Long-Term Sequelae of Status Epilepticus



Long-Term Sequelae of Status Epilepticus


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
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
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).

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Aug 1, 2016 | Posted by in NEUROLOGY | Comments Off on Long-Term Sequelae of Status Epilepticus

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