase or decrease in the Neoplasms particular hormone, but rather to indirect effects. An outstanding example is the effect of islet cell tumors, It has been said that anyone over the age of 20 hav- which secrete insulin, and, in turn, cause hypoglycemia ing a seizure for the first time should be considered as and seizures.Another example is the effect of hypo- a tumor suspect.This is true, but it should be also

20 7,SA,

be remembered that brain tumors are common in chil- if the meningioma was on the convexity, the base of dren and a convulsion may be their first manifestation. the middle fossa, or parasagittal region (incidence was Seizures from other causes are so common in children 50 percent) than if the tumor was on the olfactory that one is likely to forget the possibility of a tumor. groove or lesser wing of the sphenoid (33 percent) . Generally, in this age group, tumors manifest them- Woodcock and Cosgrove (1964) reviewed 93 pa- selves with focal signs, such as ataxia, hemiparesis, tients with seizures, starting when the patients were 50 focal convulsions, or signs of increased intracranial years old or more, and were able to follow 80 of them. pressure. Of these 80, 29 had intracranial tumors.All those Backus and Millichap (1962) reviewed 291 con- with primary intracranial tumors had some focal fea- secutive children seen for intracranial tumors.The ture, zither a type of clinical seizure, neurological sign, ages ranged from 2 months to 14 years.Forty-three or electrographic abnormality, although five contrast percent of the tumors were supratentorial and 57 per- studies were initially negative. Of the 29 patients with cent were infratentorial.Seizures occurred in 17 per- cerebral tumors, 22 had electrographic changes sug- cent of the total group.Sixty-two percent of the gestive of destructive lesions.The investigators con- patients withsupratentorial tumors hadseizures cluded that if there were focal features to the seizure whereas only 38 percent of those with infratentorial pattern, and abnormalities in the neurological exam- tumors had seizures.The average time from the onset ination or electroencephalogram, then pneumoen- of seizures to clinical diagnosis was 3 months in patients cephalography or other contrast studies were advisable with infratentorial tumors, and 2 years in others.The to aid tumor diagnosis.In patients without any focal seizures were the initial sign in 21 patients. features to the seizures, contrast studies were unlikely In determining the cause of the severe increased to show a space-occupying lesion, and might even miss intracranial pressure, with separation of the sutures, a a small tumor. In such cases, Woodcock and Cosgrove ventriculogram or some other type of contrast study suggest a careful followup and review of the neuro- usually is necessary to distinguish tumors from tubercu- logical and electroencephalographic status at various lous meningitis, lead poisoning, or subdural hema- intervals is of great importance.In their studies ap- tomas. A common cause of acute increased intra- proximately one-third of the patients followed were cranial pressure, with or without focal signs, is leukemic found to have cerebral tumors.It appears that the infiltration of the meninges.This presumably is re- majority of patients whose seizures begin past the age lated to the success of treatment for the condition else- of 50 do not have cerebral tumors. Of these, a large where in the body. proportion were atherosclerotic and others had mis- As one advances into the older age groups, tumors cellaneous diseases associated with their seizures.In become a more prominent cause of epilepsy.Sumi 25 percent, no definite cause was found for the attacks, and Teasdall (1963),in a review of 150 patients with despite a 5-year followup.These findings support focal seizures, found a 1 to 2 ratio in vascular to tumor those of White and his colleagues (1953) who con- pathology under the age of 50, but over the age of 50, cluded that cerebrovascular disease was the cause of it was 2 to 1.Meningiomas accounted for 34 percent seizures in the majority of patients over the age of 50; of the tumors causing focal seizures.Astrocytomas, or and the followup studies support the concept that tu- oligodendrogliomas, accounted for 23 percent, meta- mors are present in only a small group. static for 17 percent and glioblastomas for only 9 per- Penfield and Jasper (1954) reviewed 703 expanding cent.Generally, benign tumors, such as meningiomas, intracranial lesions of all types.In addition to neo- are more likely to produce seizures in their course of plasms, they included brain abscesses, tuberculomas, expansion before other signs or symptoms appear.In and extra- and intra-cerebral hematomas. There were the more rapidly growing tumors, such as glioblastomas 164 infratentorial tumors. The incidence of epileptic the onset of seizures is likely to coincide with the appearance of other clinical signs (Zander, 1962) .In seizures was almost zero; some 20 percent had small a study of 182 supratentorial meningiomata, DeVet attacks of a myoclonic, syncopal, vertiginous, or pa- and Ponssen (1962) found the preoperative incidence resthetic nature. Of the supratentorial tumors, there of seizures was 54 percent; this was reduced to 46 per- were 49 in the region of the pituitary.Only four of cent after surgery.Forty-two percent of patients who this group of patients had seizures.It was apparent did not have seizures before operation developed them that intrasellar tumors do not produce seizures unless postoperatively.These investigators also noted that the tumor has escaped from the sella and is large seizures were more likely to be the presenting symptom enough to press upon the brain.Of the remaining

21 they group of patients with4s,pratentorial neoplasms, there might remit or continue on for years, but that were 51 percentepileptifr cm seizures among those hav- responded satisfactorily to anticonvulsant drugs. ing intracerebral tumors, and 62 percent amongthose having extracerebral tumors.Penfield also found that Bibliography there was a lower incidence of seizures amongpatients GENETIC AND BIRTH FACTORS with tumors situated deep within thehemisphere and which did not come to the surface enough tobe as- Martini, C. H., A study of Epilepsy in itsClinical, Social Ejnar Munksgaard, Copenhagen, signed to one lobe or the other.Penfield and Jasper and Genetic Aspects. 1950. point out, like others, that whether anintracranial tu- Bray, P. F., Wiser, W. C., The genetic pattern offocal epilepsy mor produces seizuresdepends upon the location of in children.Trans. of the Amer. Neurol. Assoc., 1962. the tumor, its nature, and its chronicity.They have Colver, T., Kerridge, D. F., Birth order in epilepticchildren. done a very complete and careful analysisof this prob- J. Neurol. Neurosurg. Psychiat. 25: 59, 1962. in families of lem and reference should be made tothe original work. Eisner, V., Pauli, L. L., Livingston, S., Epilepsy epileptics.J. Piedatrics 56: 347, 1960. Evans, J. H., Posttraumatic epilepsy.Neurology 12 : 665, Heredofamilial and Degenerative Disorders 1962. Glenting, P., Course & prognosis of congenital spastichemi- Epilepsy is a frequent manifestation of allof the plegia. Develop. Med. Child. Neurol. 5 : 252, 1963. heredofamilial and degenerative disorders. The type Harvald, B., Heridity in Epilepsy.Ejnar Munksgaard, Co- of seizures is dependent more on the ageof the patient, penhagen, 1954. and degree of maturation of the brain, than onthe Lennox, W. G., The heredity of epilepsy, as told byrelatives and twins.J.A.M.A. 146: 529, 1951. nature of the degenerative processes.Since many of Lennox, W. G., Gibbs, E. L., Gibbs, F. A., Inheritanceof these disorders first manifest themselves ininfants and cerebral dysarhythmia and epilepsy.Arch. Neurol. and young children, myoclonicseizures are frequently the Psychiat. 44: 1155, 1940. outstanding feature of the disease. There is notypical Lennox, W. G., Jolly, D. H., Seizures, brain waves, andintel- electroencephalographic pattern for the leukodystro- ligence tests of epileptic twins.Res. Publ. Assoc. Nerv. Ment. Dis. 33: 325, 1954. phies, either as a whole or for a specific type.The Metrakos, J. D., Heredity as an etiological factor in convulsive EEG abnormality becomes severe early inthe course, disorders.Disorders of the Developing Nervous System, and shows a progressive deteriorationwith diffuse slow Chapter II, edited by Fields, W. S., Desmond,M. M., waves, fluctuatingspikes, and suppression bursts at one Charles C Thomas, Publ., 1961. Although the course of the disease Metrakos, J. D., Metrakos, K., Genetic of convulsivedisor- time or another. I. Introduction, Problems, methods and baselines. reported to re- ders: is not altered, myoclonic seizures are Neurology 10: 228, 1960. spond to ACTH. Metrakos, J. D., Metrakos, K., Genetic counsellingin child- In many of the disorders there may be aninborn hood epilepsy, presented before AmericanEpilepsy Society, error of metabolismwhich has not yet been identified. Dec. 7, 1961. factor In some, seizures are more common than others.For Metrakos, J. D., Metrakos, K., Is pregnancy order a J. Neurol. Neurosurg. Psychiat. November difficult in epilepsy ? example, they are a constant and extremely 1963 (in press). problem in dysynergia cerebellaris progressivawhereas Metrakos, K. Metrakos, J. D., Is the centrencephalicEEG in Friedreich's ataxia or ataxia telangiectasia,they inherited as a dominant? EEG and Clin.Neurophysiol. are much less common. 13: 289, 1961. disor- Epilepsy and trigeminal neuralgia are foundin pa- Metrakos, K., Metrakos, J. D., Genetics of convulsive ders: II. Genetic and electroencephalographicstudies in tients with multiple sclerosis.Drake and Macrae centrencephalic epilepsy.Neurology 11: 474, 1961. (1961) found 13 out of 289 patients withmultiple Ounsted, C., Genetic and social aspects of theepilepsies of sclerosis who had seizures.The seizures were com- childhood. Eugenics Rev. 47: 33, 1955. monly focal and transient, occurring often at atime Rodin, E. A., Familial occurrence of the 14 and6 positive generalized and spike phenomenon. Paper presented at the EasternAssoc. of relapse, although they also could be of Electroencephalographers meeting in New YorkCity on chronic. The electroencephalogram was abnormalin Dec. 4, 1963. two-thirds of the cases with both focal and generalized Schwartz, J. F., Photosensitivity in a family.Amer. J. Dis. of abnormalities.Ashworth and Emery studied 159 pa- children 103: 90, 1962. tients with multiple sclerosis, 29 of whom had epilepsy. 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22 .

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W., Pyridoxine dependency: A report of a case ofintractable to infantile hypoglycemia.J. Dis. Children, 99: 476, 1960. pyridoxine.Pedi- Froesch, E. R., Wolf, H. P., Bartsch, H., Prader, A., Labhart, convulsions in an infant controlled by A,, Hereditary fructose intolerance.An inborn defect of atrics, 13: 140, 1954. New York, Acad. hepatic-l-phosphate splitting aldolase. Amer. J. Med., 34: Meister, A., Biochemistry of amino acids. Press, 1957. 151, 1963. The influence of Dunlop, D., Eighty-six cases of Addison's disease., Brit.J. Oura, E., Konttinen, K. Suomalainen, H., the rat. Acta Med., 2: 887, 1963. alcohol intake on vitamin excretion in Hardy, J. D., Islet cell tumors. American J. Med, Sci.,246: Physiol. Scand. No. 213, 59: 119, 1963. Scriver, C. R., Vitamin B6 deficiency,and infantile convul- 218, 1963. Floyd, J. C. Jr., Fajans, S. S., Knopf, It. F., Conn,J. W., sions.Pediatrics, 26: 62, 1960. dependency Evidence that insulin release is the mechanism for experi- Waldinger, C., Berg, R. B., Signs of pyridoxine Pediatrics, 32: 161, 1963. mentally induced leucine hypoglycemia in man.J. Clin. manifest at birth in siblings. Wolfe, L. S., Elliott, K. A. C., Chemical studiesin relation Invest., 42: 1714, 1963. From Neurochemistry.Edited Fabrykant, M., Pace lla, B. L., Labile diabetes: Electrographic to convulsive conditions. C Thomas, status and the effect of anticonvulsanttherapy.Ann. Int. by Elliott, Page, and Quostel, Springfield, Chas. Med., 29: 860, 1948. 1962. 25 Endocrine Disorders DeVet, A. C., Ponssen, H., Meningiomes intracraniens et epilepsie. Neurochirurgie 8 : 363, 1962. Dunlop, D., Eighty-six cases of Addison's disease.Brit. J. Penfield, W. G., Jasper, H. H., Epilepsy and the functional Med., 2: 887, 1963. Laid law, J., Catarnenial epilepsy.Lancet, 271: 1235, 1956. anatomy of the human brain.Boston, Little Brown & Co., Lennox, W. G., Epilepsy and related disorders.Boston, Lit- 1954. tle Brown Co., 1960. Sumi, S. M., Teasdall, R. D., Focal seizures.A review of Logothetis, J., Harner, R., Morrell, F. Torres, F., The role of 150 cases.Neurology, 13 : 582, 1963. estrogen in catamenial exacerbation of epilepsy. Neurology. White, P. T., Bailey, A. A., Bickford, R. G., Epileptic dis- 9: 352, 1959. orders in the aged.Neurology, 3: 674, 1953. Reich lin, S., Neuroendocrinology. New England, J. Med., Woodcock, S., Cosgrove, J. B. R., Epilepsy after the age of 50. 269: 1182, 1963. Neurology, 14: 34, 1964. Storrie, V. M., Convulsions in Addision'a disease.Bull. Tufts Zander, E., LEs epilepsies symptomatique dans les affections New England Med. Cent., 1: 299, 1953. relevant de las neurochirurgie.Rev. Med. Suisserom, Way, E. L., Sutherland, V. C., Pharmacologically active brain 82: 103, 1926. substances and their relation to endocrine effects.Anesthe- siology, 24 : 543, 1963. HEREDOVAMILIAL AND DEGENERATIVE DISORDERS Woodbury, D. M., Relation between the adrenal cortex and the central nervous system.Pharmacological Rev., 10: 275, Ashworth, B., Emery, V., Cerebral dysrhythmia in dissemi- 1958. nated sclerosis.Brain, 86 : 173, 1963. Woodbury, D. M., Vernadakis, A., Relation of brain excitabil- de la Cruz, F. F., LaVeck, G. D., Tuberous sclerosis: A re- ity to brain gamma aminobutyric acid concentration.Fed. view and report of eight cases.Amer. J. of Mental Defi- Proc., 17: 420, 1958. ciency, 67: 369, 1962. Woolley, D. E., Tirniras, P. S., Gonad-brain relationship: Ef- Drake, W. E., Jr., Macrae, D., Epilepsy in multiple sclerosis. fects of castration and testosterone on electric shock convul- Neurology, 11: 810, 1961. Endocrinololgy, 71: 609, 1962. sions in male rats. Jervis, G. A., Huntington's chorea in childhood.Archives of asoas Neurology, 9: 50, 1963. Backus, R. E., Millichap, J. G., The seizure as a manifesta- Noad, K. B., Lance, J. W., Familial myoclonic epilepsy and its tionofintracranial tumor inchildhood.Pediatrics, association with cerebellar disturbance.Brain, 83: 618, 29: 978, 1962. 1960.

26 CLASSIFICAT!ON OFTHE EPILEPSIES

An aura may developand the attack spreadinto a gen- Just as there are many causesof epilepsy, there There is a question, different types of seizures.Indeed, one eralized tonic-clonic seizure. are also many whether this attack shouldbe classified according to author wisely suggestedthat there are as many types the aura, or be called ageneralized tonic-clonicseizure. of seizures as there areregions of the brain, and an at- follow- quite hope- The patient may be leftwith a postictal aphasia, tempt to distinguisheach of them would be seizure, indicating a focalcerebral Although there is sometruth in this, a classifica- ing a generalized less. arises. of seizures shouldbe estab- lesion. The same question tion of the various types Certain types of seizures areknown to originate in lished for several reasons.First, so that thoseworking of of specific areas of thebrain.For example, attacks in the field may use the sameterms for specific types originate from within the uniformity in reporting automatic behavior generally seizures.Secondly, to provide been a tendency toclassify correlate medication with temporal lobe. There has individual cases. Thirdly, to epilepsy, thus introducing Fourthly, so that the re- them as "temporal lobe" specific types of seizures. anatomical factors into adescriptive classification. lationships may be ascertainedbetween certain types of Others have usedelectroencephalographic abnormali- seizures and knownphysiological or pathological ties loosely to describeseizures.It may be true that changes. "spike and wave"abnormalities are associatedwith ab- The type of classificationwould, of necessity, vary absence attacks designed to sence attacks,however not all apparent with the need.For example, in a study abnormality on the EEG,and a properties of drugs, it maybe show a spike and wave test the anticonvulsant of spike and waveactivity into major or minor.At- patient can have a burst sufficient to divide seizures attack. patients can determine,and without having a demonstrable tendants watching the Another possible way ofclassifying seizures is ac- record, whether an attack is"major" or "minor." On cording to age. The newborntends to have focal myo- the other hand, a studydesigned to evaluate abnor- clonic types of attacks.The infant between 6months malities in the temporallobe, leading to surgical ex- and 3 years tends to havemyoclonic seizures, with mas- cortical and depth electrodestudies, would posure and sive spasms, myodonicjerks or akinetic attacks.As classification of the seizuresif any require a detailed the child gets older, absenceattacks appear, and grad- meaningful relationship is to bemade. ually change to a more matureadult type of general- classification of seizures is Another problem in the ized tonic-clonicconvulsion.Of course, generalized to know what pointin the sequence of theattack is to convulsions can appear at any age,depending on the be used for classification.Many patients have pro- site of origin of the attackarid the ability of theseizure dromal symptoms.Mothers recognize irritability or to spread withinthat particular patient. behavioral changes in childrenthat herald the onset Old terms have beenperpetuated and tend to de- The of an attack by severalhours. The "aura" mayindi- tract from an accuratedescriptive classification. generally refers to ageneralized cate in which partof the brain the seizureoriginates. term "grand mal," finds it being used for most The patient may seeflashing lights, smell a badodor, tonic-clonic seizure, but one major attack. The term"Jacksonian sei- have an unusual sensationin a hand, and so on.It is any type of zure" may refer to any typeof focal attack with auni- not entirely clearwhether this should be considered as lateral motor component."Petit mal" continues tobe the onset of the attackand used for theclassification. 27 a very useful and meaningful term,but it is not as de- III. Loss or diminution of consciousness without gross scriptive as "absence," or "loss or diminution of con- motor component. sciousness without motor component."The term A. Absencesimple "status epilepticus" intimates a continuing generalized B. Absence with minor motor accompaniment tonic-clonic convulsion.Actually, this seldom occurs, C. Absence with automatism and most continuing attacks have a focal component, D. Absence status or they are recurring generalizedtonic-clonic seizures IV. Localized onset, with or without loss of conscious- with, or without, return to consciousness.It is difficult ness (based on initial event) to part with old friends, but the timehas come for A. Motor 1. Focal motor (with or without spread) these terms to be discarded. 2. Masticatory These are some of the problems associated with the 3. Vocalization classification of seizures.Masland ( 960) reviewed 4. Adversive the problem and the various classifications that have 5. Tonic postural been proposed by distinguished workers such as Pen- B. Sensory field and Jasper, Mc Naughton, Gastaut, andSymonds. 1. Somatic The attempt by Symonds to divide the problem ac- 2. Visual cording to clinical, anatomical, physiological (EEG), 3. Auditory pathological and therapeutic aspects has many merits. t. Olfactory In our present state of incomplete knowledge, such a 5. Gustatory classification may be revised as indicated. 6. Vertiginous For some years, at the Montreal Neurological Insti- 7. Abdominal tute, an attempt has been made to classifyseizures ac- C. Aphasic cording to their anatomical site of origin, their cause, D. Automatism (apparently integrated purposeful and the pattern of the attack.These were coded, activity with amnesia) E. Psychical (delusions, hallucinations, forced think- where possible, according to the numbers of the Stand- ing) ard Nomenclature of Diseases and Operations.Cer- F. Autonomic tain new numbers had to be created for types of seizures V. Unclassified not included in this volume. The anatomical andeti- ological aspects presented no particular difficulty, Lit Duration of Seizures for reasons mentioned above, the symptomatic classification was never completely satisfactory. I. Very brief (of the order of 1 second) The classification of seizures to be suggested here H. Brief (of the order of 10 seconds) does not answer all of the problems, but it is an attempt III. Long (of the order of 1 minute or more) to provide a workable description and to separate some IV. Prolonged or continuing (of the order of 1 hour of the various components of seizures. Thus, they may or more) be related to sites of origin in the brain, maturation of Precipitating Factors the brain, physiological disturbances, causes, and responses to medication. I. Visual stimuli H. Auditory and vestibular stimuli Symptomatic Classification of Seizures III. Olfactory stimuli IV. Tactile stimuli I. Generalized convulsion V. Emotional or psychic disturbances A.Tonic-clonic VI. Sleep Tonic VII. Miscellaneous Stimuli Clonic D. Myoclonic Postictal Phenomena 1. Myoclonic jerks 2. Atonic (Salaam or drop fit) I. Confusion 3. Massive spasms II. Paresis II. Unilateral convulsion III. Aphasi#

28 The Aura IV. Amnesia V. Headache The aura is generallyconsidered to be the onsetof VI. Sleep an attack.It is the first warning tothe patient that an attack isabout to begin. Youngchildren are usually but may run to theirmother Associated Disorders unable to describe an aura, in fear.As they grow older,they frequently can de- of Behavioral DisordersAssociated with Epilepsy scribe the warning. The typeof aura depends, course, onwhere the attack originatesin the brain. I. Schizoid reaction A sensation in the handexperienced in seizures start- II. Manic or depressivereaction ing in the parietal lobe,the bad smell so often ex- III. Reactive neurosis perienced by patients with tumorsin the temporal lobe, IV. Behavior disorder the "déjà vu" phenomena seenin seizures originating V. Mental retardation in the temporal lobe, and so on,all constitute aura. VI. Specific learningdisorder Some of the best descriptions of auras arethose of Pen- field (Penfield and Jasper,1932) when he reported on Related Paroxysmal Disorders the feelings of patientsduring cortical stimulation. the crucial epileptogenic area, I. Migraine The stimulation, if near might start a seizure. Thepatient would describe the II. Syncope the attack spread. By III. Narcolepsy and cataplexy initial feelings and the events as recording directly from the cortex,the attack could be IV. Hysteria It might stop or V. Vertigo and giddiness(including Meniere's syn- followed as it spread across the cortex. develop into a generalizedtonic-clonic convulsion. Al- drome) cautious in relating a certain VI. Breath holding spells though one must be very specific areas of the brain,careful ques- VII. Paroxysmal abdominalpain type of aura to tioning of the patient is mostessential in any examina- VIII. Trigeminal neuralgia factor in revealing thesite IX. Other tion, and may be a major of origin of the attack. Patterns of Attacks The Tonic-ClonicConvulsion type of attack, of the A patient seldom has only one with the duration and severity.Consequently, A tonic-clonic convulsionstarts usually same pattern, falls to the ground,becomes it is preferable to describethe components of an at- tonic phase. The patient might start having a unconscious, and developsgeneralized tonic stiffness of tack.For example, a patient legs spreads to become a gener- the body. The head isretracted, the arms flexed, focal motor attack which the trunk are in spasm, so alized tonic-clonic convulsion,lasting 5 minutes, and extended, and the muscles of The purest example, ifthere is followed by a postictal paresis.This would be de- that respirations cease. which became gen- such a thing, is seen inpatients receiving electrical scribed as a focal motor seizure Here, the aura eralized, tonic-clonic, of longduration with postictal shock treatment for mentaldisorders. is eliminated; there is nobuildup to the seizure. With paresis. After Since each item is a separateentity, an individual the shock, the tonic phaseof the seizure starts. The classification a varyingperiod of time, the clonicphase begins. This number can be given respectively. of spasm and relaxa- used in conjunction withvarious types of consists of alternate periods can thus be clonic movements of theface, information storage systems, and easilyretrived. One tion of muscles so that attempting to classify each trunk, and extremitiesdevelop.During the clonic of the main reasons for become incon- patient's seizures is to be able to storethis informa- phase, the patient may bite his tongue or breathing is labored or jerky, tion in a uniform manner and toretrieve it at any time. tient of urine or stool; if breathing has stopped This classification has already provento be very useful and at times it may appear as storing and retrieving medicalliterature completely.Cyanosis may be profound. as a means of of events, the motor com- related to any one of the different typesof seizures. At In the normal course Neurological Diseases and ponent of the seizuresubsides and the patientgradually the National Institute of muscle tone is, then, gen- Blindness a "peek-a-boo" systemis in use which has regains consciousness. The erally poor. The patient maycomplain of fatigue or proven to behighly satisfactory. 29 headache, experience difficulty speaking, or have some interneurones, and that the brain stem and spinal cord residual paresis. The naturally occurring tonic-clonic are the sites of thisunstable repetitive neuronal firing. seizure is similar to this with the exception that the The resulting clinical disorder appears to be dependent onset is more prolonged: upon the predominant siteof involvement: midbrain, The hysteric or skillful malingerer may be able to brain stem, spinal cord, or all three.Higher struc- simulate a true attack in a very real manner.If hav- tures may influence myoclonus, but they are not essen- ing an attack provides a means of gain for the patient, tial for its occurrence.The degree of maturation of if there is no incontinence, tongue biting, nor other in- these structures, phylogenetically older than the fore- jury, if there are no reflex changes, or if the patient brain, is important in the susceptibility to myoclonic seems to be conscious during ageneralized attack, then epilepsy.A great variety of pathological conditions one must suspect that it is not a genuineepileptic attack will produce myoclonus, particularly in those disord- but, rather, of psychogenic origin. ers involving the neuraxisdiffusely, and are related to During a generalized tonic-clonic seizure, the EEG the degree of maturation of the spinal cord, brain stem reveals a bilaterally, synchronous, symmetrical pat- or midbrain. The newborninfant has localized myo- tern.There are rhythmic spikes interrupted by slow clonic jerks.With increasing age, "infantile massive waves during the clonic phase.Matsumato and spasms" and "salaam" or "drop fits" appear, indicating Ajmone-Marsan, by means of intracellular microelec- a higher level oforigin. The massive spasm consists of trode studies in cats, were able to show that during the a sudden spasm of thebody, extension of the legs, tonicphase,theneuronalmembranepotential flexion of the head and neck, and the arms extended markedly decreases, and rhythmical oscillations, usu- upwards. The atonic attack, or "drop fit," is expressed ally with active potentials, appear above a sustained, by a sudden loss of tone and the child is suddenly excessively depolarized potential level.The clonic thrown to the ground.It is not clear whether there is phase corresponds to a slow repolarization process, and which "throws" him down, or the end of the episode seems to be due to inactivation, a ...positive contraction rather than to true membrane hyperpolarization. whether it is the sudden and complete loss of tone. Some neurones appear to be activated only in the later The children frequently injure themselves. Whensit- phases of the seizure. ting in the high chair, for example, theyfrequently strike their faces on the tray.Protection with some Myoclonic Seizures type of helmet may sometimesbe required.

Myoclonic seizures refer to a series of involuntary Unilateral Convulsions shocklike contractions of a group, or groups, of muscles, or a "spasm" of the whole body.They may be restrict- The French school has emphasized the importance ed to one somatic region or appear throughout many of unilateral seizures.Certainly, they do occur (Gas- areas of the body.They may be restricted to one so- taut,1963).Whether they should be considered as a matic region or appear throughout many areas of the separate class of seizures, or purely as afocal seizure body. The myoclonic jerk may be single or repetitive that does not spread to involve the oppositehemi- for a varyingperiod :of time.Swanson and his col- sphere, is a moot point.There is a serious form of which leagues(1962),in their excellent review, point out that seizure seen in children involving one side only, the clinical picture implied by the term myoclonus is frequently leaves the child with a hemiparesis of a characterized by great variation in its degree of orga- transient or permanent nature.It may or may not be nizational complexity, and represents a wide spectrum associated with demonstrable vascular occlusion. of altered excitability at different levels or organization Gastaut suggests that unilateral attacks are, infact, within the neuraxis. When the alterations occur pre- generalized attacks, predominantly or solely unilateral, dominately at cerebral levels, they are called seizures; but sometimes with an alternative distributionof when montoneurones are involved, fasciculations are seizure pattern.All forms of generalized seizures can said to result; and when the origin is in the brain stem occur in this way, thusproducing (1) hemigrand mal or spinal cord, the term myoclonus is used. There is or unilateral majorseizures,(2)"hemitonic attacks," a growing body of evidence which suggests that the in- (3)"hemiclonic attacks," and (4) petit mal with creased excitability results from removal of some in- unilateral myoclonus or amyotonus (Faidherbe, etal., hibitory mechanism in the pools of motoneurones and 1962).

30 Absence Attacks the spike-and-wave activity is a response of the cortex to a stimulus originating from the deeper structures There are four types or degrees of absence attack : of the brain.The work of Jasper and Droogleever- Simple, with minor motor accompaniment, with auto- Fortuyn (1947),Pollen, et al. (1963),Guerrero-Fig- matism, and absence status.The term "petit mal," uero, et al.(1963),tend to substantiate this. like "grand mal," in itself is not very descriptive.It The problem is more complex than this, however. has come to mean a particular type of attack in which The degree of maturation of the brain is undoubtedly there is a sudden transient loss of consciousness with- an important factor.Guerrero-Figuero and his col- out any convulsive activity.It is of short duration, leagues were able to produce experimental "petit mal" lasting 5 to 20 seconds. During the attack, the patient only in kittens up to30days of age. Older kittens did has a blank btare, does not fall, and may not move.It not develop the pattern. Absence attacks tend to oc- is a state of "suspended animation."Unfortunately, cur in children after the age of3,and unless there is the term "petit mal" is used by many physicians to a specific cause, they tend to disappear.This is not mean any attack which is not a generalizedtonic- true in all cases, by any means, as pointed out by Holo- clonic seizure.The term "absence" is more descrip- watch, et al.(1962),and Currier, et al.(1963). tive, and is preferable to "petit mal."The least com- The problem g the prognosis in this type of minor plicated is described as absence-simple.Parents de- seizure warrants further study.Absence attacks are scribe the attacks well when they say the child for a few seen in children where there is a strong hereditary seconds is "dans la lune," or "day c.i=aming."Often background and no known pathology. They are seen parents think nothing of these attacks, and they may go also in children with a Sturge-Weber syndrome, who unnoticed for months or years.If the attacks create a have a focal cerebral lesion, and in juvenile forms of problem, particularly in school, or the child has a tonic- Tay-Sachs disease where there is diffuse lipoidosis. clonic seizure, then they are brought to the attention Surely the only common factor in these three different of the physician. types of pathology is the state of maturation of the Absence with minor motor accompaniment is a sec- brain. ond type of "petit mar seizure. The eyes may blink, One of the characteristic features of absence attacks or deviate, the head may turn a little, thelips smack, is the ease with which attacks may be precipitated by or sterotype movements of the hands maybe seen. hyperventilation and blowing off carbon dioxide. Absence with automatism is a third type of minor They are also common when the child is hungry and attack ( Penfield and Jasper, 1954) .This is really a has a low blood sugar. They are more common in the prolonged attack.If it lasted for only a minute or early hours of the morning and less common during two, and the patient moved around in a "daze," it has active exercise.Children may play at dangerous been called a "petit mal automatism."If the attack games, ride bicycles (not that it is recommended) and persisted for many minutes, or even hours, it was gen- have no trouble, but then sit down in school and have erally referred to as "petit mal status" (Tucker and one attack after another. Forster, 1950). The term "absence-status" is pre- ferred.It is highly probably that some of these at- Seizures of Localized Onset With or Without Loss of tacks in children originate deep within the temporal Consciousness lobe, and with the passage of time, the typical picture of epilepsy originating in the temporal lobe will evolve. Any of the following types of seizures may remain For the most part, during an observable absence at- localized in one region of the brain, and manifest tack the patient is unconscious. During this time the themselves by the single component, or they may electroencephalogram reveals a burst of spike-and- spread to other regions of the brain and develop into a wave activity which is characteristic of this disorder. generalized tonic-clonic convuLsion. However, a patient can have short bursts of spike-and- wave activity on the EEG for which no clinical ab- Motor normality can be seen.Also in absence-status, when The classical Jacksonian form of epilepsy is one there is continuous spike-and-wave activity being re- which originates in one part of the motor area of the corded, patients have been known to be conscious, able cortex and spreads to involve the rest of the motor strip. to talk, despite drowziness, dysarthria, and ataxia. The attack starts with tonic or clonic movements of It has been postulated, on good evidence, that ab- part of the arm or leg, usually peripherally, and spreads sence attacks originate in the diencephalon, and that to involve the rest of the body.

31 Other focal motor seizures are known asmasticatory Psychical. and when the attack starts with chewing movements, Psychical seizures consist of asudden onset of de- vocalization, if the attack starts with a cryand pro- lusions, hallucinations, forcedthinking, "déjà vu" tonic and clonic attack. Another gresses to a complete phenomena, and so on. They havebeen described in focal motor attack is the adversive scizure.Here there He has been able to repro- from the great detail by Penfield. is a turning of the eyes, head, and body away duce the attacks by stimulating theepileptogenic cor- The tonic-postural side of the brain which is firing. tex usually in the temporallobe. The attacks must be seizure is one in which the attack startswith tonic pos- from delusions indicate the intermittent and must be distinguished turing of an arm or leg which may also and hallucinations of thecontinuous nature seen in site of origin of the attack. schizophrenia. The outstanding featureof the epileptic attack is its intermittent nature,with interictal pe- Sensory riods of normal behavior. As hasbeen noted, a seizure A sensory attack involves some partof the brain may last for a longperiod of time, producing prolonged where sensations of various types areappreciated.It abnormal behavior. The EEGis of great help in dis- the temporal lobe may be somatic, visual,auditory, olfactory, vertiginous, tinguishing a seizure originating in or abdominal. Frequentlyin young children, the ori- from truly psychotic behavior in aschizophrenic. gin of the attack is not appreciated. Thechild will express fear or anxiety, or run to aparent.It is not Autonomic until the child matures and can describe thesensation Many seizures are accompaniedby disturbances of that one can appreciate the truly focal natureof the the autonomic nervous system.Such things as sweat- attack. ing,. piloerection, salivationincontinence, abdominal cramps, laughter orcrying, Penfield described as "dien- Aphasic Attacks cephalic autonomic epilepsy."It is probable that these Many patients describe clearly how they areunable seizures originate in, or near, thehypothalamus. to talk at the onset of anattack.Postictal aphasia is It is relatively easy to classify anddefine the various also frequent. One has to distinguish a trueaphasia types of seizures.It is a d:7 :ent and much moredif- from a dysarthria which may follow an attackand be ficult problem to classify theseizure of a particular part of the general picture ofconfusion that exists. patient. The lack of opportunity towitness the onset, One must also distinguish the aphasia that accom- the inability of the patient todescribe the onset, the panies a seizure. from the aura of a migraineattack. changing pattern, and variabilityoften combine to Frequently in patients having their first attackof make it impossible to determinespecifically the type of migraine, the aura is a more frightening thing tothe seizure a patient is having. Manytimes one can merely patient than the headache which follows. describe what is seen and then try toclassify it.The seizure should be classified as a symptomand not as an Automatism anatomical diagnosis, as is suggestedby "temporal epilepsy," or an electroencephalographicdiagnosis, as Attacks of automatism, or automatic behavior, con- is suggested by "wave-and-spikeattacks" or "hypsarhy- sist of apparently purposeful activity for which the thmic attacks."Having described and classifiedthe patient subsequently has no memory. The actual ac- attack, one can attempt tocorrelate it with a possible tivity, which may be conditioned by the immediate en- anatomical site of origin, theetiology, and the abnor- vironment, may be complicated activity, or it may be malities in the EEG. a simple form of repetitiveactivity such as picking at clothes and so on.Attacks have been described of Duration of Seizures prolonged periods of confused activities in otherwise healthy individuals.EEG examinations may reveal There has been some confusionin trying to classify continuous epileptic activity arising from a temporal seizures according to different stagesof their evolution Such terms as "focal lobe.Attacks of automatism are generally considered or varyingperiods of duration. to originate in the temporal lobe,particularly from the continuing," "petit mal status," or"status epilepticus," hippocampal region, but they can originate also from indicated a prolonged orcontinuing attack, whereas generally indicated an other regions of the brain.For this reason, it is not "petit mal" and "grand mal" wise to refer to them all as "temporal lobeseizures." isolated short attack.The possibility of indicating

32 This was followed by a recognition of the importance the duration as:(1) very brief (in the order of1 activity second) ; (2) brief (in the order of 10seconds) ; (3) of sleep as a means of bringing out abnormal long (in the order of 1 minute ormore) ; (4) prolonged on the EEG.About the same time photic stimulation found to be or contilming (inthe order of an hour or more) is with a flashing stroboscopic light was also of activating an EEG. recomm n led. a very useful method With the increase in sophistication of theEEG, these Precipitating Factors activating procedures have been developed to afine degree. Many different types of activatingprocedures different types Seizures may be precipitated by -rlany are now used, such asfasting, intravenous glucose, con- of stimuli.Chiidren with light sensitive epilepsy may vulsant drugs, noises, lights, reading, sudde.ishocks, their fingers be- voluntarily induce seizures by passing hyperventilation, sleep, intravenous sedatives, etc.,each There is a recent tween their eyes and a brightlight. one tailored for thepatient's needs. Apart from their when he hears certain report of a man who has seizures value as research tools, activation procedureshelp the diurch bells.There are the so-called musicogenic clinician determine whether the periodic attacks a pa- epilepsy, television epilepsy, readingepilepsy, arith- tient has are epileptic. They Are of valuein distin- A dis- metic epilepsy, olfactory epilepsy, and so on. guishing various types of epilepsy, may suggest adiag- attack occurring tressing form is the sudden myoclonic nosis of the underlying condition, and serve toclearly and harshly. Epi- in children when spoken to suddenly define epileptogenic foci which might beamenable to lepsy that is brought out by thesemechanisms is re- This indicates surgery. ferred to by some as "reflex epilepsy." This subject is extremely important inthe under- stimulusin a suscep- that the seizure is a response to a standing of epilepsy, and reference should bemade to Most seizures probably have some pre- tible brain. original articles.(Allen, 1954; Andermann, et al., Rather than referring cipitating, or triggering factor. 1962; Cobb, 1947; Forster, et al., 1949;Lang and of epilepsy, it is better to to them as a separate type Orban, 1962; Rothova and Roth, 1963) . classify the precipitating stimuli.There is probably a common mechanism,acting through thalamic nuclei, which initiates the chain of events leading to aseizure. Inhibition of Seizures The following division has proven useful as a means It is appropriate to discuss, at thispoint, the volun- of separating the various precipitatingfactors as they tary inhibition, or arrest, ofseizures.The ability of appeared in the literature: (1) visual stimuli,(2) audi- a patient to arrest aseizure is possible only if there is tory and vestibular stimuli,(3) olfactory stimuli, (4) an aura whichprecedes loss of consciousness.Paul- tactile stimuli, (5) emotional and psychicdisturbances, son (1963)studied a group of 112 patients, of whom (6) sleep, (7) miscellaneous stimuli. almost one-third believed they couldoccasionally vol- That seizures can be evoked has been knownfor a untarily inhibit seizures after the aurabegan.The long time. Hydration and pitressin were onceused to problem of inhibition of seizures wasof interest to bring out seizures. They were used before thedevelop- Hughlings Jackson and Gowers.Both reported cases ment of the, electroencephalogram.The procedure was where seizures starting in extremities couldbe arrested difficult for everyone involved and seldom used. by ligatures or massage. Symonds(1959) stated that Hyperventilation was known to blow off carbondi- 53 of 100 cases he had seen could inhibitseizures by oxide, and change the pH of the blood.It had an means of some mental orbodily activity. uncanny ability of precipitatingabsence attacks in chil- The exact mechanism of the voluntarysuppression dren. With the advent of the EEG,hyperventilation of seizures is not known, although manytheories have proved to be a very useful means of bringing outab- been propounded, based on isolatedobservations re- normalities in the record, particularly inpatients with lated to inhibition in the cortex, activationof the as- absence or tonic and clonic attacks originatingin the cending reticular system, etc.It is known that epi- diencephalic region.The next step was to use con- leptic discharges are less frequently seen in theEEG (met- vulsive drugs for this purpose. Pentylenetetrazol in patiehts who are aroused or attentive.Absence at- razol) was being used to induce convulsions in patients of activity. slowly, it tacks are less frequent during periods with various psychoses. By giving the drug stimuli of known EEG could be activated, latent Stevens (1962) showed that some was found that the potentials, epileptogenic foci made to fire, and thus epileptogenic frequency, used to evoke abnormal EEG patients with areas of the braindemonstrated without causing a activated the electroencephalograms of whereas the same stimuli caused convulsion. one type of epilepsy, 33 suppression in other patients with a different type of fuse the aphasia with dysarthria, which is a transient epilepsy.Those working with epileptic patients in phenomenon that follows most major attacks and has rehabilitation centers maintain that work and content- no localizing value except toindicate that the dien- ment are important factors in the prevention of sei- cephalon and brain stem were involved. zures. The problem of the natural inhibition, or con- The amnesia which follows an attack also varies, de- trol, of seizures is an important one with far-reaching pending upon the severity of an attack.If a patient consequences, and warrants further study. has no warning of a pending seizure, he may have a severe tonic and clonic attack.The only way he will Postictal Phenomena know that he has had a seizure, however, is that he has Headache, drowsiness, fatigue, and muscular aches bitten his tongue or has been incontinent. frequently persist after the cessation of a convulsion. For many patients, this amnesia is a blessing.For There are other more specific phenomena which per- others it constitutes a real problem. Some are unable sist, thus suggesting that the function of one area of to accept the fact that they have attacks, orthat the the brain is depressed.Following a prolonged seizure, seizures are severe.They insist on doing things which confusion may be present and suggests a slowness on may be dangerous.It is often impossible to distinguish the part of the diencephalon to return to normal the amnesia, which is part of an attack of automatism function. and automatic behavior originating in the temporal Paresis of part of the body may persist for several lobe, from postictal amnesia.In these seizures they hours, or days, after a seizure.This is referred to as may be the same. Todd's paralysis.Frequently there is a story of a child having an innoculation or a fever associated with Behavior Disorders Associated with Epilepsy a unilateral convulsion which is followed by a transient The greatest problem that confronts the patient with hemiparesis. Sometimes the paresis does not disappear epilepsy may not be the convulsions, but the effect of completely. Gastaut and his conferees have described the pathological lesion which causes the attacks on his this in great detail (1962). The explanations for this intelligence and personality. The effect may be direct postictal paralysis have been many and varied.It is and cause mental retardation, or it may be indirect probable that the loss of neuronal function is related and cause a reactive neurosis or behavior disturbance. to anoxia. The increased demand for oxygen created Superstition, fear, and prejudice continue to be very by the fever and the excessive neuronal activity, com- powerful in harming the epileptic in the eyes of him- bined with the asphyxia caused by the tonic contrac- self and others.It is not infrequent that the medica- ture of the respiratory muscles is one explanation. tion given to control the seizures is a direct cause of Another is that the seizure is a result of a vascular overactivity, impulsive acts, drowsiness, or other be- spasm or occlusion, and the damage is done before havior disorders. collateral circulation can be developed.Elderly pa- The current literature on the relationship to schizo- tients may have a profound and lasting Todd's pa- phrenia, manic-depressive psychosis, reactive neuroses, ralysis after a seizure.Indeed, it may be impossible to behavior disorders, mental retardation and specific distinguish the hemiparesis from a cerebrovascular learning problems has been reviewed and a limited occlusion.It is only the next day, when the paralysis is bibliography presented.Limitations of time have not all gone and the patient is well and wondering what all permitted a complete review of this aspect of the epi- the fuss is about, that one can be sure the paralysis lepsy problem. was secondary to the seizure.The profound loss of function in the patient with arteriosclerosis probably Related Paroxysmal Disorders is related to the inability of the vessels to dilate as readily as in younger patients.Recovery is possible A thorough study of the epilepsies should include a because there was no major vascular occlusion and the consideration of related paroxysmal disorders: mi- neurones were able to build up their energy stores. graine, syncopy, narcolepsy and catalepsy, hysteria, ver- For similar reasons, seizures involving the dominant tigo (including Meniere's syndrome) , breath-holding hemisphere may leave the patient with a transient spells, paroxysmal abdominal pain, and trigeminal aphasia. The aphasia will vary, depending upon the neuralgia.Although a detailed review of these dis- area of the cortex involved, and is likely tochange orders has been prohibited in this paper because of rapidly. This makes it difficult to decide exactly what unfortunate time limitations, bibliographies of each, type of aphasia it is.Care should be taken not to con- therefore, are included.

34 only mani- Bibliography Jaffe, R. J., Ictal behavior disturbance as the festation of seizure disorder: A case report.J. Nerv. and Allen, 1. M., Observations on cases of reflex epilepsy. New Ment. Dis. 134: 470, 1962. Zealand Med. J. 44: 135, 1945. Jasper, H. H., Droogleever-Fortuyn, J., Experimental studies Andermann, K., et al., Self-induced epilepsy.Arch. Neurol. on the functional anatomy ofpetit mal epilepsy.Res. 7: 49, 1962. Publ. Ass. Nerv. Ment. Dis. 26 : 272, 1947. Baxter, D. W., Bailey, A. A., Primary reading epilepsy. Keating, L. E., Epilepsy and behavior disorder in school Neurology 11: 445, 1961. children.J. Ment. Sci. 107: 161, 1961. Beard, A. W., Slater, E., The schizophrenic-like psychoses of Lang, J., Orban, L., Vestibulogenic epilepsy.Mschr. Ohren- epilepsy.Proc. of the Royal Soc. Med. 55: 311, 1961. heilk.96: 344, 1962. Behrman, S. Wyke, B. D., Vestibulogenic seizures.Brain 81 : Lishman, W. A., Symonds, C. P., Whitty, C. W. M., Wil- 529, 1958. lison, R. G., Seizures induced by movement, Brain 85: 93, Bickford, R. G., Mulder, D. W., Dodge, H. W., Hallucina- 1962. tory epilepsy: Complex hallucinations as focalseizures. Masland, R. L., Classification of the epilepsies.Epilepsia Amer. J. of Psychiat. 113: 1100, 1957. 1: 512, 1959-60. Bickford, R. G., Whelan, J. L., Klass, D. W., Corbin, K. B., Matsumoto, H., Ajmone-Marsan, C., Cortical cellular phe- Reading Epilepsy:Clinical and electroencephalographic nomena in experimental epilepsy:Ictal manifestations. studies of a new syndrome.Transactions Amer. Neurol. Exper. Neurol. 9: 305, 1964. Epi- Assoc. p. 100, 1956. McFaughton, F. L., The classification of the epilepsies. Bray, P. F., Temporal lobe syndrome in children.Pedi- lepsia (3) 1: 7, 1952. atrics 29: 617, 1962. Norbury, F. B., Loeffler, J. D., Primary reading epilepsy. Chao, D., Photogenic and Self-induced epilepsy.J. of Pedi- J.A.M.A. 184: 661, 1963. atrics 61: 733, 1962. Pantelakis, S. Bower., Douglas-Jones, H., Convulsions and Critchley, M., Reading epilepsy.Epilepsia 3: 402, 1962. television viewing.Brit. Med. J. (Sept.) p. 633, 1962. Cobb, S., Photic driving as a cause of clinical seizures in epi- Paulson, G. W., Inhibition of seizures.Dis. Nerv. Syst. leptic patients.Arch. Neurol. and Psychiat. 58: 70, 1947. 24: 657, 1963. Currier, R. D., Kooi, K. A., Saidman, L. J., Prognosis of Penfield, W., Jasper, H. H., Epilepsy and Functional Ana- "pure" petit mal; a followup study.Neurology 13: 959, tomy of the Human Brain.Little, Brown & Co., Boston, 1963. 1954. Faidherbe, J., Franck, G., Gastaut, H., Regis, H., The char- Pollen, D. A., Perot, P., Reid, K. H., Experimental bilateral acteristics of hemiconvulsive seizures in children.EEG wave and spike from thalamic stimulation inrelation to and Clin. Neurophysiol. 14: 775, 1962. level of arousal.EEG and Clin. Neurophysiol. 15: 1017, Falconer, M. A., Driver, M. V., Serafetinides, E. A., Sei- 1963. zures induced by movement: Report of a caserelieved by Pond, D. A., Psychiatric aspects of epileptic and brain-dam- operation.J. Neurol. Neurosurg. Psychiat. 26: 300, 1963. aged children.Brit. Med. J. 2 : 1377, 1961. Forster, F. M., Penfield, W., Jasper, H., Madow, L., Focal Poskanzer, D. C., Brown, A. E., Miller, H., Musicogenic epi- epilepsy,sensoryprecipitation and evokedpotentials. lepsy caused only by a discrete frequency band of church EEG and Clin. Neurophysiol. 1: 349, 1949. bells. Brain 85 : 77, 1962. Gastaut, H., The Epilepsies, Blackwell Scientific Publications, Rogina, V., Serafetinides, E. A., Epilepsy and behavior dis- Ltd., Oxford, 1954. Gastaut, H., Epilepsies.Encephale-Encyclopedie Medico- order in patients with generalized spike-and-wave com- Chirurgical, 1963. plexes. EEG and Clin. Neurophysiol. 14: 376, 1962. Gastaut, H., Regis, H., Bostem, F., Attacks provoked by Rothova, N., Roth, B., A case of focal reflex epilepsy induced television and their mechanism.Epilepsia 3: 438, 1962. by tactile stimuli.C. S. Neurol. 26: 33, 1963. Glaser, G. H., EEG and Behavior, New York, Basic Books, Schwartz, J. F., Photosensitivity in a family.Amer. J. Dis. 1963. of Children 103: 90, 1962. Grisell, J. L., Levin, S. M., Cotten, B. D., Rodin, E. A., Effects Servit, Z., Machek, J,. Stercova, A., Dudas, D., Kristof, M,. of subclinical seizure activity on overt behavior.Neurology Cervenkova, V., Reflex influences in the pathogenesis of epi- 14: 133, 1964. lepsy in the light of clinical statistics.Epilepsia 3: 315, Guerrant, J., Anderson, W. W., Fischer, A., Weinstein, M. R., 1962. Jaros, M., Deskins, A., Personality in Epilepsy.Charles Standard Nomenclature of Diseases and Operations, National C Thomas, Springfield, Ill., 1962. Conference on Medical Nomenclature.Fourth Edition, Guerrero-Figuero, R., Barros, A, de Balbian Verster, F., New York, Published for the A.M.A. by the Blakiston Co., Heath, R. G., Experimental "petit mal" in kittens.Arch. 1952. Neurol 9: 297, 1963. Sterc, J., Experimental reflex epilepsy (audiogenic epilepsy). Heath, R. G., Common characteristics of epilepsy and schizophrenia: Clinical observations and depth electrode studies. Epilepsia 3: 252, 1962. Amer. J. Psychiat. 118: 1013, 1962. Stevens, J., Central and peripheral factors in epileptic dis- Holowach, J., Thurston, D. L., O'Leary, J.L., Petit mal charge :Clinical studies.Arch. Neurol, 7: 330, 1962. epilepsy.Pediatrics 30: 893, 1962. Swanson, P. D., Lutrell, C. N., Magladery, J. W., Myoclonus, Ingvar, D., Nyman, E., Epilepsia arithmetices.Neurology a report of 67 cases and review of theliterature.Medicine 12: 281, 1962. 41: 339, 1962. 35 Brain Symonds, C., Classificationof the epilepsies with particular Symonds, C., Excitation anci inhibition in epilepsy. reference to psychomotorseizures.Arch. Neurol. Psychiat. 82: 133, 1959. Thomson, A. F., Alvarez, F. A., Ictal emotions intemporal 72: 631, 1954. Brit. Med. J. lobe disorder. World Neural. 3: 224, 1962. Symonds, C., Classificationof the epilepsies. Tucker, W. M., Forster, F. M., Petit mal epilepsy occur- p. 1235, 1955. ring in status.Arch. Neurol. and Psychiat. 64: 823, 1950.

36 DIAGNOSIS

patient presenting c. Time of Day.The relationship of attacks to The diagnostic evaluation of a during the day is noted. with the complaint of convulsions orseizures, regard- sleep, meals, or specific times sound medical practice. A d. Precipitating Factors.Unless specific questions less of the type, is based on precipitate careful history is taken, and aphysical examination are asked, thefact that certain stimuli can and indicated laboratorystudies are conducted. an attack maybe missed, e,Related Events,Hunger, fatigue, menses, recent television, painful stimuli, The History intake of alcohol, watching etc., should beconsidered, The technique of taking historiesvaries from doctor f. Response to Medication,The types and amount to doctor and frompatient to patient. The procedure of medication, as well aslength of time each has been used for an infant is different fromthat ora child, and taken, and any unusualreaction to the medicationis that for a child is different fromthat for an adult. noted. Whether the facts are obtained fromthe parents, the g. OtherComplaints,The development of other patient, or both, the basic formularemains the same. complaints and their relations tothe seizures is noted. If the seizures are a responseto some other medical Complaints condition, special attentionis given in obtainingthe history of this aspect, The "complaints," which constitute adescription of first and lead to a the attacks, are generally presented Family H istory "history of the present illness." The importance of an accurateand detailed family History of the Present Illness history cannot be overemphasized.Particular care must be taken ifthe history is to be usedfor genetic particularly This phase of the history is concerned research or genetic counseling.Often there is an attacks in the with localizing the site of origin of the apparent "negativefamily history" and, yet,further brain and evaluating the patterns of theseizure activity. questions may reveal the storyof febrile convulsions attack and the It starts with a description of the first or "faintingattacks" within the family. events leading up to it.This is followed by a description of each subsequent attack or,if. they are very Past History frequent, any different types of attacks.Attention is This starts with adescription of the pregnancy, paid to the following aspects: and may be obtained a. Pattern of theAttack.Every effort should be birth, and early development, description of the from different sources.Many children with seizures made to get a sufficiently accurate the child seizure.The physi- are retarded.Note should be made of when attack to permit classification of "mile stones," and of the cian must determine such questions aswhether there passed the developmental examina- warning, what happened during the school progress.From the history and the was an aura or develop his own impression attacks and what happened after theattack. tion, the physician must and decide whether further b. Frequency of the Attacks.The frequency of at- of the child's intelligence, tacks is noted, both on and offmedication. psychological evaluation is indicated. 37 A record is made of any untoward response to vac- ketonuria or metachromatic inclusion bodies in the cination or other immunizing procedures.Any acci- presence of undiagnosed encephalopathies. dents, serious illnesses, or hospitalizations are noted. Particular attention is craid to any past or present Hematological Studies behavioral or emotional disturbances.This may be the only clue to an organic disorder of the brain. A red, white, and differential cell count, and hemo- In an adult, habits of drinking, taking drugs, smok- globin estimate are requested to reveal evidence of These also provide ing, sleeping, working, and so on may provide impor- anemia or other blood dyscrasia. the patient tant information.One needs to determine whether a baseline for repeat studies during the time If diabetes, or any other metabolic there is anything in the past history to suggest organic is on medication. deterioration which might point to a brain tumor, a disorder,issuspected, appropriate blood chemistry subdural hematoma, or cerebral arteriosclerosis. studies are requested. A review of systems, or functional inquiry, is an essential part of the history.Often an adult will Radiological Investigations admit to headaches, whereas only a specific question will reveal impotency.An inquiry into possible al- X-rays of Skull lergic or hematological disorders is essential.Also, a Cranial X-rays are an essential part of the investi- careful inquiry into the social and emotional back- gation of any patient with epilepsy.Some radiologists grounds of any patient with seizures, may prove im- prefer multipleprojections atdifferenttangents; portant to the success of therapy. others prefer stereoscopic films in the beginning fol- There are no thoctcuts to a careful history, but once lowed by special projections as indicated. obtained it provides a useful and important document Of particular significance is an asymmetry of the for the future. skull, especially in the region of the middle fossa. Thickness of one side of the calvarium may indicate Laboratory Examinations smallness of the cerebral hemisphere on that side. Although some laboratory tests are described as Abnormal positions of the pineal or glomis bodies of "routine," and are requested with the vague hope that the choroid plexuses may indicate an expanding in- some unusual finding may be revealed, this should not tracraniallesion,or contracture due to cnrebral be the case.Rather, laboratory tests should be re- atrophy.Abnormal intracranial calcifications may quested with a definite purpose in mind and a knowl- indicate a tumor, tuberose sclerosis, Sturge-Weber edge of what useful information may be revealed by syndrome, an old tuberculoma, or other disorders. the test.An initial evaluation generally includes the Signs of increased intracranial pressure, such as ero- following: sion of the sella turcica, or separation of the sutures, (1) Urinalysis. may provide other clues to the cause of the seizures. (2) Hemogram. (3) X-rays of skull. X-rays of the Chest (4) EEG. Any patient who mignt possibly have a metastatic (5) Psychological evaluation. tumor warrants an X-ray of the chest.In infants (6) Social evaluation. and children, X-rays of the chest may reveal evidence of a nutritional disorder or lead poisoning in the long Urinalysis bones, or pulmonary disease, and should be considered In the young child, urinalysis may reveal evidence in the diagnostic procedure. of a latent nephrosis, and thus may influence one's decision regarding medication.In the older patient Pneumoencephalography and Ventriculography the possibility of diabetes increases.Patients taking trimethadione or paradione should have periodic uri- A pneumoencephalogram is a technique for out- nalyses to exclude a toxic nephrosis.It is also a wise lining the brain and ventricles by radiography.The precaution to advise parents to watch for swelling of CSF in the subarachnoid space and ventricles is re- the ankles or unusual increase in weight in the child. placed with air or oxygen, and the different refractive Special urinary studies may be conducted to detect index of the gas compared to that of the brain enables abnormalities of protein metabolism, such as phenyl- the gas filling the spaces to be demonstrated.In the

38 intracranial pressure, it may be mesencephalon and in the diencephalon maybe re- event of increased However, as the cortex safer to perform a ventriculograrn.Here the gas is corded through the scalp. injected directly into the ventricle.The indications matures, all impulsesoriginating in deep structures through and modified by the neu- for, and information derived from,these procedures must be "filtered" have been described well by Davidoffand Dyke, and rones of the cortex.The EEG, as recorded through of the neuronal ac- others.Should an expanding intracraniallesion be the scalp, gives only a gross picture The electrocorticogram can more suspected as a cause of seizures,then some form of tivity of the brain. activity on the contrast studies should beconsidered, whether it be accurately localize areas of abnormal surface of the brain, but it still onlyindirrctly reveals apneumoencephalogram, ventriculogram,arterio- epileptogenic activity. gram, or aradioactive isotope study.The decision the site of origin of deepseated been remarkably will depend on the nature of theproblem.Like any Newer depth electrode studies have consider what useful successful in localizing the origin ofepileptogenic test of this type, it is important to lobe and information may be obtained before itis undertaken. activity,particularlyinthetemporal Castorina and McRae (1963) reviewedthe X-ray hippocampal region. of a large findings of 100 patients with temporallobe epilepsy Seizures are due to synchronous firing who were operated on and found not tohave a tumor group of neurones and,despite its limitations, the EEG their sites of origin. or angioma.About 15 percent had asymmetry ofthe has a remarkable ability to localize vault and/or base of the skull.About 80 percent Over the years, normal controls havebeen developed variety of physio- showed radiologic signs of hypoplasia, oratrophy of the for the human at all ages, under a EEG record- lobe or hemisphere which producesthe seizures.Of logical states of wakefulness and sleep. disease or func- particular value was the combinationof relative small- ings have been made in nearly every The correlation ness of the ipsilateralmiddle fossa and relative en- tional disorder of the nervous system. findings in largement of the ipsilateral temporalhorn. of the EEG recordings with pathological disease states, as well as experimentalstudies, has aug- electroencephalographer to Arteriography mented the ability of the relate the EEG findings to specificpathology. Never- Arteriography is a technique for outliningthe vessels theless, it should be rememberedthat widely divergent of the brain with a contrast medium.Injections may pathology may give identical EEGrecordings. be made directly into the carotid orvertebral arteries, The EEG is of greatest value in thestudy of epi- or indirectly fromcatheters inserted into the brachial lepsy.In patients, particularly children,for whom one or femoral arteries.Arteriography has proven to be cannot obtain a goodhistory, the EEG helps to estab- an extremelyuseful procedure in demonstrating brain lish the clinical diagnosis, and sometimesis of value in tumors, subdural hematoma, andvascular abnormali- suggesting a pathological diagnosis.It may be of value ties.Although it is of less value as a diagnostic pro- as an indicatorof the severity of the disorder.This cedure in epilepsy, it is useful to helprule out tumors is particularly true in some ofthe infantile encephalop- or vascular abnormalities.It is also useful in demon- athies.The EEG is of value in distinguishinghysteria stratingvascularocclusionsintheunexplained or syncope from a trueconvulsive disorder.It also hemiplegia associated with convulsions frequently seen may be helpful indetermining whether therapy isindi- in children. cated.The child who has a normalEEG following his first febrile convulsion is likely tobe observed over Electroencephalogram a period of timewithout treatment. The childwho The development of theelectroencephalogram has an abnormal EEG followingsuch an incident is (EEG) has provided the clinician with the most re- more likely to bestarted immediately on prophylactic patient with markable means of evaluating the medication. electrical epilepsy.It is a means of amplifying the It would be inappropriate here todescribe the tech- activity of the brain, and recording it continuously on nique of recording or how to interpretthe EEG. These paper.When large numbers of neuronesdischarge detail, and developed have been presented elsewhere in great together in synchrony, sufficient voltage i; and textbooks. be detected on the scalp. advances have been recorded in journals on the surface of the brain to however, to pro- In a premature child, when the corticalconnections A limited bibliography is presented, covering major works are not developedand the cortex is less mature than vide the reader with information the deeper structures, impulses originatingin the or recent reviews onthe subject. 39 Reference should be made to activation procedures. too many tests are ordered unnecessarily before careful In thc early days of electroencephalography,attempts consideration is given to what useful information might were made to activate epileptogenic areas of the brain be obtained. The EEG givesa picture of the electrical by hydration. Since then, several methods of activa- activity of the brain as it is reflected through thecortex. tion have been developed.The simplest is that of It is rarely diagnostic in itself, but whe ncombined with hyperventilation, which is of particular value inpa- the clinical history and findings,may makc a complete tients with a bilaterally synchronous abnormalityon diagnosis possible. the EEG, or in "absence"or "petit mal" attacks. The convulsant, pentylenetetrazol (metrazol),given slowly Implanted Electrodes intravenously in subconvulsant doses during the time of the recording, hasproven to be a useful means of Depth electrode studies haveproven to be a useful activating the EEG. However, the danger of precip- diagnostic tool in certain patients with EEG abnormal- itating a major tonic-clonic seizuremust be anticipated ities originating in the temporal lobes. and precautions taken. EEG studies during various Crandall and his colleagues (1963) reportedon a phases of sleep have proven to bea very useful way of group of eight patients with apparently independent searching for epileptic activity.Sleep studies now are bitemporal spiking EEC activity. Bymeans of stereo- almost a standard part ofany EEG study. tactically implanted electrodes in the amygdala,pes- Intermittent photic stimulation also hasproven it- hippocampi, and hippocampal gyri, bilaterally,they self a useful method of activation. Witha stroboscopic were able to show that in six of the eight patients the light, the patient is confronted with intermittentlight disorder was primarily unilateral sinceone site dem- flashes of a high intensity.The parieto-occipital EEG onstrated greater activity and lower threshold for after- is altered in all patients with this procedure,but high- discharges, reproduced the typical seizureon electrical voltage activity may be initiated in other regions in stimulation, andwas pharmacologically activated. those patients sensitive to thistype of stimulation.It Temporal lobectomy in these patients resultedin re- is significant that certain patientscan bring on attacks lief from seizures. by waving their hand between theireyes and a bright Angeleri, et al., (1964) reviewed their results of light.Others have attacks when watching television. prolonged implantation of electrodes in regardto the Some patients have been knownto have seizures dur- electrical activity and reactivity of the rhinencephalic, ing periods of hypoglycemia. For thisreason, observa- pararhinencephalic, and thalamic structures inman. tions are carried out during periods of fastingor follow- They performed simultaneous deep cerebral recordings ing the administration of insulin.Intravenous admin- in 94 cases of neuropsychiatric patients, of whom 32 istration of glucosemay be used to abolish abnormal had epilepsy, 56 had extrapyramidal synchrony, 4 had activity.Other types of activating proceduresare schizophrenia, and 2 hadsevere psychasthenia with used, but these are usually developed for patientswhose associated motor manifestations.They pointed out attacks are brought on by unusual stimuli. Such things that our knowledge of the clinical syndrome of epilepsy as musiogenic epilepsy, reading epilepsy, tactile epi- originating in the temporal lobe isnow fairly accurate, lepsy, etc., are included here. nevertheless, our understanding is less clear in regard The advances which have taken place inthe sur- to the physiopathological phenomena whichcause the gery of epilepsy have been dependent upon the abil- syndrome and the structures thatare directly or in- ity to localize the site of origin of theepileptogenic directly involved.Also, the mechanism of transmis- focus with the EEG. With each advance iUEEG tech- sion of epileptic discharges fromone sector of the brain nology, the selection of patients forsurgery and the to another is a complicated problem which remains to surgical results have improved. Witha better under- be solved.From the studies of Angeleri and his col- standing of the EEG,as recorded through the scalp, leagues, they concluded the following: combined with depth electrode studies,one can look (1) It now appears to have been adequatelydem- forward to even better selection, and furtherimprove- onstrated that the hippocampal-amygdalarstructures ment in the results. are of predominant importance for the precipitation A word of caution is essential, however. Kellaway and maintenance of epileptic attacks, particularly of expressed it well when he said, "The electroencephalo- temporal lobe origin, and also of the so-calledcentren- gram should not be considered a means of obtaining cephalic forms.Either by synergic activity,or sep- a 'penny-in-the-slot' diagnosis." In the first place, the arately, these structuresmay be regarded as the test is expensive for the average patient, and secondly, "starter" of the temporal attacks; theymay play a 40

. very important role in the preparation ofparticular the injection while replying to "aphasia" tests.If the functional conditions of the neopallium which facili- speech area is not located in the hemisphere on the tate the occurrence of generalized attacks of the tonie- side of the injection, a contralateral hemiparesis will clonic type.Studies carried out in electrophysiolog- develop, but no aphasia. ical laboratories cannot contribute data comparable to that obta;,ned by recording and stimulating in epi- Psychological Evaluation leptic subjects. (2) The relations between the convulsive electrical In an infant and preschool child one can follow activity of the rhinencephalic structures and activities with gross tests the mental development of a child including the time the child sits, walks, talks, and so on. of the same type from the neopallium are rather complicated, but it may be stated that there is dissociation When a child with epilepsy approaches the school age, between the attacks originating from these two a careful psychological evaluation should be conducted.The difficulties that these children have re- structures. (3) The importance of the rhinencephalic system in volve around frequently impaired intellect and difficult behavior.One should have a clear picture of the genesis of the changes in so-called centrencephalic epilepsy is strongly confirmed by their experiments a child's intellectual potential, and be able to transmit this to both the parents and teachers.The same can but it has proved rather doubtful whether the thalamus be said about patients with seizure probic.:ms attempt- is also concerned in these abnormal manifestations. ing to obtain work. Frequently they cannot hold a job (4) Theirobservations,duringstimulationof rhinencephalic structures, of the appearance of after- because of their intelligence or .difficulty in getting Vocational guidance discharges in these structures contain clues which are along with their fellow workers. specialists have been of great help in seeing that a man useful in correlating the electrical aspects of temporal attacks and the accompanying clinical phenomena. is not asked to do more than he is capable, and in Finally, they again stressed the importance and interpreting the ability of patients to employers. value of depth electrode recordings and stimulation The role that psychological studies can play in eval- studies in patients with epilepsy as compared to animal uating the effect of lesions in the temporal lobe on intellect, hearing, and memory, is described well by studies. Milner and others.Reference should be made to Radioactive Isotope Studies the original articles. The use of radioactive isotopes as a means of localiz- Social Background ing epileptogenic lesions has not proven to be of value, even though changes in permeability of blood Social service workers play an essential role in a vessels to fluorescein, at areas of epileptogenic activity, convulsive disorder clinic.They can help the patient have been demonstrated.In definitive lesions, such and the physician with many problems.They in- as tumors, this technique has been valuable. vestigate the social environment of a patient, and frequently determine why a particular patient is not re- Intracarotid Injecfion of Sodium Amytal sponding well.They interpret the nature of the problem to both the patient and his family. They can offer In patients being considered for surgical excision of an epileptogenic area, it is imprtant to know what advice with schooling and employment problems, and hemisphere subserves speech.In a right-handed be of very practical help in many instances.With the person, speech is almost invariably in the left hemi- guidance of the neurologist or psychiatrist, the social sphere; however, the opposite is not true for left- worker can do much to assist in the emotional life and handed people ( Wada and Rasmussen, 1960). The adjustment of the patient with seizures. carotid amytal test, as originally described by Wada, has proven to be a useful means of determining the Bibliography dominant hemisphere for speech, particularly in left- Balthazar, E. E., Cerebral Unilateralization in Chronic epi- handed patients when operation is being considered in leptic cases: The Wechsler Object Assembly Subtest.J. of the left hemisphere.The test is performed by inject- Clin. Psychology 19: 169, 1963. ing sodium amytal into one carotid artery and record- Castorina, G., McRae, D. L., Radiologic findings in temporal ing the ability of the patient to perform voluntary lobe epilepsy of nontumoral origin.Acta Radio!. 1: .541, movement with the arms and legs on the side opposite 1963. Crandall, P. Hi, Walters, R. D., Rand, R. W., Clinical appli- Magnus, 0,, De Vet, A. C., Vander Marel, A., Meyer, E,, cation of studies on stereotactically implanted electrodes in Electrocorticography during operations for partial epilepsy. temporal-lobe epilepsy.J. Neurosurg. 20: 827, 1963. Devel. Med. and Child Neurol. 4: 35, 1962. Dugger, G. S., Pepper, F. D., The reliability of radioisotopic Milner, B., Psychological defects produced by temporal lobe encephalography; a correlation with other neuroradiological excision.Res. Pub. Au, Nerv. Ment. Dis. 36: 244, 1958. and anatomical studies.Neurology 13: 1042, 1963. Milner, B., Les troubles de la memoire accompagnant des Ellingson, R. J., Electroencephalograms of normal, full-term lesions hippocampiques bilatirales.Colloques Interna- newborns immediately after birth with observationson tionaux Centre National de la Recherche Scientifique No, arousal and visual evoked responses.EEG and Clin. 107: 257, 1962. Neurophysiol. 10: 31, 1958. Milner, B., Laterality effects in audition.In Mountcastle, Fischer-Williams, M., Cooper, R. A., Depth recording from V. (Ed.) Interhemispheric Relations and Cerebral Domi- the human brain in epilepsy.EEG and Clin. Neuro- nance,Baltimore.1962. physiol. 15: 568, 1963. Milner, B., Effects of different brain lesionson card sorting. Gastaut, H., Roger, J., Ouahchi, S., Timsit, M., Broughton, Arch. Neurol. 9: 90, 1963. R., An electroclinical study of generalized epileptic seizures Mirsky, A., Primac, W., Ajmone-Marsan, C., Rosvold, H. E., of tonic expression.Epilepsia 4: 15, 1963. Stevens, J., A comparison of the psychological test perform- Harris, R., Tizard, J. P. M., The electroencephalogram in ance of patients with focal and nonfocal epilepsy.Exper. neonatal convulsions.J. of Pediatrics.57: 501, 1960. Neurol. 2: 75, 1960. Hughes, J. R., Curtin, M. J., Brown, V. P., Usefulness of Perez-Borja, C., Rivers, M. H., Some scalp and depth electro- photic stimulationinroutineclinicalelectroencephal- graphic observations on the action of intracarotid sodium ography.Neurology 10: 777, 1960. amytal injection on epileptic discharges inman. EEG Keating, L. E., A review of the literatureon the relationship and Clin. Neurophysiol. 15: 588, 1963. of epilepsy and intelligence in school children.J. Ment. Rovit, R. L., Gloor, P., Rasmussen, T., Sphenoidal electrodes Sci. 106: 1042, 1960. in the electrographic study of patients with temporal lobe epilepsy.J. Neurosurg. 18: 151, 1961. Kimura, D., Right temporal-lobe damage.Arch. of Neurol. 8: 264, 1963. Royo, D., Martin, F., Standardized psyhcometricaltests applied to the analysis of the effects of anticonvulsive medica- Li, C. L., Baldwin, M., Implanted electrodes in the human brain. tion on the intellectual proficiency ofyoung epileptics. EEG and Clin. Neurophysiol. 13: 464, 1961. Epilepsia 1: 189, 1959-60. Liske, E. A., Gilson, W. E., Forster, F. M., Telemetricelectro- Stevens, J. R., Emotional activation of the EEG in encephalography for hospitalized patients seizure patients. with a convulsive disorder.EEG and Clin. Neurophysiol. J.A.M.A. 182: 582, 1962. 10: 177, 1958. Lundervold, A., Jabbour, J. I., A correlation of clinical, Vizioli, Raffaello, A clinical and EEGsurvey on infantile and electroencephalographic and roentogenographic findingsin childhood epilepsy.Epilepsia 3: 1, 1962. children with epilepsy.J. Pediat. 60: 220, 1962. Walker, E. A., Lichtenstein, R. S., Marshall, C., Subcortical Machek, J., On the physiopathogenesis of the wave-and-spike recording in temporal lobe epilepsy.Arch. of Neurol. 1: pattern.EEG and Clin. Neurophysiol. 14: 575, 1962. 288, 1959.

42 PATHOLOGY

Pathological lesions have been describedfor dif- Scholz, were unable to confirm the finding ofanaemia ferent types of epilepsy; however, thepathology of preceeding the onset of a seizure. idiopathic epilepsy continues to be somewhatobscure Similar problems exist with regard to thepathology Earle, and it is not clear whether the lesionsfound are the of epilepsy originating in the temporallobe. result or the cause of seizures.Scholz (1951) re- Baldwin, and Penfield (1953) claimed that"incisural viewed the pathology of epilepsy.More recently, sclerosis" was the most common cause oftemporal lobe Meyer (1958) presented a general analysisof the epilepsy.This change was noted in 100 out of 157 described pathology including his own work,particu- patients who had been operated on at theMontreal larly in relation to the temporal lobe. Neurological Institute.The extent of this sclerosis that of The oldest and most familiar lesion seen inepilepsy ranged from involvement of a single gyrus to is sclerosis of Ammon's horn. Many of theearlier in- the entire temporal lobe.The apex and the anterior vestigators reported that Ammon's horn sclerosis oc- part of the hippocampal gyrus,with the uncus and curred in approximately 50 percent of epilepticbrains, amygdaloid nucleus, were the most frequentlyinvolved. and was usually unilateral, or, if bilateral, was more The lesion was presumed to be the resultof the its marked in one hemisphere.It was observed not only herniation of the temporal lobe, or more strictly in cases of "idiopathic" but also of "symptomatic"epi- most medial and inferior parts,into the tentorial open- parturition. lepsy.It has been found even in the brains of patients ings during the head molding phase of the temporal who had not suffered from convulsions.Spielmeyer Such herniation occurs at a time when (1927),and later Scholz, confirmed and expandedthe lobe is poorly developed and thus particularly suscep- following the earlier findings.They provided clear evidence that tible to damage through local anoxia posterior the sclerosis was due to vascular disturbancesand/or compression of the anterior choroidal and anoxia.Pathological lesions have been found in the cerebral arteries against the tentorial edge. ' cortex and subcortical regions in epilepticpatients, Sano and Malamud's (1953) clinical,pathological, but they have also been found in patients whodid not post mortem studies revealed29 of their 50 cases of After excluding suffer from epilepsy.There is some question as to epilepsy had Ammon's horn lesions. whether such lesions are directly related to, or caused severely demented cases unsuitable forclinicopatho- with clinical by, the convulsions. logical analysis, they found that all cases Most of the pathological findings reported are temporal lobe symptoms had Ammon's hornsclerosis clearly the consequence of disturbance of the blood and/or traumatic frontotemporal lobe lesions.Stau- in 36 of circulation and/or lack of oxygen.They are identical der, in 1935, found Ammon's horn sclerosis with those considered to be attributable toanoxia. 53 cases of epilepsy.Thirty-three of the 36 cases with Spielmeyer suggested that disturbance of vasomotor temporal lobe lesions had clinical symptomssuggestive regulation, and in particular angiospasm, caused the of the type of epilepsy usually associatedwith the necrosis.He, therefore, postulated angiospasm as a temporal lobe.None of the 17 cases with normal possible cause of the convulsion.Some investigators Ammon's horn showed clinical signs of temporallobe have suggested that angospasm may play a rolein the involvement.Meyer studied the patients who had causation of convulsions. Others (Meyer, 1939) ,how- had an anterior temporal lobectomy by Mr.Murray ever, using histologicaltechniques similar to that of Falconer.The incidence of sclerosis of Ammon's 43 horn in their cases was justover 70 percent, followed Penfield and Jasper (1954) present, clearly and closely by lesions of the uncus (64 percent), and toa concisely, the pathology seen in focal epileptogenic lesser degree, lesions of the amygdaloid complex. lesions.They point out that thereare common fea- (Meyer, et aL, 1954). tures in all these atrophic epileptogenic lesions.In The results of these studies suggest that lesions in all, there was an area ofgrey matter in which the and near the hippocampalgyrus play an important circulation was imperfect.There was found in all part in the mechanisms of many seizures of the tem- those studied carefully, evidence of periodic closure poral lobe type.Ammon's horn, the uncus, and parts of minute blood vessels sufficient to produceprogres- of the amygdaloid complexmay be of considerable sive punctate injury or destruction.In cases of most importance as general activators of brain function such lesions, the evidence indicated that the point of (Green and Arduini, 1954; Feindel and Gloor, 1954). departure for epileptogenic dischargewas either an They may also playa role as part of the so-called area of grey matter obviously abnormal, or an area of visceral brain, or participate in the cerebral control grey matter not obviously abnormal, but influenced of emotions and emotional expression (Papez, 1937 in an abnormal manner byan adjacent lesion of the and Kluver and Bucy, 1939).Lesions in these struc- brain. tures could thus account for the autonomic andemo- Penfield also found that withinor at the periphery tional features of temporal lobe seizures. of an epileptogenic lesion isa zone in which recurring The concept that incisural sclerosis isa result of a ischemia is produced in minuteareas, due to periodic molding of the head at birth,as proposed by Earle impairment of bloodflow throughone or another of and his colleagues, is at variance with the hypothesis the small local blood vessels.A localized anoxia acts that Ammon's horn sclerosis is caused by seizures and as an irritant in the sense that greater activity occurs related to vascular spasm. in local neurones.They suggest that this increased The most recent report by Falconer and his col- local ganglionic activity is reflected in the fluctuating leagues (1964) is a review of 100 patients operated increases of electrical potential, whichmay be detected on between 1951 and 1960 for epilepsy originating in by the electroencephalographeven through skull and the temporal lobe.Forty-seven patients showed evi- scalp.The recorded waves are apt to be brief and of dence of mesial temporal sclerosis.Their evidence high amplitude, which gives to thema "spike" or suggested thatpatientswiththistypeoflesion "sharp" waveform.This irritative and stimulative generally had seizures dating from infancyor child- effect of ischemia varies, but continues locally for hood.There was frequently a history of difficult birth years.During this time the area of brain tissue prob- (28 percent), and the seizureswere first precipitated ably atrophies very gradually but continuously, and by fever.Although no wholly satisfactory explana- the frontier of maximum irritationmay thus undergo tion was forthcoming to explain the origin of the progressive advance. mesial temporal sclerosis, these investigatorswere of The investigators also showed that the epileptic the opinion that hypoxic episodes in infancy and early focus, when clearly outlined, is objectively abnormal childhood played amore important role than birth as well as physiologically abnormal.They concluded trauma.There were 21 patients with small cryptic that the various types of lesions, expandingor atrophic, tumors.Some had dual pathology,so that there were produce continuing or recurring ganglionic ischemia. 18 small glial formationsor tumors, 3 small capillary They, thus, proposed the hypothesis that this mildor angiomas, 1 dermoid cyst, 1 parasiticcyst, and 1 lesion recurrent chronic ischemia is irritating to nerve cells, suggesting tuberose sclerosis.The rest of the patients, and that it is the cause of epileptic discharge. some 32, were those with miscellaneous focal lesions Although the pathological lesionsseen in many con- and equivocal lesions. ditions which cause convulsionsare known, the exact The investigators found that the small cryptic nature of the pathological lesion at the site of the tu- origin of the attack is mors tended to be situated in, or around, the amygdala still obscure.Penfield and rather than the hippocampus, while jasper, as indeed have others, suggest that the epilep- among others, togenic area is due to localized neuronal ischemia. mesial temporal sclerosis almost invariably involved This may be the case and may account for the changes the amygdala. In view of this, as wellas physiolog- seen in the hippocampal region of the brain in epilepsy ical data, these workers believed the amygdalahas a originating in the temporal lobe.It is not, however, more important role in the production of clinical established whether the pathological lesionsseen there seizures than has the hippocampus (Ammon's horn). are the primary cause of the convulsions, or whether 44 they are secondary to ischemia which takes placebe- Lindenberg, R., Die Gerassvenorgung und ihre Bedeutung It is clear fiir Art und ort von kreislaufbedingtenGewebesschaden fore, during, or after the actual attack. und Gefiissprozeuen.Handbuch der Speziellen Patholo- that further work, including experimental and care- gischen Anatomic und Histologie by F. Henke, 0.Lubarsch, fully controlled clinical, electrographic, andpatho- and R. Rössle, vol. 31, ed. by W. Scholz; Part1, p. 1071, logical studies, is necessary. 1957. Meyer, A., Beck, E., Shepherd, M., Unusually severe lesionsin the brain following status epilepticus.J. Neurol. Neuro- Bibliography Burg. and Psychiat. 18: 24, 1955. Meyer, A., Falconer, M. A., Beck, E., Pathological findingsin Earle, K. M., Baldwin, M., Penfield, W. Incisural sclerosis temporal lobe epilepsy.J. Neurol. Neurosurg. and Psychiat. and temporal lobe seizures produced by hippocampalher- 17: 276, 1954. niation at birth.Arch. Neurol. and Psychiat. 69: 27, 1953. Meyer, A., Beck, E., Thc hippocampal formation on tempoal Falconer, M. A., Serafetinides, E. A. and Corsellis, J. A., The lobe epilepsy.Proc. Roy. Soc. Med. 48: 457, 1955. etiology and pathogenesis of temporal lobe epilepsy.Arch Papez, J. W., A proposed mechanism of emotion.Arch. of Neurol. 10: 233, 1964. Neurol. and Psychiat. 38: 725, 1937. Feindel, W., Gloor, P., Localization of discharge in temporal Penfield, W. P., Jasper, H. H., "Epilepsy and the Functional Little, Brown & Co., lobe automatism.EEG and Clin. Neuropsysiol, 6: 389, Anatomy of the Human Brain." 1954. Boston, 1954, Sano, K., Malamud, N., Clinical significance of sclerosis of the Green, J. D., Arduini, A. A., Hippocampal electrical activity cornu ammonis. Arch. Neurol. andPsychiat. 7: 43, 1953. J. Neurophysiol. 17: 533, 1954. in arousal. Schloz, W., Die Krampfschadigungen des Gehirns, Springer- Herrick, C. J., The functions of the olfactory parts of the Verlag, Berlin, 1951. cerebral cortex.Proc. Nat. Acad. Sci. 19: 7, 1933. Scholz, W., Jotten, J., Durchblultungsstorungen im Katzen- Kluver, H., Bucy, P. C., Preliminary analysis of functions of hirn nach Kurzen serien von Elektrokrampfen.Arch. the temporal lobes in monkeys. Arch. Neurol. and Psychiat. Psychiat. Nervenkr. 186: 264, 1951. 42: 979, 1939. Spielmeyer, W., Die Pathogenese des epileptischen Krampfes. Lindenberg, R., Compression of brain arteries as pathogenic Z. Ges. Neurol. Psychiat. 109: 501, 1927. factors for tissue necroses and their areas of prediction.J. Stauder, K. H., Epilepsie und schlifenlappen, Arch. Psychiat. Neuropath. and Exper. Neurol. 14: 223, 1955. Neroenkr. 104: 181, 1935.

45 Tar, 145711,55-555555,555-757T57575,1,50.515,5555,555,550535.55VIV55.5,5051-5,55,541.555,,,,,S55555- 7C 5 5,5 '55-5 5 5

TREATMENT

Introduction whole brain and spinal cord become involved and a tonic-clonic seizure ensues. "The patient is not concerned with what is causing Factors such as blood sugar level, blood gas con- his fits; he wants them stopped" (Houston Merritt). centration, body fluid, plasma, pH, body temperature, The patient's plea for direct clinical action is readily endocrine disturbances, nutritional deficiencies, spe- appreciated by his doctor. The most direct approach cific metabolic disorders, etc., are known to influence one can make toward the successful treatment of the the development and spread of a seizure. epilepsies is to determine and treat, if possible, the pri- Other factors such as hyperventilation, flickering mary underlying cause of the attack. The second lights, sudden noises, pain, and even emotional dis- approach is to control or prevent the symptomatic turbances may precipitate an attack.When planning seizures by the use of anticonvulsants and other drugs, treatment, these factors, and, indeed, the whole patient and occasionally by surgery. The third major aspect and his environment should be considered. of the treatment of epilepsy is an understanding of the total problem, of the patient as a person, his emotional Anticonvulsont Drugs life, and the relationship to his environment. The first significant advance in the medical treat- Seizures are, in a sense, a physiological disturbance. ment of epilepsy was the discovery by Sir Charles Lo- They can be elicited in normal brain by chemical or cock in 1857 (Lennox, 1960),of the value of bromides electrical stimulation.In abnormal brain tissue, as a as anticonvulsants.The report in 1912, by Alfred rule, the threshold for seizures is lower, and attacks are Hauptmann, on phenobarbital as an anticonvulsant more readily produced by chemical or electrical stimu- was the next important step forward.The structural lation.In the normal brain there is a certain stability formula of phenobarbital, or "Iuminal" asit was between the processes of excitation and inhibition. called, is: However, in a seizure, generally it is considered that the balance is lost in favor of excitation.Current investigation suggests that convulsive activity is not an enhancement of the normal excitation of neurones but a partial, or complete, block of normal inhibition. A biological abnormality of some neurones is thought to underlie the initiation of a gradually increasing depolarization in their dendritic fields,so that minimal stimuli may initiate a seizure discharge.In any case, therapy is directed at increasing the stability of the Most anticonvulsants which have been developed neuronal tissue. A seizure originating inan area of since phenobarbital was discovered have been struc- abnormal cerebral tissue may remain localizedor it turally related toit.Primidone for example has may spread to involve normal brain cells. If the dropped an oxygen atom in favor of two hydrogen spreading electrical activity is sufficiently extensive, the atoms: 46 lating effect on the pituitary and adrenal glands. Diphenylhydantoin has been shown to increase the adrenal weight and the output of adrenal cortical steroids( Woodbury, et a)., 1958). Phenobarbital is converted to an inactive derivative by hydroxylation, and therefore, like diphenylhydan- Win, the drug itself is considered to be the active anti- The structural relationships of the various anticonvul- convulsant.( Mark, 1963). sants are described exceedingly well by Goodman and Trimethadione, on the other hand, is converted to Gilman (1955 ). demethylated trimethadione which both retains anti- In 1937, Merritt and Putnam found that diphenyl- convulsant properties itself, and enhances the anti- hydantoin had a remarkable ability to prevent electri- convulsant properties of the drug.Paramethadione cally induced convulsions in cats. This compound had acts somewhat similarly. little sedative effect, was safe, and soon became widely The anticonvulsant actions of mephabarbital and used as a good anticonvulsant in man.Following primidone can be partly accounted for by theircon- this, hundreds of drugs were tested on electricallyor version to phenobarbital.Mesantoin is converted .to chemically induced seizures.A few have been proven nirvanol, a compound which has anticonvulsantprop- to be valuable in preventing or controlling various erties.The roles which these drugs play as anticon- types of seizures.Unfortunately, however, all have vulsants before they are converted are not completely some sedative effect and varying degrees of toxicity known.Most anticonvulsants are converted in the which have limited their usefulness. liver; however, acetazoleamide is excreted essentially The 'nodes of action of anticonvulsants, their ab- unchanged in the urine. sorption, distribution, excretion, and chemical action on the neurone were reviewed in 1959 by Woodbury The Evaluation of New Drugs and Esplin.Their research was related particularly The clinical toxicity or undesired side effects ofa to diphenylhydantoin and acetazoleamide as examples drug include a large variety of reactions whichmay be of drugs acting in somewhat differentmanners to divided into four general classes:(1) Overdosage, affect the sodium ratio across the cell membrane and to ( 2) exaggerated secondary effects, (3) hypersensitivity, improve neuronal stability. and (4) "true toxicity."The side effects resulting from deliberate or accidental overdosage Absorption, Distribution, and Excretion can be serious.Occasionally a. patient may prove to be un- Diphenylhydantoin has been shown to be absorbed usually susceptible to dosages whichare normally con- from the intestines into the bloodstream.Some is sidered within the therapeuticrange.The second excreted, unchanged, by the salivary glands;some, class of side effects includes those due to the secondary probably in pancreatic and intestinal secretions.It is properties which are an inherent part ofevery drug. believed that only the liver is able to metabolize di- It is hoped that the secondary propertiesare of such a phenylhydantoin.It is then excreted in the bile. low order of activity that the side effects will not be The vast majority cf the metabolitesare reabsorbed by evident at the therapeutic dose level.The third class the intestine and finally excreted in the urine.Since of side effects, hypersensitivity, includesa variety of the major metabolic product, 5-pheny1-5- ( p-hydroxy- reactions due to sensitization of some patients with phenyl) hydantoin, does not possess significant anti- certain drugs such as penicillin.The fourth class in- convulsant properties, it is tentatively concluded that cludes side effects produced by the "true toxicity" diphenylhydantoin is the active anticonvulsant agent. which is a secondary attribute of the drug.This ac- The fact that diphenylhydantoin is excreted unchanged tivity can be subtle or delayed, and thusmay not be by the salivary glands suggests that the hypertrophy revealed in the relatively short-termed studiesem- of the gums, seen in patientson relatively large doses ployed in the initial investigations. of the drug, is due toa local action of the drug.The hirsutism and thickness of the skin and subcutaneous Preclinical Investigations tissues of the face, seen in children who have received Peck (1964), at asymposium on drug safety, out- the drug in large doses for long periods of time,may be lined the preclinical investigationsnecessary to estab- due to local action of the drugor to a secondary stimu- lish the safety of a new drug and to define its toxicologi-

47 perative that the initial trialbe a well-controlledstudy. cal attributes.These investigations include thesingle and long-term The investigation should beconducted by a physician dose studies, and both short-term of clinical research,and toxicity studies. A number ofcollateral observations who is trained in this form examination, hema- performed in an environmentthat permits accurate and tests, consisting of physical and testing and extensive observations.Years of effort in research tological, liver and kidney function tests, will be included in the sub- which may have preceded thefirst clinical trial post portem examinations, may first tests in man are not ap- acute and chronictoxicity experiments.In acute have been wasted if the toxicity studies, a drug is administered to two ormore praised accurately. indicate the nature of any species of animals, by different routes,in single doses The preclinical data may the lethal range. hazard the drug might presentin man. The possible which are large enough to be in weighed against its benefi- Subacute and chronic toxicity studies,which usually hazards of the drug must be directly, and the opportunity in two or more species of animals,dif- cial effects on the patient are conducted Kohlstaedt the treatment, the to add to thephysician's armamentarium. fer primarily in the duration of difference between the number of animals used at eachdosage level, and the points out that although the quantity of a drug that willkill half the, animals number of levels employed. will give the desired effect In addition to noting thetherapeutic effect of the (LD50) and the amount that and excretion of the in half of the animals(ED50) is important, it is not drug, the absorption, metabolism, decision as to whether drug are studied in the preclinicalinvestigation.The enough on which to base the drug should be tried in man.It is gen- effect on normal metabolism and anyspecific actions or not a new determined in the basic erally accepted that a new drugshould have been ad- on tissue or organ systems are than the Knowledge of the long-term effectsis ac- minisiered in large amounts (much more studies. to obtain thedesired quired through subacute and chronicadministration amount estimated as necessary Also, post portem studies respr Ise) for atleast 30 to 60 days, to two or more of the drug to animals. is given to a should be conducted as an integral partàf the subacute sr, k:ies ofanimals before the first dose Furthermore, in- human subject. and chronic toxicity experiments. regulations issued by the vestigations should be carried out todetermine the In March of 1953, new cycle or on fetal Food and Drug Administrationmade it mandatory to effect of the drug on the reproductive the nature These studies should be designed to submit to that agency a complete report on development. and properties, the method evaluate the drug's effect on fertility,implantation of of the drug, its composition embryo and fetus, re- of preparation, tests forquality control, and the results the ovum, development of the animals as well as in vitro sorption, abortion, delivery, number oflive births, size of all preclinical tests in clinical trial must the newbcrn, growth studies. The plan for the proposed of litters, teratogensis, viability of must sign a form indi- of the young, and quality of themother's milk. be outlined and the investigator metabolic cating that he is aware of the newregulations and will The results of adequate biochemical and investi- studies, however, may permit the developmentof more abide by them.Also, his qualifications as an with the sponsor of the program. meaningful experimental designs fortoxicity studies. gator must be on file Thus, the safety of drugs may bedetermined more Recent legislation and theaccompanying regulations discourage physicians who satisfactorily by an expansion of pharmacologicaland of the FDA have served to drugs. metabolic studies than by an extension ofthe toxicity were interestedin the clinical testing of new is rapidly increasing forthe There may be certain compounds forwhich As a result, competiton studies. investigators who have adequate long-term toxicity studies will be necessary toevaluate services of competent their safety; however, in many instancesshorter toxic- research facilities. There is a need for researchunits which provide the ity studies should be adequate. proper environmentand personnel competent to con- duct initial clinical trials.These units could be estab- Clinical Investigations lished in academic centers withlarge outpatient clinics of patients and normal Kohlstaedt (1964),in his contribution to the sympo- that would provide a reservoir ward, it sium on drug safety, stated that the initialclinical trial subjects for tests.In addition to a hospital include laboratories for chemi- is a crucial matter in the developmentof a new drug. is essential that the unit The risk inherent in its first use in man,and the need cal and bacteriological tests. been thorough and animals to obtain a true evaluationof its actions before large If preclinical testing has deal of useful infor- sums of money areinvested in materials, make it im- have been closely observed, a great mation will be available for guidance in selecting the second phase of clinicaltrialis then ready to be amount of the first dose to be given to man.Neverthe- undertaken. less, it is important to remember that it is never safe If the acute trials are encouraging, a limited num- to extrapo:ate the dose from animal to man.If the ber of patients can be subjected to continuous treat- difference b :tween LD50 and ED50 is small, then the ment for a period of 3 to 6 monthsunder the direction first dose in man should be very much less than would of a single qualified clinical pharmacologist,prefer- be estimated from experience in animals.After the ably the investigator who carried out the short-term quantity to be given is selected, the amount is admin- trial.The investigator will be less inclined to publish istered to one patient.If no undesirable effects occur, prematurely if he is not competing with othersfor the same amount is given to a second and then a third priority.If severe toxicity does not occur in the small patient.Provided that there have been no untoward series, the long-term trial can be extended andaddi- symptoms, the first subject then, receives a larger dose, tional investigators enlisted in the study.These vari- but the increment should be small.During an initial ous steps represent aroutine sequence that has been trial the cardinal principles for safety are to begin with recognized as good practice for many years. a small dose, increase itgradually, and keep the patient Freis (1964) reviewed the problems of evaluation under constant surveillance.This procedure is con- of toxicity evaluation in long-term clinical trials.He tinued until the desired effect is obtained, until un- points out that if a new agent appears to be safe and toward symptoms occur, or until as much as 1 or 2 gm. effective after 3 or 4 months of treatment in alimited have been given and no activity is noted. Larger number of patients, a well-designed double-blindstudy amounts are seldom practical by the oral routeof should then be undertaken utilizing larger numbers administration. When single doses have been shown of patients.The double-blind technique is valuable to produce satisfactory responses in several subjects not only in evaluating the incidence ofside reactions, and the duration of effect has been determined, the but also in judging drug effectiveness. same dose of the drug may thenbe given at regular The target organs affected by toxic drugs usually intervals. are the liver, kidneys,and bone marrow.Sensitivity The elimination of bias is essential in all stages of reactions, such as dermatitis and arthritis, also are clinical trial, but it is especially important in the early common.Routine laboratory procedures should be stages of evaluation.Kohlstaedt outlines the meth- carried out before treatment and at regular intervals ods used to eliminate a biased experiment. during treatment.The appearance of toxicity should When sufficient data have been collected to estab- not, in itself, be a reason for discarding a newdrug lish that a drug is active in man, it is necessary to since it may be sufficiently valuabletherapeutically increase the amount given so that a "dose response" to justify a measure of risk. can be developed.The next step is a comparison with Long-term evaluation of a new drug is morediffi- a known drug.Again, experimental design becomes cult than the assessment of acute effects.Short-term very important.The patient will serve as his own studies usually permit frequent and closeobservation control in the "crossover" type of study.Randomiza- of the patient, and medication is dispensed byprofes- tion must be planned, and such devices as the "Latin sional personnel in a hospital or clinic.During long- Square" are employed to be sure that the new drug term evaluation, the patient cannot be seen atfrequent is given prior to the control drug as many times as intervals.Faithful adherence to the prescribed sched- it is administered after the control substance.When ule of medication depends on the reliabilityof the patients with disease are used as subjects, a known patient whose cooperation may be lost during a pro- drug is usually used for control, but when normal sub- longed therapeutictrial.Ingestion of medications jects are participating, the use of a placebo and may then become sporadic or evennonexistent. double-blind techniques are essential. It is rarely possible for a single investigator toob- It is always desirable to perform a battery of liver, setve or recognize every toxic reaction or tojudge kidney function, and hematological studies before be- the effectiveness of a new drug under allpossible ginning the initial clinical trial.These tests should conditions. be repeated at intervals after a dosage schedule has To compensate for unpredictable variationswhich been established.The initial clinical trial is consid- may lead to aninaccurate and too limited evaluation ered complete when dose response has been established of a new drug, the scope of the study must beextended and definite activity has been demonstrated.The en- to include a number of investigatorsworking in differ- tire procedure is usually finished within 30 days.The ent localities.The final evaluation of the usefulness 49 of a new agent, however, will depend, for various if a drug, for one reason or another will notbe useful, reasons, on the judgment of clinicalpractice. A drug and thus avoid long, expensive, and ultimatelyuseless which is valuable in the hands of the expert may be trials. too difficult for the physician in generalpractice to After the initial toxicity studies arccompleted, an manage. A serious toxic reaction may occur sorarely effective dosage is determined.This is done by stand- or in such a limitedportion of the total population ard methods of gradually increasing the doseuntil that it may not become apparent prior to its release sedative or toxic effects appear, and then byestablish- for general use. ing a dose somewhat less than this.At the same time, A new therapeutic agent is said to be good or badin blood and urine are examined for any signsof im- comparison with presently available therapy.The mediate toxicity. standard of merit for a new drug is based on effective- When a dose is established, testing can advance to ness plus ease ofadministration, minus toxicity, and patients with epilepsy.Gruber and his colleagues screening tolerance.To determine the true value of a new (1962)have developed a methodof drug, studies must be designed which provide an un- prospective drugs efficiently and quickly.Working biased comparison with placebos or an established with institutionalized epileptic patients havingfre- drug, or both. The number oi defaulters must be quent seizures, usually due to an organiclesion of the minimal, and the patients treated should be of suffi- brain, the effectiveness of the new drug can beeasily cient number and variety to form a representative and accurately compared to the effectiveness ofknown sample of the population suffering from the particulgit riticonvulsants, such as diphenylhydantoin, pheno- disease being treated. barbital, primidone, etc.This method, however, does The ideal anticonvulsant should be capable of pre- not appear to be a good one forscreening drugs de- venting an epileptic discharge, regardless of its patho- signed to control petit mal seizures.Furthermore, the of the logicalor *neurochemicalbackground.The drug stage of chemical and physiological development should develop the stability of cerebral tissue to with- region of the brain from which the seizure originates stand the normal provoking factors and be effective in may be a more importantfactor in this method of all locations in the nervous system.It should be non- screening than the type of seizure. sedative, well tolerated, and devoid of untoward ef- Compounds also have been tested in psychiatric pa- fects on vital organs and functions.When taken tients by measuring the ability of the drug to inhibit orally, its effect should be of long duration, in order convulsions induced by electric shock given for thera- to maintain a fairly stable level in the body.It is no peutic purposes.This method has many obvious dis- secret that such a compound does not exist, andthus advantages. the search for new compounds must continue. If the compound is shown to have good anticon- When a new drug is prepared with anticonvulsant vulsant properties, then groups of patients are tested properties, it is subjected to a series of tests designed under controlled conditions to determine further the to measure its efficiency and toxicity.The anticon- consistency and reliability of the effects, and to check vulsant properties are tested by measuring the ability for slowly developing toxicity or other side effects.If of the drug to raise the threshold for minimal (clonic) the drug passes these tests, then it can be released for seizures or to modify the pattern of maximal ( tonic- double-blind testing under conditions such as those clonic) seizures in animals.(Swinyard, 1949). A used by Forster and his collaborators. second method is to test the ability of the drug to protect the animal from seizures produced by con- Mode of Action vulsant drugs such as pentylenetetrazol (metrazol) . To understand the action of drugs on the central A third method, although less popular, is utilizing mice nervous system it isimportant to understand its func- A fourth method is to subject to audiogenic seizures. tional organization.There is a phylogenetically old produce epileptogenic lesions in animals, and to test diffusely projecting system and a phylogenetically new the ability of the anticonvulsant to prevent seizures discretely projecting system.The organization of and suppress abnormal electrical activity in the EEG. function and behavior is more generalized in the older If by these tests, the compound appears to have good is anticonvulsant activity, itis then tested in humans. structures; thus, the spinal cord, the oldest structure, There are different stages of testing, the object being concerned with general behavior patterns, such as to determine as quickly as possible whether thedrug walking and gross reflex patterns.The brain stem, has good potential.It is desirable to determine early containing the reticular substance, is the next stepin

50 phylogeny, and mediates the coordination of gen- depressing certain pathways in which the safety factor eralized functions such as arousal, attention, Orienta- for transmission is low. tion, and integration of movement.The archicortex Diphenylhydantoin has been shown to enhance the and diencephalon, which are the next to develop phy- activity of the neuronal sodium pump and increase logenetically, integrate basic survival behavior, such as thc ratio of extracellular to intracellular sodium con- flight-fight, sexual behavior and consumatory activity. centration. This probably increases the membrane po- The neocortex is the most recent phylogenetic devel- tential which, in turn, would be expected to reduce opment and it coordinates the highly specialized func- the amplitude of the positive after-potential (Wood- tions, such as discrimination, object identification,,and bury and Esplin, 1960). Acetazoleamide also acts decisionmaking.(Siminoff, 1963). by increasing the sodium ratio but in a somewhat dif- At the various levels, each system makes two types ferent manner.It inhibits carbonic anhydrase, and of synaptic connections with the efferent portion of reduces the rate at which H2CO3 is dehydrated.The the reflex arc.The first is the axosomatic ending increased H2CO3 within the neurone results in a lower which acts primarily to pass the activity along the steady-state concentration of sodium within the neu- reflex arc.The other, the axodendritic ending, acts, rone and a higher gradient of sodium across the cell by long-term depolarization to modulate the activity of membrane. the effector neurone.Each level relays activity up Tuttle and Preston (1963) suggest that there is an and down the central nervous system and there is con- apparent relationship between the complexity of the siderable interplay between levels.As one ascends, neural pathway and the demonstration of an effect the axodendritic endings become more numerous and of diphenylhydantoin.They felt that interneurones the modulating system becomes more important. may be of considerable importance in explaining the Drugs, depressing axodendritic endings, block gen- actions of the drug.Any condition which modifies the eralized functions such as arousal, wakefulness, and repetitive activity of the interneurone (Frank and orientation, and thereby produce unconsciousness.At Fuortes, 1956) would have a marked effect on the therapeutic doses which do not affect transmission level of background facilitation and inhibition in through the reflex pathways, these drugs, such as anaes- motoneurone pools.There is evidence that diphenyl- thetics and barbiturates, depress neocortical structures. hydantoin is particularly effective, not only in depress- The degree of depression depends on the type and ing repetitive discharge but also in depressing the re- dose of the drug. The anticonvulsants block only the sponse of nervous tissueto repetitivestimulation abnormal spread of activity through the axodrendritic ( Korey, 1951; Esplin, 1957; Morrell, et al., 1958) networks of the neocortex.It is probable that a drug Tuttle and Preston's work suggests that diphenylhy- such as diphenylhydantoin exerts its greatest effect on dantoin depresses interneural activity and has a gen- the neocortex and prevents the spread of focal seizures, eralized depressing influence on both suprasegmental whereas trimethadione has a greater effecton the facilitatory and inhibitory pathways.The latter is phylogenetically older diencephalic structures.This affected quantitatively to a greater extent. would explain their abilities to control different types Those working in the field are the first to point out of seizures. the gaps in our knowledge of the actions of anticon- The work of Esplin (1957) suggests that anticonvulsants.They are acutely aware of the need for more vulsant drugs influence neuronal processes which complete knowledge of the functions of neurones, including their axons, dendrites, and synapses. A great underlie transmission at various sites.Esplin and deal of excellent research has been conducted which Laffan (1957) showed that the effects of diphenyl- has yielded isolated information on the electrical ac- hydantoin and trimethadione act on the stellate gan- tivity and chemistry of the neurone.It seems clear glion in the identical manners in which they acton the that when all the pieces of this puzzle are available, spinal cord.This may also explain the ability of di- many factors will be found to contribute to a seizure, phenylhydantoin to affect trigeminal neuralgia. and anticonvulsant drugs will be shown to operate Woodbury and Esp lin ( 1959) suggest that trimetha- at different levels. dione exerts its anticonvulsant action by reducing transmission during repetitive discharge; diphenyl- Other Factors Contributing to Action of hydantoin decreases spread of seizure discharge by de- Anticonvulsants pressing posttetanic potentiation ( P.T.P.); and acet- Whether a discharge will spread further in the azoleamide reduces the intensity of seizure discharge by neuronal network of the nervous system depends on the intensity of the original stimulus, the organization the changes are related to the physical andchemical of excitatory and inhibitory synaptic junctions in the maturation of the brain.For example, Purpura, et al. network, and the state of irritability of the individual (1959), have shown that inhibitory synaptic activity neurones.It is the latter that is of particular concern ir relatively underdeveloped in the immature animal. in considernig the possible action of anticonvulsant It has also been shown that as the brain matures,there medication. is an increase in gamma-aminobutyric acid.Changes Toman and Goodman (1947) showed that an im- in enzymes in the brain associated with age also in- portant factor in determining seizure thresholdsis the fluence seizures.Millichap (1957) observed a rela- concentration of electrolytes in the extracellular fluid tionship between the susceptibility to maximal (tonic) and the intracellular fluid volume, which is undoubt- seizures and the level or carbonic anhydrase activity edly related to sodium ratio.At the same time they in the brain of rats and guinea pigs.He concluded showed that seizure threshold is reduced when body that brain carbonic anhydrase is of functional signifi- temperature is lowered, and increased when body tem- cance in the general spread ofthe seizure discharge perature is increased. and in the production of a modmal convulsion. Electrical stimulation of the brain causing a con- Seizure susceptibility is reduced by carbonic anhydrase vulsion has been shown by Richter and Crossland inhibitors such as acetazoleamide.In addition to (1949) to be followed by a rapid decrease of the changes in enzymes, there are significant changes with acetylcholine content of the brain to half the normal age in the acetylcholine contentof the brain (Richter level.This is attributable primarily to a rapid release and Crossland, 1949) and in the development of the of the acetylcholine bound in the nerve endings, fol- blood brain barrier. lowed by rapid breakdown of the free acetylcholine by It is well known that the hormones from endocrine cholinesterase, and the escape of parts of the free acetyl- glands have an ability to affect the nervous system. choline into the bloodstream and cerebrospinal fluid. Severe adrenal insufficiency in man is accompanied by Convulsions induced with pentylenetetrazol also cause a slowing of the electroencephalogram.This is re- a fall in acetylcholine content ofthe brain (Stone, stored with the administration of cortisone.Men- 1957). talchangesassociated withsteroidtherapyare It is well known that acute anoxia can cause con- common. Torda and Wolff(1952)and Torda vulsions and reduce the threshold in animals for (1953) showed that a single administration of ACTH seizures induced electrically by strychnine or by other causes an increase in acetylcholineand ammonia con- convulsant drugs.On the other hand, severe anoxia tent of the brain. ACTH may precipitateseizures in can reverse this effect (Richter,1960). Moderate patients with a previous history of seizures (Dorfman, anoxia increases the irritability of the brain, and severe et al., 1951; Soffer, et al., 1950) .It has been estab- anoxia reduces it.It has been suggested that acute lished that certain steroids from the adrenal cortex in anoxia causes convulsions by releasing lower centers part regulate salt and water metabolism and protein, from cortical inhibition, while severe anoxia inhibits fat and carbohydrate metabolism.Shifts in sodium convulsions by depressing the activity of the lower and potassium balance associated with changing quan- centers as well.It is clear that in order to have a tities of adrenal hormones are important in the regula- convulsion an adequate oxygen level is necessary.It tion of excitability of nerves and synaptic conduction. should also be noted that the oxygen consumption of Hodgkin and Katz (1949) showed that the resting the brain varies almost linearly with the temperature, nerve membrane is more permeable topotassium than and the effects of anoxia are reduced under hypo- sodium.However, the active, conducting membrane thermia (Schneider, 1957). Richter (1%0) points is more permeable to sodium than potassium.They out that the effects of temperature on seizure activity give evidence to show that the action potential is due are complex; they depend in part on the releaseof primarily to the movement of sodium.The nerve lower centers, through impairment of cortical control, message, itself,is subject to modification by both and partly on the combination of an increased oxygen sodium and potassium gradients across the nerve mem- demand of the neuron to a rising temperature and the brane.This phenomenon suggests the importance of increased oxygen requirement for convulsive activity. homeostatic regulation of these cations for normal Age is also an important factor in seizure threshold. function of the nervous system, including synaptic Seizures are 10 times more common in the infant than conduction. the adult.As an infant grows, the pattern of attacks The adrenocortical hormones act to restore normal changes.Many investigators have demonstrated that brain excitability regardless of the direction in which

52 the deviation lies.Woodbury, Timiras, and Vernada- vulsions.The decision of when to start a patient on kis (1957) showed that the primary effects of deoxycor- medication is an individual one. It will depend on ticosterone acetate (DCA) and 17-hydroxycorticoste- the circumstances and the results of the investigation. rone acetate (Cortisol) on brain activity are related A child who has had one seizure associated with a to their influences on active sodium transport in the febrile illness, and who has a normal electroencephalo- brain.DCA, which actslikediphenylhydantoin, gram, may be observed instead of administering imme- stimulates the active transport of Na from cells which, diate medication. On the other hand, if there is a in turn, decreases brain excitability.A single dose of positive family history, or some positive signs of postic- DCA causes an increase in electroshock seizure thresh- tal paralysis, then drug therapy should be started.In old (E.S.T.), an increase in brain concentration of an older person, a single seizure may herald a tumor. glutamic and aspartic acids, and a decrease in brain Complete investigation is indicated, and prophylactic concentration of glutamine and asparagine.In con- anticonvulsants are a wise precaution. trast, a single dose of Cortisol causes a decrease in There are some 15 to 20 anticonvulsants which have E.S.T., an inhibition of active Na transport, and an proven useful; however, the majority of patients are increase in intracellular brain Na concentration and treatedwith some combination of phenobarbital, brain excitability. diphenylhydantoin, primidone, and trimethadione. Woodbury, et al., (1957) were also able to show that Probably 75-80 percent of patients are well controlled the recovery process, which restores normal function with these drugs alone. following excitation such as seizure, requires energy; Treatment is generally started with one drug, and this is intimately associated with changes in carbo- the dosage is slowly increased until the seizures are hydratemetabolism,particularlybloodglucose. controlled or toxic symptoms develop.If the patient Glycogen stores in the brain are small, and the chief is admitted in status epilepticus or has had a prolonged energy substrate is blood glucose.Any procedure or seizure, it is well to start him on immediate large doses substance which influences blood sugar level will effect of intramuscular phenobarbital, but as soon as possible the recovery process, provided the agent does not also oral phenobarbital and diphenylhydantoin should be interfere with the utilization of glucose by the brain. substituted.As the seizure comes under control, the Woodbury's group was able to correlate the blood sugar phenobarbital can be reduced.In such a case, one is level with the duration of postictal depression which likely to continue with both drugs and slowly regulate follows maximal electroshock seizures in rats in their them.Most patients require a combination of drugs. studies, but recovery from postictal depression was The time the drugs are taken is also of some impor- not related to brain excitability or brain electrolyte tance.It is easier and more convenient to take them metabolism. at mealtimes and at bedtime.Ordering medication They were also able to show that cliphenylhydantoin at odd hours is to be discouraged since it is too easy activiates the pitutary-adrenal and the pituitary-thy- for the patient to forget.It is probable that drugs roid systems, and that the hormones released by such which are absorbed and excrete slowly, and which do activation tend to counteract the anticonvulsant effect not show a great fluctuation in blood level, could be of the drug.Thus, they were able to demonstrate given twice a day; however, the general tendency is to further that adrenocortical hormones tend to restore order them with meals, and to add a drug with a normal brain activity, regardless of the direction in greater sedative effect such as phenobarbital, at bed- which the deviation lies. time. The whole story on the role of the influence of Buchthal, Svensmark, and Schiller (1960) studied adrenocortical hormones on brain function and metab- serum levels of diphenylhydantoin and correlated them olism is not completely understood.It is clear, from with the pharmacological effect.Clinical improvement the manner in which these hormones influence infan- in patients with grand mal epilepsy treated orally re- tile myoc Ionic seizures, that their role is an important quired a serum level of 10Ag/m1-20 p,g/m1 of the drug one, but further studies related particularly to the de- which corresponded to a dosage of 4-7 mgm/kg of veloping brain are needed. body weight, and required 6 to 10 days of oral administration.It took some time to reach a steady concen- The Anticonvulsant Treatment tration.With a daily oral dose of 5 mg/kg body weight, it took about 1 week for the serum concentra- The anticonvulsant compounds are the backbone of tion to reach a maximum. The same serum level was treatment of the epilepsies, and the prevention of con- obtained whether the total daily dose was administered

- in one or in three doses. To maintain a stable serum icity, or their poor abilities to control seizures, their use concentration, administration of the drug at 12-hour has been discontinued.Some reached the stage of intervals is preferable to once a day. They showed that being assigned names; others were merely given the fall in 12 hours is insignificant, so that three or numbers. four daily doses are probably unneceasary. Some of the most commonly used anticonvulsants Buchthal and his colleagues were also able to show are: that pronounced side effects from diphenylhydantoin Celontin (methsuccinimide) . did not occur with serum levels below 30 peml, but Desoxyn (methamphetamine hydrochloride) . were present in half the patientswith serum levels of Dexedrine (dextroamphetamine) . 30-60 item!. Diamox (acetezoleamide) . Unless there is a toxic or allergic reaction to a drug, Dilantin (diphenylhydantoin ) . it should not be discarded until proven to be of no Elipten (aminoglutethimide) . benefit in maximal tolerable doses. The tendency to Gemonil (metharbital). switch from one drug to another, before the first one Librium (chlordiazepoxide). has been tested adequately, should be avoided. Mebaral (mephobarbital). The importance of taking medication regularly and Meprobamate. the dangers of precipitating status epilepticus by sud:. Mesantoin (3-methy1-5, 5-phenyl-ethyl- den withdrawals should be stressed to the patient or hydantoin). his parents. Milontin (methylphenylsuccinimide) . The decision of when to stop medication is a difficult Mysoline (primidone). one. As a general rulemedication should be continued Paradione (paramethadione). for 1 to 3 years after the last seizure.Some older Paraldehyde. patients who have had one or two occasional seizures Phenobarbital (ethyl-phenyl-barbituric acid) . after having a long free period, and stopping medica- Peganone (ethotoin). tion, probably should continue medication indefinitely. Phenurone (phenacemide) . In some of the younger children who are taking a toxic Tridione (trimethadione). drug, especially those with petit mal, one may wish to Zarontin (ethyl-methyl-succinimide) . try discontinuing medication even before aseizure-free year is passed. The length of timethe child had the ANTICONVULSANTS CURRENTLY AVAILABLE attacks and the EEG help in making the decision.In patients approaching puberty, it is better to continue Celontin: (Methsuccinimide) medication until puberty is completed. Indications: May be effective in mixed seizures, autom- Thepossibilityofthedevelopment of blood atism, akinetic or myoclonic seizures. dyscrasia, hepatitis, or nephrosis should be considered Dosage: in patients receiving trimethadione, paramethadione, 15-20 mg per kg per day. mesantoin, phenurone, and ethyl-methyl-succinimide. 600 mgm per day for adults. To detect and prevent serious suppression of hemo- Preparations: 300 mg capsules (Parke Davis) . poiesis, white blood counts should be made before Toxicity: Drowsiness, ataxia, rash. starting treatment and again every 2 weeks until main- Remarks: Worthwhile to try this drug if others fail. tenance dosage is established.Such counts should be repeated monthly, for 1 year, and every 3 months for Desoxyn: (Methomphetomine hydrochloride) the balance of treatment.If neutrophils drop to between 2,500 and 1,600 per cu. mm., counts shouldbe Indications: Absence and akinetic attacks.Counter- made every 2 weeks, and medication should be stopped acts sleepiness and effective innarcolepsy. if the count goes below 1,600. Dosage: 2.5 mgm-10 mgm per day. The following anticonvulsants are those most com- Preparations: monly used in the treatment of epilepsy.Detailed 2.5 mgm tablet (Abbott) . descriptions of their structure and pharmacology can 5 mgm tablet. be found elsewhere (Goodman and Gilman, 1955; 5, 10, 15 mgm gradument. Lennox, 1960; Gunn, Gogerty, and Wolf, 1961) . 2-5 mgm tsp. of elixir. Many other drugs have been discovered and tested Toxicity: Anorexia, irritability, insomnia. clinically, but for reasons of their sedative effects, tox- Remarks: May, be used in place of Dexedrine.

bed. ataxia, Dexedrine: (Dextroamphetamine) Toxicity: Gingival hypertrophy, nystagmus, diplopia, rash, tremor, nausea andvomiting, hir- Indication: See Desoxyn. sutism. Dosage: Remarks: A very effective drug used singly orin com- 0.25 to 0.75 mgm per kg. per day. bination; usually phenobarbital. A rash may ap- 10 mgm 3 to 5 times daily for adults. pear soon after it isstarted, ataxia is seen with over- Preparations:5 mgm tablets(Smith Kline and dosage, and gum hypertrophy and hirsutismafter French). prolonged usage.It is a safe drug. Toxicity: See Desoxyn. Remarks: This drug is sometimes effective when other Elipten: (Aminogiutethimide) drugs fail.It may be helpful in postencephalitic seizures or behavior disorders.It may also be used indications: Useful as adjuvant. in combination with other drugs to counteractthe Dosage: 750 mgm per day in adults (Ciba) . sedative effect. Preparations: 125 and 250 mg. tablet. Toxicity: Drowsiness, irritability. It is Diamox: (Acetexoleamide) Remarks: Has not proven to be tooeffective. relatively new and still requires furthertrial. Indications: May be tried in all types of seizures. More effective in minor seizures in children. Gemonil: (Metharbital) Dosage: seizures due to 15 to 90 mg. per kg. per day. Indications: Myoclonic seizures, or 250 mgm, 3 to 6 times a day. organic brain damage. Preparations: Dosage: 250 mg. tablets (Leder le) . 5 to 15 mg. per kg. per day. 500 mgm amp. i.v. or i.m. 100 to 300 mgm per day in adults. Toxicity: Loss of appetite, acidosis, numbness. Preparations: 100 mgm tablet (Abbott) . Remarks: This drug 'is more likely to be effectivein Toxicity: Drowsiness, irritability, rash. children in attacks precipitated by hyperventilation, Remarks: Is not as satisfactory as otherdrugs. and in women who have seizures in the premenstral period.It is used to supplement other medication. Librium: (Chlordiazepoxide) Indications: May be effective in mixed typesof sei- Dilantin: (Diphenyihydantoin) zures.Useful in patients with behaviordisorders. indications: Any seizure with the exception of ab- Dosage: 15 mg. to 60 mg. per day. sence, myoclonic or akineticattacks. Preparations: 5 mg., 10 mg. and 25 mg.capsules Dosage: (Roche). 3-8 mgm per kg. per day. Toxicity: Drowsiness. 100 mgm 3 times a day in adults. Remarks: Reports have been conflicting as tomerits as Preparations: anticonvulsant.Usefulinbehaviordisorders. 50 mgm infatabs (Parke-Davis) . (Livingston et al., 1961, and Watson, etal., 1964) . 30 and 100 mgm capsules. 100 mgm per tsp. suspension. Mebaral: (Mephobarbital) 100 mgm delayed action capsule. It is also prepared in combination with other Indications: Same as phenobarbital. drugs. Dosage: 2-8 mg. per kg. per day. Phelantin capsules: diphenylhydantoin 100 mgm. 100 mgm 1 to 6 times a day ( adult) . (Winthrop). phenobarbital 30 mgm. Preparations: 30, 50, 100 mgm tablets desoxyephedrine HCL 2.5 mgm. In combination with diphenylhydantoin(see Di- Mebroin ( Winthrop) tablets : lantin). diphenylhydantoin. Toxicity: Drowsiness, irritability. phenobarbital and 60 mgm. Remarks: This drug metabolized to mebarol 90 mgm. anticonvulsant activity has been attributed to this. 55 Meprobamate: Dosage: 12 to 25 mg. per kg. per day. indications: Absence attacks,convulsive equivalents 250 mgm 3 to 6 times daily. occasionally in myoclonic seizures. Preparations: Dosage: 250 mgm tablets ( Ayerst) . 20-40 mg. per kg. per day. 50 mgm tablets. 400 mgm 3 to 5 times a day inadults. 250 mgrn per tsp. suspension. Preparation: 200-400 mgm tablets (EquanilWyth). 125 mgm flavored tablet ( inCanada ). (MiltownAyerst ) . Toxicity: Drowsiness,ataxia,anorexia,irritability Toxicity: Drowsiness. vertigo, nausea, vomiting, rash. Remarks: Not very effective as ananticonvulsant, but Remarks: This drug must be startedslowly.It is safe, useful to control hyperactivebehavior. and has good anticonvulsantproperties.It metabolized to phenobarbital, but is felt tohave anticon- Mesontoin: (3 methyl-5,5-phenyl-ethyl-hydantoin) vulsant properties of its own. It maybe used simply or in combination. indications: Same as diphenylhydantoin. Dosage: 100 mgm 3 times a day foradults. Paradione: (Paramethadione) Preparations: 100 mg. tablet ( Sandoz ) . Toxicity: Rash, fever, leukopenia andagranulocytosis, Indications: Absence, akinetic andmyoclonic attacks. ataxia. Dosage: Remarks: to detect and prevent serioussuppression of 20-50 mg. per kg. per day. hemopiesis, white cell counts should bemade before 900 to 1800 mgm per day for olderchild. starting treatment and every twoweeks until mainte- Preparations: nance dosage isestablished.Thereafter, monthly 150 mgm capsules. for one year, and every threemonths for the balance 300 mg. capsules. of treatment.If neutrophils drop to between2500 300 mgm/cc elixir (drops) . and 1600/cu.mm. counts should bemade every two Toxicity: Same as trimethadione. weeks.Stop medication if count drops to1600. Remarks: Said to be less effective andless toxic than The patient or parents should bewarned. No pa- trimethadione.Same precautions should be taken tient should be given mesantoin ifhe has had it as with mesantoinand trimethadione. before and stopped.Hypertrophy of the gums will occur with thisdrug, so it should not be substituted Paraldehyde: for diphenylhydantoin for this reason.This is a good anticonvulsant, but the fear offatal agranu- Indications: Useful in status epilepticus. May be mixed with olive locytosis has limited its use. Dosage: 5-15 cc per rectum. or mineral oil. Milontin: (Methylphenylsuccinimide) Preparations: Bottles and 5 cc ampoules. Toxicity: Can cause muscle necrosisand i.m. use seizures. indications: Absence, akinetic, and myoclonic should be avoided. Dosage: 20-40 mg. per kg. per day. Phenobarbital. (Ethyl-phenyl-barbituricacid) 0.5 gm. 3 times a day. Preparations: Indications: Any type of seizure. 0.5 gm. capsules ( Parke Davis) . Dosage: 250 mg. 1 tsp. suspension. 1-5 mg. per kg. per day. Toxicity: Drowsiness, headache, slightlynephrotoxic. 7-15 mgm 3 times a day ininfants. Remarks: May be useful when othermedications fail 30 mg. 2-3 times a day inchildren. or in combination. 60 mg. 1-3 times a day inadults. Preparations: Mysoline: (Primidone) 15, 30, 60, 100 mgm tablets. indications: Generalized and focal seizuresand au- 15 mg. per tsp.elixir. i.v. or i.m. use. tomatism. 60, 120 mg. ampoules for

56 Toxicity: Drowsiness, hyperirritability in children, Toxicity: Drowsiness, nausea, vomiting. ataxia. Remarks: Has proven to be useful in minor types of Remarks: Apart from bromides, this is really the first attacks in children. anticonvulsant discovered. It is still one of the safest, and the best, but is limited by its sedative effect, and Toxic Effects of Anticonvulsants itsabilityto produce behavior disturbances in children. The acute pyschosis and severe repulsive pustules seen on the skin of patients taking prolonged over- Peganone: (Ethotoin) dosage of bromides made the advent of phenobarbital a welcome event.However, Many physicians today Indications: Same as diphenylhydantoin. still resort to bromides when all other measures fail. Dosage: Phenobarbital proved to be an excellent anticonvulsant, 250 mg. 3 times a day. and still is probably the most useful and safest known. 500 mg. 2 times a day. Many patients prefer not to take it during the day Preparations: 250 and 500 mgm tablets (Abbott). because of its sedative effect, and parents welcome a Toxicity: Drowsiness, ataxia, diplopia, tremor, rash. change from phenobarbital since it tends to produce Remarks: Worthwhile trying if other preparations fail. hyperactivity and behavior disordersinchildren. Overdosage will cause ataxia, but this is easily remedied Phenurone: (Phenacemide) by adjusting the dose.There is considerable danger Indications: In seizures originating in the temporal of precipitating status epilepticus by sudden with- lobe, when other medications fail. drawal of phenobarbital in a patient who has been re- Dosage: ceiving it for a long time.If the drug is to be stopped, 20-35 mg. per kg. per day. it should be done slowly.Severe and fatal exfoliative 500 mgm 2-4 times a day in adults. dermatitis has been reported ( Welton, 1950, and Sned- den and Leishman, 1952),but this is unusual consid- Preparations: 0.5 grn. tablets (Abbott). Toxicity: Rash, anorexia, nausea, vomiting, hepatitis, ering the tons of phenobarbital consumed annually. personality change and blood dyscrasia. Care should be taken to keep the drug from the reach Remarks: Same precautions should be taken as with of young children. The most common cause of death Mesantoin plus Urobilinogen tests monthly.The from phenobarbital is a suicidal overdose. incidence of hepatitis is high which has limited its The most serious toxic effect from the newer anti- use. convulsants is suppression of bone marrow activity leading to blood dyscrasias such as aplastic anemia Tridione: (Trimethadione) with pancytopenia, thrombocytopenia, leukopenia, or agranulocytosis, erythroid hypoplasia with pancyto- Indications: Absence, akinetic and myoclonic attacks. penia, hemolytic anemia and megaloblastic anemia Dosage: 20-50 mg. per kg. per day. (Best, 1963). Such disorders have been reported fol- r. Preparations: lowing the prolonged use of acetazoleamide, diphenyl- 300 mgm capsules ( Abbott). 150 mgm tablets. hydantoin,Mesantoin,primidone,trimethadione, 150 mgm per tsp. solution. paramethadione, phenacemide, mephobarbital, etho- Toxicity: Rash, leukopenia, agranulocytosis, photopho- toM, and ethyl-methyl-succinimide. The subject has bia, irritability and nephrosis. been well reviewed by Robins (1962) and Long, Remarks: Same precautions should be taken to prevent Childress, and Bond (1963),Benians and Hunter blood dyscrasia as for Mesantoin.Monthly urin- (1957),Mann and Habenicht (1962) , Robins ( 1962) , alysis should also be done for six months, and the and Underwood (1956) .The exact mechanisms of child watched for sudden increase in weight or suppression of hemopoiesis is not known. The ma- swelling of the ankles. jority of cases have developed secondary to the administration of methylphenylethylhydantoin ( Mesan- Zarontin: (Ethyl-methyl-succinimide) toM) and trimethadione, but it is suggested that most Indications: absence, akinetic and myoclonic attacks. of the anticonvulsant drugs could have potential toxic Dosage: 250-500 mg. 3 times a day. effects on bone marrow. Treatment has varied from Preparations: 250 mg. capsules (Parke Davis). simple withdrawal of the anticonvulsant medication

57 to simultaneous treatment with vitamin B12) folic acid, is withdrawal of the anticonvlusant and corticosteroidi. and other hematinic agents. There are other undesirable side effects of anticon- Other undesirable, but not fatal, side effects have vulsants such as dizziness, photophobia, drowsiness, been reported with diphenylhydantoin and methyl- and rashes which occur usually with the initiation of phenylethylhydantoin ( Mesantoin). These include treatment! Often theycan be controlled by starting hypertrophy of the gums, (Francis and Melville, 1958), with small doses and gradually increasing untila hirsutism,lymphadenopathysimulatingHodgkin's therapeutic level is reached. disease (Doyle and Hellstrom, 1956 ),and a syndrome simulating lymphosarcoma (Saltzstein and Ackerman, Other Drugs and Hormones 1959; and Rosenfelt, 1961). Robinow (1963) suggests that some of the untoward Tranquilizers reactions to diphenylhydantoin and related anticon- Variable reports have been made on the value of vulsant drugs presentthemselvesasallergicor such drugs as reserpine, phenothiazines (chlorproma- hypersensitive disorders.They may resemble serum sickness; they can produce widespread lymphatic zine, promazine, compazine, trilafon, pacatal), and other ataractic drugs in epilepsy. Some authors report hyperplasia, featuring lymphadenopathy and hepatos- increased incidence and others a decreased incidence plenomegaly ; or theymay mimic as erythema mul- of seizures.It is the general experience that they are tiforme,periarteritis,nodosa, or lupus erythema- not very effective as anticonvulsants, but in some in- tosus.Robinow also suggests that symptoms can be stances are useful to control associated behavior dis- controlled with corticosteroidsor, more satisfactorily, orders (Gunn, Gogerty, and Wolf, 1961). Initial by a combination of small doses of corticosteroids with reports on sulthiame (ospolot) suggest that it has good small doses of 6-mercaptopurine ( also Jacobs, 1963) . anticonvulsant properties, but the side effects limit its Gingival hyperplasia is a common complication of use.(Sutherland and Bowman 1963 ; Griffiths and prolonged diphenylhydantoinor Mesantoin therapy. Sylvester, 1964). The problem has been carefully reviewed by Francis Good results have been reported with the use of and Melville (1958).The clinical picture is described well by Gardner and his colleagues (1962) Tegretal (G 32833) ; side effects were rare, and it is . The ac- said to have a remarkable effect on personality and tual cause is not known. The excretion of dilantin,un- behavior (Lorge 1963). changed, in the saliva is probablya significant factor. Mild cases of gingival hyperplasia can be treated by ACTH and Cortisone changing to a different drug.In severe cases, gingi- vectomy makes a remarkable change in the patient's Adrenocorticotropic hormone (ACTH) and corti- appearance and comfort. sone have proven to be useful in the treatment of The use of phenacemide is limited because ofits myoclonic seizures of infancy and occasionally in petit known effect on the liver.Craddock ( 1955) points mal seizures. The effectiveness seems to be related to out that, of the commonly used anticonvulsants, the age of the child, the degree of maturation of the phenacemide is the onlyone proved to cause severe brain, and the type of seizure. Children in the younger toxic effects on the normal human liver. Hesuggests age group, regardless of the pathologywhether that the drug should be used onlyas a last resort in phenylketonuria, inclusion body encephalitis or cause "psychomotor seizures" if other drugs, suchas Mesan- unknown, have responded to such treatment and sei- toin, fail. zures have been controlled.All authors emphasize Toxic effects by anticonvulsants, particularlytri- that this type of treatment does not have any effect on methadione and paramethadione, have been reported the inental retardation associated with these disorders. on the kidney.(Wren and Nutt, 1953; Finkel and At first, the hormones were given in myoclonic epilepsy Israels,1959; Barnett, etal.,1948; Denhoff and after anticonvulsants had been tried. Many physicians Lauffer, 1950). The nephrotic syndrome included now start the hormones at once in an attempt to con- edema, albuminuria, and decreased plasmaalbumin. trol the attacks and prevent further cerebral deteriora- The diagnosis is easy with examination of theurine, tion in those children who do not have a progressive but parents should be advised to watch for swelling degenerative disease.Frequently, the seizures do not of the ankles or sudden unexplained increase inweight. stop and anticonvulsants are added.It is difficult to The condition has been knownto recur. So the assess the effect of therapy since this type of attack offending drug should not be used again.Treatment tends to stop spontaneously as the child matures (Bray,

511 V.14 .6.01.41Z7,5044.

limited (Bohn, et aL, et al., 1961; Martinez-Lage, etal., 1962; Stamps, et focal seizures; however, its use is 1959). al., 1959). Millichap and Bickford (1962) described21 patients with infantile spasms and hypsarrhythmiatreated with Quinacrine(Atabrine,Mepacrine) ACTH or cortisone, or both. TheACTH was given Reports have appeared in the literature onthe fa- dose of 20 units daily by intramuscular injection in a vorable use of quinacrine (Evans,1962 and Sibley, et The dose of cortisone for an average of 5V2 weeks. al., 1962) and chloroquine(aralen) (Vasquez, et al., was graduallyreduced from 3 mg. to 1 mtg. per lb.body with resistant petit of 6 1959) in the treatment of children weight during a period lasting for an average mal. The daily dose of quinacrinerecommended is reduced in 52 weeks. The frequency of seizures was 50 to 100 mgm daily.With this, the skin becomes percent of the cases andthe electroencephalogram be- yellow and the eyes may also be stained.Apart from This came normal, or wasimproved, in 44 percent. the staining of the skin, however,the drug has a low the causation improvement seemed to be unrelated to toxicity in the dose range employedand should be use- babies under 1 year but was far more often seen in ful in some cases with resistantpetit mal seizures. than in older children.The longer the interval be- and the start of treat- tween the onset of the seizures Dietary Treatment ment, the less wasthe lifielihood of a favorable response. In the Hippocratic collection ofmedical writings it Matthes and Mallmann-Muhlberger(1963) treated is suggested that epilepsy be treated, notby magic but 70 children suffering from massive spasmswith ACTH by diet and drugs.From that time until the present, or cortisone andfollowed them for 1 to 3 years.A diet has played a role in the treatmentof epilepsy, even therapeutic response was obtained in74 percent of the though, for the most part, there waslittle rationale. patients treated with hormones.This was better than Because of the noted effect offasting on epilepsy in the control group treated withanticonvulsants. Al- Wilder (1921) suggested that ketonebedies, produced though the steroids seemed to produce anearlier re- during starvation, might beanticonvulsant, and he versal of any pathological processes,however, they ap- proceeded to develop a diet whichwould produce parently had little effect on theultimate prognosis. ketosis.Since then, others have umithis ketogenic These and other recent reportsconfirm the opinion diet in certain types of epilepsy andreported consi er- that the hormone treatment ofmassive spasms has a able success.Recently, Keith (1963) has reviewed beneficial effect on both the incidenceof the seizures his experience with the diet.He has given a careful and the EEG abnormalities, butthe chances of pre- review of the rationale and theresults, and also preventing mental deficiency are poor.This may not be pared a manual of instructions.Patients on the diet surprising in a group of such variedcausation, where generally continue to takeanticonvulsant medication. the clinical and EEG findings seem tobe related more Keith suggests that patientsdiagnosed as idiopathic to the patient's age than to anyother factor.If brain might be expected to respond morefavorably than damage is preventable by treatmentwith steroids, as, those who are known to have anorganic lesion.Nev- for example, in seizures due toencephalomyelitis fol- ertheless, the type of epilepsy mostlikely to respond lowing inoculation, early treatment thenbecomes a to the diet is notclearly defined.Livingston found matter of great urgency.If the clinical picture is as- the diet most effective in childrenfrom 2 to 5 years of sociated with undoubted mental deficiency or neuro- age and in patientswith minor motor seizures.Di- logical disease before the onset of the seizures,it would etary treatment must bereserved for pati nts who do seem reasonable to tryanticonvulsants first, and resort not respond to regulardrug therapy since the difficulty to steroids only if theanticonvulsants fail. The sudden in preparing the diet, the cost,and the natural dislike onset of massive spasmsin an otherwise healthy baby for the diet on the part of thepatien,make it ex- should be considered and treated as an emergency. tremely difficult to carry throughwith any degree of success. Procaine and Lidocain (Xylocaine) Surgical Treatment Experimentally, French, et al., (1957) haveshown Hughlings Jackson that that procaine given intravenously is capableof pre- It was the concept of John Clinically, lidocaine has been found epileptic .attacks originate in nervecells of the brain, venting seizures. seizure depends on the to be effective in aborting statusepilepticus and some and that the pattern of the 59 4

anatomic location of these cells, which led Sir Victor (5) An epileptogenic area, particularly when it is Honley, on May 25, 1886, tooperate on a young Scot. large, may have various levels of epileptogenicity The patient was 22 years old, and since theage of15 within it and thearea of lowest seizure threshold had been having focal seizures resulting froma com- gives the local sign to the habitual seizurepatterns. pound fracture of the skull when hewas 7.The scar Removal of this area lets the epileptogenicity of the was removed, the wound healed, and the seizures adjacent areas become manifest clinically and in the ceased. EEK. Other operations followed, and in modern medicine (6) A local epileptogenicarea may induce epilep- the surgical treatment of epilepsy has beena means of togenic activity in otherareas of the brain which is de- helping many hundreds of patients whose seizures had pendent on the primaryarea and may decrease pro- not responded to medication.The historical devel- gressively and disappearsooner or later after removal opment of this form of therapy is completely covered of the primary area. by Penfield and Jasper(1954)in their classical volume (7) Active and extensive epileptiform activitymay Epilepsy and the Functional Anatomy of the Human interfere with the function of the rest of the brain, and Brain.Indeed, no one has done more than these two removal of the offending areamay result in improved colleagues to develop the surgical treatment of epilepsy brain function even thougha considerable arhount to the fine point it is at today. Penfield's object was of functioning brain tissue is removed. to eliminate the seizures, but he took advantage of the (8) The cicatrix of the surgical excision rarely be- opportunity to study the human brain.Penfield made many discoveries and encouraged others to study the comes epileptogenic, suggesting that a sizable popu- basic function of the brainas related to epilepsy. lation of nerve cells must be injured,as a general rule, It is recognized thatsome patients with epilepsy to provide a substratum for the later development of do not respond to medication.If, after adequate an epileptogenic lesion, and cortical removals carried trials on medication and careful diagnosticevaluation, out with scrupulous care to preserve untraumatized the patient meets thenecessary criteria, then surgical and normally vascularized pial surfaces at the margins exploration should be offeredto the patient.The of the excision wherever possible, rarely, ifever, pro- amount of the brain to be removed dependson the duce this substratum." degree of abnormality,as evaluated preoperatively, and the findings by electrocorticographyon exposure Indications of the cortex.It may be small and localized; itmay be a whole lobe; or in exceptionalcircumstances, a The indications for the surgical treatment of epi- whole hemisphere.Not every patient who fails to lepsy are as follows: respond to medical therapy isa candidate for surgery. (1) The clinical seizure pattern should indicatea Indeed, relatively few of themare. discharging lesion in accessible or excisable cortex. Rasmussen(1963)on the basis of his experience (2) Serial electroencephalography should localize with the surgical treatment of epilepsyoutlines clearly a cortical epileptogenic lesion. and concisely what could be called therationale for (3)A cortical pathological lesion should be sug- this type of treatment: gested by the clinical and laboratory evidence as the (1) Epilepsy is basicallyan abnormality in seizure threshold. cause of the seizures. (2) This abnormal seizure threshold,or abnormally (4) Intensive and methodical treatment must have high seizure tendency,may reside in more or less re- been tried and shown to be unable to stop the seizures stricted areas of the brain, and removal ofmost or all or rehabilitate the patient. of this area may reduce the seizure tendencyperma- (5) The mental status of the patient must be ade- nently to the level of the normal brain. quate to offer hope of rehabilitation in the event that (3)Limited removal of part ofan epileptogenic the seizures are stopped, or controlled by surgical area seldom results in a satisfactory reduction of the treatment. seizure tendency. (6)The area of abnormality of the brain is not one, (4)When the majority of this epileptogenicarea is which if removed will leave the patient with a serious removed, a residual seizure tendency, if itis small speech defect or other neurological deficit. enough, often disappears progressively during the early (7) The patient should be of such an age that postoperative months or years. recovery is not likely to occur spontaneously. 60 ,,"1",

Investigation study (Penfield and Flanigin, 1950) reported on temporal lobe excisions done between 1939 and 1949. A patient being considered for operation is usually Fifty-three percent were classed as "undoubted suc- referred because of the lack of response to medication. cess," and in another 25.4 percent the procedure was Investigation starts with a careful general and neuro . considered "worthwhile" by the patient and the doc- logical history and examination.Some reliable per- tor, which left only 21 percent with slight or noim- son should witness the attacks.Blood and urine provement.Subsequent followup on the complete studies are conducted in search of a medical disorder series showed that approximately 40 percent of pa- that might contribute to the seizures.X-rays of the tients with temporal lobe seizures can be cured by skull are taken to detect signs of asymmetry, or pre- appropriate surgical excision.However, this is not a vious injury, intracranial calcification, pineal shift, or complete statement of the benefits, nor is it an ade- other abnormalities.Repeated EEG's are performed quate evaluation of the results of operation.Many with, and without, activation procedures.Implanted patients have significant reduction in seizure tendency electrode studies may be of great value. A pneumo- without being completely free of attacks.The reha- encephalogram is usually performed.An arteriogram bilitation of many patients, from a social and eco- may be indicated to detect signsof a vascular abnor- nomic point of view, is most important and is often mality.Intracarotid sodium amytal tests confirm the dramatic, despite the occurrence of an occasional side of the brain harboring speech.Psychological seizure. studies establish a baseline, and also help localize the French (1958) reported on 25 patients with tem- site of the abnormal brain. A psychiatric evaluation poral lobe seizures in which a uniform type of surgical reveals the personality, and a social evaluation indi- excision of the major portion of the temporal lobe cates the background or environment from which the was performed.Seventy-nine percent had a cessation patient comes and to which he will return.It is of the psychomotor seizures during a followup period apparent that the preoperative evaluation of an epi- of from 2 to 7 years.Fifty percent of patients were leptic is a complicated team effort.Although the completely free of seizures, and 50 percent continued ultimate decision rests with the surgeon, he is wisest to have either major or minor seizuresoriginating who consults with all of the members of the team, other than in the temporal lobe. seeking their help and advice.The success of the Fenyes, Zoltan, and Fenyes (1961) reported on 34 operation depends, to a large measure, on the care patients operated on for epileptogenic lesions deep in with which patients are selected. the temporal lobe.Followup studies revealed the results were good in 56 percent and poor in 44 percent. Results Lack of improvement after surgery was reported in no Following the 1914-18 war, Otfried Foerster, in more than 20 percent of cases.Fenyes' group con- Breslau, started to excise brain scars from patients cluded that the operation was worthwhile even in cases who had received cranial wounds during the war. with slight improvement. By 1928, when he was visited by Wilder Penfield, he Twelve patients with epilepsy and psychosis, in a had performed about 100 such operations.Foerster group of 100 who had anteriortemporal lobectomies, and Penfield (1930) reported on 12 suitable cases, were reported on bySerafetinides and Falconer . They noted that the epilepsy preceded the 10 of which could be followed up.All of them had (1962) Five patients were remained attack free for a period varying from 20 psychosis, usually by many years. rendered completely seizure free, five had been greatly months to 5 years, with two exceptions: patient num- benefited, and the remaining two improved at least ber 7 had had one attack 4 years after operation, and 50 percent in regards to their epilepsy.The acute patient number 11 had begun to have minor seizures confusional states disappeared with the seizures.The at the end of 3 years. same improvement was not seenin the schizophrenic- In 1941 Penfield and Erickson reported on patients like states, which persisted, although with the improve- operated on between 1929 and 1939 at the Montreal ment in the epilepsy they may have becomeless florid. Neurological Institute.Forty-three percent of them The relationship between the epilepsy and the psycho- were scored as successful.In a second series, between sis remained unsettled. 1939 and 1944, Penfield and Steelman (1947) re- The problem of the surgical therapy of patients' ported that 56 percent of the cases of cortical excision temporal lobe seizures and bilateral EEG abnormali- could be placed in the successful group. A third ties, is discussed by Bloom, Jasper, and Rasmussen (1960). They found that unilateral temporal lbbec- lobe ; and (3) the improved psychological state asso- tomy in these 29 patients produced complete, or nearly ciated with the patient's feeling of increased security. complete, relief of seizures in 24 percent, whereas in All authors report that temporal lobectomy is a safe patients with unilateral temporal EEG abnormality, procedure as far as life is concerned, but transient or two patients out of three received similar benefit. permanent complications are reported. Penfield, Brain injuries, either at birth or postnatallythe two Lende, and Rasmussen ( 1961) describe a "manipula- most common causes of temporal lobe seizures, may tive" hemipiegia, associated with a homonymous hemi- cause various degrees of injury and result in epilep- anopsia, following temporal lobectomy in 8 cases of a togenicity in both temporal lobes.When unilateral series of 168. In all but one of the eight cases the com- temporal lobectomy eradicates a major portion of the plication occurred when the excision of epileptogenic epileptogenic activity, a satisfactory relief of seizures tissues extended across or mesial to, the fissure of may result in some cases, despite some persisting Sylvius.They felt it was due probably to interference epileptiform activity in the EEG from either the op- with the anterior perforating arteries as they leave the erated or unoperated temporal lobe, or in both. middle cerebral artery supplying the cortico-spinal In a comprehensive review of the surgery of epilep- tracts and the optic radiation.Green and Scheetz togenic lesions of the temporal lobe, Green and Scheetz ( 1964) describe similar complications. (1964) report on 78 patients treated by excision of Note should also be made of the report of Paillas part of the temporal lobe for "psychomotor" epilepsy. and his conferees ( 1963) on the results of temporal Chronic atrophic lesions were found in 64.2 percent lobectomies performed on 60 patients ( two of whom (hippocampal sclerosis being the most common by 2% were subjected to bilateral lobectomy) in an attempt times),neoplasms in 17.9 percent, and no demonstrat- to suppress refractory epileptic attacks. A study of able lesion in 17.9 percent of the patients.Operative mental alterations yielded different results according morbidity and mortality indicate six instances of tran- to whether bilateral or unilateral lobectomy had been sient complications and six instances of permanent com- performed.Bilateral resection caused deficiencies of plications (four patients with upper-quadratic field memory and intelligence, although there was some defect, one with hemiplegia and hemianopsia, and one improvement in character.After unilateral resection, operative fatality due to hemorrhage and massive pul- intelligence, on the whole, was unchanged so far as monary edema) .The operative mortality was 1.3 per- psychometric studies indicated.Preoperative mental cent; 17 of the 78 patients were reported as dead disorders generally showed improvement :Consider- because of factors unrelated to surgery.The most able improvement of character disturbances in 25 cases common of these factors was recurrent tumor (10 pa- out of 33, no change in 8 cases, and only 1 case ap- tients). In 60 patients with psychomotor epilepsy, peared to be worse.Seven out of 14 patients with the effects of anterior temporal lobectomy on the con- depressions showed improvement. Mental coherence, trol of seizures, behavioral abnormalities, and social on the other hand, was scarcely influenced; deficiencies and economic rehabilitation were as follows: 11.7 per- of memory, connected with recent events, were present cent no longer have seizures, warnings, or require medi- in varying degrees in 7 out of 58 patients who had cation ; 56.6 percent have marked reduction in seizures unilateral lobectomy. The rhinencephalic lesion ap- and medication ; 31 percent have not changed appre- peared to be the cause, rather than the destruction of ciably; and none is worse. Each of the 60 patients was the temporal neocortex.Improvement in character dependent and nonproductive prior to surgical treat- associated with suppression or attenuation of the at- ment; thirteen were psychotic. Now, 60 percent are tacks, and the absence of deficient intelligence after independent, productive, and self-supporting; 11.6 per- the operation accounted for the parallel improvement cent are partially self-supporting; and 28.4 percent in social behavior. remain dependent and nonproductive.Green and Following Krynauw's description in 1950 of the re- Scheetz attribute the remarkable social and economic moval of one cerebral hemisphere for the treatment of rehabilitation which has been achieved by 36 of their infantile hemiplegia, there have been many reports 60 previously disabled patients (60 percent) to a com- on hemispherectomy (Ransohoff, 1955; French, et al., bination of factors, including (1) elimination of sig- 1961). Everyone agrees that there are some patients nificant reduction of seizures and medication in 68.3 who can benefit by such a procedure, although the percent of their patients; (2) direct alteration of a por- initial reports of improved intelligence have been tion of the anatomic substrate of behavior ( limbic and questioned. Rasmussen and Gossman ( 1963) suggest reticular systems) by means of removal of the temporal the ideal patient for this procedure is one who has

62 71,17.1!

(1) intractable sizures arising from a cerebral hemi- marily at interrupting major convulsions, but there sphere badly damaged at birth or in infancy, with re- were some unexpected results.The alleviation of the sulting hemiplegia and homonymous hemianopsia ; major attacks was accompanied by an "absence" or by and (2) sufficiently good function in the rest of the an abortive episode, such as ashortening of the un- brain so that a socially useful individual can be ex- conscious period associated with a little muscle twitch- pected if the seizures are stopped.If discrete indi- ing.The authors believed that lesions in the H fields vidual finger and toe movements are lacking, as a of FOREL may interrupt not only the convulsive path- general rule removal of the hemisphere will not sig- ways, but also such reverberating circuits asthose in the nificantly increase the motor deficit, and spasticity reticular formation of hypothalamus, and in this way may be decreased.In some of these patients, because a shortening of theunconscious period.This havioral disturbances are almost as distressing and pioneer work will have to be evaluated carefully, par- incapacitatingastheseizures.Hemispherectomy ticularly to determine what effect it has on the patient's often, but not always, brings about striking improve- intelligence and mentality. ment in this sphere. Turner (1963) found that lobotomy of the temporal The possibility of using stereotaxic techniques to lobe isthmus in the roof of the descending horn greatly obliterate areas of the brain exhibiting epileptogenic improved psychomotor attacks as well as the tempera- activity has been suggested.Baird,Spiegel, and mental disturbances of uncontrollable rage and fear, Wycis ( 1960),Bancaud (1959) and Riechert and and to some extent also improved "grand mal."Al- Hassler (1957) have utilized the stereotaxic technique though this type of surgery has not proved itself, as primarily in patients with temporal lobe epilepsy, and yet, further investigation is indicated. also to investigate some specific structures in the depth One could briefly summarize the "surgical therapy" of the temporal lobe.The results have not been satis- of epilepsy by stating that there are some patients with factory in terms of control of temporal lobe seizures. focal cerebral lesions, particularly in the temporal lobe Narabayashi, etal.(1963),report on stereotaxic and hippocampal region who fail to respond to medica- amygdalotomy performed unilaterally in 39 pgients tion, but who will benefit by surgical excision of the and bilaterally in 21 patients.Forty-six of the patients cicatrix.The success of the operation depends to a were classified as having clinical epilepsy, most of which great extent on the proper selection of patients. were of grand mal type with some psychomotor or Young children,for the most part, should not be combined types.In 85 percent the operation resulted operated on, for several reasons:there is a good in a marked reduction in the emotional excitability, cluAnce that as they grow older, the seizures will come and in the normalization of the patient's social be- under control.The areas of abnormal electrical ac- havior and adaptation.There was relatively little tivity in children tend to shift with maturation of the change in the seizure patterns, themselves, in those brain.As reported by Vitale (1963) , surgical ex- patients who had an associated epileptiform disorder. cision is likely to be disappointing.Finally the prac- A new form of stereotaxic treatment of major con- tical difficulties of doing a long procedure under vulsions has been proposed by Jinnai and Nishirnoto local anaesthesia in a young child, are considerable. (1963). Based on their studies of the "conduction There are exceptions of course.Young children with pathways of epileptic convulsion," and the importance continuing focal seizures have been helped by discrete of the FORELH field, they felt that if this region cortical excision, and children with intractable seizures could be destroyed, major convulsive seizures could be and hemiplegia, as described above, have benefited by stopped.Using stereotactic techniques and a mixture hemispherectomy. Pf oil and wax or electrocautery, 43 operations were carried out on 22 patients.There was a complete Bibliography cessation of grand mal attacks in eight cases; preoperatively, two of them had several attacks daily. A Medical decrease in grand mal seizure was noted in four cases. Barnett, H. L., Simons, D. J., Wills, R. E. Jr., Nephrotic An alleviation was noted in seven cases.There was syndrome occurring during tridione therapy.Am. J. Med no effect in three cases, including a case in which only 4: 760, 1948. a one-sided operation was performed.Postoperative Benians, R. C., Hunter, R. A. Megaloblastic anemia occur- followup varied from 69 to 200 days.There was no ring during treatment of epilepsy with phenytoin sodium. J. Ment. Sci. 103: 606, 1957. detectable change in the EEG between the pre- and Best, W. R., Drug-associated blood dyscrasias.JAMA, 140, post-operative state.The procedure was aimed pri- 1963.

6 3 Ospolot, Clinical trial of Petersen, I., Effect of lidocaine Griffiths, A. W., Sylvester, P. E., Bohm, E., Flodmark, S., Brit. J. Psychiat. 110: 261,1964. (Xylocaine) on seizure and interseizureelectroencephalo- a new anti-convulsant. Gruber, C. M., Jr.,, Brock, J. T.,Dyken, M., Comparison of grams in epileptics.Arch. Neurol. and Psychiat.81: 550, the effectiveness of phenobarbital,mephobarbital, primi- 1959. ethotoin,snetharbital,and G., Kelley, V. C., Adrenocor- done,. diphenylhydantoin, Bray, P. F., Ely, R. S., Zapata, inmotorseizures.Clin. tical function in epilepsy.II. The role of corticosteroue methylphenylethylhydantoin Pharma. and Therap. 3: 23, 1962. in the mechanism and managementof epilepsy.Neurology Gunn, C. G., Gogerty, J., Wolf, S.,Clinical pharmacology of 11: 246, 1961. Clin. Pharm. and Therap. Brock, J. T., Dyken, M., Theanticonvulsant activity of anticonvulsant compounds. chlordiazepoxide and Ro 5-2807.Neurology 13: 59, 1963. 2: 733, 1961. P. J., Clinical and Hodgkin, A. L., Katz, B. T., The effectof sodium ions on Buchthal, F., Svensmark, 0., Schiller, of the squid.J. electrographic correlations with serumlevels of diphenyl- the electrical activity of the giant axone 2: 624, 1960. Physiol. 108: 37, 1949. hydantoin A.M.A. Arch. Neurol. in childhood. Butler, T. C., Waddell, W. J.,Metabolic conversion of Jacobs, J. C., Systematic lumpus erythematosus Proc. Soc. Exper. Pediatrics, 32: 257, 1963. primidone (Mysoline ) to phenobarbital. bloodflow and pH Biol. and Med. 93: 544, 1956. Jasper, H. H., Erickson, T. C., Cerebral anticonvulsant in a "thera- in excessive cortical discharge inducedby metrazol and Carter, C. H., Evaluating a new J. Neurophysiol. 4: 333, 1941. peutic community."Dis. Nerv. System 21: 50,1960. electrical stimulation. Phenacemide in epilepsy with Johnson, E. A., Haus, E., Halberg, F.,Wadsworth, G. L., Craddock, W. L., Use of changes in epi- analysis of fatal reactions and case report.JAMA 159: Graphic monitoring of seizure incidence leptic patients.Minnesota Med. 42: 1250, 1959. 1437, 1955. Children with Special Denhoff, E., Laufer, M. W., Clinicalstudies of the effects of Keith, H. M., Convulsive Disorders in 3,5,5,-trirnethyloxazolidine-2-4 dione (tridione) onthe Reference and Treatment with KetogenicDiet.Boston, hematopoietic system, liver, andkidney.Pediatrics 5: Little, Brown & Co., 1963. and government regula- 695, 1950. Kern, S. F., New drug application Dorfman, A., Apter, N. S., Smull, K.,Bergenstal, D. M., tions.Biomedical Purview, 3: 45, 1963. Richter, R. B., Status epilepticuscoincident with the use Kohlstaedt, K. G., Introduction toclinical investigation. of pituitary adrenocorticotropichormone. JAMA.146: JAMA. 187: 344, 1964. Korey, S. R., Effect of dilantinand mesantoin on the giant 25, 1951. 297, Doyle, A. P., Hellstrom, H. R.,Mesantoin lymphadenopathy axon of the squid.Proc. Soc. Exp. Biol. N.Y., 76: morphologicallystimulatingHodgkin'sDisease.Ann. 1951. Intern Med. 59 : 363, 1963. Kunkle, E. C., Dilemmas of drugtesting in the epilepsies. Dunlop, C. W., 1. Effects of carbondioxide on deep struc- AMA Arch. Neurol, 3: 481, 1960. tures of temporal lobe ofthe brain in the marsupial pha- Laidlaw, J., Catamenial epilepsy.Lancet 271: 1235, 1956. Dis. Nerv. !anger.2. Effects of carbon dioxide in therhincephalon Lambros, V. S., A new anticonvulsantElipten. in the marsupial phalanger.Am. J. Physiol. 1. 190: System 19: 349, 1958. of convulsive 172, 1957.2. 191: 200, 1957. Livingston, S., The diagnosis and treatment Elliott, K. A. C., Swank, R. L., Henderson,N., Effects of disorders in children.Springfield, Ill.Chas. C Thomas, anaesthetics and convulsants on acetylcholine contentof the 1954. brain.Am. J. Physiol. 162: 469, 1950. Livingston, S., Pauli, L., Murphy,J. B., Ineffectiveness of Esplin, D. W., Laffan, R. J., Determinantsof flexor and chlordiazepoxide hydrochloride in epilepsy,JAMA 177: extensor components of maximalseizures in cats.Arch. 243, 1961. Internat. Pharmacodyn. 113: 189, 1957. Logothetis, I., Harner, R., Morrell,F., Torres, F., The role Esplin, D. W., The effects of diphenylhydantoin onsynaptic of estrogen in catamenialexacerbation of epilepsy.Neu- transmission in cat spinal cord and stellateganglion.J. rology 9: 352, 1959. Pharmacol. and Exper. Therap. 120: 301, 1957. Long, M. T., Childress, R.H., Bond, W. H., Megaloblastic petit mal.Guy's Evans, P. R., Mepacrine in the treatment of anemia associated withthe use of anticonvulsantdrugs. Hosp. Report 3: 80, 1962. Report of a case and reviewof the literature.Neurology Feldberg, W., Acetylcholine in metabolism ofthe nervous sys- 1957. 13: 697, 1963. tem.Ed. by Richter, D., London, Pergamon, experience with a newanti-epileptic Finkel, K. C., Israels, S., Paradione nephrosis.J. Lancet Lorge, M., Clinical drug, "Tegretal" (G32833)with a particular effect onepi- 79: 243, 1959. Schweiz. Med. Wschr. 93: Francis, L. E., Melville, K. I., Effects ofdiphenylhydantoin lepticpersonality change. (Dilantin )onhistaminechangeingingivaltissue. 1042, 1963. J. of the Canadian Dental Assoc. 24: 142,1958. Mainland, D., The clinicaltrialSome difficulties and sug- Freis, E. D., Evaluation of toxicity in long-termclinical trials. gestions.J. Chron. Dis. 11 : 484, 1960. JAMA.187: 352, 1964. Mann, L. B., Habenicht,H. A., Fatal bone marrowaplasia French, J. D., Livingston, R. B., Konigsmark, B.,Richland, associated with administrationof ethosuximide (Zarontin) prevention of K. J., Experimental observations on the for petit mal epilepsy.Bull. Los AngelesNeurol. Soc. seizures by intravenous procaine injection.J. Neurosurg. 27: 173, 1962. 14: 43, 1957. of barbiturates in man.Clin. Green, R. A., Gilbert, M. G., Fatal bone marrowaplasia with Mark, L. C., Metabolism Pharmacol. and Therap. 4:504, 1963. celontin therapy.Minnesota Med. 42: 130, 1959. 64 L71,

and Martinez-Lage, J. M., Molina, P., Posada,J. T., de la Herran, Soffer, L. J., Levitt, M. F., Baehr, G., Use of cortisone adrenocorticotropic hormone in acute diueminatedlupus J. L., L'ACTH et les epilepsies.Rev. Neurol. 106: 406, erythematosus.Arch. Int. Med. 86: 558, 1950. 1962. E., Die Propulsiv- Stamps, F. W., Gibbs, E. L., Rosenthal, I. M.,Gibbs, F. A., Matthes, Von A., Mallmann-Muhlberger, 171: Petit-Mal-Epilepsie Und Ihre BehandlungMit Hormonen. Treatment of hypsarhythmia with ACTH. JAMA, 408, 1959. Dtsch. Med. Wachr. 88: 426, 1963. metabolism Millichap, J. G., Nephrotoxic effectof drugs.Lancet 1 : Stone, W. E., The role of acetylcholine in brain and function.Amer. J. Physiol. Med. 36: 222, 1957. 1074, May 3, 1953. evaluation of new anticonvul- Sutherland, J. M., Bowman, D. A., Sulthiame("Ospolot") Millichap, J. G., Methods of in the treatment of temporal lobe epilepsy.Med. J. sant compounds.Neurology 6: 484, 1956. Millichap, J. G., Development of seizure patternsin newborn Australia 2 : 532, 1963. Proc. Swinyard, E. A., Laboratory assay of clinically effectiveanti- animals.Significance of brain carbonic anhydrase. J. Amer. Pharm. A. (Scient. ed.) 38: Soc. Exper. Biol. and Med. 96:125, 1957. epileptic drugs. Infantile spasms, hyp- 201, 1949. Millichap, J. G., Bickford, R. G., Takahashi, R., Nasu, T., Tamura, T., Kariya, J.,Relation- sarhythmia, and mental retardation.J. Amer. Med. Au. ship of ammonia and acetylcholine levels to brainexcitabil- 182: 523, 1962. J. Neourchem. 7 : 103, 1961. Morrell, F., Bradley, W., and Ptaschke,M., Effect of di- ity. Toman, J. E. P., Goodman, L. S., Conditionsmodifying con- phenylhydantoin on peripheral nerve.Neurology 8 : 140, vulsions in animals.Res. Publ. Au. Nerv. Ment. Dis. 26: 1958. evaluation of a new anti- 141, 1947. Pearce, K. I., Eliptena clinical Physiol. convulsant. Canad. Med. Assoc. J. 82:953, 1960. Toman, J. E. P., Goodman, L. S., Anticonvulsants. safety evaluations. Rev. 28: 409, 1948. Peck, H. M., Adequacy of the preclinical Torda, C., Effect of convulsion-inducing agents on the ace- JAMA 187: 341, 1964. tylcholine content and on the electrical activity of the brain. Preston, J. B., The effects of chlorpromazine onthe central Am. J. Physiol. 173: 179, 1953. nervous system of the catapossible neural basis for action. the ace- 1956. Torda, C., Effect of convulsion inducing agents on J. Pharm. and Exp. Therap. 118: 100, ( ACTH ) on anunonium ion and acetylcholine contentof Rabe, F., Penin, H., Matthes, A., Someexperiences with Deutsch. Med. the brain. Amer. J. Physiol. 173: 176, 1953. Ospolot in the treatment of epilepsy. Tuttle, R. S., Preston, J. B., The effect ofdiphenylhydantoin Wochen. 87: 953, 1962. neurology.Ed. by (Dilantin) on segmental and suprasegmental facilitation Richter, D., Modern scientific aspects of and inhibition of segmental motoneurons in the cat.J. Cumings, J. N., Pub. by Edward ArnoldLtd., London, p. Pharm. and Exp. Therapeut. 141: 84, 1963. 322, 1960. Underwood, L. C., Fatal bone marrow depression after treat- Richter, D., and Crossland, J., Variationsin acetylcholine ment with acetazoleamide (Diamox).JAMA, 161: 1477, content of brain with physiological state.Amer. J. Physiol. 1956. 159: 247, 1949. Watson, C. W., Bowker, R., Calish, C., Effectof chlordi- Robinow, M., Diphenylhydantoinhypersensitivity treatment Amer. J. Dis. Child. 106: 553, azepoxide on epileptic seizures. JAMA, 188: 140, 1964. with 6-mercaptopurine. Welton, D. G., Exfoliative dermatitis and hepatitisdue to 1963. anticonvul- phenobarbital. JAMA, 143: 232, 1950. Robins, M. M., Aplastic anemia secondary to Wilder, R. M., The effect of ketonemia on course ofepilepsy. sants.Amer. J. of Diseases of Children, 104:64, 1962. Y., Morrison, Mayo Clin. Bull. 2: 307, 1921. Rosenfeld, S., Swiller, A. I., Shenoy, Y. M. Clin. induced by Williams, R. T., Detoxication mechanisms in man, A. N., Syndrome simulating lymphosarcoma Phannacol. Therapeut. 4: 234, 1963. J. Amer. Med. Ass., 176: 491, diphenylhydantoin sodium. Wolfe, L. S., Elliott, K. A. C., 'Chemical studies inrelation 1961. to convulsive conditions.Neurochemistry, Ed. by Elliott, Saltzstein, S. L., Ackerman, L. V., Lymphadenopathyinduced Page and Quastel, Chu. C Thomas, 1962. by anticonvulsant drugs and mimickingclinically and Woodbury, D. M., Effects of chronicadministration of anti- pathologically malignant lymphomas.Cancer, 12:164, convulsant drugs, alone and in combinationwith desoxy- 1959. corticosterone on electric shock, seizure thresholdand tissue Schmidt, C. F., Kety, S. S., Pennes, H. H., The gaseousmetab- J. Pharmacol. and Exper. Therap.105: 46, olism of the brain of the monkey. Amer. J.Physiol. 143: electrolytes. 33, 1945. 1952. Ed. by Woodbury, D. M., Esplin, D. W.,Neurophannacology and Schneider, M., Metabolism of the nervous system. Res. Publ. Au. D. Richter, Pub. by Pergamon Press, p. 107,1957. neurochemistry of anticonvulsant drugs. Sibley, W. A., Tucker, H. J., Randt, C. T., Quinacrinein the Nerv. Ment. Dis. 37: 24, 1959. Vernadakis, Antonia, Relation treatment of refractory petit mal epilepsy.New Eng. J. Woodbury, D. M., Koch, A., between excitability and metabolismin brain as elucidated Med. 267: 332, 1962. Neurology 8: 113, 1958. Siminoff, R., Pharmocology of the Central NervousSystem. by anticonvulsant drugs. Vernadakis, A., Influence of Progress in Neurology and Psychiatry, Ed. Spiegel, E. A., Woodbury, D. M., Timiras, P. S., adrenocortical steroids on brainfunction and metabolism. p. 134, 1963. Behavior, Academic Press, Sneddon, I. B., Leishman, A. W. D., Severe and fatalpheno- Hormones, Brain Function and barbital eruptions.Brit. M. J., 1: 1276, 1952. Inc., New York, p. 27, 1957. 65 ,

Wren, J. C., Nutt, R. L., Nephrotic syndrome occurring dur- Penfield, W., Erickson, T., Epilepsy and Cerebral Localiza- ing paramethadione therapy. JAMA, 153: 918, 1953. tion.Springfield, Ill., Thomas, 1941. Penfield, W., Flanigin, H., Surgical therapy of temporal lobe Surgical seizures.Arch. Neuroi. and Psychiat. 64: 491, 1950. Penfield, W. P., Jasper, H. H., Epilepsy and the Functional Baird, H. W., III, .Spiegel, H. T., Wycis, H., The variability Anatomy of the Human Brain.Boston, Little Brown & in the extent and position of the amygdala. Confin. Neurol. Co., 1954. 20: 26, 1960. Penfield, W., Lende, R. A., Rasmussen, T., Manipulation Baldwin, M., Bailey, P., Temporal lobe epilepsy.Spring- homiplegia an untoward complication in thesurgery of field, Ill. Chas. C Thomas, 1958. focal epilepsy.J. Neurosurg. 18 :760, 1961. Bancaud, J., Apport de l'exploration functionnelle par voie Penfield, W., Paine, K., Results of surgical therapy of focal stereotaxique A la chirurgie de l'epilepsie.Neurochirurgie epileptic seizures.Canad. M.A.J. 73: 515, 1955. 5 : 55, 1959. Penfield, W., Steelman, H., The treatment of focal epilepsy Foerster, 0., Penfield, W., The structural basis of traumatic by cortical excision.Ann, Surg. 126: 140, 1947. epilepsy and results of radical operation. Brain 53: 99, Ransohoff, J. C., Hemispherectomy in the treatment ofcon- 1930. vulsive seizures associated with infantile hemiplegia.Res. French, L. A., Resection of the temporal lobe in patients with Publ. Ass. Nerv. Ment. Die, 34: 176, 1955. convulsive disorders.Minnesota Med. 41: 373, 1958. Rasmussen, T., Surgical aspects of focal epilepsy.Electro- French, L. A., Johnson, D. R., Adkins, G. H., Cerebral hemis- enceph.Clin. Neurophysiol.15: 1050, 1963. pherectomyfor ... intractableseizures A long-term Rasmussen, T., Gossman, H., Epilepsy due to gross destruc- followup.The Journal-Lancet 81: 58, 1961. tive brain lesions (results of surgical therapy).Neurology Green, J. R., Scheetz, D. G., Surgery of epileptogenic lesions 13: 659, 1963. of the temporal lobe.Arch. Neurol. 10: 33, 1964. Jinnai, D., Nishinicto, A., Stereotaxic destruction of ForelH Riechert, T., Hassler, R., Uber einen fall von doppeiseitigen for treatment of epilepsy.Neurochir. 6: 164, 1963. FornicotomiebeisogenanntentemporalenEpilepsien. Krynauw, R. A., Infantile herniplegia treated by removing one Acta Neurochir.5: 330, 1957. cerebral hemisphere.J. Neurol. Neurosurg, Psychiat. 13: Serafetinides, E. A., and Falcomer, M. A., The effect of 253, 1950. temporal lobectomy in epileptic patients with psychosis. Narabayashi, H., Nagao, T., Saito, Y., Yoshida, M., Nagahata, J. Med. Science 108: 584, 1962. M., Etereotaxic amygdalotomy for behavior disorders. Turner, E., A new approach to unilateral and bilateral lobot- Arch. Neurol. 9: 11, 1963. omies for psychomotor epilepsy.J. Neurol. Neurosurg. Paillas, J. E., Darcourt, G., Righini, C., Heritier, A., Physio- Psychiat. 26: 285, 1963. pathologic modifications noted in epileptic subjects treated Vitale, A., The indications for surgery in infantile epilepsy. by temporal lobectomy.Presse Med. 71: 1169, 1963. Minerva Pediatrica 16: 531, 1963.

66 PROGNOSIS

Judging from the limited amount of information Neonatal Convulsions available, one might conclude that the natural history and prognosis was not an important aspect of the Neonatal convulsions regardless of causative factors, significancefor prognosis.Craig epilepsy problem.Nothing could be further from the have a serious truth.The first question parents ask, and the most (1960) reported on 374 infants who had convulsions difficult to answer is prognosiswill he get better. within 10 days of birth; 158 of these died for various Lennox (1960) presented an optimistic outlook reasons, and of those who survived a large percentage disturbance." when he stated, "Probably the majority of young chil- showed some type of"intracranial dren subject to metabolic epilepsy or febrile convul- Graham and Prichard reported a 6-year followup study Sixty- sions would recover even without the benefit of medi- of 278 children who had neonatal convulsions. three infants died in the first 3 months.Of the sur- cines.This opinion is formed because many relatives of patients have had only a few seizures, or had them vivors, 75 had some disability such as cerebral palsy The 140 remaining were con- for only a brief time, in childhood.Cases that arise or mental retardation. Del Mundo and Robb (1964) found from a damaged brain do not fare so well ; but under sidered normal. experienced treatment, most children can be substan- that the chances of there being permanent brain dam- tially freed of attacks."Most clinicians would agree age was great in newborn infants with convulsions, particularly if there were other abnormal neurological that the majority of children who have had one or signs.These papers substantiate the general opinion, more seizures, with or without medication, will recover. that one must give a very guarded prognosis in any If it were not so, the statement that seizures are 10 child having convulsions in the newborn period. times more common in children than in adults, could not be made. Myoclonic Epilepsy Although Livingston (1963) was not in a position to publish exact data, he estimated that complete con- Myoclonic epilepsy (massive infantile spasms, drop trol of seizures occurred in 60 percent of patients seen fits, etc.) generally has a poor prognosis, depending in, his clinic.In another 25 percent, seizures were re- upon the pathological nature of thecerebral lesion. duced in frequency to the extent that they probably The seizures may be arrested or controlled with ACTH or adrenocortical hormones, but the associatedmental would not significantly handicap the patient.In the retardation is not alleviated.Frequently, motor and remaining 15 percent, seizures were refractory to all mental development has been retarded, but unrecog- forms of antiepileptic therapy. nized before the onset of seizures.There are patients, When predicting the outcome of seizures in an indi- however, whose development has been normal before vidual patient, one must consider the family history, myoclonic seizures start, but who subsequently decline any known cause, the type of seizures, duration of the mentally.The attacks may "burn themselves out" disorder, presence of precipitating factors, and other and the child left seriously retarded, without the basic less tangible factors such as the attitudes of the patient cause ever being discovered.Such things as a period and his relatives, and the emotional and social environ- of hyperpyrexia, anoxia, hypoglycemia, cardiac arrest, ment of the patient.It is easy to see why "prognosis" a very severe nocturnal seizure may be suspectedlater, is such a difficult subject. but cannot be proven.At present there is no way

67 xolzer,=,

although the frequency of predicting what the outcome willbe in a child who the time of the followup study, greatly reduced. has developed myoclonic seizures.The prognosis and duration of the seizures was grand mal attacks, should be guarded. Five patients had petit mal and two patients had grandmal attacks, alone, and12 the time of followup. Febrile Convulsions patients were free of seizures at A total of 12 of the 32 hadexperienced grand mal Convulsions due to fever alone rarely cause any after the onset of the petit mal,and in five of these, irreversible brain damage.Although they may recur the seizures had stoppedspontaneously or were under with fever, generally the children grow intoadulthood complete control with medication.None of the pa- free of epilepsy.If the child has a cerebral lesion, or tientsdeveloped psychomotor seizures.Favorable a low thresholdfor seizures, however, and the fever prognostic signs included early onset(between 3 and precipitates the attack, the prognosis is different.The 10 years), nomore than 10 petitmal spells a day when EEG may help separate the two, butusuaily time at their maximum,positive family history,normal alone, determines the differentiation.M. A: Lennox mentality, and normal neurologicalexamination. (1947) studied 153 children with febrileconvulsions. Holowach, et al. (1962), reviewedthe life histories Males outnumbered females two to one.There was of 88 children with petit malepilepsy.They con- a family history ofconvuisions in 44 percent.Sixty- cluded that the condition was notnecessarily benign five percent had their first febrile convulsionbetween nor unaccompaniedby cerebral pathologicalchanges the ages of 1 and 3.Only 25 percent of the children affecting mentality and personality.It is significant had one attack.Severe convulsions occurred in 35 that 10 percent of their patientshad brain damage of percent.At t'ex,' same time, Lennox studied another recognized etiology: one congenitalmicrocephaly, one group of 52 children inwhom the initial convulsion tuberose sclerosis, one Sturge-WeberSyndrome, one occurred with fever but who later developed recurrent craniosynostosis, one neonatalintracranial hemorrhage convulsions with or without fever.In these children and four postencephalomyelitis.Also 24 percent of there was a higher incidence of abnormalbirths as their patients were retarded. well as a higher percentage with a familyhistory of These findings suggest thatthere is no such thing as epilepsy. "pure" petit mal, but, likemyoclonic epilepsy, it is In spite of this work, and the work ofFridericksen the response of the brain at aparticular stage of mat- and Melchior (1954) , Schmidt and Ward(1955), uration to a genetic defeat.The prognosis will de- Fowler (1957),Prichard and McGreal (1958), Milli- pend, not on the pattern ofthe attack, but, rather, on chap, et al. (1960), and others, the real significanceof the basic pathophysiologicallesion behind it. febrile seizures remains unknown. Theyhave been described as a benign event, but as a result of theseiz- Post-traumatic Epilepsy disorder, a severe and ure or some other associated epilepsy is depend- prolonged attack may cause profound and permanent The prognosis of post-traumatic factors, both intrinsic andextrinsic. Thus, the ability to predict the out- ent upon many cerebral damage. The problem has beenreviewed in the section on come in a child whohas one febrile seizure is poor. EtiologyTrauma. Absnce Attacks Bibliography with It is the general opinion that most patients Craig, W. S., Convulsive movementsoccurring during the first petit mal seizures will recover as they grow older.A 10 days of life.Arch. Dis. Childhood.35: 336, 1960. certain number of these will begin at puberty tohave Caveness, W. F., Onset andcessation of fits following cranio- rather cerebral trauma.J. Neurosurg. 7: 570, 1963. grand mal attacks, but this is the exception Saidman, L. J., Prognosis of Recent studies suggest that this is not Currier, R. D., Kooi, K. A., than the rule. ."pure" petit mal; a followupstudy.Neurology 13: 959, altogether true.Lees and Liversedge (1962) , from a 1963. study of 132 patients, indicated that the prognosis del Mundo-Vallarta, J., &Robb, J. P., a followup studyof Neurology could not be considered very favorable.Currier, et newborn infants with perinatalcomplications. al (1963) followed 32 patients who had a presenting 14: 413, 1964. Evans, J. H., Post-traumaticepilepsy.Neurology 12: 665, complaint of petit mal seizures with EEG verification 1962. after an average interval of 18 years.Thirteen of Evans, J. H., The significanceof early post-traumatic epi- the patients continued to have petit mal seizures at lepsy.Neurology 13: 207, 1963.

68 Febrile convulsions.Mayo Fridericksen, C., Melchior, J., Febrileconvulsions in children: Prichard, J. S., McGreal, D. A., Clin. North Amer. March 42 :379, 1958. Their frequency and prognosis.Acta Paediat. 43 (Suppl. Quadfasel, F. A., Walker, A. E.,Problems of post-traumatic 100) : 307, 1954. epilepsy in an Army generalhospital.Res. Publ. Ass. Fowler, M., Brain damage afterfebrile convulsions.Arch. Nerv. Ment. Dis. 26: 461, 1947. Dis. Child. 32 : 67, 1957. M., Studies of traumatic epi- G., Rasmussen, T., Evalua- Russell, W. R., Whitty, C. W. Jasper, H. H., Arfel-Capdeville, I. Factors influencing incidentsof epilepsy after tion of EEG and corticalelectrographic studies for prog- lepsy ; wounds.J.Neurol.Neurosurg.andPsychiat. nosis of seizures following surgicalexcision of epileptogenic brain Epilepsia 2: 130, 1961. 15: 93, 1952. lesions. Schmidt, R. P., Ward, A. A.,Febrile convulsions.Epilepsia Lees, F., Liversedge, L. A., Theprognosis of "petit mal" and 4: 41, 1955. minor epilepsy.Lancet 2: 797, 1962. epilepsy ; A 10-year in childhood.Res. Publ. Walker, A. E., Prognosis in post-traumatic Lennox, M. A., Febrile convulsions followup of craniocerebral injuriesof World War II. Ass. Nerv. Ment. Dis. 26: 342,1947. Marshall, W., Walker, A. E., Thevalue of electroencephalog- JAMA 164: 1636, 1957. Watson, C. W., Epilepsy followingcraniocerebral injury raphy in the prognostication andprognosis of post-traumatic (traumatic ).Arch. Neurol. and Psychiat. 6R :831, 1952. epilepsy.Epilepsia 2 : 138, 1961.

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