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Historical note and nomenclature

Status epilepticus was infrequently recorded up to the dissertation of Louis Calmeil, where the expression état de mal is first found, but still in the notion of generalized convulsive status epilepticus only (Calmeil 1824). The proceedings of the 10th Marseilles Colloquium of 1962 represent the first book (Gastaut et al 1967) on this subject. At the Marseilles Colloquia 1962 and 1964, definitions and classifications of seizures and of status epilepticus were proposed with the obvious notion that there are as many types of status as there are types of seizures.

Trousseau was probably the first who observed that petit mal seizures might, as with grand mal, occur in such frequency "that one seizure would become confused with the next, simulating a continuous seizure that might persist for 2 or 3 days" (Trousseau 1868). But, although Trousseau identified petit mal status, his was not the first description of nonconvulsive status epilepticus. In 1822, Prichard described cases of epileptic fugue and furor as well as "epileptic ecstasy" (Prichard 1822). Bright, as well as Charcot, described fugue states (Bright 1831; Charcot 1889), and Hughlings Jackson (Taylor 1931) described such a condition in temporal lobe epilepsy.

Clark and Prout recognized nonconvulsive forms "composed of delirium, stupor or coma, cough or hiccough, and a variety of psychic states, which have for their basis cortical discharges", and including "status comprising only psychic seizures, absences or vertigo" (Clark and Prout 1903/4). One case of Clark and Prout, identifiable as psychomotor status epilepticus, had 760 typical seizures in 12 hours and, a few days later, had a period of 500 psychic seizures (with subnormal temperature), "a most unexplainable and interesting freak in the psychic phenomena of epilepsy.” These authors also found that "psychic" status usually had a good outcome.

In 1954, Penfield and Jasper identified recurrent sensory phenomena (simple partial status epilepticus; aura continua) and found them to be "at least as common as continuing circumscribed movements" (Penfield and Jasper 1954). In 1945 and 1960, Lennox and Lennox used the term petit mal status for psychiatric conditions associated with continuous bifrontal spike-wave activity and with a duration of hours to days (Lennox 1945; Lennox and Lennox 1960).

The questions of whether psychomotor seizures (referred to the temporal lobe) also could occur as a status epilepticus and whether such status activity could be the underlying cause for prolonged twilight states was, however, for a long time controversially discussed. As late as 1963 Landolt noted, "...finally there remain those cases that we personally know from the literature only. For example the case of Gastaut and that of Schorsch, in whom obviously the "generalized state of twilight attacks" continued for days resulting in a twilight state. We have to ask us, however, if these cases have not been petit mal status". From Landolt’s statement it becomes very clear that petit mal status (ie, absence status) was sharply delineated from psychomotor status epilepticus, which was a distinction that was no longer respected with the widely used term nonconvulsive status epilepticus.

The most important early literature dealing with psychomotor status epilepticus has been focused on the phenomenological description of this condition as evidenced by the review of Wolf, who discussed 7 cases and added 2 of his own (Wolf 1970). In his description, Wolf followed Janz, who distinguished the discontinuous form, characterized by the occurrence of psychomotor attacks that follow each other at 2 to 10 minute intervals, from the continuous form (Janz 1969). Under the continuous form, Janz subsummized 2 variants; (1) long-lasting sensory or somatosensory or "psychic" seizures, and (2) epileptic twilight states with productive-psychotic signs and symptoms.

In 1979, Karbowski organized a symposium on status psychomotoricus. In his review he referred to 36 published cases with psychomotor status and added 8 of his own cases (Karbowski 1980). Karbowski accepted only cases in which the EEG has been sufficiently described and illustrated. Seven additional publications appeared in 1978 (Ambrosetto et al 1978; Engel et al 1978; Mayeux and Lueders 1978; Oller Daurella et al 1978; Perri Di and Messina 1978; Picornell Darder et al 1978; Roger et al 1978).

Major reviews on status epilepticus were the Santa Monica, California (1980) Conference (Delgado-Escueta et al 1983) and the Seventeenth Annual Merritt-Putnam in Boston, which was published as a supplement to Epilepsia (Macdonald 1999). In the same year, 5 position papers on nonconvulsive status epilepticus were published in the Journal of Clinical Neurophysiology (Kaplan 1999). Comprehensive reviews on the behavioral manifestations, presentation, evaluation, and treatment followed (Drislane 2000; Kaplan 2002).

A PubMed search with the item "nonconvulsive status" currently lists 237 papers. The search term "complex and status epilepticus" currently lists 388, "complex partial and status epilepticus" lists 302, "psychomotor and status epilepticus" 59, and "limbic and status epilepticus" 262.

Definition and problems with definition.

Status epilepticus, in general. The term status was used "whenever a seizure persists for sufficient length of time (subsequently defined as at least 30 to 60 minutes) or is repeated frequently enough to produce a fixed or enduring epileptic condition.” This definition is enshrined into the World Health Organization dictionary of epilepsy (Gastaut 1973) as well as the Handbook of clinical neurology (Roger et al 1974) and Handbook of electroencephalography and clinical neurophysiology (Gastaut and Tassinari 1975). Today, a widely accepted operational definition of status epilepticus is that of a "condition in which epileptic activity persists for 30 minutes or more, causing a wide spectrum of clinical symptoms, and with a highly variable pathophysiological, anatomical and aetiological basis.” It is important to note that this definition implicates that status is not simply a rapid repetition of seizures (in fact the word "seizure" is no longer retained) and as such an iterative version of ordinary epilepsy, but a condition (or group of conditions) in its own right with distinctive pathophysiological features.

Today it is estimated that there are between 65,000 and 150,000 cases of status epilepticus in the United States each year (Treiman 1996), and that approximately 25% are nonconvulsive (Cascino 1993; Jagoda 1994; Kline et al 1998). At least 10% of epileptic patients suffer a status epilepticus during the course of their disease, and 50% of status epilepticus appears in patients with no known history of epilepsy (Salas-Puig et al 1996). Status epilepticus is more frequent in symptomatic epilepsies, particularly those arising from trauma, tumor, or infection involving the frontal lobe. Both acute and remote cerebral insults can cause status epilepticus, as can severe systemic disease that causes status epilepticus secondary to a toxic-metabolic encephalopathy. Status epilepticus is present in nearly all epileptic syndromes, even idiopathic ones, although it is more frequent in cryptogenic and symptomatic forms. Whereas tonic-clonic status epilepticus is the best known type and its diagnosis is simple, partial status epilepticus, above psychomotor status epilepticus, presents a diagnostic challenge. Particularly difficult is the differential diagnosis of psychomotor (complex partial) status epilepticus and absence status epilepticus, above all the form termed "late-onset de novo absence status epilepticus,” which presents as confusional syndrome in the elderly (Salas-Puig et al 1996).

Nonconvulsive confusional status epilepticus. This is classically separated into 2 forms on the basis of (1) ictal EEG (ie, absence status) and (2) psychomotor (complex partial) status epilepticus. The diagnosis is difficult on the basis of clinical semiology alone. Absence status (or ‘petit mal’ status) can complicate many epileptic syndromes and is the most frequently encountered form of nonconvulsive status epilepticus. It is characterized by confusion of varying intensity and associated in 50% of cases with bilateral myoclonia (Thomas 2000). The EEG shows ictal generalized paroxysmal activity; normalization is obtained after benzodiazepine injection. In absence status, there is nosographic heterogeneity. Four groups can be distinguished (a) ‘typical’ absence status in patients with generalized idiopathic epilepsies; (b) ‘atypical’ in patients with symptomatic or cryptogenic generalized epilepsies; (c) ‘de novo’ absence status of late onset characterized by toxic or metabolic precipitating factors in middle-aged subjects with no previous history of epilepsy; and (d) absence status with focal characteristics in subjects with a pre-existing or newly diagnosed partial epilepsy, mostly of extratemporal origin. The majority of cases are in fact ‘transitional’ forms between these 4 groups. Psychomotor (complex partial) status epilepticus is characterized by continuous or rapidly recurring psychomotor (complex partial) seizures that may involve temporal or extratemporal regions. Cyclic disturbance of consciousness is characteristic of psychomotor status epilepticus of temporal lobe origin. The diagnosis of complex partial status epilepticus of frontal lobe origin remains a challenge (Licht and Fujikawa 2002). In one third of cases, a frontal lesion is revealed (Thomas 2000).

Temporal lobe or psychomotor or complex partial or limbic status epilepticus. The former conventional classification of status epilepticus was designed to parallel the seizure type classification scheme (Commission 1981; 1989). It has been questioned with regard to its appropriateness to adequately describe the plurality of the clinical forms of status. The first International Classification of Seizure Type (Gastaut 1969; 1970) and its revision (Commission 1981) divided partial seizures, and consequently, partial status epilepticus into "simple" and "complex" according to whether or not consciousness is retained or lost. Therefore, the older term psychomotor status or temporal lobe status was replaced by complex partial status epilepticus and simple partial status epilepticus. The following classification of epilepsies and epileptic syndromes (Commission 1989) included a few syndromes that might conform to the widened definition of status, eg, epilepsia partialis continua, electrical status epilepticus during slow-wave sleep (Patry et al 1971), now called continuous spike-wave discharges during sleep (Morikawa et al 1989), or the Landau-Kleffner syndrome; otherwise, it is lacking a synoptic view. In 1994, Shorvon proposed a new scheme in his monograph, grouped by age, and tried to encompass the various nonconvulsive and myoclonic forms that fit uneasily into the "seizure type approach” (Shorvon 1994).

The search for a new classification scheme for status is justified by the fact that there are types of status in which no overt "seizure" occurs, including epileptic confusional states. Moreover, there are other borderline or boundary conditions. One, for example, is periodic lateralized epileptiform discharge in the EEG (Chatrian et al 1964; Niedermeyer 1993). Periodic lateralized epileptiform discharges are a matter of controversy, and many authors believe that this EEG pattern reflects severe cerebral dysfunction rather than epileptic activity.

Other peculiar conditions are electroencephalographic status epilepticus with subtle clinical signs (Wieser et al 1985) and "epileptic" behavioral disturbances up to "epileptic" psychosis. In such cases, the EEG recorded in the epileptogenic zone might show 'high-frequency tonic spike discharges,’ 'regular clonic' or 'clonic-tonic' discharge patterns. In the vicinity of such an epileptic discharging focus, the EEG might exhibit signs of attenuation ('critical aplattisement') and the surface EEG a regional or even generalized attenuation with disappearance of interictal spikes described as 'forced normalization' by Landolt (Landolt 1960; 1963; Wieser 1998). It is obvious that such stages or conditions bear similarities to spike suppression prior to seizures (Wieser 1989), with dimensional loss in nonlinear correlation dimension analysis applied to predict seizures (Le Van Quyen et al 1998; 1999; 2001; Weber et al 1998; Moser et al 2000) and associated with changes in neurotransmitters and neuromodulators (Wieser 1999).

It is difficult to deny the intriguing possibility that some abnormal mental states (in epilepsy) are due to prolonged seizure activity. Although there is undisputed evidence that prolonged epileptiform EEG discharges (characteristic of status) in hippocampal and amygdaloid regions can be associated with behavioral abnormalities and can occur with or without clear-cut scalp EEG changes, it is quite unknown to what extent the generality of "interictal behavioral peculiarities" might be associated with such "subclinical EEG status activity" in deep structures.

Since limbic status epilepticus implies seizure discharges in the limbic system, it is not surprising that without intracranial recording from the core structures of the limbic system, such as hippocampal formation and amygdala, limbic status epilepticus is often not detectable. This might be one reason that limbic status epilepticus is rarely reported in literature in comparison to generalized convulsive status epilepticus and absence status epilepticus.

Moreover, psychomotor status often evolves from or alternates with aura continua (what was called simple partial status epilepticus) (Wieser 1980; 1997), so that many overlaps between aura continua and psychomotor status exist in literature and cases are finally categorized according to their full blown semiology (ie, as psychomotor status, although for a certain period of time they would fulfill the criteria of simple partial status epilepticus).

In Shorvon's suggested "revised classification" of status epilepticus, we find the category "nonconvulsive" status. The term "electrographic" as a characteristic status type is found in boundary syndromes “including electrographic status epilepticus with subtle clinical signs, prolonged postictal confusional status, and epileptic behavioral disturbances and psychosis.” The adjective “electrographic” furthermore appears in context with continuous spike-wave during slow sleep and the syndrome of acquired epileptic aphasia, as well as in the rubric status epilepticus confined to the neonatal period (Shorvon 1994).

Clinical manifestations

From a clinical point of view within the category psychomotor status epilepticus, Karbowski distinguished between (a) repeatedly occurring psychomotor attacks with recovery of the consciousness between attacks (= discontinuous = intermittent form) and (b) twilight states and psychotic states respectively (= continuous form), (i) with and (ii) without automatisms; (c) partial status epilepticus with rudimentary (= absence-like) or minor signs and symptoms; and (d) partial status epilepticus with mainly sensory hallucinations such as olfactory and olfactory-gustatory, complex acoustic, and visual (Karbowski 1980).

Karbowski grouped the EEG manifestations into (a) repeatedly occurring temporal or frontotemporal seizure discharges with unilateral, bilateral, or secondary generalized discharges. He also distinguished between (b) repetitive patterns with irregular or rhythmic spikes without clear-cut seizure discharges and temporal theta- and delta activity without clear-cut epileptiform graphoelements (Table 1) (Karbowski 1980).

It is obvious that all these early cases lack the documentation with long-term video-EEG monitoring and intracranial EEG recording from the limbic regions. The adequate detection of limbic status epilepticus, however, requires direct recording from these structures (Wieser 1980; Wieser and Landis1983; Wieser et al 1985).

• Recurrent psychomotor (complex partial) seizures without full recovery of consciousness between seizures, or a continuous "epileptic twilight state" with cycling between unresponsiveness and partially responsive phases (lasting greater than 30 min).

• Ictal EEG with recurrent epileptiform patterns like those seen in isolated complex partial seizures.

• With exceptions: an observable effect of IV antiepileptic drug on both ictal EEG and clinical manifestations of the status.

• Interictal EEG with a consistent epileptiform focus, usually in 1 or both temporal lobes

With modifications adapted from (Treiman and Delgado-Escueta 1983; Krumholz 1999).

For the purpose of this article, we would like to suggest the following operational definition: psychomotor or limbic status epilepticus is an epileptic condition (defined by clinical and electroencephalographic signs and symptoms) of at least 30 minutes or more duration, with a large spectrum of clinical manifestations and encompassing subtle clinical signs as well as some behavioral disturbances and psychosis-like states, in particular complex (polymodal) hallucinations, with at least a temporary alteration of consciousness. Furthermore, we ask for additional first-order-plausibility criteria that set the level in the sense that (1) observed symptoms should fit with the known functional anatomy and, thus, with localization of the EEG-discharge; and (in the case of more diffuse and difficult-to-describe personality and behavioral changes) (2) that there is a clear-cut relationship in time between particular subtle signs and symptoms and the epileptic EEG activity.

Nonconvulsive status epilepticus refers to simple partial (aura continua), psychomotor (complex partial), and absence status epilepticus. Psychomotor status epilepticus and absence status epilepticus exhibit an epileptic twilight state of altered contact with the environment. In simple partial status epilepticus, there is no impairment of consciousness, and the behavior changes reflect focal ictal discharges confined to 1 area of the cortex.

Onset can be sudden or insidious. In the best documented cases, the psychomotor or limbic status condition evolved gradually with minor symptoms (aura continua) in the beginning. The type of the aura continua depended on the initially circumscribed discharge localization reflecting the functional anatomy of the brain. In those circumstances where the onset zone was located in the neocortex, the hallucinations often were unimodal at the beginning (ie, visual if the EEG discharge was in the visual and acoustic if the discharge was in the acoustic cortex). With progressive spread of the ongoing epileptic discharges into mesial temporolimbic core structures, the quality of the hallucinations became more complex, and polymodal complex hallucinations, autonomous-vegetative signs, and signs and symptoms in the emotional and affective sphere prevailed. On the other hand, a recognizable seizure event might be at the beginning, and the psychomotor status manifests itself as postictal twilight state with ongoing discharges in some (usually temporolimbic) structures.

The typical overall gestalt of a psychomotor or limbic status epilepticus is that of a fluctuating waxing-waning condition with alterations of restless, sometimes fearful and agitated behavior with memory flashbacks, experiential hallucinations, delusions and hallucinations. Automatisms can be present. This contrasts with the more monotonous 3/sec spike-slow wave petit mal status (spike wave stupor) with clouded consciousness and slowed and impaired thinking. Nowack and Shaikh suggest that complex partial status epilepticus can progress through stages (defined by EEG) analogous to those described by Treiman in generalized convulsive status epilepticus (Trieman 1966; Nowack and Shaikh 1999).

Some authors have designated subtypes of partial nonconvulsive status epilepticus according to the prevailing signs and symptoms (McLachlan and Blume 1980; Gastaut 1983; Wieser 1997). In psychomotor or limbic status the following categories of signs and symptoms can prevail: (a) somatosensory signs and symptoms with dysesthesia as well as visual, acoustic, olfactory, gustatory, and autonomic phenomena. Abdominal status epilepticus is a special subtype that has been described in children. Scott and Masland have described somatosensory hallucinations as a "continuous symptom" (Scott and Masland 1953).

The predominance of dysphasic or aphasic signs and symptoms is far less frequent, but well-documented (Vernea 1974; Wells et al 1992; Murchison et al 1995; Ueki et al 2000; Chung et al 2002). Landau-Kleffner syndrome (syndrome of acquired epileptic aphasia) must also be mentioned here. This childhood disorder in which persisting aphasia develops in association with severe focal EEG abnormalities was described in 1957 by Landau and Kleffner and in 1971 by Worster-Drought (Landau and Kleffner 1957; Worster-Drought 1971). Since then, more than 200 cases have been reported (Shorvon 1994), but the etiology, pathogenesis, and pathophysiology are still widely unknown.

Evidence that long-lasting pain is a special form of partial status epilepticus is scanty, but this possibility should not be completely discarded (Whitty 1953; Wilkinson 1973; Young and Blume 1983; Fromm et al 1987; Siegel et al 1999).

In 1989, Sowa and Pituck described prolonged complex visual hallucinations (Sowa and Pituck 1989). Barry and colleagues have described status epilepticus amauroticus (Barry et al 1985).

Schiffter and Straschill along with Wieser described psychomotor status with auditory hallucinations (Schiffter and Straschill 1977; Wieser 1980). Wieser’s patient experienced a song well-known and familiar to her in "endless repetition”; this musical hallucination was associated with stereo-EEG documented Heschl-near restricted discharges spreading to the ipsilateral mesiobasal limbic structures.

Limbic status with olfactory symptoms has been documented (Wieser 1982). A gustatory aura continua was the leading symptom of case 4 in our 1985 paper (Wieser et al 1985), with a left hippocampal status activity in the depth EEG. But as described, was also associated with subtle higher cognitive deficits detected with a tachistoscopically presented lexical decision task.

It is also well-known that autonomic symptoms can be the leading feature (Wieser and Williamson 1993). Rabending and Fischer described nonconvulsive status epilepticus with ictal bradycardia and asystolia (Rabending and Fischer 1986). Umbilical sensations in children (Van Buren 1963) and long-lasting borborygmi, widened pupils, pilomotor phenomena, goose-flesh or periodically shivering, and so on, have been described (Brody et al 1960; Wieser 1979; 1981; 1983; 1988; 1991; Wieser et al 1981; Green 1984; Stodieck and Wieser 1986). These were often accompanied by certain peculiarities of personality and behavior and, therefore, we have described them in the context of limbic dyscontrol syndrome (Girgis and Kiloh 1980; Wieser and Landis 1983). We believe that autonomic phenomena are usually associated with overt or subtle behavioral changes such as irritability, fear, panic, and sometimes existential emptiness or some other form of pathological self-perception. A particularly rare ictal or status symptom, however, is aggression (Delgado-Escueta et al 1983).

Ictal depression and anxiety in temporal lobe disorders is far more frequent (Weil 1956); a status with fear as the outstanding clinical expression was described by Henriksen and by McLachlan and Blume (Henriksen 1973; McLachlan and Blume 1980). A large amount of literature exists on this topic (Smith et al 1991; Trimble and Bolwig 1992). Ictal laughter is usually associated with hypothalamic pathology, mainly hamartoma (Mueller and Mueller 1980).

Limbic encephalitis may sometimes present with similar features (Khan and Wieser 1994) but usually is treated as an own entity.

Hemicrania epileptica is a rare ictal phenomenon (Isler et al 1984; Andermann and Lugaresi 1987) that may last 30 min to 50 minutes or longer and, therefore, can then be labeled as a form of status epilepticus.

Localization

It is obvious that limbic status epilepticus involves the limbic system, with the hippocampal formations and nuclei amygdalae as its core structures.

The hippocampal formation has been shown to be able to discharge in a status-like manner during depth recordings (Wieser et al 1985). Discharge associated signs and symptoms might be subtle (electrical status epilepticus with minor symptoms), but consistent with hemisphere-specific deficits in tachistoscopic lexical recognition tasks and face matching tasks respectively (Wieser et al 1985). This is in line with more recent H2O positron emission tomography data attributing associative functions (ie, associative binding) to the hippocampal formation (Henke et al 1997; 1999a; 1999b).

The nuclei amygdalae are candidates for explaining the rich and multifaceted signs and symptoms observed in limbic seizures and limbic status epilepticus. This is because nearly all cortical areas of the temporal lobe, major parts of the frontal lobe, and the insular cortex project to the amygdala (Ben-Ari 1981). Some amygdaloid nuclei receive several cortical sensory projections with substantial convergence of cortical input. It is well documented that visual, auditory, olfactory, and, to some extent, taste information reaches the amygdala. Somatosensory input is less clear, but there is reason to believe that all 5 modalities have some convergence in the dorsomedial part of the lateral nucleus. For example, the dorsomedial part of the lateral nucleus receives projections from the orbitofrontal area, which responds to olfactory stimulation; this part is also the major amygdaloid projection zone of the cortical taste area. In addition, there are posterior insular cortex projections to this area carrying visceral, and probably other, somatic information. Moreover, auditory input from the temporal polar cortex projects powerfully to this region. Visual projections are directed primarily to the dorsolateral part of the lateral nucleus (Wieser 2000).

Efferent fibers from the amygdala are the stria terminalis and, to a lesser degree, the ventro-fugal bundle, with overlapping targeting areas in the medial and rostral hypothalamus and regio septalis, as well as the posterior part of the magnocellular Ncl dorso-medialis thalami. The latter connects the amygdala with the orbitofrontal cortex and constitutes a part of the second circuit (besides the Papez circuit), ie, the basolateral limbic circuit, formulated by Yakovlev and re-emphasized by Livingston and Escobar (Yakovlev 1948; Livingston and Escobar 1971).

Excepting a few illustrations with prolonged discharges in the anterior cingulate gyrus associated with confusion and emotional and autonomous signs and symptoms (Wieser 1983; Williamson 1997) and a few cases with kakosmia from frontal orbital cortices (Wieser 1982), little evidence exists on the existence of isolated limbic status epilepticus in areas other than the temporal lobe.

The same is true for the insular cortex, which has not been a favorite target for depth recording because of the increased risk of bleeding following insertion of depth electrodes. Some magnetoencephalographic studies in Landau-Kleffner syndrome, however, have localized the spike generator in this syndrome into the intrasylvian cortex (Paetau et al 1999).

Pathophysiology

In humans the underlying pathophysiology of the various subtypes of nonconvulsive status epilepticus has not been investigated in detail, so most remains speculation. Since the prolonged or frequently recurring epileptic discharges are the hallmark of a status epilepticus, the impairment of seizure terminating mechanisms in local networks may be the common denominator. The absence status and probably some borderline forms resembling psychomotor status epilepticus, may result from excessive recurrent inhibition through thalamocortical circuits, and thus, would not be mediated by excitotoxic effects of NMDA activation (Fountain and Lothman 1995; Hosford 1999). Therefore, some forms of nonconvulsive status epilepticus may be more benign than others. There is evidence of neuronal injury in complex partial status epilepticus and nonconvulsive status epilepticus associated with severe brain injury (Krumholz et al 1995; Jordan 1999; Young et al 1999). DeGiorgio and colleagues found elevated neuro-specific enolase in cerebrospinal fluid and serum during complex partial and myoclonic nonconvulsive status epilepticus (DeGiorgio et al 1996; 1999).

A rat model of nonconvulsive limbic status for 12 to 24 hours results from a 90-minute period of continuous electrical stimulation of the hippocampus (Lothman et al 1989). With a latency of approximately 1.5 months, these rats develop spontaneous recurrent seizures and pathological changes identical to human mesial temporal sclerosis (Bertram et al 1990). This model, centered in the limbic system, provides good experimental basis for suggesting that complex partial status epilepticus may induce long-term sequelae. Similar conclusions may be drawn from a recent study of pilocarpine-induced time-limited nonconvulsive status epilepticus in rats by Krsek and colleagues (Krsek et al 2001). In Lothman and colleagues’ rat model with rapid repetitive stimulation of the hippocampus, the rats with frequent limbic seizures or status epilepticus showed neuronal loss in the CA-1 region, but those with briefer and less frequent seizures did not (Lothman et al 1989; Bertram et al 1990). Sloviter and Olney and colleagues found comparable results by stimulating the perforant path (Olney et al 1983; Sloviter 1983). Shimosaka and colleagues produced with localized prepiriform bicuculline injection heat shock protein (a sign of neurologic damage) and neuronal death in the thalamus, amygdala, and pyriform cortex (Shimosaka et al 1992). With these and similar experiments, they concluded that neuronal damage was directly related to the duration and intensity of electrographic seizure activity, in particular high-frequency (about 10 Hz) discharges, lasting over 20 minutes. Spike and sharp wave discharges with a frequency less than 1 Hz produced no damage (Lowenstein et al 1991).

Gorter and colleagues found that in their rat model for mesial temporal lobe epilepsy, neuronal cell death was induced by the initial status epilepticus and not by later repeated spontaneous seizures (Gorter et al 2003).

Wasterlain and associates listed evidence that self-sustaining status epilepticus might be a condition maintained by potentiation of glutamate receptors and by plastic changes in substance P and other peptide neuromodulators (Wasterlain et al 2000). Coulter and DeLorenzo stressed the fact that status epilepticus is difficult to produce in vitro in normal extracellular medium suggesting that seizure-terminating mechanisms are normally quite robust (Coulter and DeLorenzo 1999). To produce long-duration, self-sustained epileptic discharges in vitro, they have found it necessary to include reciprocally connected entorhinal cortex with hippocampal slices. They conclude that reentrant activation from distant sites may be necessary for maintenance of status epilepticus-like activity of long duration.

Acute consequences of experimental limbic status epilepticus are alterations in membrane potential and membrane properties of hippocampal pyramidal cells accompanied by alterations in neurotransmitter-activated conductances and receptor expression. Some of these acute alterations in receptor and transmembrane iongradient may be critically involved in the development of drug resistance during the late stages of status epilepticus. Indeed the multidrug transporter P-glycoprotein (PGP) is overexpressed in several regions of the temporal lobe including endothelial cells of the dentate gyrus and parenchymal cells of the CA1 and CA3 sectors of the hippocampus and the amygdala (Seegers et al 2002). In the study of Seegers and colleagues, kainate was administered at a dose that produced a generalized convulsive status epilepticus, which was limited to a duration of 90 minutes by diazepam (Seegers et al 2002). However, most P-glycoprotein increases seen 24 hours after status epilepticus were only transient: 10 days after the kainate-induced status epilepticus, except for an increase in parenchymal P-glycoprotein expression in the dentate hilus and CA1 sector, no significant differences to controls were determined.

Suopanki and associates showed that kainic acid-induced status epilepticus induces changes in the expression and localization of endogenous palmitoyl-protein thioesterase 1, the deficiency of which causes drastic neurodegeneration (Suopanki et al 2002). Immunological stainings showed that status epilepticus in adult rats led to a progressive and remarkable increase of palmitoyl-protein thioesterase 1 in limbic areas of the brain. Within 1 week, the maximal expression was observed in CA3 and CA1 pyramidal neurons of the hippocampus. In the surviving pyramidal neurons, palmitoyl-protein thioesterase 1 localized in vesicular structures in cell soma and neuritic extensions. After seizures, colocalization of palmitoyl-protein thioesterase 1 with synaptic membrane marker (NMDAR2B) was enhanced. Further, synaptic fractionation revealed that after seizures palmitoyl-protein thioesterase 1 was readily observed on the presynaptic side of synaptic junction. These data suggest that palmitoyl-protein thioesterase 1 may protect neurons from excitotoxicity.

Rogawski and colleagues recently summarized the evidence that GluR5 (GLU(K5)) kainate receptors, a type of ionotropic glutamate receptor, play a role in the amygdala's vulnerability to seizures and epileptogenesis (Rogawski et al 2003). Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium-dependent process. The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558. Intra-amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment. Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long-term plasticity mechanisms that underlie some forms of epileptogenesis. Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments. Topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor-mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses. The use of topiramate in human refractory status epilepticus has been discussed (Towne et al 2003).

Thus from experimental evidence it might be concluded that long-term consequences of status epilepticus in the limbic system include alterations in patterns of expression of neurotransmitter receptors and in the function of excitatory and inhibitory synapses, cell loss, and circuit rearrangements within the limbic system. An episode of status epilepticus that involves the limbic system clearly elicits brain damage, at least among adult animals. This brain damage can contribute to the development of epilepsy, ie, a condition of recurrent, spontaneous seizures. Conversely, development of an epileptic condition enhances the susceptibility of the limbic system to trigger status epilepticus discharges.

Compared to experimental limbic status epilepticus, the etiology, pathogenesis, and pathophysiology of the Landau-Kleffner syndrome and related conditions are still largely unknown (Landau 1992). In 2 lobectomy specimens, nonspecific gliosis was found (Cole et al 1988); in another atypical case, an encephalitis was diagnosed by biopsy (Lou et al 1977); and in 4 children, an isolated arteritis was assumed angiographically (Pascual-Castroviejo et al 1992). Otero and colleagues described a case with Landau-Kleffner syndrome due to neurocysticercosis, with a small cysticercus deep in the left Sylvian fissure (Otero et al 1989).

More recently, some authors (Maquet et al 1995; Rossi et al 1999) have argued that Landau-Kleffner syndrome, acquired epileptiform opercular syndrome (Shafrir and Prensky 1995; Veggiotti et al 1999), and electrical status epilepticus in sleep, classified as different clinical-EEG syndromes, represent facets of the same brain dysfunction. They may exist separately or pass into the other with a change in the clinical EEG picture. Support for such a view is derived from functional brain imaging (Gaggero et al 1995; Maquet et al 1995) and neurophysiological data, including magnetoencephalographic studies (Paetau et al 1991; 1999; Sobel et al 2000) and results of neurosurgical techniques such as the multiple subpial transection (Morrell et al 1995). These pieces of evidence indeed suggest that in many of these conditions, an alteration of the normal maturation of 1 or several associative cortices is the common denominator, primarily involving local interneurons and corticocortical associative neurons (Maquet et al 1995).

The acquired epileptic aphasia and related overlapping conditions are an important model because they suggest that isolated cognitive and behavioral disturbances can be epileptic manifestations in children (Deonna 1991; Shinawi and Shahar 2001; Fujikawa et al 2003).

Differential diagnosis

The clinical characteristics of nonconvulsive status epilepticus may be highly variable. By including (arguably incorrectly) any state with altered mental status that also has epileptiform features on the EEG in the category of nonconvulsive status epilepticus, the literature encompasses a wide spectrum of clinical concomitants: from focal neurologic deficits (Hilkens and de Weerd 1995) to Wernicke aphasia (Ueki et al 2000), neuropsychiatric manifestations (Kumpfel et al 2000), and confusion (Thomas 2000), as well as learning difficulties in children and adolescents (Staufenberg and Brown 1994).

Classification is difficult and presently might be best accomplished along several axes (Table 3). Psychomotor or limbic status should certainly be distinguished from absence status. The classical absence status primary criteria have been established (Table 4), but in reality, many cases are borderline or atypical (Hess et al 1971).

* The third axis would be continuous - intermittent (discontinuous). The fourth could describe whether status appears de novo, in epileptics, or in severely ill patients; the fifth axis could list whether status epilepticus appears in wakefulness or different forms of sleep, particularly slow wave sleep, or both [adapted from (Krumholz 1999)].

• Prolonged change of consciousness or behavioral function (greater than 30 min)

• Generalized epileptic EEG abnormality (in classical cases 3/sec Spike-Slow waves) that is definitively changed from the preictal state

• A prompt observable effect of IV antiepileptic drug on both ictal EEG and clinical manifestations of the status

Adapted from (Porter and Penry 1983; Krumholz 1999)

In nonconvulsive status epilepticus, the level of consciousness may range from a barely discernible (if any) decrease in level of consciousness or alteration in cognition to comatose states in the face of severe anoxia. The term “nonconvulsive status epilepticus” is very unsatisfactory because the original use of it, which referred to "the wandering confused" (Charcot patient) has now evolved to include the comatose, gravely ill patient in the intensive care unit (Brenner 2002). Most of these patients have myriad medical and metabolic problems.

Behavioral changes may be difficult to identify as being ictal in nature. With nonconvulsive status epilepticus, effect and mood alteration may vary widely, alternating between a state of delirium or mania-like episodes with inappropriate laughter to depression. Patients will act strange or have speech problems that range from the inappropriate “word salad” to mutism. Echolalia-palilalia as the sole manifestation of nonconvulsive status epilepticus (Linetsky 2000) and global developmental delay as the main manifestation of nonconvulsive status epilepticus in a toddler (Shinawi and Shahar 2001) have been recently described.

Differential diagnosis of the Landau-Kleffner syndrome should observe several facts. In Landau-Kleffner syndrome there is a male preponderance (about 2:1). Family history is usually negative, and children have previously developed normally. The aphasia may develop in a subacute or gradual fashion over weeks and, sometimes, over years. In some cases, the speech disorder has been attributed to word deafness rather than aphasia. The course is variable: Aphasia can fluctuate; complete remission might occur or progress into mutism. Overt epileptic seizures are manifest in about 70% of cases and are usually mild. According to the review of Beaumanoir, overt status epilepticus of various types occurred in about 15% of cases (Beaumanoir 1985). The EEG is reported to consist of focal, multifocal, or generalized high voltage spikes as well as spike-wave discharges with activation in slow wave sleep evolving into nearly continuous electrographic status ("bioelectric status"). Since the EEG disturbances in Landau-Kleffner syndrome usually involve the speech-dominant temporal region, it is not surprising that a correlation between EEG abnormalities and language disorder has been found (Shoumaker et al 1974; Cole et al 1988), although the temporal relationship between electrical status epilepticus in sleep and the language disturbance in Landau-Kleffner syndrome is loose in other cases (Paquier et al 1992).

The similarities between Landau-Kleffner syndrome and epilepsy with continuous spike-waves during slow wave sleep are obvious (Morikawa et al 1989). Although the EEG changes are essentially generalized in continuous spike-waves during slow wave sleep, some authors have included cases with relatively focal abnormalities. In addition, in a study of spike-waves during slow wave sleep using phase- and coherence-analysis, Kobayashi and colleagues found that they were focal with secondary bilateral synchrony (or better "synmorphy") (Kobayashi et al 1994). According to the review of Morikawa and colleagues, continuous spike-waves during slow wave sleep is present in 0.5% (of 12,854) children with epilepsy, and about 20% to 30% have identifiable brain pathology (eg, previous meningitis, birth asphyxia, cytomegalovirus infection), 3% have a family history of epilepsy, and 15% a history of febrile seizures (Morikawa et al 1989).

The concept that electrical status epilepticus in sleep may include a large subset of developmental or acquired regressive conditions of infancy is accepted (Tassinari et al 2000; Shinawi and Shahar 2001). Variations among studies may be due to factors such as age of onset, the duration of paroxysmal activity, its intensity, and its localization. Also, if development has been distorted, subsequent progress is likely to be disturbed after the primary condition has ceased to exist (Gordon 1997).

The typical core symptoms of electrical status epilepticus in sleep include overt seizures, usually developing between the ages of 1 to 14 years (mean about 5 years), and consisting of focal motor (tonic-clonic), absence-like, atonic or complex partial, mental retardation (including impairment of memory), deficiencies in temporal and spatial orientation, hyperkinetic or aggressive behavior and psychosis, and striking abnormalities of speech (Tassinari et al 1992). However, both Landau-Kleffner and electrical status epilepticus in sleep occur at about the same age, are characterized by striking abnormalities of speech, may have multiple seizure types, and have severe EEG abnormalities in nonREM sleep.

At present, the nosological position of Landau-Kleffner syndrome and electrical status epilepticus in sleep is not clear in regard to status. As with the Lennox-Gastaut syndrome, they might represent epiphenomena of specific encephalopathy. Some authors have emphasized that even benign childhood epilepsy with centrotemporal spikes is not always benign, but that a small proportion with the disorder evolve into "atypical benign focal epilepsy of childhood," Landau-Kleffner syndrome, or epilepsy with continuous spike-waves during slow wave sleep (Aicardi and Chevrie 1982; Kobayashi et al 1988; De Negri 1997; Fejerman et al 2000; Salanopoulou et al 2000). For such boundary conditions, some French authors have used the category "erratic" and have listed other rare manifestations under this category. Acquired opercular syndrome (Veggiotti et al 1999) could be listed here.

Although the Lennox-Gastaut syndrome also has features that overlap with Landau-Kleffner syndrome and electrical status epilepticus in sleep, the typical nocturnal electrical status epilepticus in sleep pattern is rare in Lennox-Gastaut. The EEG pattern for Lennox-Gastaut is typically dominated by polyspikes rather than spike waves; and tonic seizures, typical for the Lennox-Gastaut syndrome, do not occur in typical cases of electrical status epilepticus in sleep or Landau-Kleffner syndrome (Hirt 1996).

Partial status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms only. Status-like recurrent pilomotor seizures are rare but well documented in relation to temporal lobe pathology, usually gliomas (Andermann and Gloor 1984; Roze et al 2000). For many, the so-called interictal personality and behavioral syndrome (Waxman and Geschwind 1975) as well as other described personality peculiarities also are intimately linked with an active temporal lobe epilepsy (Wieser and Landis 1983). Partial status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms exist (Wieser et al 1985). However, the causal relationship usually remains a guess because very localized ongoing epileptic discharges in deep brain regions cannot be picked up in the routine scalp EEG. Pontius has reported on motiveless firesetting and implicated partial limbic seizure kindling by revived memories of fires in what she called "limbic psychotic trigger reaction" (Pontius 1999).

Differentiating epileptic psychoses from psychomotor status epilepticus. Epileptic behavioral disturbances and psychoses might be due to prolonged nonconvulsive seizure activity. The idea that some abnormal mental states in epilepsy might be a form of partial status epilepticus is intriguing. Usually, epileptic psychosis is divided broadly into ictal, postictal, and interictal categories, each with distinctive features (Trimble and Bolwig 1992). Whereas the postictal psychosis is usually associated with delirium, altered consciousness, and amnesia, the interictal psychosis is characterized by clear consciousness, retained memory, and less severe behavioral disturbances. The ictal psychosis in complex partial status epilepticus with fluctuating or frequently recurring focal electrographic epileptic discharges, arising in temporal or extratemporal regions, presents itself as a confusional state with variable clinical state. It is said that extratemporal, frontal focal status in particular has less cycling symptomatology, and that severe confusion is less pronounced in comparison to temporal lobe status epilepticus. Fronto-orbital polar status epilepticus is said to be particularly poor in clinical symptoms.

In an attempt to re-examine interictal psychoses based on DSM IV Psychosis Classification and International Epilepsy Classification, Kanemoto and colleagues confirmed a close correlation between temporal lobe epilepsy and interictal psychoses. Within the temporal lobe epilepsy group, early epilepsy onset and a history of prolonged febrile convulsions were significantly associated with interictal psychosis. Within the symptomatic localization-related epilepsy group, complex partial seizures, autonomic aura, and temporal EEG foci were closely associated with psychoses. There was also a significantly higher incidence of ictal fear and secondary generalization in the group with localization-related epilepsies with (as opposed to without) interictal psychotic states (Kanemoto et al 2001).

Diagnostic workup

To diagnose nonconvulsive status epilepticus, 2 principal requirements have to be fulfilled: (1) some clinically evident alteration in mental status or behavior from baseline; and (2) seizure activity on the EEG. There are many difficulties in defining baseline behavioral change, and persons at risk for nonconvulsive status epilepticus are also those whose behavioral changes might often be ascribed to other conditions. For example, patients with mental retardation have clear cognitive abnormalities. Correlating behavioral change from baseline with EEG evidence of ongoing epileptic activity is essential to diagnose nonconvulsive status epilepticus.

Essential clinical features. The diagnosis of psychomotor or limbic status epilepticus should be made only if clinical signs and symptoms, typical or suggestive of, which last for more than 30 minutes, are accompanied by clear-cut localized epileptiform discharge patterns including rhythmical discharges in the corresponding brain region, which is most often the temporal area. However, one has to consider that scalp EEG might miss the ongoing discharges in deep limbic structures or reflect them incompletely or distortedly. Clinical symptoms and signs are manifold (Gibbs and Stamps 1958; Engel 1989; Degen 1994) and can combine, although very often they consist of plurimodal complex experiential hallucinations and twilight states. A psychomotor status epilepticus requires video-documentation of the behavior together with the EEG. Polygraphic recording of heart rate, respiration, and galvanic skin reflex may be very useful.

EEG evidence of ictal activity. A wide spectrum of EEG ictal morphologies may be seen with nonconvulsive status epilepticus (Kaplan 1999). Putting aside EEG changes that have doubtful clinical significance such as midtemporal theta of drowsiness, wicket spikes, or subclinical rhythmic epileptiform discharges of adults, problems of interpretation may frequently be encountered with rhythmic EEG morphologies that have sharp contours or waxing and waning progressions.

Triphasic waves, when exceeding 1 per second and suppressed by diazepam, very often straddle the borders of encephalopathy and epilepsy, particularly when they exhibit spiky morphologies and wax and wane. Triphasic waves are supposed to increase with arousal. Triphasic waves in lithium or other acute intoxication may exhibit a prominent and distinctive first phase resembling spike-slow-wave complexes; triphasic waves may decrease in the setting of hyperammonemia after IV diazepam. Periodic or "pseudoperiodic" lateralized epileptiform discharges pose a similar problem when associated with neurologic deficits.

The EEG in psychomotor or limbic status epilepticus may exhibit localized high-frequency tonic discharges restricted to limbic structures, along with fast clonic, slow clonic, or mixed pattern (Wieser et al 1985) if invasive intracranial EEG recording techniques such as depth electrodes, foramen ovale electrodes, and subdural strips and grids are available. Scalp EEG has its limitations and may not pick up localized discharges in EEG of mesial temporal lobe structures. In the scalp EEG only propagated and morphologically altered patterns might be seen. The scalp EEG discharges most often consist of rhythmic theta or theta/delta (see also Table 1), but other frequencies such as alpha (Bauer et al 2000) have also been described in generalized nonconvulsive status epilepticus, which might be viewed as a borderline form. In the 2 cases of Bauer and colleagues, nonconvulsive status epilepticus (clinically and electroencephalographically) started and ended abruptly (Bauer et al 2000). The ictal electroencephalographic pattern was a monomorphic alpha activity with a generalized bilateral distribution. Altered responsiveness, sometimes eyelid myoclonia (in 1 patient), and amnesia were the most characteristic clinical findings.

Waxing and waning as well as paroxysmal pattern changes can occur (Petsche et al 1979; Wieser 1993). Waxing and waning may be seen in terms of time (ie, appearance and disappearance of epileptiform patterns), but also in terms of enlargement and diminution of the epileptogenic area (ie, volume). Both phenomena might be interrelated and most probably are a function of the specific properties of the neuronal population pathologically recruited into the epileptiform discharges. Commonly, specific seizure suppressing maneuvers exert a recognizable effect on the formal aspects of the EEG discharges (Wieser 1980; Wieser and Hajek 1994).

Granner and Lee analyzed EEG characteristics comprehensively in a large series (85 ictal episodes in 78 patients) of nonconvulsive status epilepticus cases (Granner and Lee 1994). The ictal discharges were generalized in 59 episodes (69%), diffuse with focal predominance in 15 (18%), and focal in 11 (13%). The morphologies and patterns of persistence varied greatly. Frequency of ictal discharge was also variable and was almost always less than 3 Hz. Several findings suggested possible focal onset with secondary generalization even in so-called "generalized cases.” This study confirmed that nonconvulsive status epilepticus is a highly heterogeneous epileptic state electrographically.

Ictal SPECT may be very helpful for localizing the discharging brain area and indeed can be easily accomplished in a status condition (Mueller et al 2001).

1H-MRS and proton density- and diffusion-weighted MRI might show changes associated with the discharging epileptic focus. Corresponding to the clinical evolution, reversible and irreversible focally abnormal metabolism can be determined with 1H-MRS, reflecting both increased neuronal activity and neuronal damage (Flacke et al 2000; Lazeyras et al 2000; Chu et al 2001).

Prolactin, luteinizing hormone, creatine-phosphokinase, neurone-specific enolase, and indicators of adenosine triphosphate depletion. Concentrations of prolactin and luteinizing hormone as well as creatine-phosphokinase in blood were reported to show a good correlation with seizure frequency (Leiderman et al 1990), and it has been suggested that an increase of prolactin would be helpful for diagnosis of epileptic seizures, with a view towards differentiating epileptic from nonepileptic events in particular. Although prolactin concentrations exceeding 700 µU/mL might significantly indicate an epileptic seizure (Bauer et al 1991), the absence of elevated prolactin levels does not exclude status epilepticus (not even a grand-mal status) and certainly not nonconvulsive partial status or absence status (Tomson et al 1989; Kurlemann et al 1990; Fichsel 1991; 1994). Moreover, prolactin was found to be elevated after nonepileptic seizures (Pohlmann et al 1991). In addition, it should not be forgotten that endocrine and neuroendocrine changes can occur as a result of antiepileptic drug therapy (Lindbom et al 1992; Krause 1993), making a comparison with concentrations of persons not treated with antiepileptic drugs rather difficult, even if circadian fluctuations are taken into consideration. In conclusion, prolactin and creatine-phosphokinase might be elevated after severe epileptic seizures, but their value for differential diagnosis of epileptic versus nonepileptic seizures is limited, and it is unlikely that they contribute much to the diagnosis of nonconvulsive partial status.

DeGiorgio and colleagues and O'Regan and Brown found elevated neuron-specific enolase, a marker of acute neuronal injury, in cerebrospinal fluid and serum during complex partial and myoclonic nonconvulsive status epilepticus (DeGiorgio et al 1996; 1999; O’Regan and Brown 1998). Livingston and colleagues studied specific and sensitive indicators of neuronal adenosine triphosphate depletion (hypoxanthine, xanthine, and uridine levels) in the cerebrospinal fluid of 9 children during nonconvulsive status epilepticus (Livingston et al 1989). These nucleotide metabolites were low during nonconvulsive status epilepticus, but this was significant only for xanthine. The authors speculatively link this reduction to a reduced neuronal protein synthesis, which could lead to intellectual deterioration.

Response to treatment. In general, response to high-dosed antiepileptic drug treatment can be used in the differential diagnosis, but there are exceptions. We have encountered patients in whom classical antiepileptic drugs of first choice, such as intravenous diazepam, did not completely suppress the localized discharges associated with simple partial status epilepticus (Wieser 1980). Intravenous diazepam may serve as a valuable diagnostic tool in differentiating generalized from focal onset nonconvulsive status epilepticus.

However, rhythmic sharp waves resulting from metabolic encephalopathy can be abolished by benzodiazepines, similar to nonconvulsive status epilepticus, without improvement in mental status (Fountain and Waldman 2001). Periodic lateralized epileptiform discharges in severe vascular brain damage are known to respond only moderately, if at all, to antiepileptic drug treatment.

Syndromes and diseases in which the seizure type occurs

Nonconvulsive status epilepticus may be hidden or missed because the behavioral change from baseline is ascribed to other causes including intoxication, postictal states, cerebral ischemia, or psychiatric conditions (Kaplan 1996).

In general, psychomotor status epilepticus is relatively rare. In a German study of 100 patients with status epilepticus, 35% had nonconvulsive status epilepticus, 33% had petit mal, and 2% had psychomotor (complex partial) status epilepticus (Forster et al 1969). In a study of first seizures in Minneapolis, 6 out of 125 patients having status epilepticus as a first seizure event experienced nonconvulsive status epilepticus (Hauser 1980; 1983).

Nonconvulsive status epilepticus has been described in a wide variety of diseases such as organ failure, electrolyte imbalance, peritoneal dialysis (Chow et al 2001), hypersensitive encephalopathy, and epileptic encephalopathy (Ruegg and Dichter 2003). It also has been reported in stroke (Afsar et al 2003), with subarachnoid hemorrhage (Dennis et al 2002), malignant tumor (Chang et al 2001), cortical dysplasia (Mueller et al 2001; Ng et al 2003; Yoshimura 2003), the ring chromosome 20 syndrome (Petit 1999; Augustijn et al 2001), pituitary apoplexy (Craig and Gibson 2000), Lafora body disease (Corkill and Hardie 1999), multiple sclerosis (Maingueneau et al 1999), hypocalcemia (Kline et al 1998) and after its treatment (Kumpfel et al 2000), as well as in connection with HIV infection (Lechner et al 1998), as a complication of Mycoplasma pneumoniae infection (Jeffery et al 1995), resulting from Jarisch-Herxheimer reaction in a patient with neurosyphilis (Kojan et al 2000), with systemic lupus erythematosus (Fernandez-Torre et al 2003), and in mentally retarded adults induced by recurrent rectal diazepam overadministration (Brodtkorb et al 1993).

Medication and medication withdrawal have been repeatedly reported as inducers of nonconvulsive status epilepticus (Delanty et al 1998). Examples are microvascular endothelial cell chemotherapy of urothelial cancer (Meessen et al 1990), cyclosporine treatment (Delpont et al 1990), ifosfamide (Primavera et al 2002), cephalosporins (Dixit et al 2000; Martinez-Rodriguez et al 2002), and intrathecal fluorescein injection (Coeytaux et al 1999). Nonconvulsive status epilepticus was described as a complication of electroconvulsive therapy (Rao et al 1993; Solomons et al 1998; Szrich and Turbott 2000; Parker et al 2001), and induced by various drugs, mainly psychotropic agents (Yoshino 2000) such as antidepressants (Miyata et al 1997), neuroleptics, ketamine (which has anticonvulsive and proconvulsive actions) (Kugler and Doenicke 1994), morphine (Bertran et al 2000), and antiepileptics such as tiagabine (Schapel and Chadwick 1996; Holtkamp et al 1999; Knake et al 1999; Balslev et al 2000; Fitzek et al 2001; de Borchgrave et al 2003). In most instances tiagabine-induced nonconvulsive status epilepticus is absence status (Knake et al 1999). Abrupt withdrawal of hypnotic-sedative drugs, benzodiazepines in particular, may provoke nonconvulsive status epilepticus (Emre et al 1985; Yoshino 2000). Nonconvulsive status epilepticus has also been reported after replacement of valproate with lamotrigine (Fernandez-Torre 2001; Trinka et al 2002).

Little is known on partial status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms only. Arroyo, Cockerell and colleagues, and Rey and Papy have emphasized the "critical confusional state of frontal origin in elderly” (Rey and Papy 1987; Cockerell et al 1994; Arroyo 1997). Mewe and colleagues discussed the misdiagnosis of nonconvulsive status epilepticus as posttraumatic exogenous psychosis (Mewe et al 1989). Sailer and colleagues elaborated on the difficult question of whether prodromal manifestations and episodic symptoms are nonspecific complaints, or whether they represent nonconvulsive status epilepticus (Sailer et al 1991).

Prognosis and complications

Sequelae associated with status epilepticus are best documented with convulsive status epilepticus, but might also be associated with certain types of nonconvulsive status epilepticus, particularly psychomotor (complex partial) status epilepticus (Krumholz 1999).

There is increasing experimental as well as clinical evidence that generalized convulsive status epilepticus produces lasting neuropathological damage in the hippocampus, neocortex, and cerebellum due to associated metabolic failure. Cerebellar (Purkinje and basket cell) damage was related particularly to hyperpyrexia and hypotension, and was prevented by control of the systemic metabolic derangements (ie, hyperpyrexia, hypotension, hypoxia, acidosis, and hypoglycemia) (Meldrum et al 1973; DeGiorgio et al 1992).

Morbidity and mortality in relation to etiology. In contrast to convulsive generalized status, various age dependent syndromes of status epilepticus in neonates and children, and nonconvulsive status epilepticus in the critically ill patient after acute brain injury, morbidity and mortality is low in nonconvulsive status epilepticus. Nonconvulsive status epilepticus has been thought of as a relatively benign entity because it does not cause adverse systemic consequences of convulsive status epilepticus (Meldrum et al 1973; Simon 1985). However, taken all cases of nonconvulsive status epilepticus together (ie, including nonconvulsive status epilepticus in the critically ill patient after acute brain injury as well as emergency department studies), Treiman and colleagues found higher mortality rates in nonconvulsive status epilepticus compared to generalized convulsive epilepticus, 65% and 27% respectively (Treiman et al 1998).

Etiology is the main factor determining outcome. Other factors influencing outcomes for both convulsive and nonconvulsive status epilepticus are (1) duration, and (2) treatment of the status epilepticus, as well as (3) age of the patient. Mortality and morbidity are lower in children compared to adults: death (10% to 35%), intellectual and other neurologic morbidity (10% to 35%), chronic epilepsy (30% of children first presenting with status), and recurrent status epilepticus (15% to 20%) (Shinnar et al 1992).

Nonconvulsive status epilepticus (and focal motor seizures) at onset have been identified as risk factors for refractory convulsive status epilepticus (Mayer et al 2002).

Absence status epilepticus appears to cause no lasting effects (Niedermeyer and Khalife 1965; Andermann and Robb 1972; Thomas et al 1992; Gokyigit and Caliskan 1995).

Since classical psychomotor status epilepticus usually occurs in patients with known epilepsy, it is difficult to determine the risks and complications of psychomotor status epilepticus itself. The theoretical basis for neuronal injury resulting from psychomotor status epilepticus may be identical to that from generalized convulsive. Although most reported cases of the disorder have returned to baseline neurologic function (Mayeux and Lueders 1978; Cockerell et al 1994), several patients have had prolonged memory deficits (Engel et al 1978; Treiman and Delgado-Escueta 1983). Recently Varon and colleagues reported on a transient Kluver-Bucy syndrome following complex partial status epilepticus (Varon et al 2003). Brett reported 22 cases of minor epileptic status involving children, differentiating these cases from petit mal status by the presence of myoclonus and less frequently occurring spike-wave patterns in the EEG (Brett 1966). These status episodes lasted from days to months. Seizures preceded the onset of these status episodes in 68%. At long-term follow up, 4 of these patients had died, and only 6 patients (27%) remained intellectually normal. Degenerative neurologic syndromes were identified in 14%.

Patients with electrographic status epilepticus in the setting of serious medical illness have a terrible prognosis, but this is due mostly to serious cerebrovascular or other medical illness. A patient will naturally worsen if there is a progressive illness. In such patients, it is very difficult to dissect out that portion of the long-term harm done by epileptiform discharges or nonconvulsive status epilepticus (Privitera et al 1994; Privitera and Strawsburg 1994; So et al 1995). The existing studies are mainly pediatric and retrospective and are confounded by many variables that are difficult to control such as medication, metabolic disturbances, hypotension, and infection (Maytal et al 1989; Dodrill and Wilensky 1990; Stores et al 1995). In general, when nonconvulsive status epilepticus has been reported concurrent with acute brain injury, poor outcomes have been attributed to the acute brain injury. Nonconvulsive status epilepticus in such a constellation has been seen as an epiphenomenon, not necessarily as a contributing cause of brain damage (Kaplan 1996; Aminoff 1998a). However, recent evidence suggests, that nonconvulsive status epilepticus might significantly increase the vulnerability of the brain to permanent damage by mechanisms of secondary injury (Vespa et al 1999). Biochemical evidence supports this deleterious synergy. DeGiorgio and colleagues found the highest levels of serum neuronal enolase (a marker of neuronal injury) in patient with combined status epilepticus and acute brain injury (DeGiorgio et al 1995).

In summary, we conclude that discussion of permanent neurologic damage from nonconvulsive status epilepticus in humans remains controversial (Young and Jordan 1998; Aminoff 1998b; Drislane 1999). Taking into account various subtypes of nonconvulsive status epilepticus, the picture becomes clearer. For psychomotor (complex partial) status epilepticus several studies indicate that prolonged memory deficits can occur (Engel et al 1978; Treiman and Delgado-Escueta 1983; Krumholz et al 1995).

Management

As discussed above, psychomotor (complex partial) status epilepticus may induce long-term sequelae and might need more aggressive treatment to prevent further brain damage. Today it is widely accepted that concurrent acute brain injury and status epilepticus are synergistically deleterious (Bogousslavski et al 1992; Waterhouse et al 1998; Jordan 1999). Waterhouse and colleagues found that when status epilepticus complicates acute stroke, mortality is 3 times higher than in stroke alone (Waterhouse et al 1998). Therefore, for nonconvulsive status epilepticus in association with acute brain injury, early and intensive intervention might be necessary (Jordan 1999). The danger that patients might suffer iatrogenically from aggressive treatment makes it necessary to find a balance between the potential neurologic morbidity of nonconvulsive status epilepticus and the possible morbidity of intravenous antiepileptic drugs (Kaplan 1999). Hypotension and respiratory depression are among the most common unwarranted side effects intravenous antiepileptic drugs.

According to Shorvon, partial status epilepticus is reported to be controlled by diazepam in 88% (of 67 patients) (Shorvon 1994). Therefore, for the treatment of typical absence status epilepticus and uncomplicated complex partial status epilepticus, oral benzodiazepines are recommended (Walker 2001).

Rapid-acting anesthetic agents, such as midazolam and propofol (Begemann et al 2000), are being used more often for refractory status epilepticus, though clinical trials are lacking (Chapman et al 2001; Hirsch and Claassen 2002). The role of propofol, which has barbiturate- and benzodiazepine-like effects at the GABA-A receptor and has a potent anticonvulsant action at clinical doses, has recently been reviewed by Stecker and colleagues and Brown and Levin (Brown and Levin 1998; Stecker et al 1998).

Midazolam (MDZ) is considered an antiepileptic drug of first choice because it is short acting and, therefore, can be well titrated on prolonged infusion. The recommended regimen is for 1 or 2 bolus injections of 0.1 mg/kg to 0.3 mg/kg, to be followed by an infusion of 0.05 mg/kg to 0.4 mg/kg per hour. After intravenous injection, midazolam is widely and rapidly distributed. Distribution half-life is 15 minutes at physiological pH. The volume of distribution is 0.6 l/kg to 1.7 l/kg and is higher in women, the obese, and the elderly. Midazolam is 96% (range 94% to 98%) bound to plasma protein. It is metabolized in the liver. At steady state, the blood concentration of the metabolite (which has a shorter half-life than midazolam and contributes little to the overall antiepileptic action) is about one third that of the parent drug. Plasma clearance is 268 mL/minute to 630 mL/minute and body clearance 5.8 mL/minute to 11.1 mL/minute per kg. The elimination half life of 1.5 to 3.5 hours is prolonged to up to 10 hours in the elderly. Chronic renal failure does not strongly affect pharmacokinetics. Severe hepatic disease might, however, slow elimination. Usually mild bradycardia and usually slight fall of arterial blood pressure may occur at conventional doses. Apnea has not been reported in status, but this is clearly a potential risk (Dundee et al 1984).

Several authors have reported on the usefulness of midazolam treatment (Claasen et al.2001; Koul et al 2002; Fujikawa et al 2003). Claassen and associates have studied the efficacy of continuous intravenous midazolam for refractory nonconvulsive status epilepticus reviewing 33 episodes of refractory nonconvulsive status epilepticus in their neurologic intensive care unit over 6 years (Claassen et al 2001). All patients were monitored with continuous EEG. Midazolam infusion rates were titrated to eliminate clinical and EEG seizure activity; continuous intravenous midazolam was discontinued once patients were seizure free for 24 hours. The mean duration of status epilepticus before treatment was 3.9 days (range 0 to 17 days). In addition to benzodiazepines, 94% of patients had received at least 2 antiepileptic drugs before starting continuous intravenous midazolam. The mean loading dose was 0.19 mg/kg, the mean maximal infusion rate was 0.22 mg/kg/h, and the mean duration of continuous intravenous midazolam therapy was 4.2 days (range 1 to 14 days). Acute treatment failure (seizures 1 to 6 hours after starting continuous intravenous midazolam) occurred in 18% of episodes, breakthrough seizures (after 6 hours of therapy) in 56%, posttreatment seizures (within 48 hours of discontinuing therapy) in 68%, and ultimate treatment failure (frequent seizures that led to treatment with pentobarbital or propofol) in 18%. Breakthrough seizures were clinically subtle or purely electrographic in 89% of cases and were associated with an increased risk of developing posttreatment seizures. The authors concluded that although most patients with refractory status epilepticus initially responded to continuous intravenous midazolam, over half developed subsequent breakthrough seizures, which were predictive of posttreatment seizures and were often detectable only with continuous EEG.

As mentioned above, the situation is different in those epileptiform encephalopathies in which EEG spikes and sharp waves may not impair clinical function but merely reflect damage from severe brain injuries. In disorders such as anoxic encephalopathy or in some patients with periodic lateralized epileptiform discharges very aggressive treatment is perhaps not indicated. In periodic lateralized epileptiform discharges, increased mesiotemporal lobe metabolism has been found in 1 patient, and this has been used as an argument that periodic lateralized epileptiform discharges are manifestations of partial status epilepticus (Handforth et al 1994). Abolition of sharp waves by benzodiazepines might help to decide on treatment, but it is known that rhythmic sharp waves resulting from metabolic encephalopathy can be abolished by benzodiazepines, similar to nonconvulsive status epilepticus, without improvement in mental status suggesting that definitive electrographic diagnosis of primary nonconvulsive status epilepticus should not be based entirely on abolition of sharp waves by benzodiazepines (Fountain and Waldman 2001). Clearly, more work needs to be done regarding the significance of certain EEG patterns (particularly periodic discharges) and when and how to treat them (Hirsch and Claassen 2002).

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Abbreviations

cIV-MDZ:continuous intravenous midazolam

NMDA:N-methyl-D-aspartate

NCSE:nonconvulsive status epilepticus

PLED:periodic lateralized epileptiform discharges

PPT1:palmitoyl-protein thioesterase 1

Synonyms

Complex partial status epilepticus

Continuous status of partial seizures with complex symptomatology

Electroencephalographic status epilepticus with subtle clinical signs

Epileptic twilight states with productive-psychotic signs and symptoms

Limbic status epilepticus

Temporal lobe status epilepticus

Subtopics

Acquired epileptiform opercular syndrome

Aura continua

Continuous spikes and waves during slow wave sleep

Epilepsy with continuous spike waves during sleep

Epileptic behavioral disturbances

Epileptic psychosis

Subclinical status

Major keyword descriptors

continuous forms

discontinuous forms

epileptic twilight state

limbic system

nonconvulsive status epilepticus

psychomotor status epilepticus

seizure discharges

status epilepticus

temporal lobe

Minor keyword descriptors

alteration in mental status

behavioral change

cognitive abnormalities

depth recording

EEG seizure pattern

ictal activity

ongoing discharge

Age of presentation

06-12 years

13-18 years

19-44 years

45-64 years

65+ years

Age of typical presentation

06-12 years

13-18 years

19-44 years

45-64 years

Permuted topic, synonyms, variants

Limbic status epilepticus (psychomotor status)

Limbic status epilepticus

staus epilepticus, Limbic

psychomotor status

epilepticus, Complex partial status

partial status epilepticus, Complex

status epilepticus, Complex partial

seizures with complex symptomatology, Continuous status

status epilepticus with subtle clinical signs, Electroencephalographic

epilepticus with subtle clinical signs, Electroencephalographic status

twilight states with productive-psychotic signs and symptoms, Epileptic

productive-psychotic signs and symptoms, Epileptic twilight states with

psychotic signs and symptoms, Epileptic twilight states with productive

Temporal lobe status epilepticus

opercular syndrome, Acquired epileptiform

epileptiform opercular syndrome, Acquired

continua, Aura

sleep, Continuous spikes and waves during slow wave

continuous spike waves during sleep, Epilepsy with

disturbance, Epileptic behavioral

behavioral disturbance, Epileptic

psychosis, Epileptic

status, Subclinical

Related topics

Benign epilepsy of infancy with partial seizures

Benign myoclonic epilepsy in infancy

Electrical status epilepticus during slow sleep

HIV-associated dementia

Lennox-Gastaut syndrome

Migrating partial epilepsy in infancy

West syndrome

Differential diagnosis

focal neurologic deficits

Wernicke aphasia

neuropsychiatric manifestations

confusion

learning difficulties

absence status