The second series of Epilepsia
The century of international epileptology was seriously affected by the two world wars. The last issue of Epilepsia’s first period was in 1915. It was 21 years before the first issue of the second series appeared, in February 1937. This issue contains no information whatsoever pertaining to our topic. During this period, Epilepsia was published once a year. In the 1938 issue Stauder (1938) reported on progress in epileptology in Germany. He mentioned studies of Fritsch, who posited that there is a vicarious influence of albumin and globulin levels on epilepsy. Fritsch had noticed an increase in albumin levels shortly before seizures occurred. When increased globulin levels were induced in dogs, thrice normal stimulus strength had to be used to provoke seizures by electrical stimulation of the cortex. Kroll posited that extracts of brain areas that had been electrically stimulated to provoke seizures and extracts from a surgically removed human epileptic focus could provoke severe seizures if injected in other animals. Stauder cautioned that these experiments still needed independent confirmation. (In the 1939 issue of the journal, William Lennox reported that Keith and McEachern had punctured the reports of Kroll.) Lennox (1938) reviewed the literature of 1936; few articles are relevant for our purposes. Spiegel and Spiegel had done work on physicochemical mechanisms in convulsive reactivity. They concluded that epileptogenous agents probably act in two ways: “by production of a change in concentration of ions at cell surfaces,” which when supra threshold, results in a convulsion and “by diminution in the density of the cell surface film” (p. 150), resulting in increased permeability and, therefore, lowering of convulsive reactivity.
In the third issue of this second series, H. P. Stubbe Teglbjaerg (1939) from Denmark lamented. “If we go through the scientific results which in the course of the past 20 years—the period I have witnessed—have been reputed and ascertained as facts, we are disgraced on behalf of science by much uncritical acceptance of new allegations, which are even frequently joined on a defective basis and carried on, the result being that epilepsy researchers have repeatedly been led into a blind alley, I am especially thinking of certain ‘pathognomonic’ metabolic anomalies which are demonstrated over and over again. When conscientious researchers arrive at the true recognition of such mistakes they are often disillusioned as to the possibility of yielding a lasting positive contribution in this domain” (p. 189). In any event, the yield of information about scientific contributions in the field of neurochemistry in this issue is nil.
The fourth issue again is almost void of information relevant for this review. There is, however, mention in the report of P. C. Cloake (1940) on English studies of a paper by Tod and Stalker on neuropsychiatric aspects of bromide intoxication. In this paper, which can be considered a first example of “monitoring anti-epileptic drugs in body fluids,” the authors posit that a blood level of bromide under 100 mg produces no symptoms; 100–200 mg produces symptoms occasionally in elderly patients with cardiorenal inefficiency; and over 200 mg usually produces symptoms. In a report by Lennox (1940) from the United States, the only remarkable information concerns the “discovery and clinical use of sodium diphenyl hydantoinate as a new and effective anti-epileptic drug” (p. 285).
The Second World War made it necessary to move publication of Epilepsia to the United States, where volume II of the second series starts with issue 1 in July 1941. The number of full reports had declined, and there were delays in reviewing the literature. In the December 1942 issue Lennox presented papers published in various journals in 1940 (Lennox, 1942). Gibbs and Gibbs compared the oxygen and carbon dioxide content in arterial blood and that from the internal jugular vein in persons with epilepsy and healthy controls. While the respiratory quotient of healthy controls was 0.98, the investigators found that, especially in patients with “petit mal,” this was reduced to 0.90. Accordingly, they concluded that in these patients there is a deviation in glucose metabolism in the brain (p. 121). In a second paper they stated that, “whereas the oxygen, sodium and potassium were normal in epileptic persons, the value of carbon dioxide in both the arterial and internal jugular blood were abnormal in the following respects: in patients subject to petit mal seizures carbon dioxide values tended to be abnormally low, whereas in those subject to grand mal seizures they tended to be abnormally high; spontaneously occurring grand mal and petit mal seizures were preceded by abnormal fluctuations in the carbon dioxide content of arterial and internal jugular blood, time relations indicating a causal linkage between the carbon dioxide content of blood and seizures” (p. 123–124). Chick, El Sadr, and Worden were reported to have demonstrated that within 8–38 weeks of depriving rats of pyridoxine (vitamin B6) seizures would occur. Re-establishing a normal diet relieved the condition. There are many papers about the effects of antiepileptic drugs, in particular the recently introduced phenytoin. One paper by Cohen, Coombs, Cobb, and Talbott addressed the putative mechanism of action of azosulfamide. They found a decrease in carbon dioxide content and carbon dioxide-combining power and an elevation of chlorides in serum. The authors concluded that the anticonvulsant effect of both azosulfamide and phenobarbital coincided with a positive potassium balance. Ammonium chloride produced the same degree of acidosis as azosulfamide, without changing potassium chloride content, and did not have anticonvulsant action.
The first postwar issue was volume III, issue 1 of the second series. The acting editor, William Lennox, 1945, wrote: “Because of the enlarged subscription list publication of original communications is now possible” (p. 7). Yet a large portion of the issue still consisted of reviews of the literature.
Schütz posited that barbiturate withdrawal seizures could be due to the fact that phenobarbital therapy reduced serum cholinesterase and that it could take a while for normal values to be restored. From the précis (p. 35) presented it is not clear whether, before treatment, persons with epilepsy exhibited normal levels or low levels of serum cholinesterase.
This issue also has a paper by Houston Merritt and Tracy Putnam (Merritt & Putnam, 1945), who first reported their method to determine anticonvulsant properties of chemical compounds in 1937 (Putnam & Merritt, 1937) by applying electroshocks to cats, and here present a report on 700 compounds that, according to their structural formula, belong to barbiturates: benzoxazoles; hydantoins; ketones and phenyl ketones; oxazolidinediones; phenyl sulfides, sulphones, and sulfoxides; and miscellaneous. Of all compounds tested, 76 had a maximum rating for seizure suppression on a five-point scale.
The December 1946 issue contained a review of a paper by Boszormenyi claiming increased permeability of the blood–brain barrier during convulsions, and of one by Foster who posited that “the physiological cause of epilepsy may be defined as abnormalities of acetylcholine metabolism” (p. 141). A paper by Madsen published in 1943 was reviewed in which the study of ammonia output and electrolyte balances led to the statement: “Thus these studies confirm the theory of a reversible increase in cellular permeability, with altered colloid-osmotic conditions, resulting in increased irritability of the brain cells.” Lennox, the editor, added the following note to this review: “Kidneys are far from the brain. Can these urinary findings be backed by blood and brain wave change?” (pp. 142–143).
The September 1947 issue cited a paper by Pope, Morris, Jasper, Elliot and Penfield studying epileptogenic areas of cerebral cortex in man and the monkey. Interstitial fluid pH was measured with a glass electrode described by Nims. pH was not considered to be an important factor in determining heightened neuronal excitability in epileptogenic lesions as described, nor was an indicator of the cytochrome oxidase system significantly altered in the human foci studied. However, comparative studies on cholinesterase activity in normal and epileptogenic lesions both in humans and monkeys demonstrated increased activity of the enzyme in areas showing epileptiform electrical discharges (p. 234).
In a paper by Davies and Rémond (Anon, 1947) (appraised by the review editor as a brilliant demonstration of cortical physiology), following onset of electrocorticographic epileptiform changes, a decline in the oxygen tension of the cortical tissue and of the cortical venules was demonstrated without change in the oxygen tension of the arterioles. Direct measurement of the oxygen consumption of the cortical tissue demonstrated an increase coincident with the convulsion (p. 249).
A report by Alexander in the December 1948 issue titled “Neuropathology and Neurophysiology Including Electroencephalography in Wartime Germany” contained a remarkable statement: “Hallervorden, to whom went the brains of those dying in the ‘killing centers for the insane’, was offered but refused the brains of epileptics because he found that nothing of significance would be found in them” (p. 309).
Three abstracts concern agene (nitrogen trichloride), which at the time was used to whiten bread more. An editorial in the British Medical Journal of December 1947 signaled the finding of Mellanby that dogs fed such bread would develop running fits. Newell et al. reported in the Journal of the American Medical Society of November 1947 that the toxic factor was associated with the protein but not with the lipid or carbohydrate. Furthermore, they found that cats fed agene developed seizures, monkeys some electroencephalography (EEG) changes but no seizures, and rats, chicks, guinea-pigs, and people neither seizures nor EEG changes. (The editor wonders what would have happened if also people with epilepsy had participated in this last study.) In the same issue of JAMA, Silver et al. reported that following treatment with agene, mixtures of amino acids and the individual amino acids cysteine and cystine produced the same effect.
December 1949 heralded a new volume of Epilepsia, which eventually consisted only of two issues, 1949 and 1950. R. Eeg-Olofsson reviewed a book titled Total Protein, Globulin and Albumin in Lumbar Fluid in Cryptogenic Epilepsy. The book contained more than 200 references. Epilepsy hyperproteinorrhachia—an increase in spinal fluid total protein to 65 mg or above without an abnormal number of cells—was encountered in six cases. Abnormal low globulin-albumin quotients (under 0.14) were found in 14 patients. These abnormalities were not related to duration of the disease or to the near approach of a seizure. Refereed papers from various journals debated the role of acetylcholine and anticholinesterases. The section on pharmacology mentioned a paper by Torda and Wolff, who studied a long list of convulsant and anticonvulsant agents in terms of their influence on the synthesis and hydrolysis of acetylcholine and the sensitivity of effector organs to the substance. They state that their results indicate that most convulsants cause an accumulation of acetylcholine and most anticonvulsants a decrease.
Local oxygen consumption measured with an oxygen cathode was studied following strong stimulation of a cortical area. Another interest of the time appeared to be the role of glutamic acid in brain function; seven papers on the topic were cited. In 1949, Epilepsia lost the support of the organization that had carried it through the war (the American Epilepsy League) and ceased operation. It did not pick up again until 1952.
The third series of Epilepsia
The first volume of the third series of Epilepsia appeared in November 1952 and contained a statement that the annual abstract journal, Epilepsia had lost its “raison d’être.” The present editors (the publications committee of the American League Against Epilepsy, chaired by Jerome K. Merlis) wished to offer an opportunity to people desiring to critically examine what had been done in the past, to point out what new facts were required.
One such paper was by Toman and Taylor about the mechanism of action and metabolism of anticonvulsants. The following remarks can be found in this treatise: Action on cholinergic mechanisms had frequently been considered either as a factor in the production of seizures, or in the effects of protective drugs. It had been noted that acetylcholine-binding substances are altered in tissues from epileptogenic foci and that some anticonvulsants were capable of changing the biochemistry toward normal. In general, it could be said that there is as yet no consistent body of information relating cholinergic mechanisms either to epilepsy or antiepileptic drug action. In another part of the review the authors observed that, for some drugs like phenobarbital, there was a rapid rebound in “grand mal” after withdrawal, in others such as trimethadione remission of “petit mal” could persist for weeks to months following drug withdrawal. The paper ended with a remark which, although devoid of any biochemical explanation, is curious enough to be repeated: “Aureomycin can be used in the control of otherwise refractory ‘petit mal’ of viral etiology long after the acute infection has subsided, although aureomycin has no demonstrable general anticonvulsant properties.”
A paper by Pope updated epileptologists about the Krebs cycle. Pope noted that metabolic increments can be seen as the result of excessive neuronal discharges, but that convulsions may well be caused by oxygen or glucose deprivation or poisoning of critical enzymes such as the cytochrome system. He mentioned an important role of glutamic acid, which plays a part in buffering ammonia. Alone among amino acids, glutamic acid supported brain respiration in vitro and appeared to have an important role in regulating membrane permeability in the brain. Pope did not wish to take a stand in the discussion on the controversial role of acetylcholine in the production, propagation, and synaptic passage of nerve impulses; but he did emphasize that the enzyme systems for formation and hydrolysis of acetylcholine were ubiquitously present in excitable tissues and must be intact for normal function. Pope abstained from discussing what he nevertheless called “the revolutionary observations” of Caspersson and Hydén showing rapid intracellular protein and nucleoprotein turnover during neuronal discharge.
Tower, in contrast, took the acetylcholine system as point of attack to better understand the metabolic processes involved in seizure occurrence. He observed that in epileptogenic cortex there was an impairment of bound acetylcholine production without reduction in synthesis of free acetylcholine. Furthermore, he considered it likely that glutamic acid was involved in the mechanism that forms bound acetylcholine. With a defect in the mechanism responsible for retaining acetylcholine in its bound form, the presence of abnormal amounts of free (active) acetylcholine was certainly possible. And, according to Tower, “by now it is well recognized that experimentally acetylcholine can give rise to epileptiform activity in the electroencephalogram.” In reporting the deliberations of the Committee on Research on Experimental Epilepsy, Ward noted that Stavraky had presented evidence that led him to believe that the “law of denervation” applied to the central nervous system (CNS) as well as to the peripheral system. Therefore, deafferented neurons would become hypersensitive to acetylcholine, which explained the hyperactivity displayed by epileptogenic areas.
The opening paper of the third series, issue 2, November 1953, is a biochemistry-related paper, but it is the only one. Glaser (1953) discussed the relationship between adrenal cortical activity and the convulsive state. The author refers to many and often contradictory studies. In his opinion the mechanisms by which adrenal hormone imbalance causes brain hyperexcitability and seizures, and the nature of the antagonistic effect of desoxycorticosterone and cortisone had up to then not been adequately elucidated.
In the third volume of this series, a third-year student from New York, Jerome Fabricant (1954), was awarded a first prize for a paper on the role of adrenaline in epilepsy (According to PubMed, apart from this paper on epilepsy, Fabricant published on veterinary topics between 1950 and 1999.) This is the only paper in this volume to treat the biochemical aspects of epilepsy. From a study of the literature Fabricant posited that in patients with epilepsy, the electrolyte effects of adrenaline were not sufficiently checked by adrenocortical hormones, owing to adrenocortical hypofunction. In conditions of stress these ionic effects could be sufficient to excite discharges. Several mechanisms by which adrenaline might act were suggested: promotion of acetylcholine synthesis; anticholinesterase activity; and inhibition of carbohydrate metabolism leading to permeability defects with consequent leakage of potassium, increased free acetylcholine, and increased permeability to acetylcholine. Large amounts of adrenaline, however, depressed the action of acetylcholine. This was invoked as the mechanism by which the seizure ceased and the epileptic patient fell asleep.