The historical evolution of, and the paradigms shifts in, the therapy of convulsive status epilepticus over the past 150 years

Authors


Address correspondence to Simon Shorvon, UCL Institute of Neurology, Box 5, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, U.K. E-mail: s.shorvon@ucl.ac.uk

Summary

The evolution of the treatment of convulsive status epilepticus since the mid- nineteenth century is outlined. Therapy has been advanced not only by the use of new drugs, but also by advances in the approach to therapy. The major pharmacologic developments were the introductions of bromide, anesthetics, barbiturate, phenytoin, paraldehyde, chlormethiazole, and the benzodiazepines. Throughout this period, the emphasis of therapy was on “sedation” and anesthesia, and the development of technologies for safe anesthesia in the postwar years were an important step. Since 1970, changes to the approach to therapy have been more important than any pharmacologic advance, and it is only recently that new drugs have been introduced into the therapy of status epilepticus. We may now be on the threshold of significant new paradigm shifts.

A study of the historical evolution of therapy in status epilepticus helps put in context the current position of therapy and the reasons for the current approach. It is convenient to date the history of modern therapies to the mid-nineteenth century, for up until this time, the therapy of epilepsy was essentially generic and similar to that of many other medical conditions. The list of Delasiauve is a useful summary of contemporary approaches, with categories of therapy divided into the following: (1) debilitating therapies (such as bleeding, tepid baths); (2) evacuant therapies (including emetics and purgatives); (3) sedative therapies (including ether); and (4) specifics (including valerian and opiates; Hunter, 1959/60; Shorvon, 1994; Neligan & Shorvon, 2009). From the mid-nineteenth century, however, a series of advances took place that were, in effect, paradigm shifts in the treatment of status epilepticus.

Early Antiepileptic Drugs in Status epilepticus

The bromides were the first strikingly effective antiepileptic drugs, and their introduction in the 1860s coincided with the first detailed descriptions of status epilepticus and, for the first time, the differentiation of “status epilepticus” as a distinct entity from the rest of epilepsy. At this time, it was also realized that inducing “sedation,” often to the level of anesthesia, was the best approach to the treatment of status epilepticus, and this is still a predominant assumption. The antiepileptics used included bromide given orally, hypodermally, rectally, or even by direct injection into the stomach, as well as amyl nitrate, apomorphine, atropine, chloral, chloroform, ether, hyoscine, morphia, opium, quinine, strophanthus, and valerian. It is interesting to note that most of these drugs are γ-aminobutyric acid (GABA)ergic in action, and GABAergic drugs are still today first-line therapies. Gowers, writing in 1881 commented: “In the status epilepticus, and where bromide, even in large does was useless, I have found small hypodermic injections of morphia of great service.” Turner (1907) wrote: “During the height of a status attack nothing will arrest the seizures except the inhalation of chloroform.” Physical therapies were also advocated, including the use of enemata, cerebrospinal fluid (CSF) drainage, cold baths, and venesection. At the turn of the century, there was a strong emphasis on cleansing the bowel, and Shanahan (1915), for instance, stated: “the most urgently indicated procedure in status is a free irrigation of the lower bowel, using gallons of water given at frequent intervals to completely empty the bowel of fecal matter. After the bowel irrigation, choral hydrate or amylene hydrate should be given by enema in sufficient quantity for sedation.” Clark and Prout (1904) gave a very detailed account of their approach to treatment, which included dividing therapy into the prodromal, convulsive, stuporose, and postictal periods, and with different approaches to treatment in each. Theirs was an approach very similar to that employed today, and indeed it is clear that many of the basic principles in the clinical management of status were established by this time.

Barbiturates and Anesthesia

The introduction of intravenous barbiturates was the next paradigm shift in the approach to therapy. The first barbiturate to be used was somnifene, introduced in 1921, and then hexobarbitone in 1932 and thiopentone in 1934. The first reference to the use of intravenous phenobarbitone was in 1923. Pentobarbital was introduced in the 1930s, but used then largely in veterinary medicine (and later, as well as for status, also for euthanasia and capital punishment!). Barbiturates were used initially in subanesthetic doses, and subanesthetic phenobarbital remains the mainstay of treatment for established status to this day in many countries and institutions.

Also used as anesthesia were ether, nitrous oxide (discovered in 1772) and chloroform (discovered in 1831), at least since 1860, and the potential for anesthesia was well recognized throughout this period. The anesthesia was dosed at that time to the level of induction of “twilight sleep,” and clearly there were dangers in this approach without the paraphernalia of modern intensive care. However, the introduction of direct laryngoscopy in the years before the World War I, and then of positive pressure ventilation in the years after World War II, allowed deeper anesthesia to be given. The use of barbiturate anesthesia in status epilepticus became widespread in routine clinical care when curarization, intravenous anesthesia, and positive pressure ventilation were possible (by the late 1950s). Intravenous propofol was introduced in 1977 and intravenous midazolam in 1978. Propofol, midazolam, and thiopental/pentobarbital remain the anesthetics of choice throughout the world today in the treatment of refractory and superrefractory status epilepticus.

Phenytoin, Paraldehyde, Benzodiazepines, and Other Antiepileptics: 1940–1970

Phenytoin was first used by intravenous injection in status epilepticus in 1958, and is still widely used today. However, in these years, paraldehyde introduced earlier was still the most commonly recommended subanesthetic antiepileptic (and from the 1950s onward also in larger doses, given intravenously, as an anesthesic). It was highly effective, and Lennox, for instance, in 1960, wrote that paraldehyde is: “The drug of choice in status epilepticus … by rectum, muscle or vein.” It has fallen out of favor now, largely because of the inconvenience of its administration and storage, but remained in general use well into the 1980s and in pediatric practice until the last 10 years. I remember in the 1970s using intravenous paraldehyde with darkened glass bottles and glass tubing in complicated regimens on the medical wards. Chlormethiazole (hemineurin) given by continuous intravenous infusion was also commonly used and highly effective. With the use of these antiepileptic and anesthetic drugs, physical therapies of status epilepticus fell from favor.

The next major paradigm shift in therapy was the introduction of the benzodiazepines, a class of drugs that would eclipse the effects of all other antiepileptics. The first benzodiazepine was introduced into clinical practice for anxiety and then epilepsy in 1960. The first report of benzodiazepine use in status epilepticus was in 1965, when Gastaut et al. (1965) described the treatment of status epilepticus with diazepam as: “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.” And by 1971, Gastaut wrote of clonazepam: “We do not hesitate to affirm that [clonazepam] 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). The use of rectal diazepam was also rapidly popularized and became standard out-of-hospital therapy for status epilepticus by the mid-1970s. The use of benzodiazepines such as lorazepam, diazepam, clonazepam, and midazolam, as first-line therapy in status remains to this day universal practice.

Advances in Therapy Since 1970

Surprisingly, and despite the enormous increase in the range of drugs for chronic epilepsy, the drugs and drug classes used in the therapy of status epilepticus have remained largely unchanged, at least until the introduction in the last 5–10 years of intravenous levetiracetam and valproate, although the exact place of these two newer drugs still remains uncertain. The type of drug used may not have changed much, but in recent years there have been very important advances in the principles and approaches to therapy, and these have been extremely important in improving management and outcome. These therapeutic advances have been predicated on a much greater understanding of the molecular, physiologic, and basic science of status epilepticus.

Among the more important developments in the therapy of status epilepticus since 1970 are (this list is illustrative not exhaustive, and represents some of the advances which, to the author, seem to have contributed most to the therapy of SE in clinical practice):

  1. The recognition that status epilepticus causes cerebral damage via excitotoxicity and that early therapy is important in preventing this brain damage (derived from the experiments of Meldrum and colleagues in the 1970s; Meldrum & Brierley, 1973; Meldrum et al., 1973; Meldrum, 1991 and since then the subject of a hugh literature).
  2. The recognition that urgent therapy of febrile status will prevent longer-term neurologic damage, largely through the work of Aicardi and his colleagues in the 1970s (Aicardi & Chevrie, 1970).
  3. The first trials and widespread adoption of rectal diazepam (Knudsen & Vestermark, 1978) for out of hospital therapy of acute seizures. Also, the recognition of the importance of receptor trafficking and its implications for urgent drug therapy.
  4. The use of blood level monitoring of phenobarbital and phenytoin, particularly for the control of dosing in status epilepticus (in the 1970s).
  5. The rapid advances in neuroimaging and clinical investigation to improve the detection of the underlying causes of status epilepticus, and the recognition that the effectiveness of treatment is dependent to a great extent on underlying cause (1980s onward).
  6. The development of ITU technologies and therapies for the care of patients anesthetised for long periods of time (1990s onward; Walker et al., 1995).
  7. The first staged protocols for the treatment of SE, dividing the therapy of the condition into early, established, and refractory stages, and the recognition of the “premonitory phase” (early 1990s; EFA Working Group on Status Epilepticus, 1993; Shorvon, 1994).
  8. The first randomized-controlled trial (RCT) in status epilepticus (the Veterans Study; Treiman et al., 1998) comparing diazepam/phenytoin, phenytoin, phenobarbital, and lorazepam.
  9. The widespread introduction of buccal midazolam as out of hospital treatment (following the study of Scott et al., 1999; McIntyre et al., 2005).
  10. Other large scale RCTs—notably the study comparing lorazepam, diazepam and placebo in an out-of-hospital setting (Alldredge et al., 2001) and the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) study comparing intravenous lorazepam and intramuscular midazolam (Silbergleit et al., 2012).
  11. The introduction of the concept of superrefractory status epilepticus and treatment protocols for therapy at this stage (Shorvon & Ferlisi, 2011).

Conclusions

A number of additional points are apparent from this history:

  1. The delineation of a disease is a stimulus to differentiation of therapy.
  2. The specific therapy of status epilepticus has been largely with sedatives and anesthetics, and many of the widely used drugs have been GABAergic in action. This general approach has not changed in 150 years.
  3. Most of the conventional drugs used in status epilepticus today have been in use for many decades, and advances in pharmacologic therapy have rather lagged behind advances in basic science and other clinical aspects. This may be partly because the pharmaceutical industry does not see the development of new drugs for status epilepticus as an important market.
  4. Advances in general care (artificial ventilation, ITU care, and so on) have been important.
  5. Many important recent advances have been in treatment approaches and in the evaluation of therapy (for instance—an emphasis on early treatment, staged protocols, buccal therapy, and RCTs) rather than the introduction of any new drugs.

In the last decade, however, there are evolving therapies, which open the hope for new treatments, and which if successful would be paradigm shifts; these include gene therapy, optogenetics, use of antagomirs, and new biochemical targets. It is possible that we are on the edge of major new advances in therapy.

Acknowledgments

The work was partially undertaken at UCLH/UCL a proportion of the funding from the UK Department of Health's NIHR Biomedical Research Centres' funding scheme.

Disclosure

The author has no conflict of interest to declare in relation to this paper.

The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.

Ancillary