history of aet: from brain trephination to the modern...

American Epilepsy Society Annual Meeting

History of AET: From Brain Trephination

to the Modern Era December 3, 2011

Howard P. Goodkin, MD, PhD

University of Virginia

American Epilepsy Society | Annual Meeting

Disclosures Financial Disclosures

Avanir Pharmaceuticals

Acknowledgements

Consultant


Owsei Temkin

1902 - 2002 William G. Lennox

1884-1960

Mervyn Eadie

Walter Friedlander

Anthony Glazko

Donald F. Scott

*Brand names are used in those instances when the original publication

incorporated the brand name

Objectives • Share the stories involved in the discovery of

antiepileptic therapy.

• What does an organization gain by retelling its

history?

– Sharing of organizational history assists in the development

of an organization’s identity

– What happened in the past can orient present and future

actions of an organization

• What can be learned from the history of AET – Sagacity: the quality of being discerning, sound in

judgment, and farsighted

– Common concern: Side effects

– Common goal: Finding a cure for epilepsy


Lennox & Lennox, 1960

Pre-bromide period

Rise and fall of bromides

The importance of Putnam and

Merritt: Diphenylhydantion and

animal models

The Epochs of AET History

The era of

phenobarbital

Treatment in the Pre-Bromide Period

Lennox & Lennox, 1960; Wilson & Reynolds, 1990; Eadie & Bladin, 2001

718-612 B.C.E.

If at the time of his possession, while

he is sitting down, his (left) eye moves

to the side, a lip puckers, saliva flows

from his mouth, and his hand, leg, and

trunk in the left side jerk (or twitch) like

a (newly) slaughtered sheep, it is

miqtu. If at the time of the possession

his mind is consciously aware, (the

demon) can be driven out; if at the time

of the possession his mind is not so

aware, (the demon) cannot be driven

out.

Sakikku (“All Diseases”)


Lennox & Lennox, 1960

Head •Bleeding of the forehead and elbow

•Cupping

•Cutting of arteries before and behind ears

•Trephining/cauterization of the skull

•Application of rubefacients to the head

•Purging

Middle part of the body (intestines) •Remedies to help digestion (castoreum)

Galen

ca 130 – ca 200

Aretaeus

ca 130 – ca 200


Treatments

1. Mistletoe worn around the neck

2. Roman peony

3. Rue (smelled frequently)

4. Thongs of wolf hide worn next to the flesh

5. Blood of weasel mixed with its urine,

eaten in quantity

6. Powder from the cuckoo

7. Blood letting and cautery

8. Trephining

9. Diet

10.Amulets bearing words of the Gospel for

the Ember Days of September

Lennox, 1941 Courtesy of Historical Collections & Services, Claude Moore Health Sciences Library, University of Virginia

Bernard of Gordon

(1260 – ca 1318)

Lilium Medicinae

(“Lily of Medicine”)

1305

Seizure action plan 1. Extremities should be rubbed

vigorously

2. Stick of wood inserted

between the teeth

3. Juice of rue should be

injected into the nose

4. Head and body rubbed with a

downward motion

5. Place mouth over the

patient’s ear and repeat the

following 3 times:

Gaspar bears the myrrh,

Melchior the frankincense,

Balthasar the gold, Whoso

bears with him the names

of these three Kings is

delivered from epilepsy by

the holiness of Christ


Bernard of Gordon, 1305

•Hellebore

•Mistletoe

•Lily of the valley

•Swallow stones

•Cuckoo powder


Sir Thomas Willis 1621-1675

An Essay of the Pathology of the Brain and Nervous Stock: In which

convulsive diseases are treated of

“as often as the Devil

is permitted to afflict

miserable Mortals

with his delusions, he

is not able to draw

more cruel Arrows . . .

than by the assaults

of this monstrous

Disease”

A Growing Frustration

Mental maladies; a treatise on insanity, 1858

Jean-Etienne D. Esquirol

1772-1840

I employed successively, sanguine evacuations and purgatives, baths of every temperature, issues, the cautery, fire, and antispasmodics, vegetable and mineral. I confined myself to hydrocyanic acid. I procured and purchased secret remedies. Every spring and autumn, I chose thirty epileptic women, with the history of whose malady I was best acquainted. . . A new medicine invariably suspended attacks . . After this period, they returned. . but, I shall confess it! I did not obtain a single cure.

A Growing Frustration

Hitherto, I say, our search for a specific against epilepsy has been in

vain; for who will venture to say that, out of the long list of anti-

epileptic remedies which our materia medica supplies us, any one

really deserves the name?

Robert B. Todd

1809-1860

Tuesday May 12, 1857

Lancet, 1857; Medical Time Gazette, 1857

Edward Sieveking

1816-1904

I would beg to offer my apologies to the Society for presenting these desultory

observations .. . I have been particularly anxious not to make a further

addition to the rudis indigestaque moles [rough unordered mass; chaos] of

mere hypothesis already existing in this department of medical science.

Tuesday May 12, 1857 The President said the author had omitted to mention

one or two causes which were frequently productive of

epilepsy . The first was dentition . . . Another very

fruitful cause was sexual indulgence, and especially

onanism, which he believed might be attributed the

greater frequency of the disease in the late years.

There was another form of epilepsy to which special

notice had not been drawn, which he had been in the

habit of regarding as hysterical epilepsy. It was

confined to women, and observed a regularity of

return with menstruation. It was as baffling a form of

epilepsy as any other . . . He had been led within the

last twelve months to try a remedy . . . answered

his expectations . . should have a larger trial . . Some years ago he chanced to

see a paragraph in the British and Foreign Medical Review, . . . a German had

been making with bromide of potassium. . . he became impotent . . He (the

President) accordingly thought he would try bromide . . . unconnected with

epilepsy in which there was a great deal of sexual excitement . . . calming the

excitement. German = Otto Graf


Sir Charles Locock

1799-1875

About fourteen months ago he was applied to by the

parents of a lady who had hysterical epilepsy . . he

tried all remedies . . without effect. She began to take

the bromide . . . The result had been that she had not

had another attack . . . He tried the remedy in fourteen

or fifteen cases, and it had only failed in one, and in

that one the patient had fits not only at the times of

menstruation, but also in the intervals. In answer to Dr.

Webster, the President stated that the patients whom

he had treated with bromide of potassium were all

under the age of thirty.

Tuesday May 12, 1857


Sir Charles Locock

1799-1875

The Rise of Bromides

On Epilepsy and Epileptiform Seizures, their Causes, Pathology, and Treatment (1858; 2nd ed. 1861)

1858

1861

Edward Sieveking

1816-1904

The Introduction of Bromides

, and it was evident that a very

valuable specific remedy had

been obtained . . . I was not

aware at that time that Sir C.

Locock had recommended its

use . . .

Sir Samuel Wilks

1824-1911

The Fall of Bromides

You may play all the tricks you will, using arsenic, hot baths, and what

not, and still you will sometimes be driven to conclude that a man had

better have epilepsy than be overdrugged with bromides (Mitchell, 1912)

Bromism

• Restlessness

• Irritability

• Ataxia

• Confusion

• Hallucinations

• Psychosis

• Weakness

• Stupor

• Coma

• Loss of gag reflex

• Nausea

• Vomiting

• Anorexia

• Constipation

• Acne

• Pustule

• Erythematous rash

S. Weir Mitchell

1829 – 1914

Potassium and sodium bromide most common • Initial dose: 10 – 30 grains

• Potassium: more reliable, less expensive

• Sodium: less nausea, tasted better

The Fall of Bromides

Bromism

• Restlessness

• Irritability

• Ataxia

• Confusion

• Hallucinations

• Psychosis

• Weakness

• Stupor

• Coma

• Loss of gag reflex

• Nausea

• Vomiting

• Anorexia

• Constipation

• Acne

• Pustule

• Erythematous rash

Potassium and sodium bromide most common • Initial dose: 10 – 30 grains

• Potassium: more reliable, less expensive

• Sodium: less nausea, tasted better

“[Patients are] stupified with sedatives and made to live a living death” (Graves, 1914)

W.C. Graves

December 4, 1864

J.F. Adolf von Baeyer

1835-1917

Von Baeyer’s synthesis of barbituric acid

Uric acid

Barbituric acid

*1828 – Synthesis of urea from inorganic compounds by Wohler

December 4, 1864: St. Barbara Day

St. Barbara

Patron Saint of Artillerymen

1. Schlusselbart (the bit or “beard” of a key,

from L. barba, beard).

2. Sentimental reasons

3. Waitress named Barbara

4. “A derivative of uric acid, and discovered

on Saint Barbara’s day,” exclaimed the

officer, “its name shall be barbituric acid”

Barbitursaure

Kendall, 1946

Barbital Phenobarbital

Phenobarbital: Hauptmann’s Serendipitous

Discovery

However, I should draw attention to the susceptibility of epilepsy or

rather of epileptic attacks through [phenobarbital]. This became apparent

when using the new medication as a tranquilizer, also with epileptic

patients, whereupon I proceeded systematically to use [phenobarbital] in

severe cases of epilepsy over long periods of time

Up to this point, our experience adds nothing to previous knowledge.

Alfred Hauptmann

1881-1948

Hauptmann, 1912; as translated by D.F. Scott


Discovery

I have chosen this particular case because the data available allow a precise

comparison of the number of attacks over a full year. The reduction in the

number of attacks from February 1912 shows up clearly, not only in

comparison with the latter month of 1911, but also compared with the

corresponding months of February to June 1911.

Hauptmann, 1912


Discovery

c

Grinker, 1920

1 phenyl: 2 phenyl:: phenobarbital: phenytoin

Glazko, 1986; Putnam, 1970

Barbiturates Hydantoins

I combed the Eastman Chemical Company’s catalogue,

and other price lists, for suitable phenyl compounds that

were not obviously poisonous. I wrote to other major

pharmaceutical firms, asking if they had had available or

could make suitable compounds. The only one of them

that showed any interest was Parke, Davis and Company.

They wrote back to me that they had on hand 19 samples

of 19 different compounds analogous to phenobarbital,

and that I was welcome to them.

Tracy Putnam

1894-1975

H. Houston Merritt

1902-1979

Glazko, 1986; Putnam, 1970


In a recent letter, Dr. Tracy J. Putnam . . . expressed an

interest in cooperating with us in a search for a barbituric

acid hypnotic of the luminal type. He expressed the

opinion that certain substances, although rejected as

hypnotics, might possess anticonvulsant activity. (Kamm,

April 3,1936)

Tracy Putnam

1894-1975

H. Houston Merritt

1902-1979


Glazko, 1986


Tracy Putnam

1894-1975

H. Houston Merritt

1902-1979


The Development of Animal Models

•1870, Fritsch and Hitzig produce seizures in animals by

electrical stimulation of the cerebral cortex

• 1882, Albertoni examined the actions of bromides, atropine,

and cinchona alkaloids against electroshock-induced seizures

in dog

• 1935, Krasnogorsky (and 1937, Speigel) describes

technique for inducing seizures in experimental animals

without surgery

We are indebted to Dr. Frederic A.

Gibbs for suggesting that a

modification of these methods could

be used for our purpose and to Dr.

Paul Hoefer for help in devising one

which has proved simple and

practical.

Putnam & Merritt, 1937

Tracy Putnam

1894-1975

H. Houston Merritt

1902-1979

1938

May: Clinical observation on 200 patients published in JAMA

June 23: Dilantin sodium added to Parke, Davis catalogue

1950/1975: Generic name Phenytoin appears in Europe/US

From Bench to Bedside

Glazko, 1986

May 28: First public announcement published in Science

August: Parke, Davis receives first news of clinical efficacy

Tracy Putnam

1894-1975

H. Houston Merritt

1902-1979

1937

The Importance of Putnam and Merritt • 1944, Richards & Everett, Trimethadione prevents PTZ-induced seizures

• 1951, Chen et al, phensuximide and methsuximide

• 1953, Goodman et al demonstrates differential effectiveness of drugs in MES

and PTZ models

•1975, formal establishment of the NIH-sponsored Anticonvulsant

Development Program

Loscher and Schmidt, 2011

Louis Goodman

1906-2000

Dixon Woodbury

1921-1991

Ewart Swinyard

1909-1997

J. Kiffin Penry

Gerry Fischbach

Harvey Kupferberg

Roger Porter H. Steve White

The Importance of the NIH and the ADD


1993 Felbamate 1993 Gabapentin 1994 Lamotrigine 1996 Fosphenytoin 1996 Topiramate 1997 Tiagabine 1999 Levetiracetam 2000 Zonisamide 2000 Oxcarbazepine 2005 Pregabalin 2008 Rufinamide 2010 Lacosamide 2011 Ezogabine

Other tales of serendipity not told Ezogabine


Chlordiazepoxide

Valproate

Lamotrigine

Gabapentin

Levetiracetam

Ezogabine

But is it better than Bromides?

The mental agility was nevertheless enhanced. The

state of nutrition and strength which had suffered

greatly as the result of the administration of bromide

over many years improved to a quite extraordinary

degree.

Because, naturally, [PB] is not a cure for epilepsy, it

does not specifically influence the epileptiform brain

process, it is merely capable of reducing the

sensitivity of the cerebral cortex and by so doing to

stall the attacks.

Hauptmann, 1912

Alfred Hauptmann

1881-1948

What happened in the past can orient the present and future actions

of an organization

A New Era of Growing Frustration

Loscher & Schmidt, 2011; Mohanraj & Brodie, 2005

A New Era of Growing Frustration: Historical Advice

Hitherto the search has been for some remedy which would cure

epilepsy . . . which has now been continued for so many years in

vain, we must nevertheless, not abandon. It may be that a remedy

of this kind may yet be vouchsafed to us, nor can one conceive a

more inestimable blessing for mankind. Among the stores of the

vegetable kingdom, there may yet be discovered some subtle agent

. . . which may exercise the beneficial influence so earnestly

desired, and diminish or remove this dreadful scourge (1849)

Robert B. Todd

1809-1860

Summary

• The history of AET development is a history shaped

by serendipity and sagacity.

• Great progress has been made between May 12,

1857 and December 3, 2011.

• Yet, we find ourselves once again in a new era of

growing frustration.

• However, the future holds promise for the

development of antiepileptogenic drugs and of

individualized treatment.

history of aet: from brain trephination to the modern...

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