Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of dyscognitive focal status epilepticus, complex partial status epilepticus, continuous status of partial seizures with complex symptomatology, epileptic twilight states with productive-psychotic signs and symptoms, limbic status epilepticus, psychomotor status epilepticus, and temporal lobe status epilepticus. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Dyscognitive focal (limbic, psychomotor, or complex partial) status epilepticus represents a most intriguing epileptic condition. Variable confusion and responsiveness, impaired memory of the event, fluctuating and often bizarre behavior—including automatisms—and sometimes lateralizing signs, such as aphasia, are usually present. However, if dyscognitive focal status presents only with subtle signs and symptoms of cognitive and autonomic impairment, it might be difficult to recognize and differentiate from psychiatric conditions. EEG remains essential to diagnose dyscognitive focal status epilepticus and to differentiate it from generalized nonconvulsive status epilepticus (absence status). Causes of dyscognitive focal status epilepticus include acute and chronic focal cerebral injuries, including ischemic stroke, intracranial hemorrhage, abscess, meningoencephalitis, neoplasias, malformations, and a history of epilepsy. Medications and other metabolic and systemic stressors (eg, infections, hypoxemia) may be implicated or superimposed. The list of differential diagnosis includes toxic or metabolic encephalopathy, delirium, psychiatric conditions, limbic encephalitis, and transient global amnesia. Of particular importance are the more recently described syndromes associated with antibodies against synaptic proteins that may occur with or without cancer, including limbic encephalitis with antibodies directed towards the antigens of the voltage-gated potassium channel complex (LGI1, CASPR2, Contactin-2), as well as other antibodies (to NMDA receptors [NMDARs], AMPA receptors [AMPARs], and GABA type B receptors [GABABRs]). In this updated article, the author discusses evidence about diagnosis and treatment of dyscognitive focal status epilepticus.
• Dyscognitive seizures produce impairment in cognition, including perception, attention, emotion, memory, or the ability to perform complex executive functions. The clinical presentation may not be recognized as a seizure manifestation, and EEG is crucial for diagnosis and management of dyscognitive status epilepticus.
• Dyscognitive status epilepticus, as in other types of status epilepticus, is defined as dyscognitive seizures lasting 30 minutes or longer. However, a clinical operational definition of 5 minutes of continuous seizure provides an appropriate indication for initiating treatment.
• Dyscognitive and other forms of nonconvulsive status epilepticus are often misdiagnosed. A high index of suspicion is necessary in patients who received treatment for convulsive status epilepticus and do not recover, in critically ill patients with acute encephalopathy, and in patients with focal epilepsy with inappropriate behavior of confusional state.
• The treatment of status epilepticus has potential risks, and aggressive treatment with sedation and intubation may not be appropriate for some patients with dyscognitive status epilepticus, in particular for older patients with serious comorbidities. In these situations, treatment with less sedative antiepileptic drugs should be considered.
Status epilepticus was infrequently recorded up to the dissertation of Louis Calmeil, where the expression “etat de mal” is first found, but still in the notion of generalized convulsive status epilepticus only (40). The proceedings of the 10th Marseilles Colloquium of 1962 represent the first book on this subject (113). 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 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" (319). 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" (247). Bright, as well as Charcot, described fugue states, and Hughlings Jackson described such a condition in temporal lobe epilepsy (34; 46; 305).
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" (239). 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 (188; 189).
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 were, however, for a long time controversially discussed (184; 111).
The most important early literature dealing with psychomotor status epilepticus has been focused on the phenomenological description of this condition, distinguishing the discontinuous form, characterized by the occurrence of psychomotor attacks that follow each other at 2 to 10 minute intervals, from the continuous form (149; 363).
Major reviews on status epilepticus were the Santa Monica, California Conference (130) and the Seventeenth Annual Merritt-Putnam in Boston, which was published as a supplement to Epilepsia (70; 201). In the same year, 5 position papers on nonconvulsive status epilepticus were published in the Journal of Clinical Neurophysiology (155). Comprehensive reviews on the behavioral manifestations, presentation, evaluation, and treatment followed (82; 156; 170).
The London Innsbruck Colloquia on Status Epilepticus have discussed and reviewed current advances on molecular and basic science, as well as clinical and therapeutic aspects of status epilepticus (281; 281), and a new proposal for definition and classification of status epilepticus was proposed by a ILAE task force (316).
Status epilepticus. 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 as well as the Handbook of clinical neurology and Handbook of electroencephalography and clinical neurophysiology (110; 257; 114). 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 implies 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.
It is estimated that there are between 65,000 and 150,000 cases of status epilepticus in the United States each year, and that approximately 25% are nonconvulsive (41; 148; 311; 163). 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 (268). 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 clinically is the differential diagnosis of dyscognitive focal status epilepticus, absence status epilepticus, and above all, the form termed "late-onset de novo absence status epilepticus,” which may present as confusional syndrome in the elderly (268; 31; 171; 276).
Nonconvulsive confusional status epilepticus. Nonconvulsive confusional status epilepticus has been categorized into groups having focal or generalized EEG epileptic activity and by etiology and level of consciousness, which predict outcome (157; 282). Based on ictal EEG, a classical separation is: (1) absence status and (2) psychomotor (complex partial) status epilepticus. The differential 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 (307). 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 preexisting or newly diagnosed partial epilepsy, mostly of extratemporal origin. “Transitional” forms between these 4 groups exist.
Dyscognitive focal (in the old terminology psychomotor, complex partial, temporal lobe, or limbic) status epilepticus. Psychomotor status epilepticus is characterized by continuous or rapidly recurring psychomotor (complex partial) seizure activity that may involve temporal or extratemporal - most often limbic - 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 (190; 158). In one third of cases, a frontal lesion is revealed (307).
The former conventional classification of status epilepticus was designed to parallel the seizure type classification scheme (58; 59). 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 and its revision divided partial seizures, and consequently partial status epilepticus, into "simple" and "complex" according to whether or not consciousness is retained or lost (Gastaut 1969; 109; 58). Therefore, the older term psychomotor status or temporal lobe status was replaced by complex partial status epilepticus (CPSE) and simple partial status epilepticus (SPSE). The following classification of epilepsies and epileptic syndromes include a few syndromes that might conform to the widened definition of status, eg, epilepsia partialis continua, electrical status epilepticus during slow-wave sleep (now called continuous spike-wave discharges during sleep), or Landau-Kleffner syndrome; otherwise, it is lacking a synoptic view (238; 59; 218). 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” (280).
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 (PLED) in the EEG (47; 225). PLEDs are a matter of controversy, and many authors believe that this EEG pattern reflects severe cerebral dysfunction rather than epileptic activity. However, when PLED occurs in a comatose patient after a generalized tonic-clonic status epilepticus, the diagnosis of subtle status epilepticus should be considered. By contrast, PLED or continuous EEG abnormalities in the context of acute cerebral damage, such as anoxic or traumatic brain damage, are more difficult to interpret (299).
Because 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.
The 2006 proposal of the ILAE Classification Core Group (87), an attempt to complete the earlier work of the Task Force on Classification and Terminology, differentiates "self-limited epileptic seizure types" from "Status epilepticus". Under "Status epilepticus," this report lists 9 headings: (I) epilepsia partialis continua of Kojevnikov, (II) supplementary motor area (SMA) status epilepticus, (III) aura continua, (IV) dyscognitive focal (psychomotor, complex partial) status epilepticus, (V) tonic-clonic status epilepticus, (VI) absence status epilepticus, (VII) myoclonic status epilepticus, (VIII) tonic status epilepticus, and (IX) subtle status epilepticus.
The category (IV) dyscognitive focal (psychomotor, complex partial) is divided into (A) mesial temporal and (B) neocortical. The explanatory text for these 2 subtypes is as follows: "Mesial temporal: Focal status epilepticus, predominantly involving mesial limbic structures, consists of serial dyscognitive focal ictal events without return of clear consciousness in between. Onset can be limited to one side, or can alternate between hemispheres,” and "Neocortical: Focal status epilepticus originating in various neocortical regions can present with a wide variety of unpredictable clinical patterns. Status epilepticus from some frontal foci can resemble absence status or generalized tonic-clonic status. It can present as repetitive discrete behavioral seizures. To some extent, this type of status epilepticus can reflect the neocortical region of origin. For example, occipital status epilepticus might present with unexplained blindness, whereas dysphasia or aphasia could represent focal status in language cortex" (87).
The 2015 report of the ILAE Task Force on Classification of Status Epilepticus proposes the following 4 axes for defining subtypes of status epilepticus: 1) semiology; 2) etiology; 3) EEG correlates; and 4) age (316). Ideally, every patient should be categorized according to each of these 4 axes; however, they acknowledge that this will not always be possible. Axis 1 (semiology) refers to the clinical presentation and is, therefore, the backbone of this classification. The 2 main taxonomic criteria are the presence or absence of prominent motor symptoms and the degree (qualitative or quantitative) of impaired consciousness. Those forms with prominent motor symptoms and impairment of consciousness may be summarized as convulsive as opposed to the nonconvulsive forms of status epilepticus (NCSE) (316).
Dyscognitive focal status epilepticus often begins with a history of recurrent or prolonged simple partial seizures, or it may follow or precede a generalized convulsive seizure. Patients with mesial temporal status often are confused and exhibit variable responsiveness. Memory of the event usually is impaired. Behavior may fluctuate or be bizarre. Often, patients exhibit clinical automatisms as with typical complex partial seizures, including repetitive lip-smacking, fumbling, or swallowing movements. Subtle nystagmus may be observed. The range of confusion can be great. Some patients present with mildly diminished responsiveness and others with frank stupor or a catatonic state. Aphasia and other localizing signs and symptoms (eg, dystonic hand posturing) may accompany mesial temporal dyscognitive focal status.
• Recurrent dyscognitive (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). However, a clinical operational definition of 5 minutes of continuous seizure provides an appropriate indication for initiating treatment.
• Ictal EEG with recurrent epileptiform patterns like those seen in isolated dyscognitive (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 (312; 176)
For the purpose of this article, we would like to suggest the following operational definition (Table 1): dyscognitive focal (psychomotor, complex partial) status epilepticus is an epileptic condition (defined by clinical and electroencephalographic signs and symptoms) of at least 30 minutes or more in 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 (2) (in the case of more diffuse and difficult-to-describe personality and behavioral changes) 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), dyscognitive (complex partial), and absence status epilepticus. Dyscognitive focal status epilepticus and absence status epilepticus exhibit an epileptic twilight state of altered contact with the environment. In simple partial status epilepticus, no impairment of consciousness occurs, and the behavior changes reflect focal ictal discharges confined to a circumscript area of the cortex.
Onset can be sudden or insidious. In the best documented cases, the dyscognitive 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 dyscognitive focal mesial temporal (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 per second 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 (Treiman 1966; 227).
Some authors have designated subtypes of partial nonconvulsive status epilepticus according to the prevailing signs and symptoms (212; 112; 352). In dyscognitive focal status, the following categories of signs and symptoms can prevail: 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" (272).
The predominance of dysphasic or aphasic signs and symptoms is far less frequent but well documented as the sole manifestation of focal status epilepticus (328; 111; 127; 76; 249; 342; 222; 123; 75; 322; 51; 318; 242; 129). Kirshner and colleagues describe aphasia secondary to partial status epilepticus of the basal temporal language area (162). Ozkaya and colleagues describe aphasic status epilepticus with periodic lateralized epileptiform discharges in a bilingual patient with a clinical course, which supports the belief that a second language area for a second language learned in later stages of life is located in an area of the brain different from that for the native language (230).
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 (183; 364; 182). Billard and colleagues describe 4 cases with acquired aphasia with electrical subclinical status epilepticus and acquired aphasia in epileptic children (26). Although more than 200 cases have been reported, the etiology, pathogenesis, and pathophysiology are still widely unknown (280).
Halasz and colleagues presented a unifying concept of the syndromes of benign focal childhood epilepsies, Landau-Kleffner syndrome, and electrical status epilepticus in sleep, treating them as a spectrum of disorders with a common transient, age-dependent, nonlesional, genetically based epileptogenic abnormality (125).
Symptoms and signs observed in dyscognitive focal status epilepticus of the neocortical subtype usually reflect the functional specialization of the neocortical area of origin.
It is well known that autonomic symptoms can be the leading ictal feature (351). Rabending and Fischer describe nonconvulsive status epilepticus with ictal bradycardia and asystolia (253). Umbilical sensations in children and long-lasting borborygmi, widened pupils, pilomotor phenomena, goose-flesh or periodically shivering, and so on have been described (36; 323; 345; 358; 348; 349; 350; 358; 121; 296). In Panayiotopoulos syndrome, Panayiotopoulos and Koutroumanidis document recurrent autonomic status epilepticus with emesis (233; 234; 173; 306; 97). Autonomic status epilepticus is often accompanied by certain peculiarities of personality and behavior; therefore, we describe autonomic phenomena in the context of limbic dyscontrol syndrome (116; 348). Common overt or subtle behavioral changes are irritability, fear, panic, and sometimes existential emptiness or some other form of pathological self-perception. Particularly rare ictal or status symptoms, however, are aggression (70) or fear (138; 212).
Limbic encephalitis may sometimes present with similar autonomic features but usually is treated as a separate entity (160). Wieser and colleagues describe a pilomotor status epilepticus in nonparaneoplastic limbic encephalitis with antibodies to voltage-gated potassium channels (332; 360).
Evidence that long-lasting pain is a special form of partial status epilepticus is scant, but this possibility should not be completely discarded (344; 361; 269; 369; 106; 285; 274).
Hemicrania epileptica is a rare ictal phenomenon that may last 30 to 50 minutes or longer and, therefore, can then be labeled as a form of status epilepticus (147; 08).
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 (176).
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) (214; 68).
Morbidity and mortality in relation to etiology. In contrast to convulsive generalized status, various age-dependent syndromes of status epilepticus in neonates and children, as well as 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 (214; 287). However, when all cases of nonconvulsive status epilepticus were taken into account (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 (313). In fact, the outcome of nonconvulsive status epilepticus is worse in patients without previous history of epilepsy than in patients with epilepsy (246).
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%) (279).
Nonconvulsive status epilepticus (and focal motor seizures) at onset have been identified as risk factors for refractory convulsive status epilepticus (208).
Absence status epilepticus appears to cause no lasting effects (Niedermeyer and Khalife 1965; 09; 308; 117).
Because classical dyscognitive status epilepticus usually occurs in patients with known epilepsy, it is difficult to determine its risks and complications. The theoretical basis for neuronal injury resulting from dyscognitive status epilepticus may be identical to that from generalized convulsive. Although most reported cases of the disorder have returned to baseline neurologic function, several patients have had prolonged memory deficits (88; 209; 312; 53). Varon and colleagues reported on a transient Kluver-Bucy syndrome following complex partial status epilepticus (325). 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 (33). These status episodes lasted from days to months. Seizures preceded the onset of these status episodes in 68%. At long-term followup, 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 difficult to dissect out that portion of the long-term harm done by epileptiform discharges or nonconvulsive status epilepticus (251; 252; 290). 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 (210; 79; 297). 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 (154; 05). However, evidence suggests that nonconvulsive status epilepticus might significantly increase the vulnerability of the brain to permanent damage by mechanisms of secondary injury (329). Biochemical evidence supports this deleterious synergy. DeGiorgio and colleagues found the highest levels of serum neuronal enolase (a marker of neuronal injury) in patients with combined status epilepticus and acute brain injury (67).
In summary, we conclude that discussion of permanent neurologic damage from nonconvulsive status epilepticus in humans remains controversial (06; 370; 81). Taking into account various subtypes of nonconvulsive status epilepticus, the picture becomes clearer. For dyscognitive status epilepticus, several studies indicate that prolonged memory deficits can occur (88; 312; 177).
A 43-year-old man is brought to the emergency room by paramedics because he was seen in a shopping mall “confused,” exhibiting inappropriate behavior, and unable to speak clearly. The attending physician prescribed haloperidol, which worsened his confusion and made him fluctuate between agitation and somnolence. Later on a family member arrived at the hospital and informed that the patient had temporal lobe epilepsy and may have forgotten to take his medications. A neurologist was called for consultation and ordered an EEG that showed diffuse slow waves and frequent rhythmic sharp waves in the temporal lobes, as well as repetitive ictal discharges over the left temporal lobe region. He was given intravenous diazepam with improvement of the EEG seizure activity. After receiving a loading dose of intravenous phenytoin, he gradually improved his cognition and was back to normal 12 hours later.
Dyscognitive status epilepticus is pleomorphic and often misdiagnosed. This diagnosis should always be considered in patients with focal epilepsies with abrupt inappropriate behavior of confusional state, as well as in patients who received treatment for convulsive status epilepticus and do not recover, and in critically ill patients with acute brain damage.
It is obvious that dyscognitive focal status epilepticus of the mesial temporal subtype 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 (354). 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 (354). This is in line with H2O positron emission tomography data attributing associative functions (ie, associative binding) to the hippocampal formation (134; 137; 136; 135).
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 (22). 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 (353).
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 reemphasized by Livingston and Escobar (365; 195).
Excepting a few illustrations with prolonged discharges in the anterior cingulate gyrus associated with confusion and emotional and autonomous signs and symptoms and a few cases with kakosmia from frontal orbital cortices, little evidence exists on the existence of isolated limbic status epilepticus in areas other than the temporal lobe (347; 348; 362).
Dyscognitive focal status epilepticus of the neocortical subtype usually reflects the functional specialization of the neocortical area of origin, ie, it is associated with a rather specific pattern of signs and symptoms.
The role of the insular cortex in dyscognitive focal status epilepticus is not well established. Insular cortex 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 (231).
In humans, the underlying pathophysiology of the various subtypes of nonconvulsive status epilepticus has not been investigated in detail, so most conclusions remain speculative. Because the prolonged 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 (104; 145). Therefore, some forms of nonconvulsive status epilepticus may be more benign than others. There is some evidence of neuronal injury in complex partial status epilepticus (133) and nonconvulsive status epilepticus associated with severe brain injury (177; 152; 371). DeGiorgio and colleagues found elevated neuro-specific enolase in cerebrospinal fluid and serum during complex partial and myoclonic nonconvulsive status epilepticus (66; 67).
With the wide availability of magnetic resonance imaging and positron emission tomography, a large amount of peri- and post-ictal changes on both anatomic and functional imaging examinations has been recognized (56; 80; 144; 301; 16).
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 (198). With a latency of approximately 1.5 months, the rats developed spontaneous recurrent seizures and pathological changes identical to human mesial temporal sclerosis (24). Nairismagi and colleagues reported similar findings demonstrating progressive neurodegeneration in amygdala and hippocampus after status epilepticus induced in rats by electrical stimulation of the amygdala (223).
These models, centered on the limbic system, provide good experimental basis for suggesting that complex partial status epilepticus may induce long-term sequelae (223). Similar conclusions may be drawn from a study of pilocarpine-induced time-limited nonconvulsive status epilepticus in rats by Krsek and colleagues (175). 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 (198; 24). Sloviter and Olney and colleagues found comparable results by stimulating the perforant path (228; 289). 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 (277). 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 (199).
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 (119).
Van Eijsden and colleagues present a detailed study of the lithium-pilocarpine-induced status epilepticus in the rat, performing in vivo 1H magnetic resonance spectroscopy and T2-weighted and diffusion-weighted MRI (324). T2 was globally decreased, most pronounced in the amygdala and piriform cortex, in which a significant decrease in apparent diffusion coefficient was also found. In contrast, apparent diffusion coefficient values increased transiently in the hippocampus and thalamus. In the MR spectra, N-acetylaspartate and choline were decreased and lactate increased in the hippocampus. The T2 decrease, attributed to raised deoxyhemoglobin, and the presence of lactate both indicate a mismatch between oxygen demand and delivery. The apparent diffusion coefficient decrease, indicative of excitotoxicity, confirms that the amygdala and piriformic cortex are particularly vulnerable in this model. The transient apparent diffusion coefficient increase in the thalamus may reflect the breakdown of the blood-brain barrier, which occurred in this region. Neuronal damage and failure of energy-dependent formation of N-acetylaspartate are likely causes of the observed decrease in N-acetylaspartate.
Wasterlain and colleagues list 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 (338). 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 robust (62). 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 ion-gradient 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 (273). 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 (273). However, most P-glycoprotein increases seen 24 hours after status epilepticus were only transient: 10 days after the kainate-induced status epilepticus, no significant differences to controls were determined except for an increase in parenchymal P-glycoprotein expression in the dentate hilus and CA1 sector.
Suopanki and colleagues 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 (298). 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 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 (256). 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 and showed good efficacy (310; 29).
Thus, experimental evidence suggests that the brain reorganizes itself in response to excess neural activation. Contributing factors to this reorganization include activation of glutamate receptors, second messengers, immediate early genes, transcription factors, neurotrophic factors, axon guidance molecules, protein synthesis, neurogenesis, and synaptogenesis. Some of the resulting changes contribute to seizure susceptibility. Neuronal loss as a consequence of limbic status activity contributes to circuit restructuring. Loss of selective types of interneurons, alteration of GABA receptor configuration, or decrease in dendritic inhibition contribute to the development of spontaneous seizures (103; 217; 219; 10; 211). Conversely, development of an epileptic condition enhances the susceptibility of the limbic system to trigger status epilepticus discharges. An episode of status epilepticus that involves the limbic system clearly elicits brain damage, at least among adult animals. Furthermore, evidence exists that some effects of status epilepticus in rats, such as the one on hippocampal GABA-A receptors, are age-dependent (373).
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.
Some authors have argued that Landau-Kleffner syndrome, acquired epileptiform opercular syndrome, and electrical status epilepticus in sleep, classified as different clinical-EEG syndromes, represent facets of the same brain dysfunction (203; 275; 261; 326; 125). 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 and neurophysiological data, including magnetoencephalographic studies and results of neurosurgical techniques such as the multiple subpial transection (232; 231; 108; 203; 220; 291). These pieces of evidence indeed suggest that in many of these conditions, an alteration of the normal maturation of 1 or more associative cortices is the common denominator, primarily involving local interneurons and corticocortical associative neurons (203).
The acquired epileptic aphasia and related overlapping conditions are important models because they suggest that isolated cognitive and behavioral disturbances can be epileptic manifestations in children (74; 278; 107; 200) and adults (23).
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 to Wernicke aphasia, neuropsychiatric manifestations, confusion, and learning difficulties in children and adolescents (294; 140; 179; 307; 322; 170).
Classification is difficult and presently might be best accomplished along several axes (Table 2). Dyscognitive or limbic status should certainly be distinguished from absence status. The classical absence status primary criteria have been established (Table 3), but in reality, many cases are borderline or atypical (139). Rona and colleagues present a semiological classification of status epilepticus focusing on the main clinical manifestations and the evolution of the status episode (258). The clinical manifestations are subdivided into semiological components and classified along 3 axes: the type of brain function predominantly compromised by the seizure activity, the body part involved, and its evolution over time. Each axis contains several subcategories, so that many different levels of accuracy are possible.
Dyscognitive (complex partial, psychomotor)
• Other related epileptiform encephalopathies
• Electro-encephalographic status epilepticus
• Subtle status epilepticus
Note: 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 (176).
• 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 (245; 176)
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 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 (32). Most of these patients have myriad medical and metabolic problems (334).
Behavioral changes may be difficult to identify as being ictal in nature. The gold standard is EEG, but in several instances depth recordings were required to record the narrowly confined limbic discharges (354). Confirmation of nonconvulsive limbic status epilepticus with the sodium amytal test has been reported (39). Seshia and McLachlan argue that symptom abolition after surgery might be sufficient to prove the epileptic nature (274).
With nonconvulsive status epilepticus, affect and mood alteration may vary widely, alternating between a state of delirium or mania-like episodes with inappropriate laughter to depression. Patients will act strangely or have speech problems that range from the inappropriate “word salad” to mutism. Echolalia-palilalia as the sole manifestation of nonconvulsive status epilepticus and global developmental delay as the main manifestation of nonconvulsive status epilepticus in a toddler have been described (192; 278).
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 (19). 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"). Because 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, although the temporal relationship between electrical status epilepticus in sleep and the language disturbance in Landau-Kleffner syndrome is loose in other cases (284; 57; 236).
The similarities between Landau-Kleffner syndrome and epilepsy with continuous spike-waves during slow-wave sleep are obvious (218). 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") (166). According to the review of Morikawa and colleagues, continuous spike-waves during slow-wave sleep are 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 (218).
The concept that electrical status epilepticus in sleep may include a large subset of developmental or acquired regressive conditions of infancy is accepted (303; 278; 77). 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 (118).
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 (302). 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 non-REM 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 (03; 165; 72; 92; 267). For such boundary conditions, some French authors have used the category "erratic" and have listed other rare manifestations under this category (60). Acquired opercular syndrome could be listed here (326).
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 (07; 262; 360). For many, the so-called interictal personality and behavioral syndrome as well as other described personality peculiarities are also intimately linked with an active temporal lobe epilepsy (341; 348). Partial status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms exist (354). 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 fire-setting and implicated partial limbic seizure kindling by revived memories of fires in what she called "limbic psychotic trigger reaction" (244).
Differentiating epileptic psychoses from dyscognitive 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 (314). Although 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 reexamine interictal psychoses based on DSM IV Psychosis Classification and International Epilepsy Classification, Kanemoto and colleagues confirm 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 (153).
Various diseases, drugs, and other factors have been associated with nonconvulsive status epilepticus and must be considered in the list of differential diagnoses. Causes of dyscognitive focal or nonconvulsive status epilepticus are acute and chronic focal cerebral injuries, including ischemic stroke, intracranial hemorrhage, abscess, meningoencephalitis, neoplasias, malformations, and a history of epilepsy. Medications (eg, cyclosporin and lithium), other metabolic (eg, hyponatremia, hypo- and hypercalcemia, hypoglycemia) and systemic stressors (eg, infections, hypoxemia) may be implicated or superimposed. The list of differential diagnoses includes toxic or metabolic encephalopathy, delirium, psychiatric conditions, and transient global amnesia. Furthermore, limbic encephalitis [both paraneoplastic (89; 161) and nonparaneoplastic], and herpes simplex encephalitis can be challenging differential diagnoses (331; 259; 374). Creutzfeldt-Jakob disease can present with focal or regional EEG abnormalities that might mimic nonconvulsive status epilepticus (55; 96; 357). Also, psychogenic status epilepticus has to be considered (235; 84), as well as metastatic CNS disease (27). In a review of nonconvulsive status epilepticus in children, acute hypoxic-ischemic injury was the most frequent etiology (5 of 19; 26%), followed by exacerbation of underlying metabolic disease (21%), acute infection (16%), and change in antiepileptic drug regimen (16%) (304).
In general, dyscognitive status epilepticus is relatively rare or underdiagnosed. In a German study of 100 patients with status epilepticus, 35% had nonconvulsive status epilepticus, 33% had petit mal, and 2% had dyscognitive (complex partial) status epilepticus (102). 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 (130; 131).
In a retrospective review of all pediatric patients who were admitted or transferred to the PICU with an unexplained decrease in level of consciousness, no overt clinical seizures, and EEG recordings performed within 24 hours of onset of an altered state of consciousness, 23 of 141 patients who met criteria for inclusion in the study were found to have nonconvulsive status epilepticus. The largest group of patients (43%) had no preexisting neurologic condition prior to the onset of nonconvulsive status epilepticus. In the remainder, the etiology of nonconvulsive status epilepticus included acute structural brain lesion (48%), acute nonstructural brain lesion (22%), epilepsy-related seizure (13%), and others (17%) (265). Nonconvulsive status epilepticus is common in children with acute encephalopathy, and features may be misleading; therefore, a high index of suspicion and EEG are mandatory in these situations (01; 122).
Factors associated with nonconvulsive status epilepticus have been described in a wide variety of diseases such as organ failure, electrolyte imbalance, peritoneal dialysis, hypersensitive encephalopathy, and epileptic encephalopathy (49; 263). It also has been reported in the following cases:
• Stroke (02)
Afsar and colleagues identified 30 patients (out of 121 = 25%) with poststroke status epilepticus (02). Two thirds were early-onset and one third late-onset status epilepticus. Only ischemic stroke was found in the late-onset group. Nonconvulsive status epilepticus was more frequent in the early-onset group.
Medication and medication withdrawal (207) have been repeatedly reported as inducers of nonconvulsive status epilepticus (69). Examples are:
• Microvascular endothelial cell chemotherapy of urothelial cancer (213)
Nonconvulsive status epilepticus was described as a complication of electroconvulsive therapy (254; 292; 293; 237; 126) and induced by various drugs, mainly psychotropic agents (368) such as antidepressants (216), neuroleptics, ketamine (which has anticonvulsive and proconvulsive actions) (178), morphine (25), and antiepileptics such as tiagabine (270; 143; 164; 15; 100; 64; 146; 202; 288; 167; 333; 151). In most instances, tiagabine-induced nonconvulsive status epilepticus is absence status (164). Abrupt withdrawal of hypnotic-sedative drugs, benzodiazepines in particular, may provoke nonconvulsive status epilepticus (85; 368; 94). Nonconvulsive status epilepticus has also been reported as a result of acute carbon monoxide poisoning (37), in association with valproate-induced hyperammonemic encephalopathy (327), after replacement of valproate with lamotrigine (315), and precipitated by carbamazepine (205) and levetiracetam (13). Star fruit ingestion was also described (43) as a cause in a dialysis patient.
Little is known on focal status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms. Several studies have emphasized the "critical confusional state of frontal origin in elderly” (255; 53; 12). Mewe and colleagues discuss the misdiagnosis of nonconvulsive status epilepticus as posttraumatic exogenous psychosis (215). Sailer and colleagues elaborate on the difficult question of whether prodromal manifestations and episodic symptoms are nonspecific complaints, or whether they represent nonconvulsive status epilepticus (266).
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. Many difficulties exist 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 dyscognitive or limbic status epilepticus should be made only if clinical signs and symptoms, which last for more than 30 minutes, are accompanied by clear-cut localized epileptiform discharge patterns. These patterns include 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 and can combine, although often they consist of plurimodal complex experiential hallucinations and twilight states (115; 86; 65). A dyscognitive status epilepticus requires video-documentation of the behavior together with the EEG. Polygraphic recording of heart rate, respiration, and galvanic skin reflex may be useful. The so-called hairline EEG as a screening tool for nonconvulsive status epilepticus has a low sensitivity and is no longer recommended (169). Continuous video-EEG monitoring in ICU significantly improves detection of seizures and status epilepticus and is the only way to detect subclinical seizures and some forms of nonconvulsive status in comatose or confused patients (11).
EEG evidence of ictal activity. A wide spectrum of EEG ictal morphologies may be seen with nonconvulsive status epilepticus (155). 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, 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 dyscognitive or limbic status epilepticus may exhibit localized high-frequency tonic discharges restricted to limbic structures, along with fast clonic, slow clonic, or mixed pattern if invasive intracranial EEG recording techniques such as depth electrodes, foramen ovale electrodes, and subdural strips and grids are available (354). 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, but other frequencies such as alpha have also been described in generalized nonconvulsive status epilepticus, which might be viewed as a borderline form (18).
Waxing and waning as well as paroxysmal pattern changes can occur (241; 351). 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 (346; 355).
Granner and Lee analyzed EEG characteristics comprehensively in a large series (85 ictal episodes in 78 patients) of nonconvulsive status epilepticus cases (120). 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 (120), as well as a systematic review (299), demonstrate that nonconvulsive status epilepticus is a highly heterogeneous epileptic state electrographically.
Ictal SPECT. Ictal SPECT may be helpful for localizing the discharging brain area and indeed can be easily accomplished in a status condition (221).
1H-MRS and proton density- and diffusion-weighted MRI. 1H-MRS and proton density- and diffusion-weighted MRI might show changes associated with the discharging epileptic focus (101; 50). Villalobos-Chavez and colleagues related sequential MRI changes to vasogenic and cytotoxic oedema secondary to the status with disrupture of the blood-brain barrier (330). 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 (185; 50). 1H-MRS during or shortly after focal seizures shows abnormally high lactate levels in the area of seizure onset, but during absence seizures, or absence status, the lactate levels are normal (42).
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, and it has been suggested that an increase of prolactin would be helpful for diagnosis of epileptic seizures, with a view towards differentiating, in particular, epileptic from nonepileptic events (187). Although prolactin concentrations exceeding 700 µU/mL might significantly indicate an epileptic seizure, 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 (309; 180; 17; 98; 99). Moreover, prolactin was found to be elevated after nonepileptic seizures (243). In addition, it should not be forgotten that endocrine and neuroendocrine changes can occur as a result of antiepileptic drug therapy, making a comparison with concentrations of persons not treated with antiepileptic drugs rather difficult, even if circadian fluctuations are taken into consideration (191; 174). 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 (66; 67; 229). 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 (194). 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 (346). Nevertheless, 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 also can be abolished by benzodiazepines, similar to nonconvulsive status epilepticus, without improvement in mental status (105). Periodic lateralized epileptiform discharges in severe vascular brain damage are known to respond only moderately, if at all, to antiepileptic drug treatment (299).
As discussed above, dyscognitive (complex partial) status epilepticus may induce long-term sequelae and might need more aggressive treatment to prevent further brain damage. However, the treatment of status epilepticus has potential risks, and aggressive treatment with sedation and intubation may not be appropriate for some patients with dyscognitive status epilepticus, in particular for older patients with serious comorbidities. In these situations, treatment with less sedative antiepileptic drugs should be considered (339; 281). In addition, patients with status epilepticus receiving intravenous anesthetic drugs (thiopental, midazolam, propofol, and high-dose phenobarbital) have a higher proportion of infection and an increased risk of death as compared to patients not receiving intravenous anesthetic drugs (300).
Today it is widely accepted that concurrent acute brain injury and status epilepticus are synergistically deleterious (30; 340; 152). Waterhouse and colleagues found that when status epilepticus complicates acute stroke, mortality is 3 times higher than in stroke alone (340). Therefore, for nonconvulsive status epilepticus in association with acute brain injury, early and intensive intervention might be necessary (152). 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 (155; 170; 336). Hypotension and respiratory depression are among the most common unwarranted side effects of intravenous antiepileptic drugs.
Partial status epilepticus is reported to be controlled by diazepam in 88% of 67 patients (280). Therefore, for the treatment of typical absence status epilepticus and uncomplicated complex partial status epilepticus, oral benzodiazepines are recommended (335).
Rapid-acting anesthetic agents, such as midazolam and propofol, are being used more often for refractory status epilepticus (20; 45; 141; 132). 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 been reviewed by Stecker and colleagues and Brown and Levin (38; 295). Propofol-associated fatal myocardial failure and rhabdomyolysis has been reported by Zarovnaya and associates (372). Therefore, propofol infusion for the treatment of status epilepticus should be carefully weighted against its risk to develop propofol infusion syndrome. Prolonged propofol infusion at high doses for the treatment of status epilepticus should be used with caution, and in all cases careful monitoring for rhabdomyolysis and acidosis must be performed. Midazolam and lidocaine for status epilepticus in neonates has been analyzed by Yamamoto and colleagues (366).
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 to 0.3 mg/kg, to be followed by an infusion of 0.05 to 0.4 mg/kg per hour. It is metabolized in the liver. 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. However, severe hepatic disease might slow elimination. Usually mild bradycardia and 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 (83).
Several authors have reported on the usefulness of midazolam treatment, which can be administered intravenously, intramuscular (IM), or intranasal (Claasen et al 2001; 172; 107; 317). 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 (52). 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 per hour, 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. A double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults and concluded that intramuscular midazolam is as safe and effective as intravenous lorazepam for prehospital seizure cessation (286).
Topiramate may be useful in refractory partial status epilepticus. High efficacy of rapidly titrated topiramate via nasogastric tube in 2 young children has also been reported (29). Intravenous levetiracetam might be useful in elderly patients, in particular in those with multiple medications (90; 264; 271). Intravenous sodium valproate and levetiracetam appear to be an alternative in patients with dyscognitive status epilepticus, as well as in patients with liver disease, or to avoid intubation (260; 339).
The use of intravenous lacosamide as an alternative treatment in status epilepticus has been reported in retrospective case series (class IV evidence) (159; 142).
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 (128). 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 (105). Clearly, more work needs to be done regarding the significance of certain EEG patterns (particularly periodic discharges) and when and how to treat them (141; Ferlisi and Shorvon 2012).
Fernando Cendes MD PhD
Dr. Cendes of the University of Campinas - UNICAMP has no relevant financial relationships to disclose.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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