Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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The most recent classification of seizure types by the International League Against Epilepsy (ILAE) proposed to eliminate the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized seizures (94). The term focal seizures with impaired awareness substituted that of complex partial seizures (94). However, this position paper of the ILAE commission for classification and terminology did not consider “dyscognitive” as a synonym for “complex partial” (94).
The term dyscognitive seizures was described by Lüders and colleagues as seizures causing “interference of high cognitive functions essential for fully intact consciousness, including alterations of praxis (apraxia), language (aphasia), and the patient's ability to form memories (amnesia). These alterations of consciousness do not affect the arousal system or postural muscle tone, and the patient remains partially aware of the external and internal environment, even if the alterations of cognition may interfere somewhat with its perception. Dyscognitive seizures are best identified by listing the specific cognitive disturbance (apraxic seizures, aphasic seizures, amnestic seizures, and so on)” (187). Thus, dyscognitive seizures could be translated as focal seizures with impaired awareness that do not affect the arousal system or postural muscle tone. However, most of the studies discussed herein do not differentiate dyscognitive status from focal status epilepticus with impaired awareness that affect the arousal system or postural muscle tone. In keeping with the most recent ILAE proposal, we will use here the term focal seizures with impaired awareness or focal unaware seizures instead of dyscognitive seizures (94).
Focal unaware status 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 focal unaware 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 focal unaware status epilepticus and to differentiate it from generalized nonconvulsive status epilepticus (absence status). Causes of focal unaware 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 focal unaware status epilepticus.
• Focal unaware 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.
• Focal unaware epilepticus, as in other types of status epilepticus, is defined as focal unaware seizures lasting 10 minutes or longer. However, a clinical operational definition of 5 minutes of continuous seizure provides an appropriate indication for initiating treatment.
• Focal unaware 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 focal unaware 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 (35). The proceedings of the 10th Marseilles Colloquium of 1962 represent the first book on this subject (104). 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" (297). 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" (228). Bright, as well as Charcot, described fugue states, and Hughlings Jackson described such a condition in temporal lobe epilepsy (30; 41; 281).
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" (220). 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 (177; 178).
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 (173; 102).
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 (138; 338).
Major reviews on status epilepticus were the Santa Monica, California Conference (120) and the Seventeenth Annual Merritt-Putnam in Boston, which was published as a supplement to Epilepsia (66; 188). In the same year, 5 position papers on nonconvulsive status epilepticus were published in the Journal of Clinical Neurophysiology (146). Comprehensive reviews on the behavioral manifestations, presentation, evaluation, and treatment followed (75; 147; 159).
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 (258; 258), and a new proposal for definition and classification of status epilepticus was proposed by a ILAE task force (291).
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 (101; 239; 105). A widely accepted operational definition of status epilepticus was that of a condition in which epileptic activity persists for 30 minutes or more (276). The ILAE Task Force on Classification of Status Epilepticus proposed a new definition of status epilepticus to account for the heterogeneous etiology, phenomenology, and prognosis of nonconvulsive status epilepticus (291). This definition incorporates elements of time (termed T1 and T2) and 4 additional axes (semiology, etiology, EEG correlate, and age). T1 indicates when seizures need to be acutely treated (eg, 10 minutes for focal status epilepticus with impaired awareness and 10 to 15 minutes for absence status epilepticus). T2 indicates the time at which the likelihood of permanent neuronal injury increases, and more aggressive therapy may be justified (more than 60 minutes for focal status epilepticus with impaired awareness and unknown for absence status epilepticus) (291).
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 (36; 137; 287; 152). At least 10% of patients with epilepsy suffer a status epilepticus during the course of their disease, and 50% of status epilepticus appears in patients with no known history of epilepsy (248). Status epilepticus is more frequent in developmental and epileptic encephalopathies and epilepsies with structural etiologies, 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 types and syndromes. Tonic-clonic status epilepticus is the best-known type, and its diagnosis is simple, but focal 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 (248; 28; 160; 254).
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 (148; 259). Based on ictal EEG, a classical separation is: (1) absence status and (2) focal unaware status epilepticus. The differential diagnosis is difficult on the basis of clinical semiology alone. Absence status can complicate many epileptic syndromes; it is characterized by confusion of varying intensity and is associated in 50% of cases with bilateral myoclonia (283). The EEG shows ictal generalized paroxysmal activity; normalization is obtained after benzodiazepine injection.
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 as, for example, lateralized periodic discharges (LPDs) or periodic lateralized epileptiform discharges (PLEDs) in the EEG (42; 209; 179). LPDs are a matter of controversy, and many authors believe that this EEG pattern reflects severe cerebral dysfunction rather than epileptic activity (135; 294; 179). However, when LPDs occur in a comatose patient after a generalized tonic-clonic status epilepticus, the diagnosis of nonconvulsive status epilepticus should be considered. By contrast, LPDs or continuous EEG abnormalities in the context of acute cerebral damage, such as stroke or anoxic or traumatic brain damage, are more difficult to interpret (274; 135; 179). However, ictal EEG patterns with a typical spatiotemporal evolution faster than 2.5 Hz in a comatose patient reflect nonconvulsive seizures or nonconvulsive status epilepticus and should be treated (294).
The 2006 proposal of the ILAE Classification Core Group (81), 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) focal unaware (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 focal unaware 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" (81).
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 (291). 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 (291).
Focal unaware status epilepticus often begins with a history of recurrent or prolonged focal 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 focal seizures with impaired awareness, 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 focal unaware 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 10 minutes). 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 focal unaware 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
For the purpose of this article, we would like to suggest the following operational definition (Table 1): focal unaware status epilepticus is an epileptic condition (defined by clinical and electroencephalographic signs and symptoms) of at least 10 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 focal seizures without impaired awareness (aura continua), focal unaware status, and absence status epilepticus. Focal unaware status epilepticus and absence status epilepticus exhibit an epileptic twilight state of altered contact with the environment. In focal status epilepticus without impaired awareness (aura continua), 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 focal unaware 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 focal unaware status manifests itself as ictal twilight state with ongoing discharges in some (usually temporolimbic) structures.
The typical overall gestalt of a focal unaware 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 absence status (spike wave stupor) with clouded consciousness and slowed and impaired thinking. Nowack and Shaikh suggest that focal unaware status epilepticus can progress through stages (defined by EEG) analogous to those described by Treiman in generalized convulsive status epilepticus (287; 211).
Some authors have designated subtypes of focal nonconvulsive status epilepticus according to the prevailing signs and symptoms (198; 103; 328). In focal unaware 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.
The predominance of dysphasic or aphasic signs and symptoms is far less frequent but well documented as the sole manifestation of focal status epilepticus (305; 102; 118; 71; 230; 319; 206; 114; 70; 300; 47; 296; 223; 119). Kirshner and colleagues describe aphasia secondary to focal status epilepticus of the basal temporal language area (151). 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 (213). Cases where aphasia is the sole ictal symptom or long-lasting aphasia of epileptic origin, as in aphasic status epilepticus, could present a challenging diagnosis (234; 139; 144).
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 (172; 339; 171). Billard and colleagues describe 4 cases with acquired aphasia with electrical subclinical status epilepticus and acquired aphasia in epileptic children (23). Although more than 200 cases have been reported, the etiology, pathogenesis, and pathophysiology are still widely unknown (257).
Halasz and colleagues presented a unifying concept of the syndromes of self-limited 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 (116).
Symptoms and signs observed in focal unaware 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 (327). Rabending and Fischer describe nonconvulsive status epilepticus with ictal bradycardia and asystolia (235). Umbilical sensations in children and long-lasting borborygmi, widened pupils, pilomotor phenomena, goose-flesh or periodically shivering, and so on have been described (32; 301; 322; 334; 324; 325; 326; 334; 112; 272). In Panayiotopoulos syndrome, Panayiotopoulos and Koutroumanidis document recurrent autonomic status epilepticus with emesis (215; 216; 162; 282; 91). 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 (107; 324). 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 (66) or fear (127; 198).
Limbic encephalitis may present with similar autonomic features and other typical semiology of mesial temporal lobe seizures. Autonomic symptoms occur in 50% or more of patients with autoimmune encephalitis associated with leucine-rich glioma-inactivated protein 1 (LGI1) and glutamic acid decarboxylase (GAD) antibodies (143). Déjà-vu and other ictal experiential phenomena occur in patients with GAD and less frequently in N-methyl-D-aspartate receptor (NMDAR) antibodies (143). New onset focal status with experiential symptoms and acute memory complaints are more frequent in NMDAR encephalitis (143). Wieser and colleagues describe a pilomotor status epilepticus in nonparaneoplastic limbic encephalitis with antibodies to voltage-gated potassium channels (309; 336).
Evidence that long-lasting pain is a special form of focal status epilepticus is scant, but this possibility should not be completely discarded (321; 337; 249; 342; 100; 262; 253).
Sequelae associated with status epilepticus are best documented with convulsive status epilepticus, but might also be associated with certain types of nonconvulsive status epilepticus (165). The morbidity of nonconvulsive status epilepticus that follows a nonconvulsive status is high (44; 77). One study in patients with status showed that older age, long duration, and nonconvulsive status epilepticus in coma were associated with new neurologic deficits, which were predictors of long-term mortality (237).
There is 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) (200; 64).
Morbidity and mortality in relation to etiology. The previous notion that nonconvulsive status epilepticus is a relatively benign entity is not true (200; 264; 77). Treiman and colleagues found higher mortality rates in nonconvulsive status epilepticus compared to generalized convulsive epilepticus, 65% and 27% respectively (289). The outcome of nonconvulsive status epilepticus is worse in patients without previous history of epilepsy than in patients with epilepsy (227).
Etiology is the main factor determining outcome (295). 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 (77; 237). 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%) (256).
Nonconvulsive status epilepticus (and focal motor seizures) at onset have been identified as risk factors for refractory convulsive status epilepticus (195).
Absence status epilepticus appears to cause no lasting effects (Niedermeyer and Khalife 1965; 08; 284; 108).
Because classical focal unaware 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 focal unaware 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 (82; 196; 288; 49). Varon and colleagues reported on a transient Kluver-Bucy syndrome following complex partial status epilepticus (302).
It is difficult to dissect out that portion of the long-term harm done by epileptiform discharges or nonconvulsive status epilepticus from that related to the underlying illness (232; 233; 267; 343). 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 (145; 05). However, evidence suggests that nonconvulsive status epilepticus might significantly increase the vulnerability of the brain to permanent damage by mechanisms of secondary injury (306; 237). 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 (63).
For focal unaware status epilepticus, several studies indicate that prolonged memory deficits can occur (82; 288; 166; 237).
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.
Focal unaware 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 focal unaware 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 (330). 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 (330). This is in line with H2O positron emission tomography data attributing associative functions (ie, associative binding) to the hippocampal formation (123; 126; 125; 124).
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 (20). 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 (329).
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 (214).
In humans, the underlying pathophysiology of the various subtypes of nonconvulsive status epilepticus remains largely undetermined. 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 dyscognitive status epilepticus, may result from excessive recurrent inhibition through thalamocortical circuits, and, thus, would not be mediated by excitotoxic effects of NMDA activation (98; 134). Therefore, some forms of nonconvulsive status epilepticus may be more benign than others. There is some evidence of neuronal injury in focal unaware status epilepticus (122) and nonconvulsive status epilepticus associated with severe brain injury (166; 142; 344). DeGiorgio and colleagues found elevated neuro-specific enolase in cerebrospinal fluid and serum during focal unaware and myoclonic nonconvulsive status epilepticus (62; 63).
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 (52; 74; 133; 277; 14).
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 (185). With a latency of approximately 1.5 months, the rats developed spontaneous recurrent seizures and pathological changes identical to human mesial temporal sclerosis (21). 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 (207).
These models, centered on the limbic system, provide good experimental basis for suggesting that focal status epilepticus with impaired awareness may induce long-term sequelae (207). Similar conclusions may be drawn from a study of pilocarpine-induced time-limited nonconvulsive status epilepticus in rats by Krsek and colleagues (164). Sloviter and Olney and colleagues found comparable results by stimulating the perforant path (212; 266). 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 (186).
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 (110).
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 (315). 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 (57). 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 (252). 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 (252). 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 produces changes in the expression and localization of endogenous palmitoyl-protein thioesterase 1, the deficiency of which causes drastic neurodegeneration (273). 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 (238). 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 (286; 26).
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 (97; 202; 204; 09; 197). 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 (346).
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. Conversely, development of an epileptic condition enhances the susceptibility of the limbic system to trigger status epilepticus discharges.
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 (270; 129; 168; 283; 300; 159).
Classification is difficult and presently might be best accomplished along several axes (Table 2). Focal unaware 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 (128). Rona and colleagues present a semiological classification of status epilepticus focusing on the main clinical manifestations and the evolution of the status episode (240). 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 (focal non-motor with impaired awareness)
Focal nonmotor without impaired awareness (aura continua)
• Other related epileptiform encephalopathies
• Prolonged change of consciousness or behavioral function (greater than 15 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
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 (29). Most of these patients have myriad medical and metabolic problems (313).
Behavioral changes may be difficult to identify as being ictal in nature. The gold standard is continuous EEG monitoring (294; 69). Seshia and McLachlan argue that symptom abolition after surgery might be sufficient to prove the epileptic nature (253).
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 (181; 255).
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 (17). 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 (261; 53; 218).
The similarities between Landau-Kleffner syndrome and epilepsy with continuous spike-waves during slow-wave sleep are obvious (203). 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") (155). 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 (203).
The concept that electrical status epilepticus in sleep may include a large subset of developmental or acquired regressive conditions of infancy is accepted (279; 255; 72). 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 (109).
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 (278). 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; 154; 60; 86; 247). For such boundary conditions, some French authors have used the category "erratic" and have listed other rare manifestations under this category (54). Acquired opercular syndrome could be listed here (303).
Focal 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; 243; 336). 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 (318; 324). Focal status epilepticus with the expression of emotional/affective and subtle vegetative-autonomous symptoms exist (330). 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 focal limbic seizure kindling by revived memories of fires in what she called "limbic psychotic trigger reaction" (225).
Differentiating epileptic psychoses from focal unaware 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 (290). 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 focal status epilepticus with impaired awareness and 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 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.
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 focal unaware 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 (83; 150) and nonparaneoplastic], and herpes simplex encephalitis can be challenging differential diagnoses (308; 241; 347). Creutzfeldt-Jakob disease can present with focal or regional EEG abnormalities that might mimic nonconvulsive status epilepticus (51; 90; 333). Also, psychogenic status epilepticus has to be considered (217; 78), as well as metastatic CNS disease (24). 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%) (280).
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%) (246). 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; 113).
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 (45; 244). 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 (194) have been repeatedly reported as inducers of nonconvulsive status epilepticus (65). Examples are:
• Microvascular endothelial cell chemotherapy of urothelial cancer (199)
Nonconvulsive status epilepticus was described as a complication of electroconvulsive therapy (236; 268; 269; 219; 117) and induced by various drugs, mainly psychotropic agents (341) such as antidepressants (201), neuroleptics, ketamine (which has anticonvulsive and proconvulsive actions) (167), morphine (22), and antiepileptics such as tiagabine (250; 132; 153; 13; 95; 59; 136; 189; 265; 156; 310; 141). In most instances, tiagabine-induced nonconvulsive status epilepticus is absence status (153). Abrupt withdrawal of hypnotic-sedative drugs, benzodiazepines in particular, may provoke nonconvulsive status epilepticus (79; 341; 88). Nonconvulsive status epilepticus has also been reported as a result of acute carbon monoxide poisoning (33), in association with valproate-induced hyperammonemic encephalopathy (304), after replacement of valproate with lamotrigine (292), and precipitated by carbamazepine (192) and levetiracetam (11). Star fruit ingestion was also described (38) as a cause in a dialysis patient.
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 (295).
Essential clinical features. The diagnosis of focal unaware status epilepticus should be made only if clinical signs and symptoms, which last for more than 10 minutes, are accompanied by clear-cut localized EEG 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 (106; 80; 61). 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 (158). 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 (10).
EEG evidence of ictal activity. A wide spectrum of EEG ictal morphologies may be seen with nonconvulsive status epilepticus (146). 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 (135; 179).
The EEG in focal unaware 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 (330). 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 (16).
Waxing and waning as well as paroxysmal pattern changes can occur (222; 327). 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 (323; 331).
Granner and Lee analyzed EEG characteristics comprehensively in a large series (85 ictal episodes in 78 patients) of nonconvulsive status epilepticus cases (111). 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 (111), as well as a systematic review (274), 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 (205).
1H-MRS, T2-weighted fluid attenuated inversion recovery (T2-FLAIR), and diffusion-weighted (DWI) MRI. 1H-MRS, T2-FLAIR, and diffusion-weighted MRI might show changes associated with the discharging epileptic focus (96; 46). Increased signal of the cerebral cortex and subcortical structures, including hippocampus, thalamus, claustrum, caudate and splenium, on T2-FLAIR and DWI are the most common ictal MRI changes in convulsive and nonconvulsive status. These changes may be reversible, appearing within hours of seizure onset and resolving within days or weeks (191). Seizure-related MRI changes during status were associated with a higher risk of neurologic deterioration, duration of status, and worse prognosis (56).
Villalobos-Chavez and colleagues related sequential MRI changes to vasogenic and cytotoxic oedema secondary to the status with disrupture of the blood-brain barrier (307). 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 (174; 46). 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 (37).
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 (176). 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 focal status or absence status (285; 169; 15; 92; 93). Moreover, prolactin was found to be elevated after nonepileptic seizures (224). 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 (180; 163). 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 focal unaware status.
Response to treatment. In general, response to high-dosed antiseizure medications can be used in the differential diagnosis, but there are exceptions. There are patients in whom classical antiseizure medications of first choice, such as intravenous diazepam, did not completely suppress the localized discharges associated with focal status epilepticus (323). 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 (99). Periodic lateralized epileptiform discharges in severe vascular brain damage are known to respond only moderately, if at all, to antiseizure medication (274).
As discussed above, focal unaware 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 focal unaware status epilepticus, in particular for older patients with serious comorbidities. In these situations, treatment with less sedative antiseizure medications should be considered (316; 258). Aggressive treatment of status epilepticus with anesthetic drugs (thiopental, midazolam, propofol, and high-dose phenobarbital) can provide rapid seizure control, but it might lead to serious medical complications and worse outcomes (275; 06; 77).
It is widely accepted that concurrent acute brain injury and status epilepticus are synergistically deleterious (27; 317; 142). Waterhouse and colleagues found that when status epilepticus complicates acute stroke, mortality is 3 times higher than in stroke alone (317). Therefore, for nonconvulsive status epilepticus in association with acute brain injury, early and intensive intervention might be necessary (142). 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 (146; 159; 312; 295). Hypotension and respiratory depression are among the most common unwarranted side effects of intravenous antiseizure medications.
Focal status epilepticus is reported to be controlled by diazepam in 88% of 67 patients (257). Therefore, for the treatment of typical absence status epilepticus and uncomplicated complex partial status epilepticus, oral benzodiazepines are recommended (311).
Rapid-acting anesthetic agents, such as midazolam and propofol, are being used more often for refractory status epilepticus (18; 40; 130; 121). 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 (34; 271). Propofol-associated fatal myocardial failure and rhabdomyolysis has been reported by Zarovnaya and associates (345). 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 (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 (76).
Several authors have reported on the usefulness of midazolam treatment, which can be administered intravenously, intramuscular (IM), or intranasal (48; 161; 293). 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 (48). 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 (263).
Topiramate may be useful in refractory focal status epilepticus. High efficacy of rapidly titrated topiramate via nasogastric tube in 2 young children has also been reported (26). Intravenous levetiracetam might be useful in elderly patients, in particular in those with multiple medications (84; 245; 251). Intravenous sodium valproate and levetiracetam appear to be an alternative in patients with focal unaware status epilepticus, as well as in patients with liver disease, or to avoid intubation (242; 316).
The use of intravenous lacosamide as an alternative treatment in status epilepticus has been reported in retrospective case series (class IV evidence) (149; 131).
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 like anoxic encephalopathy or in some patients with periodic epileptiform discharges, very aggressive treatment is perhaps not indicated. Furthermore, the presence or absence of periodic discharges does not predict the timing of the first seizure or status in critical care patients (69). 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 (99). Clearly, more work needs to be done regarding the significance of certain EEG patterns (particularly periodic discharges) and when and how to treat them (130; 87).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
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 an honorarium from Eisai as a consultant.See Profile
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