The history of status epilepticus and its treatment

Authors


Address correspondence to Simon D. Shorvon, M.D., UCL Institute of Neurology, University College London, Box 5, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom. E-mail: s.shorvon@ion.ucl.ac.uk

Summary

Despite the fact that status epilepticus was been recognized since antiquity, its existence was largely ignored until the mid-nineteenth century. In this review we cover the medical literature of status epilepticus from the late nineteenth century until the early 1970s when the modern era of status epilepticus began. We pay particular attention to the impact of the ILAE and its principal members on the understanding and awareness of status epilepticus. We also cover the evolution of treatment regimens advocated for status epilepticus from the late nineteenth century to the early 1970s when the benzodiazepines were established as first line treatments.

The 20th century was, for epilepsy, the century of the International League Against Epilepsy (ILAE). This professional association, founded in 1909, dominated the organization of epilepsy care through the century (and particularly in its second half). Many of the main individuals at the center of clinical epilepsy were also officers of the ILAE, or at least heavily involved with the league in other capacities. Two major contributions of the ILAE were the publication of the scientific journal Epilepsia and the holding of medical and scientific conferences; it is by the agency of these two activities that much of the epilepsy research and clinical advances of the 20th century were evaluated and coordinated. So it was for status epilepticus, the topic of this paper.

Status epilepticus was for many years very much at the margins of epilepsy. In the early period of its modern history, it was considered rare but hazardous, a relatively minor footnote in a distant corner of the epilepsy panorama. Since the mid-1970s, though, it has assumed much greater importance. The reasons for this new focus are 4-fold: (1) status epilepticus has proved an essential model for the experimental investigation of the mechanisms of epileptic seizures, and in particular for the understanding the mechanisms of seizure cessation; (2) it has been crucial in the massive research effort undertaken to elucidate how epilepsy might result in cerebral damage, both from the clinical and experimental perspective, and particularly in formulating theories of excitotoxicity; (3) its importance clinically and epidemiologically in the elucidation of the mortality and morbidity of epilepsy has been recognized, as has the fact that the condition can take many clinical forms and is not as uncommon as originally assumed; and finally, (4) it has been a subject of pharmacologic and therapeutic advances, which have had significance in epilepsy more widely, beyond the therapy of status epilepticus itself. The ILAE has played an important role through its journal and conferences in all these areas.

In this article, brief consideration is given to the history of the development of the concept of status epilepticus and of its clinical treatment, covering the period from its modern origins (in 1824) until the introduction of benzodiazepine therapy for status epilepticus in 1973. In the brief space allotted, a clinical not experimental perspective is taken, much is left out, and we have omitted any discussion of the evolution of the basic science knowledge of status epilepticus. The role of the ILAE (from 1909 onward) is emphasized. The end point of this paper, 1973, in many ways marks the end of a period of relative obscurity for status epilepticus. The major experimental and basic science discoveries were beginning to be made, launched particularly by the work of Meldrum and colleagues, and status epilepticus was by then also beginning to assume a central position in the firmament of clinical epilepsy. This paper charts its history in brief to this jumping-off point of modern status epilepticus. We have attempted to make reference to what we consider to be the major studies and writings in the field of status during this period but are aware also that we have taken an Anglophonic perspective and may have overlooked important contributions emanating particularly from work in continental Europe.

The Concept and Clinical Features of Status Epilepticus: Pre-1909

A condition that we would now term status epilepticus was recognized in antiquity, and described on a Babylonian cuneiform tablet dated 600–700 B.C. (Shorvon, 1994). However, the existence of prolonged seizures was largely ignored, or at least not written about, until the 19th century. Indeed Hunter (1959) in his masterly literature review of the history and incidence of status epilepticus found only a handful of references to cases resembling status epilepticus, and with no recognition of the distinction between status epilepticus and epilepsy.

The initial clinical descriptions

It is traditionally claimed that the term état de mal was first used in the medical literature by Louis Calmeil in 1824 as part of his doctoral thesis for the University of Paris (Calmeil, 1824). Calmeil’s writing was based on his experiences of epilepsy in the Parisian asylums of the Salpêtrière and Charenton. He pointed out that the expression (état de mal) was in common usage by the patients themselves at the Salpêtrière and furthermore recognized to have a severe and often fatal outcome. In his thesis, he distinguished between status epilepticus and a succession of fits by the fact that in status epilepticus the patient did not recover consciousness between fits—and this distinction was repeatedly emphasized by subsequent authors (see Turner, 1907; for instance) and remains valid to this day. Moreover, Calmeil was the first to recognize that the grave prognosis of status epilepticus was related to the succession of fits without recovery and not to the number or duration of individual seizures in the cluster. Delasiauve, who was based at the Bicêtre, then described the symptoms, prognosis, and treatment of status epilepticus in 1854 (Delasiauve, 1854), emphasizing that the real danger of status epilepticus lay not in the intensity or the frequency of the fits but rather in the failure of the “embarrassed functions to recover their equilibrium” in between successive seizures. This was the period in which the clinical descriptions and definitions of status epilepticus were being formulated. A major landmark was the work of Desiré Magloir Bourneville who took up the subject of status epilepticus first in 1869 and wrote on it extensively while based at the Bicêtre. Indeed Bourneville’s description of the characteristic features of status in the case of Marie Lamb, a 19-year-old retarded and hemiplegic epileptic girl at the Salpêtrière, published in 1876, remains a masterful depiction of secondarily generalized tonic–clonic status (Bourneville, 1878). Bourneville identified two periods in status epilepticus: the convulsive stage and the meningitic (the latter stage has been recently rediscovered and named the stage of subtle status). The convulsive period manifests as an increasingly rapid succession of seizures associated with the consistent feature of a dramatic rise in temperature heralding the second stage. Indeed Bourneville believed that the pyrexia induced by the status was the principal prognostic factor (Shorvon, 1994). This phenomenon was investigated by others including Westphal and Charcot, who confirmed that the hyperpyrexia of status epilepticus could not be explained by the presence of a concomitant infection and concluded that it was of primary central nervous system (CNS) origin and confirmed Bourneville’s observation that the higher the temperature the worse the prognosis. Charcot also distinguished hystero-epilepsy stimulating true status epilepticus by the absence of a high temperature (Charcot, 1875). Indeed the concept of hystero-epilepsy and hystero-epilepsy stimulating status epilepticus were well recognized in this period, with representative reports published in 1897 (Thomson, 1897) and 1898 (Kindon, 1898), in the latter of which it is commented that hystero-epilepsy appeared to be much more commonly found on the continent than in England (Kindon, 1898).

The first appearance of the latinized English expression “Status Epilepticus” was in Bazire’s translation of Trousseau’s lectures in clinical medicine in 1868 (Trousseau, 1867). In this Trousseau states “You have heard of cases in which the attacks have lasted two or three days, and have terminated in death. This is the condition which has been termed status epilepticus at Bicêtre and Salpêtrière … characterised not by a single attack but a series of attacks.” He goes on to differentiate status from ordinary seizures, indicating that a different process is involved. “In the status epilepticus, when the convulsive condition is almost continuous, something special takes place which requires an explanation … it is no longer an attack of haut-mal [grand mal], but a different and special form of seizure, dependent on a peculiar irritable condition of the brain and spinal cord” (Trousseau, 1867).

It was recognized immediately by all the aforementioned authors that the condition often ended fatally, and the subject of mortality became an important topic of speculation in the early writings. Crichton Browne (Browne, 1873) writing of his experience with treating epilepsy in the West Riding asylum in Wakefield, stated that of 22 deaths in patients with epilepsy, 7 (32%) were due to status epilepticus and that “a considerable number of epileptics die in the status - indeed in this asylum, it is perhaps the most common mode of death in epileptics.” He goes on to say that he had only ever seen cases of status in patients with long-standing chronic epilepsy. The high mortality was reported by others—for instance, 50% mortality by Binswanger, 40% by Lorenz, and 33% by Clark and Prout, cited by Turner (Turner, 1907).

The condition in these early years was described almost entirely by alienist physicians from their asylum practice, and in this setting it was beginning to be realized that the condition was possibly not rare. Wood describing patients in an asylum in 1882 states “A third of the patients here are subject to epileptic fits, and many have twenty and sometimes more during the day, besides the status epilepticus into which many of them fall; so that I am frequently called to the wards of epileptics” (Wood, 1882). Following this, multiple isolated reports of status begin to appear in the literature.

In London in 1860 the first hospital dedicated to the study and treatment of neurologic conditions, the National Hospital for the Paralysed and the Epileptic, opened its doors in Queen Square in London, and it was here that Jackson, Gowers, and Turner treated patients with epilepsy and status epilepticus, and wrote on the subject. They brought to the subject the experience of more representative nonasylum ambulatory cases, and the condition was found to be rare. Gowers in 1881 wrote about status that “A large proportion of the cases however end fatally. Fortunately this severe degree of the status epilepticus is very rare, at any rate out of the asylums for the insane. No instance in which death occurred has come under my own observations” (Gowers, 1881). That status was a rare event outside of asylums for those with a prior diagnosis seems to have been widely held, as for instance shown by the report of Towbridge and Mayberry to the American Medical Association in 1891. The authors state that little attention has been given to the condition outside of asylums because it is rare in nonasylum practice, that it was the climax of the neurosis (with two stages—a convulsive one and a comatose one) and in the absence of any demonstrable lesion is likely to be fatal (Anonymous, 1891).

Today, status epilepticus occurs most commonly de novo, in patients without a history of epilepsy, as the result of acute brain injury—but interestingly, such cases do not seem to feature at all in the writings on status epilepticus until the 1960s. A rare exception was the fatal case report published by Rake who remarks “Would not this be a case of death in the status epilepticus, which Bristowe mentions as a rare termination; and was it not strange that the patient had never before shown any symptoms of this disease? His father and several brothers and sisters had died in fits” (Rake, 1888).

In 1901, Gowers presented statistics from the National Hospital. Of the 2,828 patients with epilepsy seen at the hospital, 38 had died and 12 deaths were directly related to epilepsy, 7 of which were due to status epilepticus. Gowers made, for the first time, the suggestion that most cases were “caused by the sudden cessation of the administration of bromides; the cessation of this controlling influence apparently allowed the convulsive tendency to burst forth with intense vigour” (Gowers, 1901; Hunter, 1959). This view of causation was often repeated in subsequent years, and argued by many since, most notably by Hunter (1959).

Status Epilepticus: A Clinical and Pathological Study in Epilepsy by L. Pierce Clark and Thomas Prout (1903/1904)

What has been described as the first phase of the study of status epilepticus, the phase of classical description (Shorvon, 1994) can be said to have come to an end with the publication of a series of papers published in 1903/1904 by L. Pierce Clark and Thomas Prout. Clark was a physician and Prout a pathologist in Craig Colony, an asylum in Sonyea in New York State. In these papers, a definitive and meticulous clinical and pathologic description of tonic–clonic status epilepticus is given (Clark & Prout, 1903/4). Their work was based on the study of 38 cases of status epilepticus, five cases of serial seizures or état mal de passage and four cases of status hystericus from the asylum. They defined true status epilepticus as follows: “Status epilepticus is the maximum development of epilepsy, in which one paroxysm follows another so closely that the coma and exhaustion are continuous between seizures.” This is usually associated with marked rise in temperature, pulse, and respiratory frequency. Presaging the work of Henri Gastaut 60 years later, they recognized that there were many varieties and equivalents of status as epilepsy. In reviewing the literature on status epilepticus, they noted that Bourneville tried to classify status epilepticus into three or four varieties and état de mal de passage into two categories, and latter category of which he viewed as an inevitable prelude to the onset of true status epilepticus.

Clark and Prout noted that there had been at least 300 reports of status epilepticus since its documentation in the early 19th century. One of the largest series was of 30 cases reported by Lorenz (1890) in Kiel. For the purpose of classification, they divided epilepsy into idiopathic and symptomatic. They recognized that different forms of status occur, for instance petit mal (absence status), focal motor, and grand mal (tonic–clonic) status epilepticus, and that was the predominant form of fatal status epilepticus. They were probably also the first to record that patients with symptomatic epilepsy were particularly likely to develop status and that the status epilepticus in symptomatic and idiopathic epilepsy were similar: “All symptomatic epilepsies dependent upon gross organic brain lesions, as abscess, tumour, etc are particularly prone to develop status, with which the majority die. In such, the status is usually designated as but a mode of death and is rarely elevated to the dignity of a disease per se, or even given great clinical prominence as a symptom-complex; the status pareticus being a signal instance of this viewpoint. Undoubtedly as there is a clear pathologic analogy between all convulsive phenomena, so the different manifestations of status resulting from different brain lesions must bear a certain close relationship to true status epilepticus.” They also recognized de novo status epilepticus, in the presence of brain injury, and were probably the first to do so.

As with previous authors, Clark and Prout concluded that epilepsy must become well established before status will supervene and they termed the event, in true fin de siècle style, as the “true climax of the disease and less a chance termination which by proper treatment could be avoided.” Status epilepticus was attributed as the cause of death in 50% of patients with epilepsy. Ominously, they go on to warn that “an epileptic is foredoomed to die of the status as the maximum development of the disease, of all possible causes such as intercurrent infections are removed.” This remarkably pessimistic view of prognosis in epilepsy possibly reflects their asylum practice.

With regard to cause, they like Gowers, list the too sudden withdrawal of sedatives, a third of reported cases arising directly or indirectly as a result, and the resulting status epilepticus they warn is almost incapable of control by a renewed administration of even the most powerful sedatives. In their series, in 32 of the 35 patients, status epilepticus was heralded by a steady increase in the paroxysmal frequency of the epilepsy in the preceding days prior to the onset of status epilepticus. These serial seizures or état de mal de passage were considered by Clark and Prout to be a form of pseudo-status, heralds of true status epilepticus, aborted, imperfect, or incomplete status periods, and the absence of such a herald in some cases is explained by the modulating effect of bromide therapy. As advocated by others, this period offers a window of opportunity for treatment prior to the onset of true status epilepticus.

As with Bourneville, they divided status epilepticus into two stages: the convulsive and the stuporous, with the latter being the resultant exhaustion from the former. A moderately severe episode was defined as not less than 30 h, with the majority of their case lasting between 2 and 9 days. Fourteen of 42 patients died, giving a mortality rate for their series of 33%, but overall there were 100 cases of status epilepticus, 14 of which were fatal, adjusting the mortality figure to 14%.

They also carried pathologic postmortem examination on seven patients. Main features reported were the extreme degree of chromatolysis and destruction of the large pyramidal cells of the third cortical layer. They also noted the very striking evidence of the destructive lesion in progress among the cortical cells, with the invasion of the cortex by leukocytes. Microscopically there was destruction of the nuclear membrane and the nucleus with the disappearance of many neurons, particularly from the second and third layers. They noted that neuroglia proliferation takes the place of the destroyed nerve cells, particularly in the outer cortical layer, and is proportional to the duration and severity of the epilepsy. Their findings did not support the theory that the primary pathologic changes in status epilepticus were vascular lesions, particularly in the medulla in cases of fatal status epilepticus (Weber, 1899). They conclude that epileptic fits are a destructive process and that the hereditary instability of the cerebral cortex is the real basis of the causation of epilepsy.

Prout and Clark were awarded the triennial prize of Columbia University for original research in June 1903, but the impact of their work was marginal. Indeed status epilepticus was largely ignored for the next 30 years, as a rare complication of chronic idiopathic epilepsy seen in asylums after too rapid withdrawal of bromides and later luminal (phenobarbital) (Hunter, 1959; Shorvon, 1994).

William Aldren Turner—Epilepsy: A Study of the Idiopathic Disease (1907)

Another important book from the point of view of the clinical aspects of status epilepticus was the landmark work by William Aldren Turner, Epilepsy: A Study of the Idiopathic Disease, published in 1907 (Turner, 1907). Turner was a founding editor of Epilepsia and an important figure in the early ILAE. His summary of the clinical importance of status brought the condition firmly into focus, and his was essentially a view of the condition from the perspective of mainline clinical neurology. The section in his book devoted to status epilepticus (4 of 270 pages) sums up very succinctly knowledge at the time, and in many ways the basic conclusions he draws about clinical features, causes, and outcome are very similar to those of today. He cites the definition of Clark and Prout (Clark & Prout, 1903/4) of status epilepticus as the maximum development of epilepsy. He commented that although many epileptics never develop status epilepticus, it is undoubtedly more common than generally supposed. In his series of 280 cases, 5% developed status epilepticus. The patterns he noted included status epilepticus as the first manifestation of epilepsy, as a recurrent phenomenon in established epilepsy, and as a recurrent event without other seizure types (he was probably the first to recognize these patterns). He also noted that status could be the result of sudden cessation of bromide therapy or precipitated by such factors as “strong emotional or psychical excitement, the puerperium, an acute inflammatory disorder, and a fall or blow upon the head.” He recognized that minor and major types occurred, although the former were more common, and as was usual at the time, he restricts his descriptions to what would now be called tonic–clonic status epilepticus. He noted too that the onset of status was usually “foreshadowed by an increase in the number of seizures of the customary type,” and when there was an abrupt onset this was often due to bromide withdrawal or some other acute causes. He clearly described the phases of status, including what would now be termed the phase of “subtle status.” He noted that the prognosis was grave, but not inevitably so, and in his own series of 28 attacks, the death rate was 10.7%.

1909–1969: Status Epilepticus in The First 50 Years of the International League Against Epilepsy (ILAE)

In 1909, the International League Against Epilepsy (ILAE) was formed in Budapest, and in tandem the journal Epilepsia was launched. This was the first neurologic subspecialty journal solely dedicated to the study of epilepsy. The prevailing view that status epilepticus was a rare anomaly of chronic epilepsy of little interest to epileptologists in general was reflected by the meager references to status epilepticus in Epilepsia in these early years. Case reports were published, for instance that of a case of fatal status epilepticus lasting 9 days associated with hyperpyrexia (day 4: 103.2°F) followed by unusually low temperature (day 9: 81°F) just prior to death (Ross, 1909). However, the first substantial paper in Epilepsia on status epilepticus was by William T. Shanahan. Shanahan was a major figure in the ILAE and on the American epilepsy scene. He was a president of the National Association for the Study of Epilepsy and the Care and Treatment of Epileptics (the main professional epilepsy group in America), and was the author also of the first statutes of the ILAE. His report, a review of the treatment of status epilepticus, was based on a presentation given at the meeting of the American association in Baltimore in 1914 (Shanahan, 1915). He followed Clark and Prout in describing status epilepticus as the climax of epilepsy, and divided it into three stages: the premonitory stage, the convulsive stage, and the comatose stage. Among the common causes of status epilepticus, he listed sudden stopping of sedatives taken over a long period, opium bromide treatment, and treatment of large doses of bromides. Relative constipation increasing to the point of obstruction is also listed as a frequent cause of status epilepticus. He noted that for those who recover from status epilepticus, there may be an exhaustion paralysis, which may be permanent. He gave a conservative estimate for the mortality of status epilepticus to be 20–25%, adding that any treatment to be of any value must be prompt and energetic.

The advent of the World War I seems to have halted most innovative work in the field of status and indeed of epilepsy in general. The ILAE went into hibernation until 1935, and Epilepsia ceased publication in 1915 only to resume again in 1937. Little interest seems to have been taken in the subject of status in this period. In 1924, Louis Muskens who one of the founders of Epilepsia, a member of its first editorial team and later Secretary-General and Vice-President of ILAE, for instance, published a major book on epilepsy in 1926, which went into several editions and was translated into English in 1928 (Muskens, 1928), but his work on status was slight and regressive. He considered status epilepticus generally to be due to the accumulation of toxins, as is the case in ordinary seizures, but status ensues when long-standing epilepsy has additionally resulted in “the weakening of certain organs.” As previously observed by others (Cameron, 1894), he remarks that should the patient recover from the episode of status epilepticus, he will be free of fits for a long time. He repeated the now familiar opinion that “status epilepticus almost always follows upon such an error as the complete cessation of the taking of bromide or luminal, when the patients have been long accustomed to these drugs.” He believed primary status epilepticus was rare, and indeed had never seen a case himself, that “It is highly probable that if the proper degree of care necessary for each case of epilepsy were given, status epilepticus might never occur” and that “probably there are no cases where there is not a long history of epilepsy” (Muskens, 1928).

There was little other published research in this period on status. One interesting report of urea concentration in cerebrospinal fluid (CSF), found this elevated in three fatal cases but normal in a fourth nonfatal case, and concluded that a raised urea was of grave import (Binyon & Fox, 1930).

S. A. Kinnear Wilson’s magisterial textbook of neurology was published in 1940 (posthumously, but written largely in the few years before this) (Kinnear Wilson, 1940), and became the standard textbook of its period. The clinical features of status were described in one page (of 1,836 pages). Wilson mentions that the condition is sometimes precipitated by too rapid a drug reduction, and that “not a few chronic demented epileptics die in status.” He does, however, clearly acknowledge the existence of absence status (before the description of Lennox) and includes Epilepsia Partialis Continua as a form of status. He commented too on the large number of seizures that could occur, without necessarily a poor outcome. As he wrote “Moderate attacks however numerous need not alarm; in the cases of a girl of 13 … a group of 3,231 major fits occurred in 17 days; of these 2,258 were observed in six consecutive days, being at the rate of one every 3–8 min. Despite this well nigh unbelievable record perfect recovery ensued.”

In the period after the World War II, the interest in status epilepticus increased. By now, the physicians writing on the clinical features of status were almost all neurologists practicing in settings other than asylum settings. The work of this period reflected a new focus on descriptive and statistical clinical research. A series of important clinical studies of the condition were published, focusing now more on cause and clinical associations. In Britain, Whitty and Taylor (1949) published a large study of status epilepticus, emphasizing the prognostic importance of duration, both prior to the initiation of treatment and of the status epilepticus itself: “In the fatal cases the interval between the onset of status epilepticus and the beginning of treatment was usually much longer than in the non-fatal cases, and the duration of status epilepticus was longer in the fatal cases than in the others…. The longer the fits continue unchecked the more probable is a fatal outcome.” In total there were 36 patients, 12 of whom died, giving a mortality rate of 33.3% (Whitty & Taylor, 1949). The concept of outcome related to duration seems to have been pioneered by these authors and forms the theoretical basis for all treatment protocols to this day. Causation and anatomic location were addressed in the paper by Janz, (Janz, 1964), then future ILAE President, based on 42 cases with localized brain tumors or injuries and status epilepticus (83% involving the frontal lobes), who noted both that status epilepticus was much more common in the symptomatic compared to idiopathic epilepsies and noted also that frontal lobe pathologies were more likely than pathologies in other areas of the brain to result in status epilepticus. These conclusions too have stood the test of time. He speculated on the possible cortical networks involved, commenting: “It also seems likely that the rather uninhibited recurrence of attacks which characterises status is somehow linked with a structural of functional interruption of frontothalamic fibres belonging to a nonspecific projection system passing from the reticular formation up to the cortex via the thalamus.” Better understanding of the etiology, epidemiology, and prognosis of status epilepticus in children (Aicardi & Chevrie, 1970), adults (Oxbury & Whitty, 1971b), and in the syndrome of isolated status epilepticus (Oxbury & Whitty, 1971a) was obtained in large case series in the respective populations published in 1970 to 1971. Hunter (1959) investigated mortality rates in Britain using the figures of the Register General from 1949 to 1956 (status epilepticus was indexed separately from this year), and found that more than one-third of the total deaths, of which epilepsy was a factor, were due to status epilepticus. Indeed in 1 year (1954), the number of deaths from status epilepticus in patients with epilepsy exceeded deaths from other causes. Moreover status epilepticus accounted for 51% of total deaths from epilepsy for patients inside mental hospitals and 38% for those outside. Looking at epileptic admissions to National Hospital, Queen Square, he found that 30 of 2,404 had status epilepticus (1.3%), of whom 22 had symptomatic epilepsy. In seven (23%), status epilepticus was precipitated by change in medication and in nine (30%) by intercurrent infection. No cause was found in 11 cases. Seven died, giving an overall mortality rate of 23%.

Aicardi and Chevrie reviewed 239 cases of status epilepticus in children (<15) over an 8-year period, noting that status epilepticus was the first ictal manifestation in the majority of cases (77%, 184). No cause for the status epilepticus was found in 53% (126) of cases, of which 53% (67) were associated with fever, underlining the importance of febrile status epilepticus in children. Overall mortality was 11% (27), half of which was attributable to the seizures and a morbidity of 37% (88) (Aicardi & Chevrie, 1970). In this study, Aicardi pointed out that the post-status hemiplegia and the other major morbidities of status epilepticus occurred only after prolonged seizures. He was the first to insist that status epilepticus—especially febrile status epilepticus—should, therefore, be treated with great urgency. This emphasis on treating status as an emergency is now universally accepted, but this was a major change in practice, a change that has probably saved many lives. Aicardi considers this paper on status epilepticus as his most important single contribution.

The pathologic and physiologic mechanisms of death in status were also the topic of renewed research. Meyer et al. (1955) reported a case of a 9-year-old child with a history of Still’s disease, during the course of which he unexpectedly developed status epilepticus followed by 3 days in a coma and pneumonia. Upon recovery he was profoundly demented and died 12 months later. Postmortem examination showed widespread damage, particularly in the temporal lobe and hippocampus, underlying the destructive nature of prolonged status epilepticus as previously discussed by Clark and Prout, (1903/4). A further case of a boy who developed status epilepticus 24 h after a trivial head injury and died, showed widespread but asymmetrical damage typical of anoxic damage. This raised the possibility that anoxia was the primary pathologic mechanism in status epilepticus (Small & Woolf, 1957).

Experimental studies of status were also initiated in this period. One notable investigation was the finding in cats with penicillin-induced status epilepticus, with complete muscle relaxation and artificial ventilation, which continued electrical activity in severe seizures was the cause of irreversible changes despite adequate ventilation. Pathologically severe cellular damage was found, and the authors concluded that anoxic brain damage was not the primary mechanism of destruction in status epilepticus as previously thought (Epstein & O’Connor, 1966). This was another important finding on which was based the future work of Meldrum and colleagues.

The impact of EEG on status epilepticus, Henri Gastaut and Les Colloques de Marseille 1962

The introduction of electroencephalography (EEG) into clinical practice was of course the major advance in the field of epilepsy in the first half of the 20th century, and had a profound impact on almost all areas of epilepsy; the ILAE was heavily involved in promoting this work. Status epilepticus was no exception, and EEG has been instrumental in helping define, classify, and elucidate basic mechanisms. Initially, however, EEG work was focused on other topics, and there was little or no reference to status in much of the earlier work, even up until 1950 (Williams, 1950). Petit mal status was defined by Lennox, then ILAE president, on the basis of the EEG in 1938, when he induced a case by the injection of insulin in his cousin, Ann, who had petit mal epilepsy and in whom studies of the effect of blood sugar on the EEG were being investigated (Lennox, 1960). The most detailed EEG studies of status had to wait for the collaborative efforts of Gastaut and colleagues a few years later. Henri Gastaut (see Fig. 1) was the President of the ILAE and was also ILAE Secretary General and Editor of Epilepsia at various times in the 1950s and 1960s. Gastaut’s work culminated in the Xth Marseille Colloquium, held in 1962, and led by Gastaut (Gastaut et al., 1962). This was the first major meeting held that was devoted solely to the study of status. At the meeting, 103 participants presented 237 cases with both clinical and EEG findings of abnormally prolonged or serially repeated seizures. A new and influential definition of status was proposed: “ a term used whenever a seizure persists for a sufficient length of time or is repeated frequently enough to produce affixed or enduring epileptic condition.” Although no duration was specified in the definition, Gastaut later specified a duration of 60 min to define status epilepticus. Another development of great importance coming from the colloquium was the concept, as Gastaut put it, that “there were as many types of status as there were types of epileptic seizure.” The International Classification of Seizure Type was another project of Gastaut at the time, and Gastaut and his colleagues drew the parallel between the classification of status epilepticus and this new seizure type classification. Gastaut had claimed that the term was prior to this confined to tonic–clonic status (as Bourneville had defined it); a claim not, however, entirely accurate, as there were already many references to other forms. Nevertheless at a stroke, Gastaut broadened the clinical range of status, which was a conceptual advance of great importance, although the yoking of the classification of status too closely to the classification of seizure type is to an extent artificial, and has in recent years proved too great a straitjacket. Gastaut had already published the first cases of “complex partial status” in 1958, and the inclusion of nonconvulsive and other forms of prolonged seizures into the framework of status epilepticus opened the way to the great expansion in research and interest in the topic over the next 30 years. The definition of status proposed at the conference was in fact included in the International Classification of Seizure Type eventually published in 1969/1970, but there mentioned only as an addendum (Gastaut, 1969, 1970), and also in the WHO Dictionary of Epilepsy (Gastaut, 1973), and the influential Handbook of Clinical Neurology and Handbook of Electroencephalography (Gastaut & Tassinari, 1975) and Clinical Neurophysiology, all written by Gastaut and affiliates (Roget et al., 1974).

Figure 1.


Henri Gastaut (front row, center) with participants at the 1964 Marseille Colloquium.

Treatment of Status Epilepticus

The treatment of status epilepticus before 1909

A list of treatments used in status epilepticus is found in Table 1. In Bourneville’s classic description of secondarily generalized status epilepticus in Marie Lamb at the Salpêtrière in 1874, “Treatment was given with sinapismes (a topical remedy with a base of mustard flour), lavement purgative and quinine sulphate—to no effect” (Bourneville, 1878), and up until this time, no really truly effective therapy existed.

Table 1.   A list of the some of the drug and physical treatments used in the treatment of status epilepticus during the period 1824–1973
  1. ACTH, adrenocorticotropic hormone; CSF, cerebrospinal fluid; IV, intravenous.

Drug treatments
 ACTH
 Aldosterone
 Amyl nitrate
 Amylene hydrate (rectal)
 Amyline choral (rectal)
 Amobarbital
 Amylobarbital (intracarotid)
 Atropine sulphate
 Bromide of potassium (injected into bowel)
 Bromide salts (various) (oral, rectal, hypodermic, intrathecal, IV)
 Camphor (subcutaneous)
 Chlordiazepoxide
 Chlomethiazole IV
 Clonazepam IV
 Chloral hydrate (rectal, IV)
 Chloroform (inhaled)
 Diazepam IV/IM
 Diethyl barbituric acid
 Donath’s solution (infusion)
 Digitalis (rectal)
 Hyoscine hydrobromate (hypodermic)
 Lignocaine IV
 Morphia/apomorphine (hypodermic)
 Oxygen inhalation
 Paraldehyde (rectal, IV)
 Pentobarbital
 Phenobarbital (hypodermic, IV)
 Phenytoin IV
 Procaine IV
 Quinine sulphate
 Scopolamine (hydodermic)
 Sinapismes (mustard plasters)
 Strophanthus (rectal)
 Suxamethonium IV
 Tribromethanol IV
 Tridione
 d-Tubocuraine IV
 Urea IV
Physical treatments included
 Cold douches or baths
 Dark room, with rest
 Lumbar puncture/CSF drainage
 Multiple enemata/free irrigation of the bowel
 Saline infusions
 Venesection

Perhaps the first efficacious treatment was the use of amyl nitrate, a vasodilator, the use of which in status seems to have been described first by Hamilton (1876) and also by Kempster in 1876: “Cases liable to attacks, where one fit followed another so rapidly that the unconsciousness continued for hours (the status epilepticus), were almost immediately relieved by the prompt use of the medicine, and the maniacal fury usually succeeding these attacks was entirely relieved in every case” (Anonymous, 1876).

This was also the time of the introduction of bromides, other strong sedatives, and anesthetics, and these were soon to dominate the treatment of status epilepticus, indeed right up until the 1950s. Gowers, writing in 1880 commented “In the status epilepticus, in which attacks occur with great frequency and severity, and where bromide, even in large doses was useless, I have found small hypodermic injections of morphia of great service” (Gowers, 1880). Other treatments of the time included amyl nitrate (Ireland, 1881; Robinson, 1896), bromide of potassium injected into the bowel (Beach, 1877), and a hypodermic injection of one-tenth of a grain of apomorphine (Latimer, 1889). Towbridge and Mayberry (Anonymous, 1891) recommended treatment with hypodermic injection of hydrobromate of hyoscine combined with sulphate of morphia. Inhalation of chloroform, which had been used as an anesthetic since 1847, was also adopted.

Clark and Prout divided treatment by stage. For the convulsive stage they advocated use of emergency treatment after the first six attacks, either by mouth or rectum. If the attacks continued, chloroform should be used and bromide and chloral continued by rectum, or (for bromides) by injection. They warn that only the minimum amount of sedation as is necessary to control the fits should be used. In the comatose period, the aim of treatment was to counteract the exhaustion and sedation of the convulsive period and to monitor for a possible return of seizures (Clark & Prout, 1903/4).

An anonymous (1905) editorial on the treatment of status epilepticus (JAMA), probably summarizes the treatment approaches of advanced physicians of the time: “As gastrointestinal disorders, especially constipation, often act as determining causes of the convulsive seizures, the closest attention should be given to the quantity and the quality of the food and the state of the digestive organs and their activities.” Alcohol, use of morphine, emotional disturbances including sexual excess, and sun rays were to be avoided. After gastrointestinal disturbance, an abrupt withdrawal of the bromides was the next most important cause of status epilepticus, the treatment consists in the administration of bromides by mouth or by rectum. They advise that the seizure should be brought to an end as speedily as possible and that the patient should be shielded from light and noise and a high enema given. Should these measures fail, then resort may be to add to sedatives (dormiol, opium preferably administered per rectum) or inhalation of chloroform. A long cold bath or douche may be given to treat high temperature, whereas venesection may also be beneficial. Venesection has previously been advocated for the treatment of severe epilepsy and status epilepticus (Pye-Smith, 1891; Fox, 1922).

The treatment of status between 1909 and 1958: The period of bromide, barbiturate, sedatives, and anesthetics

In 1910 Turner wrote “If a gradual increase in the number of fits suggests the onset of status epilepticus, the dose of bromide salt should be doubled, and 10 or 15 grains (grs) of chloral hydrate added and prescribed every 4 or 6 h. During the height of a status attack nothing will arrest the seizures except the inhalation of chloroform. Hydrobromate of hyoscine (1/75–1/50 grs) may be of temporary use. In the after stage of stupor careful nursing, abundance of light nourishment and tonics are essential.”Turner and Street (1910) recognized in severe cases that “no remedy is of greater benefit than the inhalation of chloroform, given up to complete anaesthesia,” and in milder cases bromide 20 grs and chloral 10 grs can be given repeated very 2–3 h. They also mentioned that that hypodermic or intrathecal bromide were advised by some, the latter in a dose of 10 cc of bromide diluted in sterile solutions of 30 grs per ounce.

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Contemporary advertisement for diazepam.
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The introduction of phenobarbital in 1912 was of course a landmark in epilepsy therapeutics, and the drug was also soon recognized to be of great assistance in status, although not superseding bromides or other sedatives, which continued to be widely administered. The first reference to the use of intravenous phenobarbital as a method of choice was by Patterson, Damon, and Levi for the treatment of status epilepticus in Sonyea in 1926, noting that the intravenous method was the most rapid in bringing about therapeutic effects (Patterson et al., 1926). In 1928, Pratt mentioned that chloroform anesthesia together with double doses of HMC No1 or chloral enema (30–60 mg) were the treatments relied upon at the Woodstock colony in Ontario (Pratt, 1928). Binyon (Binyon & Fox, 1930) treated those in status epilepticus with 1–3 g of luminal sodium (phenobarbitone) hypodermically in addition to repeated enemata and bromide. Other barbiturates progressively introduced after World War II, and given parenterally, were all used in status epilepticus.

In the early part of this period, other drugs were also popular. These included hypodermic injections of scopolamine (0.1 or 0.2 mg) (1922) and atropine sulfate at high doses (Dorner, 1915) (for severe status epilepticus—mild and moderate status epilepticus being controlled by dietary rules). The most important though was paraldehyde. This had been in use in clinical practice as a sedative (and to lesser extent as a anticonvulsant) since 1874, but its unique place in status seems first to have been reported in 1914 (Collier, 1914).

Nonpharmacologic therapies were also universally employed. To modern eyes, the emphasis on enema and bowel irrigation seems bizarre, but the benefits of these approaches were universally accepted. In 1915, Shanahan stated that the most urgently indicated procedure in status was a free irrigation of the lower bowel, using gallons of water given at frequent intervals to completely empty the bowel of fecal matter (Shanahan, 1915). After the bowel irrigation, choral hydrate or amylene hydrate should be given by enema in sufficient quantity for sedation. Several authorities also advocated the use of draining of the CSF by lumbar puncture for the treatment of status epilepticus (Drew, 1921). Muskens in 1926 wrote that treatment of status epilepticus was best achieved by “placing the patient in a perfectly quiet, darkened room; by administering enemata to empty the rectum and colon, and the administration of bromide choral, or better still, dormiol, per rectum (dormiol 10 parts, water 150 parts) … amylene hydrate (Alt) is also good” (Muskens, 1928). Muskens also lists lumber puncture, infusion with saline or ‘Donath’s solution and venesection, and Clark and Prout’s medicinal remedies.

The descriptions of the treatment of status in the textbook of Kinnear Wilson (Wilson, 1940) provide a snapshot of advanced practice in the 1930s. As already noted by other authors, he realized that status was often caused by too rapid drug withdrawal, and in these cases large doses of bromide and chloral (60 grs and 30 grs, respectively) per rectum every 4–6 h should be used. Other methods of treatment mentioned are hypodermic injection of luminal sodium (1–3 grs), with the intravenous route being the most preferable (Patterson et al., 1926), or bromide (10%). Repeated drainage of the spinal fluid by lumbar puncture may sometimes be beneficial, whereas intrathecal administration of bromide may also be used. He believed that chloroform was only of temporary benefit but should be used early. Other drugs mentioned included hyoscine hydrobromide (grs 1/75 or 1/50) or paraldehyde in doses up to 8 dr and mixed with an equal quantity of olive oil and given per rectum (a method still employed). As he also commented “venesection and saline injections may also be used in the robust.”

The treatment of status epilepticus after 1958: Phenytoin and the benzodiazepines

Within a year of the death of Kinnear Wilson, phenytoin was introduced into clinical epilepsy practice, and this of course was to change epilepsy therapeutics totally. There was initially no parenteral formulation, and this was used only after a parenteral form had been developed by the pharmacy department of the Massachusetts General Hospital for use in convulsions during and after neurosurgical operations, when oral therapy was impossible. The first reported use of intravenous phenytoin was by Murphy and Schwab (1956), who described the results of 5 years use of intravenous phenytoin in the treatment of seizures associated with neurosurgical procedures as well as in three patients with continuous seizures with no side effects noted. Carter (1958) published a series of 71 cases of status epilepticus in 49 patients in the Florida Farm Colony treated with intravenous phenytoin. He found that a dose of 250 mg controlled most episodes, with some requiring a second dose of 250 mg. In 121 episodes of status epilepticus in another 85 patients, 97 were controlled by one intravenous dose of 250 mg of phenytoin, whereas a further 17 episodes were controlled by a second intravenous dose of 250 mg. The remaining seven episodes required the addition of a further drug. No major side effects were noted. In a case series of 11 children with continuous seizures or status epilepticus treated with intravenous phenytoin (McWilliam, 1958), the effective dose ranged from 25–500 mg and was effective within 10 min.

The primacy of phenytoin in the treatment of established status epilepticus had to wait, however, for several decades, and other drugs remained in widespread use. Paraldehyde particularly was a popular choice. Whitty (Whitty & Taylor, 1949) recommended the use of intramuscular paraldehyde 5–10 ml in adults and 2–3 ml in children to control status epilepticus, a therapeutic regimen recommended by others (Nattrass, 1949), and Denis Williams at the National Hospital Queen Square wrote in 1958 that paraldehyde (5 ml intramuscularly) repeated every 2 or 3 h until attacks had stopped was probably the safest drug. Intravenous anesthesia could also be used if a positive-pressure apparatus was available (Williams, 1958). Lennox, writing in 1960, also believed paraldehyde, given either by rectum or into a muscle or vein was an excellent choice for the treatment of status epilepticus because of its rapid excretion (Lennox, 1960).

A report of the effectiveness of intravenous lignocaine as an anticonvulsant in three patients with status epilepticus (two focal, one generalized) was published the same year. It was found that the anticonvulsant action had a linear relationship to the logarithm of the dose used (Taverner & Bain, 1958). A series of case reports was published in 1959–1961 of status epilepticus controlled by muscle relaxants (suxamethonium) (Evanson, 1959) and d-tubocurarine (Nisbet, 1959). The rationale at the time was to prevent presumed anoxic brain damage due to prolonged seizure activity. James and Whitty (1961) published a case report of a woman with refractory status epilepticus treated with curarization and artificial ventilation. Using a portable EEG, the cerebral epileptic discharge was followed and the level of sedation was managed based on the EEG findings, demonstrating the enormous value of EEG monitoring with regard to treatment of prolonged status epilepticus. In 1963 Bladin published a series of cases of focal status epilepticus (13) secondary generalized status epilepticus (3) and generalized fits with inconsistent focal signs (6), treated with intracarotid amylobarbital (dosage 100–450 mg) with excellent results (seizure control in 19 of 22 cases) (Bladin, 1963). At the time, too, the various different forms of barbiturate were all widely used in status epilepticus.

One treatment that was reported to be highly effective, but which did not seem to be taken up widely, was the use of intravenous urea. Carter (1962) published a series of cases of status epilepticus in 57 patients at the Sunland Training Center in Florida treated with intravenous urea (Urevert) at a dose of 1.5 g/kg started usually within 10 min of the initiation of the status epilepticus. Control was achieved in 11 patients 3 min after the beginning of the infusion, whereas the average time to achieve control overall after commencement of the infusion was 5.2 min. Only six patients remained in status more than 6 min and only three patients for greater than 10 min, all of whom responded to a second infusion. There was no reported morbidity or mortality.

Of course, from the point of view of status epilepticus, the most important new discovery, and the one that ends this review of the history of therapy, was that of the benzodiazepines. Chlordiazepoxide (Librium) was the first to be licensed in 1960 and this was followed by diazepam (Valium) in 1963. The value of intravenous benzodiazepine in status epilepticus was rapidly recognized. By 1965, Gastaut (Gastaut et al., 1965) could write of diazepam in the treatment of status epilepticus, that it was: “outstanding for the reliability and rapidity of action, which together make it a more effective drug than others we have used in the past, among which have been: injectable Phenobarbital, Somnifene, chloral hydrate, Eunoctal, Sodium Bromide, Rectanol, Novocain and Hemineurin.” The effects were noted in 15 cases of tonic–clonic status epilepticus. Gastaut was even more excited by the effects (complete resolution) among six cases of generalized absence status epilepticus. “In this group, the most spectacular and dramatic results were obtained, signs disappearing often after only 5–7 mg Valium had been injected intravenously. We have never obtained such results in the past, although we have used a variety of drugs, including: Tridione, Pentothal, Eunoctal, Hemineurin, ACTH and aldosterone.” Gastaut reported the use of bolus doses, intramuscular doses, and also intravenous infusions up to 100 mg/day, without any respiratory or cardiac side-effects (although how he avoided respiratory depression is not clear). Valium, it was proclaimed “is the drug of choice for the emergency treatment of all cases of status epilepticus.”

Browne and Penry (1973) reviewed the use of diazepam in status epilepticus. Thirty-five articles were found to have been published reporting 439 patients with various forms of status epilepticus (although interestingly they failed to record Gastaut’s papers on the topic). Lasting control was found in 83% of 30 cases absence status epilepticus, 73% of 103 cases of focal motor status epilepticus, and 68–74% of 126 cases of primarily and secondarily generalized tonic–clonic status epilepticus. It was reported by then that most authorities used diazepam as first-line therapy [for instance Carter and Gold (1969); McMorris and McWilliam (1969); Wojcik (1971); Couch (1971)], but the dangers of respiratory and hypotension were recognized and several dissented from this view (Baird, 1970).

Browne and Penry largely ignored clonazepam in their review. This was a very American position, as the drug was not licensed in the United States at that stage. It had, however, been in use since 1963 in Europe, where it was widely considered to be superior to diazepam. In 1971, Gastaut et al. reported the treatment of SE with clonazepam (Ro 5-4023), “a new benzodiazepine—more active than diazepam.” Thirty-nine cases were reported in which the status epilepticus was controlled in all but one, despite earlier unsuccessful therapy with phenobarbital (up to 120 mg) and diazepam (up to 30 mg). Gastaut was again enthusiastic: “We do not hesitate to affirm that Ro 05-4023 is by far the most effective agent which we have at present for the treatment of status epilepticus of whatever form or aetiology” (Gastaut et al., 1971). It was as a result of such reports that helped establish the benzodiazepines (especially diazepam and clonazepam) as the first-line treatments for status epilepticus at the beginning of the 1970s, although it was argued by some that paraldehyde should remain the first-line treatment (Whitty & Oxbury, 1972).

Conclusions

The history of status epilepticus outlined in this paper ends in 1973. As mentioned in the introduction, this time was a jumping-off point for status epilepticus, which in the subsequent three decades was to assume a central importance in the field of experimental and clinical epilepsy research. An outline consideration of this period was succinctly given by Meldrum recently (Meldrum, 2007), and the major achievements of these years rather overshadow the more modest growth of knowledge in the previous 150 years. Treatment with benzodiazepine, phenobarbital, phenytoin, and anesthesia was well established by 1973, and has remained to this day the bulwark of therapy, but the current protocol-driven regimens had to wait for the Veterans trial and for a further decade to develop. A new phase of pathological and experimental research of status epilepticus was initiated in the following years. Despite these advances, however, status epilepticus today remains a feared and hazardous condition for which therapy is not uniformly successful. Newer therapies are now, in 2009, currently under development and with luck in the next decade, major improvements in therapy will accrue from the intense current experimental and clinical work in this area.

Acknowledgment

Disclosure: The authors declare no conflicts of interest.

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