Long-Term Sequelae of Status Epilepticus

Chapter 65

Shlomo Shinnar

Thomas L. Babb

Solomon L. Moshé

Claude G. Wasterlain

Introduction

Status epilepticus (SE) is a common neurologic emergency that can result in significant morbidity and mortality. Convulsive status epilepticus is the most common and potentially detrimental form of status, but long-term sequelae have been reported even following nonconvulsive status. Three major population-based prospective studies investigated the epidemiology of SE. The annual incidence of SE around Richmond, Virginia, was 41/100,000 individuals.³⁷ It was 27/100,000 for young adults and 86/100,000 for the elderly. The mortality rate was also higher in the elderly: 14% for young adults and 38% for the elderly, but only 3% in children. The annual incidence from two prospective studies in Europe was 17.1/100,000 in Germany⁷⁶ and 10.3/100,000 in the French-speaking part of Switzerland.³¹ These findings are close to the incidence of 18.1/100,000 found in an early retrospective study of SE from 1965 to 1984 in Rochester, Minnesota.⁷²

It is estimated that, in the United States alone, status epilepticus affects 100,000 to 150,000 individuals each year, approximately half of whom are children. In >50% of the cases, there is no prior history of seizures.⁴⁰^,⁶⁷ Status epilepticus can occur either as part of an established seizure disorder or in the context of an acute illness. Approximately 10% of children and adults who have epilepsy initially present with status epilepticus.¹⁵^,⁴⁰^,⁶⁷^,¹⁴²

In the past, status epilepticus was associated with a high morbidity and mortality. This has changed dramatically, especially in children. Recent clinical data (see Chapter 126) indicate that with proper treatment, the acute morbidity and the mortality of status per se is quite low, particularly in children. The adult data still show a significant morbidity and mortality, much of which is related to the underlying etiology.³^,³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁹²^,¹⁶⁶^,¹⁷¹ This chapter reviews the potential long-term sequelae of status epilepticus with an emphasis on the issue of whether status epilepticus results in a chronic seizure disorder. The old definition of status epilepticus was a condition in which epileptic seizures are sufficiently prolonged or repeated at sufficiently brief intervals to produce “an unvarying and enduring epileptic condition.”⁶⁰^,¹²⁶ More recent data suggest that if this occurs in humans, it is not very common. In this context we also review the association between status epilepticus, particularly in early life, and mesial temporal sclerosis.

Cognitive Deficits Following Status Epilepticus

In animal models, status epilepticus has been associated with neuronal changes, particularly in the adult animals.³²^,⁹⁵^,⁹⁶^,⁹⁷^,¹²⁶^,¹²⁷^,¹³¹^,¹³²^,¹⁵⁷^,¹⁵⁸ In humans, chronic intractable seizure disorders have been associated with cognitive deficits and in some cases even intellectual decline.³⁸^,⁵⁴^,¹²⁵ Isolated case reports of cognitive impairment following status epilepticus, whether convulsive or complex partial or even absence, are frequent,⁴¹^,¹³⁵ but none gives a sense of how commonly this occurs. In an entity associated with a significant morbidity and mortality, one would expect that cognitive impairment might occur. However, much of the morbidity and mortality of status epilepticus is associated with the precipitating acute neurologic insult.³^,³⁶^,³⁹^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁶⁶^,⁹²^,¹¹⁶^,¹⁶⁶^,¹⁷¹ The morbidity and mortality have dramatically declined over the last 50 years, especially in children, and other sequelae may have decreased as well.²^,³^,⁴^,⁷^,³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁹²^,¹²⁷^,¹⁶⁶^,¹⁷¹ Therefore, the high rate of adverse sequelae reported in the older series are probably not representative of the current reality.³⁹^,⁴⁰^,⁶⁴ In this section we address the issue of whether status epilepticus per se results in long term-cognitive impairment.

To answer this question, we need to identify the appropriate group of patients. This turns out to be a very difficult task. Status epilepticus is often seen in the context of an acute brain insult such as trauma, stroke, or encephalitis.³^,³⁹^,⁴⁰^,⁹² In this setting, it is difficult if not impossible to differentiate cognitive impairment due to prolonged status epilepticus from that caused by the acute brain injury itself. Status epilepticus also occurs in the context of chronic intractable epilepsy. In this setting it may be difficult to separate the effect of status epilepticus from the cumulative effects of many briefer seizures. Ideally, one would look at patients who had an isolated episode of status epilepticus near the onset of their epilepsy. This is a not an infrequent occurrence. Approximately 10% of patients who present with a first unprovoked seizure or with newly diagnosed epilepsy present with status epilepticus.¹¹^,¹⁶^,⁶⁴^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁹¹^,¹³⁹ However, very few of these patients have had neuropsychological testing before their episode of status. Thus, when a subtle deficit is found, it is difficult to know whether it was a result of status or preexisted. These considerations apply to both adults and children. In children, there is the additional difficulty that status epilepticus most often occurs in very young children, with half the cases under age 15 years occurring under age 3 years.⁹² At this young an age it is very difficult to get an accurate estimate of premorbid intellectual function unless the child was very severely impaired.

The data regarding cognitive impairment following status epilepticus were reviewed by Dodrill and Wilensky.³⁹ They excluded case reports and reviewed 14 studies of status.³^,⁷^,²⁹^,³⁸^,⁴²^,⁴⁶^,⁴⁷^,⁴⁸^,⁵⁸^,⁵⁹^,⁶⁶^,⁸¹^,⁹²^,¹¹⁷^,¹²⁷ They noted that most studies are of children, and few studies of children or adults used any formal psychological testing. In addition, many studies were retrospective. Of the 14 studies reviewed, the more recent and prospective ones were the ones that reported the lowest morbidity, including cognitive outcomes. This may be attributable to less skewed patient samples in prospective

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studies, an improved ability to identify etiologies (e.g., some older studies included cases of meningitis in the category of febrile status epilepticus), and perhaps improved treatment in the modern era.

There are some excellent prospective data on adults. Dodrill and Wilensky performed complete neuropsychological testing on 143 adults on two occasions 5 years apart.³⁹ Of these, 9 had a definite episode of status epilepticus in the 5-year period, including cases of both generalized tonic–clonic status and complex partial status. These were compared to matched controls that had not experienced an episode of status in the 5-year period. The group with status epilepticus had lower IQ scores and performed worse on a variety of cognitive measures. However, some of these differences were present at the baseline testing prior to the episode of status. This is consistent with the epidemiologic data that status epilepticus is more common among those who are neurologically abnormal.⁴⁰^,⁶⁶^,⁶⁷^,⁶⁸^,⁹² The authors concluded that most investigators described at least a few adverse changes attributable to SE rather than to underlying neurologic disease. However, in general, status epilepticus has only a modest adverse effect on cognitive abilities and in many individuals no effects are discernible.³⁹

The data on children are even more difficult to tease out. However, data from the National Collaborative Perinatal Project (NCPP) suggest that status epilepticus per se has few if any adverse effects on the young child. Ellenberg and Nelson examined 27 children with febrile convulsions lasting >30 minutes and found no differences in cognitive function at 7 years of age between them and their siblings.⁴⁷ They also found no evidence of decline in cognitive function in children with onset of epilepsy between ages 4 and 7 years who had cognitive testing as part of the NCPP at ages 4 and 7 years.⁴⁸ The group included 8 children who experienced status. Dunn⁴⁶ and Maytal et al.⁹² also found few long-term sequelae following status epilepticus in children unless it was associated with an acute or progressive central nervous system (CNS) insult. Animal data also suggest that the immature CNS, while more susceptible to developing status epilepticus, is more resistant to adverse sequelae.⁶^,²¹^,²⁷^,³³^,⁶⁵^,⁷³^,⁷⁴^,⁷⁵^,⁸³^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹¹²^,¹¹⁶^,¹⁵⁰^,¹⁵¹^,¹⁵²^,¹⁶⁷^,¹⁶⁸

In summary, there are case reports that document the occurrence of cognitive deficits following status epilepticus in both children and adults. These deficits may occur not only following convulsive status, but also following complex partial status and perhaps absence status. However, in large studies the morbidity of status epilepticus is primarily a function of the underlying etiology. Patients with status epilepticus are more likely to have had prior cognitive deficits. The incidence of demonstrable cognitive deficits following an episode of status appears to be low. More studies are needed to address this issue.

Hemiconvulsion-Hemiplegia-Hemiparesis Syndrome

A particular neurologic syndrome frequently found in the older series of convulsive status in children was an acquired hemiplegia, the so-called hemiconvulsion-hemiplegia-epilepsy syndrome (HHE).³^,⁵⁹^,⁶¹ In one series, the syndrome was present in 25 of 79 children with convulsive SE lasting >1 hour.⁵⁹ The association is well established in the older literature.³^,⁵^,²⁸^,⁵⁹^,⁶¹^,¹²⁶ These cases of acquired hemiplegia were also almost invariably associated with subsequent intractable seizures.

However, more recent studies report not only a much lower acute morbidity and mortality of status epilepticus,³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁶⁷^,⁹²^,¹⁶⁶^,¹⁷¹ but also a lower rate of adverse sequelae. The syndrome of HHE is notably absent from studies of status epilepticus over the last two decades.³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁶⁷^,⁹²^,¹⁶⁶^,¹⁷¹ Whether this is a result of improved therapy or of other factors remains a matter of speculation. However, it does coincide with the decrease in mortality and other acute and long-term adverse sequelae of status epilepticus.

Status Epilepticus and the Development of Future Seizures

The textbook definition of status epilepticus as “a seizure of such duration as to create a fixed epileptic condition”⁶⁰^,¹²⁶ might lead one to assume that all cases of status epilepticus are inevitably associated with a subsequent chronic seizure disorder. Indeed, if “seizures beget seizures” as has been argued by some authors,⁴⁹^,⁶²^,¹²²^,¹²³ then one would expect that the occurrence of a prolonged seizure such as status epilepticus would inevitably result in subsequent seizures. However, the epidemiologic data do not support this conclusion.¹⁵^,^17a^,⁶⁷^,⁶⁹^,⁷⁰^,¹⁰⁶^,¹³⁰^,¹³⁷^,¹³⁹ This section reviews the data regarding the development of a subsequent seizure disorder following an episode of status epilepticus.

Experimental Data

Status epilepticus–induced epileptogenesis is a widespread phenomenon that reproducibly occurs in the vast majority of animals after many types of experimental status epilepticus. The majority of subjects develop spontaneous recurrent seizures after status epilepticus induced by kainate, pilocarpine with or without lithium, tetanus toxin, stimulation of excitatory pathways such as the perforant path, or stimulation of limbic structures such as amygdala¹¹¹ or ventral hippocampus in a number of animal species.²⁰^,²²^,⁷⁹^,⁸²^,¹²⁹^,¹³³^,¹⁶⁰ Acutely, neuronal loss in the dentate hilus and CA1 and increases in diffusion-weighted and T2-weighted imaging (by magnetic resonance imaging [MRI]) are seen in hippocampus.⁵⁰^,¹²⁴ Chronically, an increased T2 signal reveals hippocampal cell loss coupled to gliosis, a combination that is reminiscent of human medial temporal sclerosis.¹²⁴ The respective role in epileptogenesis of loss of GABAergic interneurons¹¹⁵^,¹⁴⁷ and of sprouting of excitatory fibers¹⁵⁴^,¹⁵⁵^,¹⁶⁹ is debated. In immature animals, SE can lead to spontaneous recurrent seizures and chronic epilepsy, although the immature brain is more resistant than the adult brain.^{71a,71b,132,133} However, this epileptogenicity is highly model dependent: Whereas the lithium-lipocarpine model is highly epileptogenic,¹³³^,¹⁵³ the perforant path model of status epilepticus generates spontaneous recurrent seizures in only about 15% of subjects.¹³⁴^,¹⁶⁹

Domoic acid (a close analog of kainic acid) ingested from mussels induced status epilepticus in a man who later developed chronic epilepsy, and this case may offer the closest human approximation to the animal models.²⁶

Status Epilepticus as a First Unprovoked Seizure

Approximately 10% of patients who come to medical attention with a first unprovoked seizure present with SE.¹¹^,¹⁶^,⁴⁰^,⁶⁴^,⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰^,⁹¹^,¹³⁹ The majority of these have a cryptogenic or idiopathic etiology. In both children and adults, the risk of seizure recurrence following a cryptogenic/idiopathic first unprovoked seizure is not influenced by the duration of the initial seizure.¹¹^,¹⁵^,⁶⁹^,⁷⁰^,¹³⁹^,¹⁴²^,¹⁴³^,^143a This is true whether one

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examines seizure duration as a continuous variable or compares those with status epilepticus as their first unprovoked seizures with those who presented with a brief first seizure. These studies, which include follow-up periods of >15 years, support the view that status epilepticus per se does not create a permanent seizure disorder.⁷⁰^,¹⁴²^,¹⁴³^,^143a

In both children and adults who present with status epilepticus as their first unprovoked remote symptomatic seizure, the risk of recurrence is increased.¹⁶^,⁶⁹^,⁷⁰^,¹³⁹ As discussed later, these patients are at increased risk not just for recurrent seizures, but also for recurrent status epilepticus.¹⁵^,⁴³^,¹⁴⁰^,^143a However, it should be noted that status epilepticus as the initial seizure is relatively uncommon in this group. In one study of childhood status epilepticus, 29 (63%) of 46 children with idiopathic status epilepticus had no prior history of seizures, whereas 34 (75%) of 45 children with remote symptomatic status had a prior history of seizures.⁹² The fact that status epilepticus is a risk factor for subsequent seizures in remote symptomatic cases but not in idiopathic ones suggests that either it is a marker for epilepsy in those cases or that the already compromised brain is more susceptible to injury as a result of status. More research is needed on this point, and animal models are being developed to address this issue (see Chapter 36).

When one looks at long-term outcomes following an initial episode of status epilepticus, the epidemiologic data in children also do not show long-term adverse effects of an isolated episode of status epilepticus. The occurrence of status epilepticus does not influence long-term remission rates in children who present with status epilepticus as their first unprovoked cryptogenic seizure.^141a^,¹⁴² In a case–control study of predictors of intractability in children with newly diagnosed epilepsy, the occurrence of status epilepticus was found to be a marker for future intractability.¹⁸ The best predictor, however, was the presence of an underlying neurologic abnormality. Furthermore, of the four children believed to have cryptogenic epilepsy whose presentation included an episode of status epilepticus, one was later diagnosed as having a brain tumor, one had retardation, and one had a progressive neurologic disorder. Thus, status in this population seems to be a marker for an abnormal brain, which is known to be a predictor of future intractability.¹⁸ Similarly, in Sillanpaa’s study, the occurrence of status epilepticus was more common in remote symptomatic cases, which are also more prone to recurrent status. However, it had an only modest effect on long-term outcome once one controls for etiology.¹⁴⁵^,¹⁴⁶ Few data are available on this question in adult-onset epilepsy.

Epilepsy Following Febrile Status Epilepticus

The literature regarding this issue is confusing. Retrospective studies from tertiary epilepsy centers reported that many adults with intractable temporal lobe epilepsy had a history of prolonged or atypical febrile seizures in childhood.¹^,¹⁹^,²⁴^,²⁵^,⁵²^,⁵³^,⁵⁸^,⁸⁴^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹ However, population-based studies failed to find this association, nor did prospective studies of febrile seizures.⁸^,¹⁰^,⁴⁸^,⁹⁰^,¹⁰⁸^,¹⁶³^,¹⁶⁴ In this section we review some of the data as they relate to the association of prolonged febrile seizures and subsequent epilepsy.

One must be careful to distinguish between very prolonged febrile convulsions, which are the extreme end of the complex febrile seizure spectrum,¹⁰⁷ and status epilepticus associated with fever. The latter term often includes cases of encephalitis, meningitis, and other forms of acute brain injury as well as children with already established epilepsy who decompensate in the context of an acute febrile illness. These are discussed in the section on acute symptomatic status epilepticus. This section focuses on the data on the consequences of prolonged febrile seizures (for a more detailed discussion see Chapter 63).

Studies that limit themselves to children with prolonged febrile seizures uniformly report a low morbidity and mortality.⁸^,¹⁰^,³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁴⁸^,⁶⁴^,⁶⁷^,⁸⁹^,⁹⁰^,¹⁰⁸^,¹⁶³^,¹⁶⁴^,¹⁶⁶^,¹⁷¹ As with all forms of complex febrile seizures, there is a somewhat higher risk of epilepsy compared to children with a simple febrile convulsion.⁸^,¹⁰^,¹⁷^,⁴⁰^,⁴⁸^,⁵¹^,⁸⁹^,⁹⁰^,¹⁰⁸^,¹⁶³^,¹⁶⁴ In a study of a British cohort of 16,004 children born during a single week in April 1970, the proportion of those who developed afebrile seizures was 3.4% after febrile convulsions lasting <30 minutes but 21% after febrile convulsions lasting >30 minutes.¹⁶⁴ This increased risk may express itself many years later.⁸^,¹⁰^,¹⁶⁴ At highest risk are those whose febrile seizures are both prolonged and focal¹⁰ and those who are already neurologically abnormal prior to the febrile seizure.¹⁰^,¹⁶^,⁹⁰ In children who were previously neurologically abnormal, even the short-term risks of developing epilepsy are substantial.⁹⁰

The difficulty in interpreting the data centers on whether the febrile seizures are markers for subsequent epilepsy or a cause of the epilepsy. Those who argue that there is a causal relationship point to the retrospective studies of temporal lobectomy patients, autopsy studies,¹^,¹⁹^,²⁴^,²⁵^,³²^,⁵¹^,⁵²^,⁵³^,⁵⁸^,⁸⁴^,⁸⁹^,¹⁷² and adult animal data on the sequelae of status epilepticus.⁸³^,⁹⁵^,⁹⁶^,⁹⁷^,¹⁴⁸ On the other hand, there are those who would argue that febrile seizures are simply an age-specific marker for subsequent epilepsy.¹⁴¹ Namely, those patients with a predisposition to epilepsy based on a genetic predisposition or based on underlying structural abnormalities will, at the age-specific developmental window, also be more likely to experience febrile seizures, possibly even prolonged ones. The data in favor of this view include the fact that the risk of subsequent epilepsy is highest in those with focal seizures or prior neurologic abnormality.⁸^,¹⁰^,^17a^,⁹⁰^,¹⁰⁸^,^139a^,¹⁶³^,¹⁶⁴ The risk of epilepsy is also high in those with four or more febrile seizures even if they are brief.¹⁰ This population tends to have a high incidence of generalized spike-and-wave abnormalities on the electroencephalogram (EEG) when older, pointing again to probable genetic causes.⁴²^,^139a^,¹⁶¹ Finally, in the study of Annegers et al.,¹⁰ which provided the longest follow-up, those with generalized status developed a generalized seizure disorder, whereas those with focal status developed a focal disorder, which is what one would expect if the prolonged febrile seizure were a marker for subsequent epilepsy.¹⁰ By contrast, if one proposed a causal relationship between status per se and later epilepsy, then one would expect a high rate of focal seizure disorders regardless of whether the initial episode of status was generalized or focal.

In reviewing the data from retrospective series of epilepsy surgery candidates,¹^,¹⁹^,²³^,²⁴^,²⁵^,³²^,⁵²^,⁵³^,⁵⁸^,⁸⁴^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹ one must keep in mind that these are highly selected patient groups. Many of these patients had complex febrile seizures or at least seizures associated with fever, but few actually had status epilepticus. It is often very unclear whether they truly had febrile seizures or if seizures were associated with fever in patients who may have had an acute brain insult such as encephalitis or in patients with a preexisting epilepsy. Atypical febrile seizures of the latter type have been associated with a worse prognosis for remission¹⁸^,¹³⁸^,¹⁴¹ but should not be confused with febrile seizures. If febrile seizures are simply a marker for seizure susceptibility, then quite possibly those most susceptible will experience more frequent and/or more prolonged febrile seizures.^139a Note that complex febrile seizures in general and very prolonged febrile seizures in particular are much more common in children who are already neurologically abnormal and are most likely to be focal, suggesting prior focal pathology.¹⁰^,²⁸^,⁴⁷^,¹⁰⁸^,¹⁶³^,¹⁶⁴ Current prospective studies on the long-term outcomes of febrile SE with an emphasis on the development of mesial temporal sclerosis and epilepsy will provide the answer to these questions, but given the long latency, it will be some time before the precise relationships between

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febrile SE and subsequent epilepsy are defined (see Chapter 63).

Epilepsy Following Acute Symptomatic Status Epilepticus

A proportion of patients with acute symptomatic status epilepticus develop a seizure disorder at some time in the future. This proportion varies and is a function of the severity of the underlying insult. In most cases it is on the order of 15% to 30%. However, the seizure disorder may not develop for several years.⁹^,⁶⁸^,⁷¹^,¹⁵⁶ There are few data that support prophylactic antiepileptic drug (AED) treatment to prevent the subsequent development of epilepsy in acute symptomatic seizures.⁵⁶^,¹⁰⁴^,¹³⁷^,¹⁵⁶ There is some evidence that acute symptomatic seizures, including status epilepticus, are associated with an increased risk of subsequent epilepsy in patients with acute CNS injury. However, it is unclear whether patients with acute symptomatic status epilepticus have a higher risk than other patients with briefer acute symptomatic seizures.⁶⁶^,⁶⁷^,⁷⁰^,⁷¹ The majority of patients with acute symptomatic or febrile status epilepticus do not have unprovoked seizures later, even with long follow-up periods.⁸^,¹⁰^,⁵⁶^,⁶⁶^,⁶⁷^,⁶⁸^,⁹⁰^,¹⁰⁸^,¹⁵⁶^,¹⁶³^,¹⁶⁴

Recurrent Status Epilepticus

Although not clearly a sequela of status epilepticus, the issue of recurrent status is best dealt with in this chapter because it is closely related to the issue of status epilepticus and subsequent seizures. Most of the available data in this regard are in pediatric series, which are discussed first. Pediatric studies report that 11% to 25% of children with status epilepticus experience at least two episodes.³^,⁴³^,⁴⁶^,⁹²^,¹⁴⁰ These studies included both prospective and retrospective cases. Shinnar et al.¹⁴⁰ followed 95 children from the time of their first episode of status. Sixteen children (17%) experienced recurrent status, including 5 with three or more episodes. All but 2 of the 16 had prior neurologic abnormalities. The risk of recurrent status epilepticus in the remote symptomatic and progressive encephalopathy group was almost 50%, compared with only 3% in children who were otherwise neurologically normal. The neurologically abnormal group constituted 32 (34%) of the 95 children, but they accounted for 14 of 16 (88%) of children with recurrent status epilepticus and all 5 children with three or more episodes of status epilepticus.

It is of interest that the increased risk of recurrent status epilepticus for neurologically abnormal children was present not only in the remote symptomatic and progressive encephalopathy group, but also in the febrile⁹²^,¹⁴⁰ and acute symptomatic group. Driscoll et al.⁴³ reported similar findings in a retrospective review. Thus, it would appear that the risk of recurrent status epilepticus is primarily in children with preexisting neurologic abnormalities. This is also the population that is at higher risk for developing seizures¹⁴^,⁶⁸^,⁷¹^,¹⁰⁹ and status epilepticus in the first place.³^,³⁶^,⁴⁰^,⁴⁵^,⁴⁶^,⁶⁴^,⁶⁷^,⁹²^,¹⁶⁶^,¹⁷¹ These data support the notion that status epilepticus is primarily a marker for an abnormal or injured brain destined to be epileptic rather than the cause of an injury sufficient to produce an epileptic condition. In adults there is one study with similar conclusions.¹³

More recently, there is an accumulation of data that suggest that there is a subgroup of children with a predisposition to prolonged seizures.^{17,18a,18b,31a,139,143,143a,146a} These children are not necessarily at risk for frequent or intractable seizures, but are at increased risk for prolonged seizures. The evidence comes from several studies. In children with febrile seizures, an initial prolonged febrile seizure is not associated with an increased risk of recurrent febrile seizures. However, if another febrile seizure does occur, it is likely to be prolonged.¹⁷ Similarly, in children with a first unprovoked seizure who are neurologically normal, a prolonged first seizure including status does not increase the risk of recurrence, but if a recurrence does occur, it is likely to be prolonged.¹³⁹^,¹⁴³^,^143a In the Finnish childhood onset epilepsy cohort, the majority of cases of status occurred early in the disorder. If status did occur, there was a high likelihood of recurrent status. However, if there was no episode of status in the first few years of the disorder, then status did not occur even if there was a continuing active seizure disorder for many years.^146a In the Connecticut study, the majority of cases of status also occurred early, but there were more late cases.^18a,18b Finally, genetic studies of twins have shown that, if one twin has status, there is an increased risk of not just seizures, but also status in identical but not fraternal twins.^31a

Status Epilepticus and Mesial Temporal Sclerosis

The pathological entity of mesial temporal sclerosis is described in detail in Chapter 13. In this section we review the data regarding whether MTS is a sequela of status epilepticus, particularly in early childhood (see also Chapter 65).

Falconer et al. described the pathologic findings in temporal lobes obtained from 100 patients with intractable temporal lobe epilepsy.⁵³ Forty-seven percent had mesial temporal sclerosis, varying from loss of cells in Sommer (H1) sector of the hippocampus to more widespread involvement of the temporal lobe. Of those with MTS, 40% had a history of prolonged convulsions in infancy. The major controversy regarding mesial temporal sclerosis is whether it is a sequela of status epilepticus, particularly of prolonged febrile seizures in early life or due to some other cause.¹²⁸ We review the data for and against the hypothesis that MTS is a sequela of status.

In favor of this hypothesis are the elegant experiments in adult animals that have produced MTS with a variety of models of status including kainic acid, pilocarpine, and fluorothyl.²¹^,⁸³^,⁹⁵^,⁹⁶^,⁹⁷^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹⁵⁰^,¹⁵¹^,¹⁵² Meldrum et al. showed that in the adult monkey, even if one paralyzes the animal and adequately ventilates and oxygenates it, neuronal changes occur as a sequela of status.⁹⁵^,⁹⁶^,⁹⁷ Such changes are readily produced in the adult rat as well.²¹^,⁸³^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹⁵⁰^,¹⁵¹^,¹⁵²

In patients with refractory complex partial seizures who undergo epilepsy surgery and are found to have mesial temporal sclerosis, a substantial number have a history of complex febrile seizures in early life, although, as discussed previously, not necessarily of status epilepticus.¹^,¹⁹^,²⁴^,²⁵^,³²^,⁵¹^,⁵²^,⁵³^,⁵⁸^,⁸⁴^,⁸⁹^,¹⁷²

A number of imaging studies found cerebral edema acutely, and atrophy chronically, after convulsive or nonconvulsive status epilepticus,³⁰^,⁷⁷^,⁷⁸ but others did not.¹²⁹ One 5-year-old patient had a normal brain MRI before and atrophy after nonconvulsive status epilepticus,¹¹⁹ and neuronal loss was found at autopsy in areas that became atrophic after his bout of status epilepticus.¹¹³ Focal atrophy has been reported to develop in areas of intense seizure activity,⁵⁷^,¹⁰⁰^,¹⁰¹ supporting a mechanistic explanation. However, the problem with these studies is that although they establish that sequelae can occur, they do not give any sense of how common the event is.¹³⁶

Although this view of a causal relationship between prolonged seizures in early childhood and subsequent MTS has become entrenched in the literature, there is a large body of data that do not support this view. The animal and clinical data simply do not match in this regard. The clinical

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data from adults evaluated for epilepsy surgery suggest that MTS is associated with an insult or seizure onset in early childhood but not in adult life.¹^,¹²^,²⁴^,²⁵^,⁵⁸^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹ The animal data indicate that although the immature CNS is more susceptible to seizures in general and status epilepticus in particular, it is far more resistant to its sequelae.⁶^,²¹^,²⁷^,³³^,⁶⁵^,⁷³^,⁷⁴^,⁷⁵^,⁸³^,¹⁰²^,¹⁰³^,¹⁰⁵^,¹¹²^,¹¹⁶^,¹⁵⁰^,¹⁵¹^,¹⁵²^,¹⁶⁷^,¹⁶⁸ In many, although not all, animal models of status, rat pups who experience an episode of status do not develop MTS. This is true in a variety of models, including kainic acid, pilocarpine, flurothyl, and kindling.¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁵⁰^,¹⁵¹^,¹⁵² Reversible hippocampal injury has been shown in the infant rat using the kainic acid model.²⁷ Based on the use of Timm staining, aberrant reinnervation has been demonstrated following status in the adult rat, but it only occurs in some models in the rat pup.¹³³^,¹³⁴^,¹⁵⁰^,¹⁵¹^,¹⁵² Rat pups that experience kainate status and are allowed to reach adulthood have the same seizure threshold as control adult animals using the kindling model,¹¹⁶ but in other models, after status epilepticus at P15, a majority of animals show spontaneous recurrent seizures.¹⁵³

The pathologic data show that MTS is often associated with developmental abnormalities such as migration defects, suggesting that there is preexisting pathology.¹²^,⁸⁰^,⁸⁶^,⁸⁷^,⁹³ The association of MTS with brain tumors of the adjacent temporal lobe, particularly when these tumors are adjacent to the hippocampus, also points to preexisting pathology as a frequent correlate of MTS.¹²^,⁸⁹ Using autopsy material of patients who died following an episode of status epilepticus is problematic because these are extreme cases, which do not necessarily represent the effects of status per se, which has a low mortality, but rather probably represent the results of acute brain injuries associated with status epilepticus.⁵⁵^,⁹⁴^,¹⁴⁹^,¹⁷²

The clinical data are also problematic. MTS is most common in cases with childhood onset. However, MTS is not diagnosed in childhood but many years later. In fact, documentation of MTS under age 6 years is uncommon.⁴⁴^,¹¹⁰ Whether this is because MTS occurs later in the course of the epilepsy or is simply due to lack of early diagnosis is unclear. Recent data indicate that mesial temporal sclerosis, similar to that found in adults, can be seen in children with intractable mesial temporal lobe epilepsy.⁸⁸

Radiologic evidence of hippocampal damage is reported primarily in adults. An example is a paper in which five adults with status had magnetic resonance imaging with fast spin echo techniques demonstrating reversible abnormal hyperintensity and swelling of the hippocampus and amygdala.¹⁵⁹ Two of these patients subsequently had evidence of hippocampal atrophy. In children, the data are sparse. One case report of a very young child with status epilepticus followed by MTS has been reported.¹¹⁴ The child was neurologically abnormal previously, had focal status suggesting focal pathology, and had almost no latent period between the status and the intractable seizures. Although this case is interesting in demonstrating that MTS can occur early in life, it is hardly a demonstration of the proposed paradigm of a prolonged seizure followed by a silent interval and then complex partial seizures. In fact, most childhood intractable epilepsy is extratemporal.⁴⁴^,¹⁰⁴^,¹¹⁰ Although temporal lobe epilepsy does occur in children and can be associated with MTS, other etiologies such as cortical dysplasia and developmental tumors are more common.⁴⁴^,⁶³^,¹⁷⁰ Status epilepticus is actually much more common in frontal lobe epilepsy and in Lennox-Gastaut syndrome, neither of which is associated with MTS. The clinical data regarding the association of prolonged febrile seizures and subsequent MTS or temporal lobe epilepsy were discussed previously.

More recently a number of case reports and series have shown that febrile SE can cause increased T2 signal in the hippocampus, which in some cases is associated with subsequent hippocampal volume loss.^{80a,80b,101,144,162} Some of those radiologic findings were confirmed at autopsy.¹¹³ Recent animal data from rats with hyperthermic seizures have also indicated increased T2 signal,^43a although in that model it was not associated with cell death. Thus, it is now clear that febrile status epilepticus can lead to hippocampal atrophy, although the frequency with which this occurs and the required seizure duration are unclear.^135a^,¹³⁶ For a detailed review of this important topic see Chapter 63.

Mathern et al. have tried to document the relationship between mesial temporal sclerosis and various preceding insults.⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹ They found that an injury prior to age 5 years, whether or not associated with a seizure, was most likely to be associated with MTS. Those with MTS were most likely to have initial precipitating injuries, including trauma and encephalitis. In addition, severe hippocampal neuronal losses (hippocampal sclerosis) were often associated with mesial temporal lesions or masses adjacent to the body of the hippocampus.⁸⁹ Longer durations of temporal lobe epilepsy were associated with some secondary neuron losses. The data “support the hypothesis that the etiology of hippocampal sclerosis is an acquired injury to the hippocampus and that the pathogenesis is a combination of acute, subacute, and progressive changes following the initial injury.”⁸⁶ Note that the initial injury need not necessarily be a seizure.

The entire field is being rewritten as newer studies with better imaging techniques are leading to a better understanding of the relationship of very prolonged febrile seizures and subsequent MTS. For a better discussion, see Chapter 63.

Other Pathologic Sequelae of Status Epilepticus

In postmortem examinations of five children who died after status epilepticus associated with a febrile illness, Fowler described neuronal necrosis in the cerebral cortex, basal ganglia, and cerebellum.⁵⁵ The exact etiology of these seizures, which lasted from 1 to 6 hours, is unclear, although the children were febrile. Similar findings were described in several other reports.⁹⁴^,¹⁴⁹ Of particular interest is the case of a 20-year-old who died following prolonged focal status epilepticus associated with fever and had unilateral pathology.¹⁴⁹ It is unclear whether the pathologic changes were due to hypoxia as suggested by Fowler, to the underlying brain insult, or to the status epilepticus. Cell loss in the cerebellum has also been described in patients with long-standing seizure disorders even without a history of status epilepticus.¹² Brain damage is often seen in children or adults who died from SE,³² although the complexity of clinical situations usually makes it very difficult to tell whether damage resulted from the seizures themselves or from medical complications such as hypoxia or hypotension. DeGiorgio et al.³⁴ found decreased hippocampal neuronal densities in five patients who died after complex partial status epilepticus. Given the overall low morbidity and mortality of SE per se, it is difficult to extrapolate from these postmortem findings to those who survive an episode of SE, particularly when it is not associated with an acute neurologic insult.

What Further Studies are Needed

Further studies are needed in several areas. Prospective long-term follow-up studies after episodes of status epilepticus are needed to determine whether status epilepticus is associated with subsequent mesial temporal sclerosis and, if so, how often

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this occurs. These studies should take into account differences in etiology and age that may affect outcome. Given the recent association of mesial temporal sclerosis with migration defects, studies are needed on whether preexisting brain abnormality or injury makes the brain more susceptible not only to developing status epilepticus, but also to sustaining damage as a result. Modern imaging techniques should also allow for better studies of pathologic changes associated with status epilepticus in humans as well as in animal models. Animal and human studies are also needed on ways to not just stop the seizures, but also to prevent the damage. The role of N-methyl-D-aspartate antagonists and other agents that may prevent secondary neuronal damage following brain injury is being evaluated in animals but not yet in humans.

Summary and Conclusions

The morbidity and mortality of status epilepticus have declined significantly in the last two decades. In the absence of an acute or progressive CNS insult, the morbidity and mortality of status epilepticus are low, particularly in children. Long-term sequelae are also difficult to document in the absence of an acute associated neurologic insult. Motor and cognitive sequelae, although they may occur, are rare. The epidemiologic data do not support the idea that status epilepticus is necessarily associated with a subsequent chronic seizure disorder. Status epilepticus is most common in young children. However, although the immature brain is more prone to develop status epilepticus, both human and animal data suggest that it is more resistant to its adverse sequelae.

Textbook definitions of status epilepticus that imply that it is always associated with subsequent chronic epilepsy need to be revised. The relationship between status epilepticus and mesial temporal sclerosis also needs further study. Defining the precise role of status epilepticus in human epileptogenesis requires further research.

Acknowledgments

This work was supported in part by grants R01-NS26151 (S.S.), R01-NS-43209 (S.S.), RO1-NS-13515 (C.G.W.), and R01-NS 20253 (S.L.M.) from the National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, and by the research service of the Veterans Health Administration.

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	Epilepsy: A Comprehensive Textbook 2nd Edition
	© 2008 Lippincott Williams & Wilkins

Epilepsy: A Comprehensive Textbook2nd Edition

Epilepsy: A Comprehensive Textbook
2nd Edition