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Which EEG patterns in coma are nonconvulsive status epilepticus?

  • Eugen Trinka
    Correspondence
    Corresponding author at: Department of Neurology, Paracelsus Medical University, Ignaz Harrer Strasse 79, A-5020 Salzburg, Austria. Tel.: +43 662 4483 3001; fax: +43 662 4483 3004.
    Affiliations
    Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria

    Centre for Cognitive Neuroscience, Salzburg, Austria
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  • Markus Leitinger
    Affiliations
    Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria
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Open AccessPublished:July 03, 2015DOI:https://doi.org/10.1016/j.yebeh.2015.05.005

      Highlights

      • Nonconvulsive status epilepticus is a common problem in comatose and critically ill patients.
      • The prognostic implications of status epilepticus, or status like EEG patterns in coma are unclear.
      • In this paper we review the EEG patterns in coma and nonconvulsive status epilepticus.
      • We propose new diagnostic criteria for EEG in nonconvulsive status epilepticus.

      Abstract

      Nonconvulsive status epilepticus (NCSE) is common in patients with coma with a prevalence between 5% and 48%. Patients in deep coma may exhibit epileptiform EEG patterns, such as generalized periodic spikes, and there is an ongoing debate about the relationship of these patterns and NCSE. The purposes of this review are (i) to discuss the various EEG patterns found in coma, its fluctuations, and transitions and (ii) to propose modified criteria for NCSE in coma.
      Classical coma patterns such as diffuse polymorphic delta activity, spindle coma, alpha/theta coma, low output voltage, or burst suppression do not reflect NCSE. Any ictal patterns with a typical spatiotemporal evolution or epileptiform discharges faster than 2.5 Hz in a comatose patient reflect nonconvulsive seizures or NCSE and should be treated. Generalized periodic diacharges or lateralized periodic discharges (GPDs/LPDs) with a frequency of less than 2.5 Hz or rhythmic discharges (RDs) faster than 0.5 Hz are the borderland of NCSE in coma. In these cases, at least one of the additional criteria is needed to diagnose NCSE (a) subtle clinical ictal phenomena, (b) typical spatiotemporal evolution, or (c) response to antiepileptic drug treatment. There is currently no consensus about how long these patterns must be present to qualify for NCSE, and the distinction from nonconvulsive seizures in patients with critical illness or in comatose patients seems arbitrary.
      The Salzburg Consensus Criteria for NCSE [
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ] have been modified according to the Standardized Terminology of the American Clinical Neurophysiology Society [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ] and validated in three different cohorts, with a sensitivity of 97.2%, a specificity of 95.9%, and a diagnostic accuracy of 96.3% in patients with clinical signs of NCSE. Their diagnostic utility in different cohorts with patients in deep coma has to be studied in the future.
      This article is part of a Special Issue entitled “Status Epilepticus”.

      Keywords

      1. Introduction

      Consciousness is maintained through the integrity of the ascending reticular system, the thalamus and its cortical connections, and the temporolimbic system. Structural or functional impairment of the ascending reticular system, either directly or indirectly, leads to profound disturbances of quantitative consciousness or coma. The various EEG patterns in coma correlate with the degree of impairment of consciousness and the depth of coma [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ] and have been used for several decades to prognosticate the outcome of coma. However, the characteristic EEG patterns are by no means specific for the etiology of coma [
      • Synek V.M.
      Value of a revised EEG coma scale for prognosis after cerebral anoxia and diffuse head injury.
      ,
      • Synek V.M.
      Revised EEG, coma scale in diffuse acute head injuries in adults.
      ,
      • Synek V.M.
      Validity of a revised EEG coma scale for predicting survival in anoxic encephalopathy.
      ,
      • Synek V.M.
      EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults.
      ,
      • Synek V.M.
      Prognostically important EEG coma patterns in diffuse anoxic and traumatic encephalopathies in adults.
      ,
      • Rossetti A.O.
      • Oddo M.
      • Liaudet L.
      • Kaplan P.W.
      Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.
      ]. Its causes encompass a wide range of etiologies, such as supratentorial or infratentorial space occupying lesions, toxic/metabolic causes, infections, or inflammatory causes, brain trauma, stroke, and hypoxic–ischemic brain injury after cardiopulmonary arrest (CPA) [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ]. As an example, a burst suppression pattern may be caused by intoxication with barbiturates or by hypoxic brain injury. While the former is completely reversible, for example, with anesthesia, the latter may lead almost invariably to death, persistent vegetative state, or minimal conscious state. Thus, the prognosis of coma is to the largest extent dependent on its cause and not its depth. It is well recognized that there are often epileptic causes of coma: generalized tonic–clonic seizures are followed by a short and transient phase of postictal coma [
      • Shorvon S.
      • Trinka E.
      Nonconvulsive status epilepticus and the postictal state.
      ]. More prolonged phases of a decreased level of consciousness are found with various types of nonconvulsive SE (NCSE) [
      • DeLorenzo R.J.
      • Waterhouse E.J.
      • Towne A.R.
      • Boggs J.G.
      • Ko D.
      • DeLorenzo G.A.
      • et al.
      Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
      ,
      • Bauer G.
      • Aichner F.
      • Mayr U.
      Non-convulsive status epilepticus following generalized tonic–clonic seizures.
      ], such as complex focal SE (or SE with impaired consciousness), but they rarely reach deeper stages of coma, especially in patients with a previous epilepsy diagnosis. In case of prolonged refractory and super-refractory SE, the patient is deeply comatose as a rule, with only minor motor phenomena, or even complete absence of clinical signs of SE. The causes of SE are largely overlapping with the causes of coma, but the epileptic activity may lead to an additional disturbance of consciousness, a deeper stage of coma, and, potentially, also to additional brain damage [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ].
      In a recently published ILAE proposal, status epilepticus (SE) is defined as “Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures”. Like seizures, SE too is a clinically defined event, and its EEG correlates are confirmatory in most cases, but the EEG may also be normal or non-specific (without ictal discharges) in other forms of SE, such as in aura continua. While clinical recognition of convulsive forms of SE is not difficult, the diagnosis of NCSE is not straightforward. Nonconvulsive status epilepticus encompasses a wide range of conditions with “reduced or altered consciousness, behavioral, vegetative, or merely subjective symptoms, such as auras, but without major convulsive movements” [
      • Drislane F.W.
      Presentation, evaluation, and treatment of nonconvulsive status epilepticus.
      ]. When ictal manifestations of NCSE are mild or nonspecific, such as in delirium or confusional states [
      • Shorvon S.
      • Trinka E.
      Nonconvulsive status epilepticus and the postictal state.
      ], or purely subjective [
      • Bauer G.
      • Dobesberger J.
      • Bauer R.
      • Embacher N.
      • Benke T.
      • Unterberger I.
      • et al.
      Prefrontal disturbances as the sole manifestation of simple partial nonconvulsive status epilepticus.
      ], or the patient is in deeper stages of coma, the diagnosis cannot be made reliably without EEG [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ]. In refractory (or advanced) convulsive status epilepticus, the patients' condition evolve into a comatose or subcomatose state with only subtle or hardly discernible clinical phenomena [
      • Bauer G.
      • Aichner F.
      • Mayr U.
      Non-convulsive status epilepticus following generalized tonic–clonic seizures.
      ,
      • Clark L.P.
      • Prout T.P.
      Status epilepticus: a clinical and pathological study in epilepsy. [An article in 3 parts.].
      ,
      • Clark L.P.
      • Prout T.P.
      Status epilepticus: a clinical and pathological study in epilepsy [part 1].
      ,
      • Clark L.P.
      • Prout T.P.
      Status epilepticus: a clinical and pathological study in epilepsy [part 3].
      ,
      • Treiman D.M.
      • DeGiorgio C.M.A.
      • Salisbury S.M.
      • Wickboldt C.L.
      Subtle generalized convulsive status epilepticus.
      ]. Treiman et al. coined the term “subtle SE” for this condition to emphasize the electroclinical dissociation with decreasing motor phenomena and ongoing ictal EEG activity [
      • Treiman D.M.
      • DeGiorgio C.M.A.
      • Salisbury S.M.
      • Wickboldt C.L.
      Subtle generalized convulsive status epilepticus.
      ]. In these cases, the EEG confirms the clinical diagnosis of NCSE. The two extremes of the spectrum of NCSE have been beautifully described by Fujikawa as “The Walking Wounded and the Ictally Comatose” [
      • Fujikawa D.G.
      The two faces of electrographic status epilepticus: the walking wounded and the ictally comatose.
      ], giving words to Niedermeyer's metaphor of the Janus head of NCSE (Fig. 1) [
      • Niedermeyer E.
      • Ribeiro M.
      Considerations of nonconvulsive status epilepticus.
      ]. On one end of the spectrum is absence SE or focal SE with only mild impairment of consciousness; on the other end are the comatose forms of NCSE, such as “subtle” SE, or the deeply comatose patients with epileptiform EEG discharges. Bauer and Trinka [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ] have discussed the relationship between the degree of impairment of consciousness, down to the level of coma, the structural pathology of the underlying etiology, and the contribution of the functional impairment caused (or reflected) by the ictal discharges (Fig. 2). They suggested the terms NCSE-proper, summarizing absence SE, focal SE with or with impairment of consciousness, aphasic SE, and aura continua and comatose-NCSE, where the patient is deeply comatose and only mild motor phenomena, such as epileptic nystagmus, mild myoclonus, or unequivocal ictal EEG discharges, allow the positive diagnosis. Patients in deep coma, with epileptiform EEG discharges, but without a clear ictal evolution and no response to treatment were classified as having coma with lateralized epileptiform discharges or coma with generalized epileptiform discharges (coma-LEDs and coma-GEDs, respectively) [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ].
      Figure thumbnail gr1
      Fig. 1Cartoon depicting the similarities of EEG patterns in absence status and generalized periodic discharges in the comatose patients (from 22, ).
      Figure thumbnail gr2
      Fig. 2The relationship of the depth of coma and the contribution of the epileptic activity during nonconvulsive status epilepticus (modified from 14, ). Abbreviations: AS: absence status epilepticus, EPC: epilepsia partialis continua, GPDs: generalized periodic discharges, IGE: idiopathic generalized epilepsy, LPDs: lateralized periodic discharges, NCSE: nonconvulsive status epilepticus.
      In this review, we will follow this classification and adopt the new standardized terminology (Table 1); hence, we call these conditions coma with lateralized periodic discharges (coma-LPDs) and coma with generalized periodic discharges (coma-GPDs); both can be summarized as coma-PDs. In the new SE classification, coma with epileptiform EEG patterns is not included as definite SE but listed separately as “boundary condition” (or “currently undetermined condition”) to make clear that there is a considerable degree of uncertainty, whether this represents true SE, or an epiphenomenal activity of a severely damaged or dying brain. In our current understanding, the border between comatose-NCSE and coma-PDs is difficult to draw. Many authors argue against the inclusion of coma-EDs into the realm of epilepsy mainly due to the poor prognosis, its underlying cause, or both. For the clinicians, the discussion is far more than a nosologic, academic discussion about classification; these patients have to be treated, and their EEG has to be interpreted in the clinical context. Despite the ongoing debate about the classification of coma-EDs, the clinician has to answer the following questions [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ]: (1) Is the coma caused by SE or by the underlying brain condition itself?; (2) To what degree does the epileptic activity contribute to the depth of coma?; (3) Does the ongoing epileptic activity worsen the prognosis?; and (4) Should we treat all epileptiform activity found in comatose patients?
      Table 1Old and new terms of EEG patterns in the patients with critical illness, modified according to the 2012 version of the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      .
      Commonly used terminologyNew terminology
      Triphasic waves (TWs)Continuous 2/s GPDs with triphasic morphology
      Periodic lateralized epileptiform discharges (PLEDs)Lateralized periodic discharges (LPDs)
      Bilateral periodic epileptiform discharges (BiPLEDs)Bilateral periodic discharges (BPDs)
      Generalized periodic epileptiform discharges (GPEDs)Generalized periodic discharges (PDs)
      Frontal intermittent rhythmic delta activity (FIRDA)Occasional frontally predominant brief 2/s generalized rhythmic delta activity
      Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) with focal evolving rhythmic delta activityStimulus-induced-evolving lateralized rhythmic delta activity (SI-evolving LRDA)
      Lateralized seizure, delta frequency rangeEvolving lateralized rhythmic delta activity (LRDA)
      Semirhythmic deltaQuasi RDA
      Coma with lateralized epileptiform discharges (coma-LEDs)
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      Coma with lateralized periodic discharges (coma-LPDs)
      Coma with generalized epileptiform discharges (coma-GEDs)Coma with generalized periodic discharges (coma-GPDs)
      This review aims to (i) summarize the EEG patterns in coma which represent SE, to further delineate the borders between comatose forms of NCSE and coma-EDs and (ii) to propose modified EEG criteria for SE in coma.

      2. Definition of terms

      • (a)
        Consciousness exists, but it resists definition [
        • Honderich T.
        The Oxford companion to philosophy.
        ]. For operational purposes, it can be defined as state of awareness of self and the environment. It can be examined by the patient's response to external stimuli and preserved memory. It depends on the integrity of the ascending reticular formation, the temporolimbic system, and the corticosubcortical connections [
        • Trinka E.H.J.
        EEG in coma and brain death.
        ,
        • Bauer G.
        • Trinka E.
        Nonconvulsive status epilepticus and coma.
        ].
      • (b)
        Coma is defined as unarousable unresponsiveness in which the subject lies with eyes closed [
        • Plum F.P.
        • J.B.
        The diagnosis of stupor and coma.
        ]. The diagnosis is dependent on neurological examination showing loss of consciousness and signs of disturbed brainstem function. Coma has to be differentiated from confusional states with impairment of consciousness, which can be SE by itself [
        • Kaplan P.W.
        Nonconvulsive status epilepticus.
        ], or observed during the development of coma (e.g., in transtentorial herniation or infratentorial lesions) [
        • Plum F.P.
        • J.B.
        The diagnosis of stupor and coma.
        ]. Coma is a transient condition that either evolves to death, vegetative state (apallic syndrome), minimal conscious state, or conscious wakefulness.
      • (c)
        Nonconvulsive status epilepticus is an epileptic condition with reduced or altered consciousness and behavioral, vegetative, or merely subjective symptoms, such as auras, but without major convulsive movements, lasting for at least 10 min (modified after [
        • Drislane F.W.
        Presentation, evaluation, and treatment of nonconvulsive status epilepticus.
        ]).
      • (d)
        Comatose-NCSE is a condition in which coma may be accompanied by continuous or periodic epileptiform or rhythmic discharges with or without minor motor activity (modified after [
        • Bauer G.
        • Trinka E.
        Nonconvulsive status epilepticus and coma.
        ]).
      • (e)
        Coma-PD is a condition with deep coma without motor activity accompanied by epileptiform or rhythmic EEG discharges, which can be coma with lateralized periodic discharges (coma-LPDs) or coma with generalized periodic discharges (coma-GPDs) (modified after [
        • Bauer G.
        • Trinka E.
        Nonconvulsive status epilepticus and coma.
        ]).
      • (f)
        The EEG terminology is used according to [
        • Beniczky S.
        • Hirsch L.J.
        • Kaplan P.W.
        • Pressler R.
        • Bauer G.
        • Aurlien H.
        • et al.
        Unified EEG terminology and criteria for nonconvulsive status epilepticus.
        ,
        • Hirsch L.J.
        • LaRoche S.M.
        • Gaspard N.
        • Gerard E.
        • Svoronos A.
        • Herman S.T.
        • et al.
        American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
        ,
        • Trinka E.H.J.
        EEG in coma and brain death.
        ,
        • Bauer G.
        • Trinka E.
        • Kaplan P.W.
        EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
        ]. See also Table 1.

      3. EEG patterns in comatose patients

      The EEG patterns in coma correlate with the depth of coma and the clinical examination. In mild disturbances of consciousness, diffuse alterations with decrease in alpha and increase in theta and delta activities prevail; more characteristic patterns come with deeper stages of somnolence, spoor, and coma. Faster activities at this stage are most often due to benzodiazepines and barbiturates.

      3.1 Intermittent rhythmic delta activity

      Intermittent rhythmic delta activity occurring most often over the frontal regions, occasionally also posteriorly, is found in more superficial stages of coma (i.e., obtundation, somnolence, and sopor) and deep midline lesions affecting the thalamocortical projections [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Schaul N.
      • Gloor P.
      • Gotman J.
      The EEG in deep midline lesions.
      ,
      • Scollo-Lavizzari G.
      • Matthis H.
      Frontal intermittent rhythmic delta activity. A comparative study of EEG and CT scan findings.
      ,
      • Accolla E.A.
      • Kaplan P.W.
      • Maeder-Ingvar M.
      • Jukopila S.
      • Rossetti A.O.
      Clinical correlates of frontal intermittent rhythmic delta activity (FIRDA).
      ,
      • Sutter R.
      • Kaplan P.W.
      Clinical and electroencephalographic correlates of acute encephalopathy.
      ,
      • Husain A.M.
      Electroencephalographic assessment of coma.
      ]. They may also be found in patients with epilepsy but clearly do not represent an ictal pattern [
      • Kubota F.
      • Ohnishi N.
      Study on FIRDA and 3 Hz rhythmic slow wave bursts occurring in the frontal area of epileptic patients.
      ] (Fig. 3).
      Figure thumbnail gr3
      Fig. 3Woman, 54 years of age; mild drowsiness; posterior reversible encephalopathy syndrome; TC 01, HF 70: frontal intermittent rhythmic delta activity.

      3.2 Prolonged bursts of slow-wave activity

      Prolonged bursts of slow-wave activity can occur in a variety of etiologies in deeper stages of coma [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Kubicki S.
      • Rieger H.
      The EEG during acute intoxication with hypnotics.
      ,
      • Kubicki S.R.
      • H.
      • Busse G.
      Elektroencephalographische Befunde bei schweren Schlafmittelvergiftungen.
      ,
      • Schwartz M.S.
      • Scott D.F.
      Pathological stimulus-related slow wave arousal responses in the EEG.
      ,
      • Bauer G.
      Coma and Brain Death.
      ]. They are most often diffuse but can also be lateralized without any spatiotemporal evolution. Reactivity to external stimuli indicates a better prognosis than very slow (<1 Hz) unreactive patterns [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ].

      3.3 Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs)

      In comatose patients, ictal-appearing or periodic discharges may be evoked after any altering stimulus. They are reproducible and often correlate with the duration of the stimulation [
      • Hirsch L.J.
      • Claassen J.
      • Mayer S.A.
      • Emerson R.G.
      Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): a common EEG phenomenon in the critically ill.
      ]. In a series of 33 patients with SIRPIDs, 21 patients had periodic epileptiform discharges (nine lateralized), and 18 had rhythmic patterns with evolution that fulfilled criteria for ictal discharges (12 unilateral). Only 8 patients had prior epilepsy, and 24 had acute brain injury [
      • Hirsch L.J.
      • Claassen J.
      • Mayer S.A.
      • Emerson R.G.
      Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs): a common EEG phenomenon in the critically ill.
      ]. Most of the time, they occur in deeply comatose patients, but some of them will have clinical seizures [
      • Hirsch L.J.
      • Pang T.
      • Claassen J.
      • Chang C.
      • Khaled K.A.
      • Wittman J.
      • et al.
      Focal motor seizures induced by alerting stimuli in critically ill patients.
      ]. Only continuous video-EEG recording or meticulous documentation of any stimulus allows clear identification of SIRPIDs, especially in the noisy environment of an ICU. Because of their close association with clinical seizures, they should be differentiated from other EEG reactions to alerting stimuli, which most likely resemble pathological K-complexes or spindles.

      3.4 Generalized periodic and rhythmic discharges

      Generalized periodic and rhythmic discharges are frequently found in various stages of coma because of a wide range of etiologies [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Husain A.M.
      Electroencephalographic assessment of coma.
      ,
      • Brenner R.P.
      • Schaul N.
      Periodic EEG patterns: classification, clinical correlation, and pathophysiology.
      ,
      • Rossetti A.O.
      • Logroscino G.
      • Liaudet L.
      • Ruffieux C.
      • Ribordy V.
      • Schaller M.D.
      • et al.
      Status epilepticus: an independent outcome predictor after cerebral anoxia.
      ]. Periodic discharges (PDs) can be defined as waves with “relatively uniform morphology and duration with a quantifiable interdischarge interval between consecutive waveforms and recurrence of the waveform at nearly regular intervals” [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ] (Fig. 4, Fig. 5). The interval at which PDs occur is regular and ranges between 0.3 Hz and several seconds [
      • Brenner R.P.
      • Schaul N.
      Periodic EEG patterns: classification, clinical correlation, and pathophysiology.
      ]. The discharges have no more than 3 phases (i.e., crosses the baseline no more than twice) or any waveform lasting 0.5 s or less, regardless of the number of phases [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. The discharges can also appear as spike-and-wave or sharp-and-wave (SW) resembling absence SE in generalized epilepsy [
      • Niedermeyer E.
      • Ribeiro M.
      Considerations of nonconvulsive status epilepticus.
      ,
      • Niedermeyer E.
      • Fineyre F.
      • Riley T.
      • Uematsu S.
      Absence status (petit mal status) with focal characteristics.
      ,
      • Niedermeyer E.
      • Khalifeh R.
      Petit mal status (‘spike–wave stupor’): an electroclinical appraisal.
      ]. In the latter, the impairment of consciousness is never down to the level of coma (“walking wounded”, Fig. 6), while in the former, the patients are deeply comatose (“ictally comatose” or coma ED; Fig. 4, Fig. 5). Both EEG patterns do not show spatiotemporal evolution, but absence SE reacts promptly to antiepileptic drugs, while coma-EDs, especially in hypoxic brain injury, show virtually no response to any currently available treatments. Rhythmic (delta) activity (RDA) designates a “repetition of a waveform with relatively uniform morphology and duration and without an interval between consecutive waveforms” [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. Rhythmic (delta) activity is “less than 4 Hz”, and “the duration of one cycle (i.e., the period) of the rhythmic pattern should vary by less than 50% from the duration of the subsequent cycle for the majority (i.e., >50%) of cycle pairs to qualify as rhythmic” [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. Generalized PDs may result from severe dysfunction or disruption of the thalamocortical pathways, the impairment of cortical inhibitory interneurons, or both. This can be the consequence of metabolic derangements or ischemia associated with structural brain damage, with excessive energy demand in NCSE or in intoxications [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications of periodic epileptiform discharges.
      ,
      • Husain A.M.
      • Mebust K.A.
      • Radtke R.A.
      Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis.
      ]. The relationships of generalized PDs and NCSE or nonconvulsive seizures have been studied in retrospective series, with inconclusive results [
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications of periodic epileptiform discharges.
      ,
      • Husain A.M.
      • Mebust K.A.
      • Radtke R.A.
      Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis.
      ,
      • Yemisci M.
      • Gurer G.
      • Saygi S.
      • Ciger A.
      Generalised periodic epileptiform discharges: clinical features, neuroradiological evaluation and prognosis in 37 adult patients.
      ,
      • Kuroiwa Y.
      • Celesia G.G.
      Clinical significance of periodic EEG patterns.
      ]. In a retrospective series of 118 patients with PDs, about one-third had seizures [
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications of periodic epileptiform discharges.
      ]. In a larger case–control study of 200 cases with critical illness (56% were comatose) with generalized PDs, a total of 46% had a seizure during the hospital stay (versus 36% of controls), and 22% had NCSE (versus 8% of controls) [
      • Foreman B.
      • Claassen J.
      • Abou Khaled K.
      • Jirsch J.
      • Alschuler D.M.
      • Wittman J.
      • et al.
      Generalized periodic discharges in the critically ill: a case–control study of 200 patients.
      ]. In this study, the EEG patterns were considered ictal if they showed a clear evolution in frequency, location, or morphology (Fig. 7). Nonconvulsive status epilepticus was defined as continuous ictal-appearing patterns lasting more than 30 min or ictal patterns present more than 50% of 1 h of EEG with subtle movements (facial twitching and eye deviation) observed in the video or reported in the chart [
      • Foreman B.
      • Claassen J.
      • Abou Khaled K.
      • Jirsch J.
      • Alschuler D.M.
      • Wittman J.
      • et al.
      Generalized periodic discharges in the critically ill: a case–control study of 200 patients.
      ]. In sum, generalized PDs were highly associated with the appearance of nonconvulsive seizures but not with worse outcome after matching for age, etiology, and level of consciousness [
      • Foreman B.
      • Claassen J.
      • Abou Khaled K.
      • Jirsch J.
      • Alschuler D.M.
      • Wittman J.
      • et al.
      Generalized periodic discharges in the critically ill: a case–control study of 200 patients.
      ].
      Figure thumbnail gr4
      Fig. 4Man, 66 years of age. Coma after cardiorespiratory arrest; TC 1.0, HF 70. Machine-like generalized 1/s (poly)spikes and waves. Outcome: died.
      Figure thumbnail gr5
      Fig. 5Woman, 83 years of age. Coma after cardiorespiratory arrest; TC 1.0, HF 70: periodic generalized discharges with intermittent brief (<2 s) periods of amplitude depression and intermingled frequencies in the alpha and the theta range. Died two days later.
      Figure thumbnail gr6
      Fig. 6Man, 33 years of age. Atypical absence status in late-onset (16 years) Lennox–Gastaut syndrome. Obtunded, withdrawn, inadequate reaction for 3 weeks. Continuous 2/s sharp and slow waves with triphasic appearance. Recovered after 3 weeks.
      Figure thumbnail gr7ab
      Fig. 7(a–i): woman, 89 years of age. Nonresponsive, ongoing chewing-like movements. Hemiplegia L due to remote large media territory infarction. IV MDZ: 5 mg. In hospital: LZP: 4 mg, LEV: 2000, VPA: 2000 — failed to respond due to general bad condition (many comorbidities), no escalation of treatment. Lateralized periodic discharges left temporoparietal with fluctuating intervals between the discharges. Flat periods with 0.5- to 2-second duration. Outcome: died.
      Figure thumbnail gr7cd
      Fig. 7(a–i): woman, 89 years of age. Nonresponsive, ongoing chewing-like movements. Hemiplegia L due to remote large media territory infarction. IV MDZ: 5 mg. In hospital: LZP: 4 mg, LEV: 2000, VPA: 2000 — failed to respond due to general bad condition (many comorbidities), no escalation of treatment. Lateralized periodic discharges left temporoparietal with fluctuating intervals between the discharges. Flat periods with 0.5- to 2-second duration. Outcome: died.
      Figure thumbnail gr7ef
      Fig. 7(a–i): woman, 89 years of age. Nonresponsive, ongoing chewing-like movements. Hemiplegia L due to remote large media territory infarction. IV MDZ: 5 mg. In hospital: LZP: 4 mg, LEV: 2000, VPA: 2000 — failed to respond due to general bad condition (many comorbidities), no escalation of treatment. Lateralized periodic discharges left temporoparietal with fluctuating intervals between the discharges. Flat periods with 0.5- to 2-second duration. Outcome: died.
      Figure thumbnail gr7gh
      Fig. 7(a–i): woman, 89 years of age. Nonresponsive, ongoing chewing-like movements. Hemiplegia L due to remote large media territory infarction. IV MDZ: 5 mg. In hospital: LZP: 4 mg, LEV: 2000, VPA: 2000 — failed to respond due to general bad condition (many comorbidities), no escalation of treatment. Lateralized periodic discharges left temporoparietal with fluctuating intervals between the discharges. Flat periods with 0.5- to 2-second duration. Outcome: died.
      Figure thumbnail gr7i
      Fig. 7(a–i): woman, 89 years of age. Nonresponsive, ongoing chewing-like movements. Hemiplegia L due to remote large media territory infarction. IV MDZ: 5 mg. In hospital: LZP: 4 mg, LEV: 2000, VPA: 2000 — failed to respond due to general bad condition (many comorbidities), no escalation of treatment. Lateralized periodic discharges left temporoparietal with fluctuating intervals between the discharges. Flat periods with 0.5- to 2-second duration. Outcome: died.

      3.5 Lateralized periodic discharges

      Lateralized periodic discharges (LPD; previously periodic lateralized epileptiform discharges, PLEDs) can occur in a broad range of conditions, in which the patient is fully alert [
      • Westmoreland B.F.
      • Klass D.W.
      • Sharbrough F.W.
      Chronic periodic lateralized epileptiform discharges.
      ], such as focal cortical dysplasia, or presents with impaired consciousness [
      • Bauer G.A.
      • F.
      • Hengel W.
      Der diagnostische Wert periodischer lateralisierter Komplexe im EEG.
      ,
      • Terzano M.G.
      • Parrino L.
      • Mazzucchi A.
      • Moretti G.
      Confusional states with periodic lateralized epileptiform discharges (PLEDs): a peculiar epileptic syndrome in the elderly.
      ,
      • Lee B.I.
      • Schauwecker D.S.
      Regional cerebral perfusion in PLEDs: a case report.
      ,
      • Reiher J.
      • Rivest J.
      • Grand'Maison F.
      • Leduc C.P.
      Periodic lateralized epileptiform discharges with transitional rhythmic discharges: association with seizures.
      ,
      • Handforth A.
      • Cheng J.T.
      • Mandelkern M.A.
      • Treiman D.M.
      Markedly increased mesiotemporal lobe metabolism in a case with PLEDs: further evidence that PLEDs are a manifestation of partial status epilepticus.
      ,
      • Beaumanoir A.
      • Andre-Obadia N.
      • Nahory A.
      • Zerbi D.
      Special types of periodic lateralized epileptiform discharges associated with confusional state in cerebral circulation insufficiency.
      ,
      • Assal F.
      • Papazyan J.P.
      • Slosman D.O.
      • Jallon P.
      • Goerres G.W.
      SPECT in periodic lateralized epileptiform discharges (PLEDs): a form of partial status epilepticus?.
      ,
      • Garzon E.
      • Fernandes R.M.
      • Sakamoto A.C.
      Serial EEG during human status epilepticus: evidence for PLED as an ictal pattern.
      ,
      • Cury R.F.
      • Wichert-Ana L.
      • Sakamoto A.C.
      • Fernandes R.M.
      Focal nonconvulsive status epilepticus associated to PLEDs and intense focal hyperemia in an AIDS patient.
      ,
      • Jette N.
      • Claassen J.
      • Emerson R.G.
      • Hirsch L.J.
      Frequency and predictors of nonconvulsive seizures during continuous electroencephalographic monitoring in critically ill children.
      ], down to the level of coma (coma-LPDs) [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Lowenstein D.H.
      • Aminoff M.J.
      Clinical and EEG features of status epilepticus in comatose patients.
      ]. As with other EEG patterns, LPDs can be found in a variety of etiologies with cortical pathology (e.g., encephalitis, stroke, subarachnoidal bleeding, trauma, tumors, cysticercosis, and intoxication) [
      • Pohlmann-Eden B.
      • Hoch D.B.
      • Cochius J.I.
      • Chiappa K.H.
      Periodic lateralized epileptiform discharges — a critical review.
      ] or subcortical pathology [
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.
      ]. There is a long-lasting debate whether they represent an ictal, interictal, or semiictal pattern [
      • Pohlmann-Eden B.
      • Hoch D.B.
      • Cochius J.I.
      • Chiappa K.H.
      Periodic lateralized epileptiform discharges — a critical review.
      ]. Neuroimaging studies (PET and SPECT) as well as improvement after treatment argue for the ictal nature of some forms of LPDs (Fig. 8). In the comatose patients (coma-LPDs), they can appear in the form of PLED-proper [
      • Claassen J.
      • Hirsch L.J.
      • Frontera J.A.
      • Fernandez A.
      • Schmidt M.
      • Kapinos G.
      • et al.
      Prognostic significance of continuous EEG monitoring in patients with poor-grade subarachnoid hemorrhage.
      ,
      • Claassen J.
      • Mayer S.A.
      • Hirsch L.J.
      Continuous EEG monitoring in patients with subarachnoid hemorrhage.
      ] and PLED-plus (Fig. 9), with superimposed faster activity [
      • Reiher J.
      • Rivest J.
      • Grand'Maison F.
      • Leduc C.P.
      Periodic lateralized epileptiform discharges with transitional rhythmic discharges: association with seizures.
      ], but most often are accompanied by diffuse slowing or alternating or bilateral independent LPDs (or BiPLEDs) [
      • de la Paz D.
      • Brenner R.P.
      Bilateral independent periodic lateralized epileptiform discharges. Clinical significance.
      ,
      • Nicolai J.
      • van Putten M.J.
      • Tavy D.L.
      BIPLEDs in akinetic mutism caused by bilateral anterior cerebral artery infarction.
      ,
      • Bauer G.
      • Niedermeyer E.
      Acute convulsions.
      ,
      • Bertolucci P.H.
      • Da Silva A.B.
      Periodic lateralized epileptiform discharges. I. Clinical and electroencephalographic aspects.
      ,
      • Bertolucci P.H.
      • Silva A.B.
      Alternating periodic lateralized epileptiform discharges (cerebral bigeminy).
      ,
      • Silbert P.L.
      • Radhakrishnan K.
      • Sharbrough F.W.
      • Klass D.W.
      Ipsilateral independent periodic lateralized epileptiform discharges.
      ] or multifocal LPDs [
      • Lawn N.D.
      • Westmoreland B.F.
      • Sharbrough F.W.
      Multifocal periodic lateralized epileptiform discharges (PLEDs): EEG features and clinical correlations.
      ].
      Figure thumbnail gr8ab
      Fig. 8(a) Man, 56 years of age, obtunded, no response to verbal stimuli; EEG with lateralized periodic discharges left temporal over T3; (b) right: CT scan and MRI showing left temporoparietal intracerebral bleeding due to rupture of a large arteriovenous malformation; left: F18FDG-PET immediately after the EEG recording indicating a focal hypermetabolic area left temporoparietal, corresponding to the maximum of the negativity of the lateralized periodic discharges, arrow (c) EEG recording left temporoparietal lateralized periodic discharges immediately after PET scan (b), before 2-mg lorazepam IV followed by 2000-mg phenytoin IV over 30 min. (d) EEG recording a day after treatment with occasional sharp waves left temporoparietal, which disappeared with the following day (e).
      Figure thumbnail gr8cd
      Fig. 8(a) Man, 56 years of age, obtunded, no response to verbal stimuli; EEG with lateralized periodic discharges left temporal over T3; (b) right: CT scan and MRI showing left temporoparietal intracerebral bleeding due to rupture of a large arteriovenous malformation; left: F18FDG-PET immediately after the EEG recording indicating a focal hypermetabolic area left temporoparietal, corresponding to the maximum of the negativity of the lateralized periodic discharges, arrow (c) EEG recording left temporoparietal lateralized periodic discharges immediately after PET scan (b), before 2-mg lorazepam IV followed by 2000-mg phenytoin IV over 30 min. (d) EEG recording a day after treatment with occasional sharp waves left temporoparietal, which disappeared with the following day (e).
      Figure thumbnail gr8e
      Fig. 8(a) Man, 56 years of age, obtunded, no response to verbal stimuli; EEG with lateralized periodic discharges left temporal over T3; (b) right: CT scan and MRI showing left temporoparietal intracerebral bleeding due to rupture of a large arteriovenous malformation; left: F18FDG-PET immediately after the EEG recording indicating a focal hypermetabolic area left temporoparietal, corresponding to the maximum of the negativity of the lateralized periodic discharges, arrow (c) EEG recording left temporoparietal lateralized periodic discharges immediately after PET scan (b), before 2-mg lorazepam IV followed by 2000-mg phenytoin IV over 30 min. (d) EEG recording a day after treatment with occasional sharp waves left temporoparietal, which disappeared with the following day (e).
      Figure thumbnail gr9ab
      Fig. 9(a) Man, 88 years of age, postictal coma after acute symptomatic generalized tonic–clonic seizure with left medial cerebral artery occlusion; TC 1.0, HF 70; lateralized periodic discharges over left frontocentral with fluctuation of interburst interval; (b) the same trace with increase in interburst frequency, decrease in amplitude, and superposition of faster frequencies (red arrow; old term: “periodic lateralized epileptiform discharges (PLED)-plus”) merging into an ictal activity (=begin of electrographic seizure; blue arrow). Note also the longer periods of suppressed background over the left hemisphere. (c, d) The same trace as before with polyspikes over left temporoparietal (=electrographic seizure).
      Figure thumbnail gr9cd
      Fig. 9(a) Man, 88 years of age, postictal coma after acute symptomatic generalized tonic–clonic seizure with left medial cerebral artery occlusion; TC 1.0, HF 70; lateralized periodic discharges over left frontocentral with fluctuation of interburst interval; (b) the same trace with increase in interburst frequency, decrease in amplitude, and superposition of faster frequencies (red arrow; old term: “periodic lateralized epileptiform discharges (PLED)-plus”) merging into an ictal activity (=begin of electrographic seizure; blue arrow). Note also the longer periods of suppressed background over the left hemisphere. (c, d) The same trace as before with polyspikes over left temporoparietal (=electrographic seizure).

      3.6 Triphasic waves (TWs)

      Triphasic waves (TWs) have been regarded as rather specific for metabolic (hepatic) causes [
      • Foley J.M.
      • Watson C.W.
      • Adams R.D.
      Significance of the electroencephalographic changes in hepatic coma.
      ,
      • Bickford R.G.
      • Butt H.R.
      Hepatic coma: the electroencephalographic pattern.
      ] but can be found in coma of any cause [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Sundaram M.B.
      • Blume W.T.
      Triphasic waves: clinical correlates and morphology.
      ,
      • Nowack W.J.
      • King J.A.
      Triphasic waves and spike wave stupor.
      ,
      • Fountain N.B.
      • Waldman W.A.
      Effects of benzodiazepines on triphasic waves: implications for nonconvulsive status epilepticus.
      ,
      • Boulanger J.M.
      • Deacon C.
      • Lecuyer D.
      • Gosselin S.
      • Reiher J.
      Triphasic waves versus nonconvulsive status epilepticus: EEG distinction.
      ]. They are now termed continuous 2-Hz generalized PDs with triphasic morphology [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. Generalized sharp waves with triphasic morphology can be found in Lennox–Gastaut syndrome, which can be extremely difficult to differentiate from TWs (Fig. 6) [
      • Niedermeyer E.
      • Khalifeh R.
      Petit mal status (‘spike–wave stupor’): an electroclinical appraisal.
      ,
      • Bauer G.
      • Aichner F.
      • Mayr U.
      Status atypischer Absencen im Jugend- und Erwachsenenalter.
      ,
      • Blume E.
      The EEG, features of the Lennox Gastaut syndrome.
      ,
      • Niedermeyer E.
      The Lennox–Gastaut syndrome: a severe type of childhood epilepsy.
      ]. Some authors suggested considering NCSE in any patients who present with altered consciousness or confusional state and “atypical” TWs. Atypical TWs were defined as “localized or lateralized sharp waves with triphasic configuration” and considered to be of epileptogenic origin if they disappeared following AED treatment [
      • Kaya D.
      • Bingol C.A.
      Significance of atypical triphasic waves for diagnosing nonconvulsive status epilepticus.
      ]. In a retrospective study of 87 EEGs of 71 patients with TWs and 27 EEGs of 13 patients with NCSE, the authors found epileptiform discharges in NCSE of higher frequency (2.4 Hz versus 1.8 Hz), with a shorter duration of phase one, and more often extraspike components (69% versus 0%), and less generalized background slowing [
      • Boulanger J.M.
      • Deacon C.
      • Lecuyer D.
      • Gosselin S.
      • Reiher J.
      Triphasic waves versus nonconvulsive status epilepticus: EEG distinction.
      ]. There was also an increase in TWs after noxious stimuli, which was not present in NCSE [
      • Boulanger J.M.
      • Deacon C.
      • Lecuyer D.
      • Gosselin S.
      • Reiher J.
      Triphasic waves versus nonconvulsive status epilepticus: EEG distinction.
      ]. Despite the well-characterized patients in this study, there were still 31% of the patients with NCSE and TWs without any spike component. Unfortunately, all proposed criteria to differentiate epileptic TWs from nonepileptic TWs [
      • Husain A.M.
      • Mebust K.A.
      • Radtke R.A.
      Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis.
      ,
      • Boulanger J.M.
      • Deacon C.
      • Lecuyer D.
      • Gosselin S.
      • Reiher J.
      Triphasic waves versus nonconvulsive status epilepticus: EEG distinction.
      ,
      • Kaya D.
      • Bingol C.A.
      Significance of atypical triphasic waves for diagnosing nonconvulsive status epilepticus.
      ] have not been validated in prospective studies.

      3.7 Burst suppression patterns

      Burst suppression patterns (BSs) are only found in deep stages of coma and some rare childhood encephalopathies (e.g., Ohtahara syndrome). Burst suppression pattern was originally described as a pattern found in deep anesthesia but is now recognized a fingerprint of a poor prognosis in cerebral hypoxia/anoxia after cardiopulmonary arrest [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Niedermeyer E.
      The burst-suppression electroencephalogram.
      ]. Burst suppression pattern can also be found in various etiologies (structural, toxic, and metabolic) or during hypothermia [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Bauer G.
      Coma and Brain Death.
      ,
      • Stecker M.M.
      • Cheung A.T.
      • Pochettino A.
      • Kent G.P.
      • Patterson T.
      • Weiss S.J.
      • et al.
      Deep hypothermic circulatory arrest: II changes in electroencephalogram and evoked potentials during rewarming.
      ,
      • Stecker M.M.
      • Cheung A.T.
      • Pochettino A.
      • Kent G.P.
      • Patterson T.
      • Weiss S.J.
      • et al.
      Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials.
      ]. The pattern consists of periodic high voltage, sharply contoured waveforms, including spikes and polyspikes, at times with a buildup or salvos of spikes alternating with periods of severe suppression or even isoelectricity. The bursts last from less than a second to 10 s or more, and the period of suppression may be a second to 10 s or much longer (Fig. 10a, b ). The suppression period may have a variable degree of residual activity of low voltage or is completely isoelectric [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Bauer G.
      Coma and Brain Death.
      ,
      • Niedermeyer E.
      The burst-suppression electroencephalogram.
      ,
      • Zaret B.S.
      Prognostic and neurophysiological implications of concurrent burst suppression and alpha patterns in the EEG of post-anoxic coma.
      ,
      • Niedermeyer E.
      • Sherman D.L.
      • Geocadin R.J.
      • Hansen H.C.
      • Hanley D.F.
      The burst-suppression electroencephalogram.
      ,
      • Ohtahara S.
      • Ohtsuka Y.
      • Yamatogi Y.
      • Oka E.
      • Inoue H.
      The early-infantile epileptic encephalopathy with suppression-bursts.
      ,
      • Reeves A.L.
      • Westmoreland B.F.
      • Klass D.W.
      Clinical accompaniments of the burst-suppression EEG pattern.
      ]. Patients are in deep coma, but salvos of myoclonic jerks in the arms, face, chest, or legs may occur [
      • Bauer G.
      • Niedermeyer E.
      Acute convulsions.
      ,
      • Butenuth J.
      • Kubicki S.
      Über die prognostische Bedeutung bestimmter Formen der Myoklonien und korrespondierender EEG Muster nach Hypoxien.
      ,
      • Pampiglione G.
      • Harden A.
      Resuscitation after cardiocirculatory arrest. Prognostic evaluation of early electroencephalographic findings.
      ,
      • Pampiglione G.
      • Harden A.
      Prognostic value of neurophysiological studies in the first hours that follow resuscitation: study of 120 children after cardiac arrest.
      ]. In many patients, they appear after stimuli [
      • Niedermeyer E.
      • Bauer G.
      • Burnite R.
      • Reichenbach D.
      Selective stimulus-sensitive myoclonus in acute cerebral anoxia. A case report.
      ]. Various patterns of transitions to or from diffuse slow activity, alpha coma, theta coma, low output voltage, isoelectric EEG, LPD, or GPD have been described [
      • Synek V.M.
      Prognostically important EEG coma patterns in diffuse anoxic and traumatic encephalopathies in adults.
      ,
      • Kubicki S.R.
      • H.
      • Busse G.
      Elektroencephalographische Befunde bei schweren Schlafmittelvergiftungen.
      ,
      • Stecker M.M.
      • Cheung A.T.
      • Pochettino A.
      • Kent G.P.
      • Patterson T.
      • Weiss S.J.
      • et al.
      Deep hypothermic circulatory arrest: II changes in electroencephalogram and evoked potentials during rewarming.
      ,
      • Stecker M.M.
      • Cheung A.T.
      • Pochettino A.
      • Kent G.P.
      • Patterson T.
      • Weiss S.J.
      • et al.
      Deep hypothermic circulatory arrest: I. Effects of cooling on electroencephalogram and evoked potentials.
      ,
      • Fischgold H.
      • Mathis P.
      Onubliations, comas et stupeurs.
      ,
      • Thomke F.
      • Marx J.J.
      • Sauer O.
      • Hundsberger T.
      • Hagele S.
      • Wiechelt J.
      • et al.
      Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus.
      ,
      • Prior P.F.
      The EEG, in acute cerebral anoxia.
      ,
      • Bortone E.
      • Bettoni G.
      • Giorgi C.
      • Murgese A.
      • Stocchetti M.
      • Manica D.
      Adult postanoxic ‘erratic’ status epilepticus.
      ,
      • Abend N.S.
      • Topjian A.
      • Ichord R.
      • Herman S.T.
      • Helfaer M.
      • Donnelly M.
      • et al.
      Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.
      ].
      Figure thumbnail gr10
      Fig. 10Woman, 54 years of age; TC 1.0, HF 70; spindle coma due to intoxication with tricyclic antidepressants. Spindle activity in the alpha range over the frontal regions. Full recovery within a few days.

      3.8 Alpha and theta coma patterns

      Alpha and theta coma patterns were initially described as a result of direct damage of the brainstem due to stroke or tumors but can also be found in many other etiologies including cerebral hypoxia/anoxia [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ,
      • Chatrian G.E.
      • White Jr., L.E.
      • Shaw C.M.
      EEG pattern resembling wakefulness in unresponsive decerebrate state following traumatic brain-stem infarct.
      ,
      • Loeb C.
      • Poggio G.
      Electroencephalograms in a case with ponto-mesencephalic haemorrhage.
      ,
      • Hauge T.
      • Loken A.C.
      • Lundervold A.
      Unusual EEG in unconscious patient with brain stem atrophy.
      ,
      • Rohmer F.
      • Kurtz D.
      • Kiffer A.
      Critical study of EEG activity in vascular syndromes of the brain stem.
      ,
      • Westmoreland B.F.
      • Klass D.W.
      • Sharbrough F.W.
      • Reagan T.J.
      Alpha-coma. Electroencephalographic, clinical, pathologic, and etiologic correlations.
      ,
      • Binnie C.D.
      • Prior P.F.
      • Lloyd D.S.
      • Scott D.F.
      • Margerison J.H.
      Electroencephalographic prediction of fatal anoxic brain damage after resuscitation from cardiac arrest.
      ,
      • Chokroverty S.
      “Alpha-like” rhythms in electroencephalograms in coma after cardiac arrest.
      ,
      • Grindal A.B.
      • Suter C.
      “Alpha-pattern coma” in high voltage electrical injury.
      ,
      • Grindal A.B.
      • Suter C.
      • Martinez A.J.
      Alpha-pattern coma: 24 cases with 9 survivors.
      ]. In contrast to the alpha rhythm during wakefulness, the alpha pattern in coma is diffuse, at times with anterior preponderance and as a rule not reactive to external stimuli. It must be distinguished from slow spindles in apallic syndrome (unresponsive wakefulness) or reemerging remnants of alpha rhythm in minimally conscious states. Like other coma patterns, alpha coma and theta coma are transient and may evolve into low output or isoelectric EEG as an imminent sign of brain death. There is typically no spatiotemporal evolution, but rarely ictal activity can emerge from an alpha coma pattern [
      • Unterberger I.
      • Trinka E.
      • Bauer G.
      Involuntary motor phenomena in advanced coma states.
      ].

      3.9 Sleep-like EEG patterns in coma

      Sleep-like EEG patterns in coma contain spindles, slow activity, K-complexes, and arousal reactions [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ,
      • Bauer G.
      Coma and Brain Death.
      ,
      • Chatrian G.E.
      • White Jr., L.E.
      • Daly D.
      Electroencephalographic patterns resembling those of sleep in certain comatose states after injuries to the head.
      ]. They have been initially described in brain trauma but can be found also with other etiologies [
      • Nogueira de Melo A.
      • Krauss G.L.
      • Niedermeyer E.
      Spindle coma: observations and thoughts.
      ,
      • Seet R.C.
      • Lim E.C.
      • Wilder-Smith E.P.
      Spindle coma from acute midbrain infarction.
      ,
      • Rumpl E.
      • Prugger M.
      • Bauer G.
      • Gerstenbrand F.
      • Hackl J.M.
      • Pallua A.
      Incidence and prognostic value of spindles in post-traumatic coma.
      ,
      • Dadmehr N.
      • Pakalnis A.
      • Drake Jr., M.E.
      Spindle coma in viral encephalitis.
      ,
      • Mouradian M.D.
      • Penovich P.E.
      Spindle coma in benzodiazepine toxicity: case report.
      ] (Fig. 11). Spindles may occur at faster and lower frequencies than physiologic spindle activity and can be of longer duration than usual. However, there is no spatiotemporal evolution, which clearly distinguishes them from ictal rhythmic discharges.
      Figure thumbnail gr11
      Fig. 11(a) Man, 77 years of age; TC 1.0, HF 70; deep coma after cardiopulmonary arrest. Burst suppression pattern with bursts of mixed frequencies and interposed spikes and sharp waves. Despite the buildup within the bursts in amplitude, there is no spatiotemporal evolution suggestive of an ictal activity. Severe suppression of activity between the bursts. Outcome: died within days. (b) Boy, 2 weeks, Ohtahara syndrome due to olivary–dentate dysplasia and agenesis of mammillary bodies
      [
      • Trinka E.
      • Rauscher C.
      • Nagler M.
      • Moroder T.
      • Ladurner G.
      • Irnberger E.
      • et al.
      A case of Ohtahara syndrome with olivary–dentate dysplasia and agenesis of mammillary bodies.
      ]
      ; TC 1.0, HF 70; bursts with mixed frequencies (fast and slow waves) with less severe suppression between the bursts than in hypoxic encephalopathy. Later, a hypsarrhythmic EEG pattern developed. Outcome: died at the age of 3 years.

      4. Transient fluctuations of EEG patterns in coma

      In a standard EEG with 30-minute duration, various fluctuations can be found. With continuous EEG (cEEG), these are the rules and not the exceptions. Among others, they are defined as modifiers in the standardized terminology: at least three changes, not more than 1min apart, in frequency (by at least 0.5/s), morphology, or changes in location (by at least 1 standard interelectrode distance) [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. Whether these fluctuations are spontaneous or result as reaction to exogenous or endogenous painful and noxious stimuli is extremely difficult to define, especially in the noisy environment of an ICU. There seems to be an association of fluctuations and a reproducible EEG reactivity, which indicates a better prognosis than a static EEG pattern [
      • Kaplan P.W.
      Electrophysiological prognostication and brain injury from cardiac arrest.
      ]. Fluctuations are per definition different from evolving patterns, which represent electrographic seizures or NCSE and should, therefore, be carefully distinguished [
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ,
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ,
      • Noachtar S.
      • Binnie C.
      • Ebersole J.
      • Mauguiere F.
      • Sakamoto A.
      • Westmoreland B.
      A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. The International Federation of Clinical Neurophysiology.
      ]. The Salzburg Consensus Group has suggested using the term “possible NCSE” in cases with fluctuating epileptiform discharges or rhythmic delta activity [
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ]. Though several authors [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Thomke F.
      • Brand A.
      • Weilemann S.L.
      The temporal dynamics of postanoxic burst-suppression EEG.
      ] have discussed the occurrence of fluctuations, there are no systematic studies, and the proposed definitions [
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      ,
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ] have not been validated yet. The following types of fluctuations in the EEG in coma have been described [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ]: blocking of triphasic-like GPDs combined with accentuation of superimposed low amplitude frequencies in the alpha range [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ], flattening of a theta pattern coma [
      • Trinka E.H.J.
      EEG in coma and brain death.
      ], blocking of theta frequencies superimposed on GPDs [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ], blocking of GPDs [
      • Synek V.M.
      Value of a revised EEG coma scale for prognosis after cerebral anoxia and diffuse head injury.
      ], and trains of polyspikes in GPDs.

      5. Transition of EEG patterns in coma

      Transitions of EEG patterns refer to a longer-lasting change of the type of EEG abnormality [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ]. They are operationally not defined in the standardized terminology [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ]. We suggest the following definition: a change in morphology (e.g., generalized PDs to rhythmic delta) and Gestalt (e.g., alpha coma to BS, evolving to nonevolving) of the pattern or a change in frequency of more than 1Hz, which is longer apart than a minute. It has to be emphasized that, even in a 30-minute EEG recording, two or more EEG patterns may occur [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ]. The transition may occur in both ways: from a less severe to a more severe pattern and from a severe to a less severe pattern [
      • Abend N.S.
      • Topjian A.
      • Ichord R.
      • Herman S.T.
      • Helfaer M.
      • Donnelly M.
      • et al.
      Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.
      ,
      • Synek V.M.
      • Synek B.J.
      Transition from alpha to theta pattern coma in fatal cerebral anoxia.
      ]. However, it is clear that the prognosis of the patients does not change from minute to minute, and for prognostication, it has been advised to use repeated recordings on consecutive days [
      • Synek V.M.
      Value of a revised EEG coma scale for prognosis after cerebral anoxia and diffuse head injury.
      ,
      • Synek V.M.
      Revised EEG, coma scale in diffuse acute head injuries in adults.
      ,
      • Synek V.M.
      Validity of a revised EEG coma scale for predicting survival in anoxic encephalopathy.
      ,
      • Synek V.M.
      EEG abnormality grades and subdivisions of prognostic importance in traumatic and anoxic coma in adults.
      ]. The transition from a nonevolving to an evolving pattern of generalized or lateralized PDs in coma is regarded as a sign of comatose-NCSE by some authors, irrespective of whether there is any clinical seizure activity present or not [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ]. It has to be emphasized that transitions have been described with intermittent classical EEG recordings and not with cEEG.

      6. Ictal EEG pattern in the comatose patient

      The epileptic etiology of a coma, such as the postictal coma after generalized tonic–clonic seizures, can be suspected by history, the temporal pattern, and neurologic examination with progressive improvement of reactivity and awareness [
      • Shorvon S.
      • Trinka E.
      Nonconvulsive status epilepticus and the postictal state.
      ]. The differentiation between the ictal and the postictal period is almost impossible without the EEG and even difficult with EEG. The EEG exhibits focal, lateralized, or generalized EEG pattern, with various transitions [
      • Bauer G.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Bauer G.
      • Bauer R.
      • Pfausler B.
      • Trinka E.
      Nonconvulsive status epilepticus and coma.
      ,
      • Sutter R.
      • Kaplan P.W.
      The neurophysiologic types of nonconvulsive status epilepticus: EEG patterns of different phenotypes.
      ]. Persisting epileptiform discharges were found in 48% of 164 consecutive patients in whom generalized convulsive status epilepticus was presumably controlled [
      • DeLorenzo R.J.
      • Waterhouse E.J.
      • Towne A.R.
      • Boggs J.G.
      • Ko D.
      • DeLorenzo G.A.
      • et al.
      Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
      ]. The authors reported that these patients were “comatose and showed no overt clinical signs of convulsive activity” [
      • DeLorenzo R.J.
      • Waterhouse E.J.
      • Towne A.R.
      • Boggs J.G.
      • Ko D.
      • DeLorenzo G.A.
      • et al.
      Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
      ].
      The epileptic etiology in a comatose patient is exclusively suggested by the presence of continuous or intermittent epileptiform discharges or rhythmic slow-wave patterns with evolution in the EEG. Lowenstein and Aminoff evaluated clinical and EEG features of status epilepticus (SE) in 47 comatose patients retrospectively [
      • Lowenstein D.H.
      • Aminoff M.J.
      Clinical and EEG features of status epilepticus in comatose patients.
      ]. In all of them, SE was suspected clinically or because the EEG revealed ictal activity or continuous spike-and-wave activity. In 33 patients, both clinical SE and ictal EEG were concordant, and in 9 patients, subtle motor phenomena were associated with irregular diffuse slowing with or without frequent spikes and sharp waves, an irregular mixed-frequency background with episodic accentuation, or intermittent burst suppression. Five (11%) lacked any sign of clinical seizures, but the EEG showed repetitive electrographic seizures or continuous spike-and-wave activity [
      • Lowenstein D.H.
      • Aminoff M.J.
      Clinical and EEG features of status epilepticus in comatose patients.
      ]. In a prospective study in 236 comatose patients without clinical signs of SE, 8% had continuous or nearly continuous electrographic seizure activity lasting at least 30 min [
      • Towne A.R.
      • Waterhouse E.J.
      • Boggs J.G.
      • Garnett L.K.
      • Brown A.J.
      • Smith Jr., J.R.
      • et al.
      Prevalence of nonconvulsive status epilepticus in comatose patients.
      ]. The authors used the following EEG criteria for NCSE: discrete electrographic seizures, continuous spike-and-wave activity, or rhythmic recurrent epileptiform activity with marked improvement after the injection of an IV benzodiazepine [
      • Towne A.R.
      • Waterhouse E.J.
      • Boggs J.G.
      • Garnett L.K.
      • Brown A.J.
      • Smith Jr., J.R.
      • et al.
      Prevalence of nonconvulsive status epilepticus in comatose patients.
      ].
      In a retrospective study of 517 consecutive patients who underwent cEEG monitoring over a 6.5-year period for the detection of seizures or unexplained decrease of level of consciousness, 19% (n = 110) had seizures and 92% (n = 101) had nonconvulsive seizures [
      • Claassen J.
      • Mayer S.A.
      • Kowalski R.G.
      • Emerson R.G.
      • Hirsch L.J.
      Detection of electrographic seizures with continuous EEG monitoring in critically ill patients.
      ]. Among the patients with seizures, 89% (n = 98) were in ICUs, and 49% (n = 54) were in coma at the time of the cEEG. Thus, overall, 10% of patients with cEEG had ictal patterns. The authors defined electrographic ictal activity as rhythmic discharge or spike-and-wave pattern with definite evolution in frequency, location, or morphology lasting at least 10 s; evolution in amplitude alone did not qualify. The number of comatose patients who did not undergo cEEG in the same period was not reported [
      • Claassen J.
      • Mayer S.A.
      • Kowalski R.G.
      • Emerson R.G.
      • Hirsch L.J.
      Detection of electrographic seizures with continuous EEG monitoring in critically ill patients.
      ].
      In 19 comatose children who underwent cEEG, electrographic seizures occurred in 47% (9/19) and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). In this study, electrographic seizures were defined as “abnormal, ictal EEG events lasting longer than 10 s with evolution of morphology, frequency, and amplitude, and a plausible electrographic field” and NCSE as state of impaired consciousness with a single 30-minute electrographic seizure, or independent ictal electrographic seizures adding up to 30 min within 1 h [
      • Abend N.S.
      • Topjian A.
      • Ichord R.
      • Herman S.T.
      • Helfaer M.
      • Donnelly M.
      • et al.
      Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.
      ].
      Overall, cEEG in patients with critical illness revealed ictal activity and/or seizures in 5% to 48% found in various etiologies [
      • DeLorenzo R.J.
      • Waterhouse E.J.
      • Towne A.R.
      • Boggs J.G.
      • Ko D.
      • DeLorenzo G.A.
      • et al.
      Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus.
      ,
      • Claassen J.
      • Hirsch L.J.
      • Kreiter K.T.
      • Du E.Y.
      • Connolly E.S.
      • Emerson R.G.
      • et al.
      Quantitative continuous EEG for detecting delayed cerebral ischemia in patients with poor-grade subarachnoid hemorrhage.
      ,
      • Swisher C.B.
      • Shah D.
      • Sinha S.R.
      • Husain A.M.
      Baseline EEG pattern on continuous ICU EEG monitoring and incidence of seizures.
      ,
      • Carrera E.
      • Claassen J.
      • Oddo M.
      • Emerson R.G.
      • Mayer S.A.
      • Hirsch L.J.
      Continuous electroencephalographic monitoring in critically ill patients with central nervous system infections.
      ,
      • Shafi M.M.
      • Westover M.B.
      • Cole A.J.
      • Kilbride R.D.
      • Hoch D.B.
      • Cash S.S.
      Absence of early epileptiform abnormalities predicts lack of seizures on continuous EEG.
      ,
      • Vespa P.M.
      • O'Phelan K.
      • Shah M.
      • Mirabelli J.
      • Starkman S.
      • Kidwell C.
      • et al.
      Acute seizures after intracerebral hemorrhage: a factor in progressive midline shift and outcome.
      ,
      • Dennis L.J.
      • Claassen J.
      • Hirsch L.J.
      • Emerson R.G.
      • Connolly E.S.
      • Mayer S.A.
      Nonconvulsive status epilepticus after subarachnoid hemorrhage.
      ,
      • Vespa P.M.
      • Nenov V.
      • Nuwer M.R.
      Continuous EEG monitoring in the intensive care unit: early findings and clinical efficacy.
      ]. It has been shown that cEEG monitoring improves the detection rate of subclinical epileptiform activity in patients with critical illness significantly [
      • Sutter R.
      • Fuhr P.
      • Grize L.
      • Marsch S.
      • Ruegg S.
      Continuous video-EEG monitoring increases detection rate of nonconvulsive status epilepticus in the ICU.
      ]. Of note, not all of the patients who undergo cEEG are comatose; hence, the “true” incidence of ictal EEG patterns without other clinical manifestations is unknown. In addition, there is always a clinical indication as to why cEEG is applied to the patient. To date, there is no prospective study using cEEG in all comatose patients, irrespective of the cause of coma.

      7. Ictal semiology in coma

      Clinical and “electrographic” seizures are robust predictors of poor outcome in patients with critical illness [
      • Rossetti A.O.
      • Oddo M.
      • Liaudet L.
      • Kaplan P.W.
      Predictors of awakening from postanoxic status epilepticus after therapeutic hypothermia.
      ,
      • Sutter R.
      • Kaplan P.W.
      Clinical and electroencephalographic correlates of acute encephalopathy.
      ,
      • Rossetti A.O.
      • Logroscino G.
      • Liaudet L.
      • Ruffieux C.
      • Ribordy V.
      • Schaller M.D.
      • et al.
      Status epilepticus: an independent outcome predictor after cerebral anoxia.
      ,
      • Foreman B.
      • Claassen J.
      • Abou Khaled K.
      • Jirsch J.
      • Alschuler D.M.
      • Wittman J.
      • et al.
      Generalized periodic discharges in the critically ill: a case–control study of 200 patients.
      ,
      • Mani R.
      • Schmitt S.E.
      • Mazer M.
      • Putt M.E.
      • Gaieski D.F.
      The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia.
      ,
      • Rossetti A.O.
      • Oddo M.
      The neuro-ICU patient and electroencephalography paroxysms: if and when to treat.
      ,
      • Rossetti A.O.
      • Oddo M.
      • Logroscino G.
      • Kaplan P.W.
      Prognostication after cardiac arrest and hypothermia: a prospective study.
      ,
      • Rossetti A.O.
      • Urbano L.A.
      • Delodder F.
      • Kaplan P.W.
      • Oddo M.
      Prognostic value of continuous EEG monitoring during therapeutic hypothermia after cardiac arrest.
      ,
      • Rossetti A.O.
      • Carrera E.
      • Oddo M.
      Early EEG correlates of neuronal injury after brain anoxia.
      ,
      • Sutter R.
      • Stevens R.D.
      • Kaplan P.W.
      Clinical and imaging correlates of EEG patterns in hospitalized patients with encephalopathy.
      ]. The semiology of seizures in comatose patients is rarely generalized tonic–clonic; rather, it is more often focal clonic, or myoclonic, inconspicuous, and limited to only some parts of the body, face, or eyes [
      • Wijdicks E.F.
      • Sharbrough F.W.
      New-onset seizures in critically ill patients.
      ]. Myoclonic jerks are most often encountered in deep coma, specifically after hypoxic/anoxic brain injury [
      • Celesia G.G.
      • Grigg M.M.
      • Ross E.
      Generalized status myoclonicus in acute anoxic and toxic–metabolic encephalopathies.
      ,
      • Krumholz A.
      • Stern B.J.
      • Weiss H.D.
      Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus.
      ,
      • Madison D.
      • Niedermeyer E.
      Epileptic seizures resulting from acute cerebral anoxia.
      ,
      • Madison D.
      • Niedermeyer E.
      Epileptic seizures during and after acute cerebral anoxia.
      ,
      • Young G.B.
      • Gilbert J.J.
      • Zochodne D.W.
      The significance of myoclonic status epilepticus in postanoxic coma.
      ,
      • Wijdicks E.F.
      • Parisi J.E.
      • Sharbrough F.W.
      Prognostic value of myoclonus status in comatose survivors of cardiac arrest.
      ]. The EEG sometimes does not reveal accompanying ictal activity; hence, the question whether these clinical activities were epileptic phenomena or not remains unresolved. According to Bauer et al. [
      • Bauer G.
      • Trinka E.
      • Kaplan P.W.
      EEG patterns in hypoxic encephalopathies (post-cardiac arrest syndrome): fluctuations, transitions, and reactions.
      ], myoclonus can be classified as follows: (1) myoclonic status, (2) myoclonia-like diffuse shivering, (3) myoclonus with or without an EEG correlate, and (4) focal myoclonus [
      • Hirsch L.J.
      • Pang T.
      • Claassen J.
      • Chang C.
      • Khaled K.A.
      • Wittman J.
      • et al.
      Focal motor seizures induced by alerting stimuli in critically ill patients.
      ,
      • Koutroumanidis M.
      • Tsatsou K.
      • Bonakis A.
      • Michael M.
      • Tan S.V.
      Stimulus-induced bilateral central periodic discharges, cortical myoclonus and arousal responses in mild reversible coma.
      ]. Other involuntary motor phenomena in coma are decorticate and decerebrate posturing and abnormal tonic eyelid movements and eye-opening [
      • Reeves A.L.
      • Westmoreland B.F.
      • Klass D.W.
      Clinical accompaniments of the burst-suppression EEG pattern.
      ,
      • Unterberger I.
      • Trinka E.
      • Bauer G.
      Involuntary motor phenomena in advanced coma states.
      ]. They can easily be distinguished from epileptic nystagmus [
      • Kaplan P.W.
      • Lesser R.P.
      Vertical and horizontal epileptic gaze deviation and nystagmus.
      ,
      • Kaplan P.W.
      • Tusa R.J.
      Neurophysiologic and clinical correlations of epileptic nystagmus.
      ,
      • Neugebauer H.
      • Winkler T.
      • Feddersen B.
      • Pfister H.W.
      • Noachtar S.
      • Straube A.
      • et al.
      Upbeat nystagmus as a clinical sign of physostigmine-induced right occipital non-convulsive status epilepticus.
      ,
      • Stolz S.E.
      • Chatrian G.E.
      • Spence A.M.
      Epileptic nystagmus.
      ,
      • Tusa R.J.
      • Kaplan P.W.
      • Hain T.C.
      • Naidu S.
      Ipsiversive eye deviation and epileptic nystagmus.
      ].

      8. EEG criteria for NCSE in the comatose

      Various EEG criteria have been used in previous studies to identify patients in comatose-NCSE, yielding a prevalence between 8% and 32%, but the true incidence of NCSE in coma is still not known. Based on previous criteria [
      • Hirsch L.J.
      • Brenner R.P.
      • Drislane F.W.
      • So E.
      • Kaplan P.W.
      • Jordan K.G.
      • et al.
      The ACNS subcommittee on research terminology for continuous EEG monitoring: proposed standardized terminology for rhythmic and periodic EEG patterns encountered in critically ill patients.
      ,
      • Kaplan P.W.
      EEG criteria for nonconvulsive status epilepticus.
      ,
      • Sutter R.
      • Kaplan P.W.
      Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey.
      ], an expert panel at the 4th London Innsbruck Colloquium on acute Seizures in Salzburg, Austria proposed the working criteria for NCSE listed in Table 2 (Salzburg Consensus Criteria for NCSE; SCNC) (for the purpose of a validation study, the following modifications have been made in concordance with the standardized critical care terminology of the American Clinical Neurophysiology Society [
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • Gerard E.
      • Svoronos A.
      • Herman S.T.
      • et al.
      American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version.
      ].
      • Rhythmic delta activity: “rhythmic = repetition of a waveform with relatively uniform morphology and duration and without an interval between consecutive waveforms. RDA = rhythmic activity < 4 Hz. The duration of one cycle (i.e., the period) of the rhythmic pattern should vary by <50% from the duration of the subsequent cycle for the majority (>50%) of cycle pairs to qualify as rhythmic.”
      • Fluctuation: “fluctuating is defined as follows: >3 changes, not more than 1 min apart, in frequency (by at least 0.5/s), >3 changes in morphology, or >3 changes in location (by at least 1 standard interelectrode distance) but not qualifying as evolving. This includes patterns fluctuating from 1 to 1.5 to 1 to 1.5/s; spreading in and out of a single electrode repeatedly; or alternating between 2 morphologies repeatedly.”
      • Evolution: “evolving is defined as follows: at least 2 unequivocal, sequential changes in frequency, morphology, or location defined as follows: evolution in frequency is defined as at least 2 consecutive changes in the same direction by at least 0.5/s, e.g., from 2 to 2.5 to 3/s or from 3 to 2 to 1.5/s; evolution in morphology is defined as at least 2 consecutive changes to a novel morphology; evolution in location is defined as sequentially spreading into or sequentially out of at least two different standard 10–20 electrode locations.”
      • Response to IV AEDs: reactivity to IV AEDs within 10 min after AED was fully applied and tested clinically; improvement is defined as better performance in one of the following three domains: (i) “say your surname”, (ii) “repeat 1, 2, 3”, and (iii) “raise your arms” (document the response which can be no response, patient opens eyes to i–iii, and patient looks at the examiner in response to i–iii. If no response repeat procedure after strong tactile stimuli on both sides of the body. Electroencephalographic response: improvement is defined as reduction to “occasional occurrence”, i.e., 1–9% of epoch).
      Table 2The Salzburg Consensus Criteria for nonconvulsive status epilepticus (SCNC)
      • Beniczky S.
      • Hirsch L.J.
      • Kaplan P.W.
      • Pressler R.
      • Bauer G.
      • Aurlien H.
      • et al.
      Unified EEG terminology and criteria for nonconvulsive status epilepticus.
      .
      Patients without known epileptic encephalopathy
      • EDs > 2.5 Hz, or
      • EDs ≤ 2.5 Hz or rhythmic delta/theta activity (>0.5 Hz) AND one of the following:
        • EEG and clinical improvement after IV AEDs*, or
        • Subtle clinical ictal phenomena, or
        • Typical spatiotemporal evolution**
      Patients with known epileptic encephalopathy
      • Increase in prominence or frequency when compared with baseline with observable change in clinical state
      • Improvement of clinical and EEG features with IV AEDs*
      *If EEG improvement without clinical improvement, or if fluctuation without definite evolution, this should be considered possible NCSE
      **Incrementing onset (increase in voltage and change in frequency), or evolution in pattern (change in frequency >1 Hz or change in location), or decrementing termination (voltage or frequency)
      EDs: epileptiform discharges (spikes, polyspikes, sharp waves, and sharp-and-slow-wave complexes)
      IV AEDs: intravenous antiepileptic drugs
      These criteria have been applied to 50 consecutive patients with NCSE and to 50 controls with abnormal EEG but without clinical suspicion of NCSE in a single center study at Paracelsus Medical University Salzburg, Austria. Different interpretations of rhythmic delta activity (RDA) were tested to optimize test performance. The false positive rate dropped significantly from 28% (rhythmic delta activity as “continuous, as opposed to periodic activity” without any further denominator) to 2% (ASCN criterion of RDA) and finally to 0% (SCNC: ASCN criteria of RDA and fluctuation). Various EEG patterns supporting the diagnosis of “NCSE” according to SCNC were found: frequency of epileptiform discharges (ED) > 2.5 Hz: in 8.2%, EEG and clinical response to AED in 2.0%, subtle clinical ictal phenomenon with ED in 12.2%, spatiotemporal evolution (STE) of epileptiform discharges in 18.4%, and STE of rhythmic delta activity in another 14.3%. For diagnosis of “possible NCSE”: fluctuation without evolution of ED occurred in 46.9% and rhythmic delta activity in 10.2%, whereas an EEG without clinical response to AED was noted in 14.2% [
      • Leitinger M.
      • Beniczky S.
      • Rohracher A.
      • Gardella E.
      • Kalss G.
      • Qerama E.
      • Höfler J.
      • Hess Lindberg-Larsen A.
      • Kuchukhidze G.
      • Dobesberger J.
      • Langthaler P.B.
      • Trinka E.
      Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus – approach to clinical application.
      ]. Based on these data and other findings, modified SCNC were proposed (Fig. 12, Fig. 13) and applied retrospectively to 109 patients with clinical suspicion of NCSE in three independent retrospective cohorts (Salzburg, Austria, and Aarhus and Dianalund, Denmark) with two independent reviewers blinded for the diagnosis, scoring either the Danish or the Austrian EEG. Overall, in these preliminary data, SCNC had a sensitivity of 97.2%, a specificity of 95.9%, and an accuracy of 96.3% (Leitinger et al. in preparation).
      Figure thumbnail gr12
      Fig. 12Algorithm for diagnosis of nonconvulsive status epilepticus with the modified Salzburg Consensus Criteria for NCSE (mSCNC) (see text for further details)
      [
      • Leitinger M.
      • Beniczky S.
      • Rohracher A.
      • Gardella E.
      • Kalss G.
      • Qerama E.
      • Höfler J.
      • Hess Lindberg-Larsen A.
      • Kuchukhidze G.
      • Dobesberger J.
      • Langthaler P.B.
      • Trinka E.
      Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus – approach to clinical application.
      ]
      .
      Figure thumbnail gr13
      Fig. 13Algorithm for EEG definition of typical spatiotemporal evolution (see text for further details) and definitions required for mSCNC.

      9. Conclusions

      Seizures and status epilepticus are clinically defined events. Coma is also a clinically defined syndrome, caused by a variety of etiologies, and many of them are causes of NCSE. In some patients, coma is caused by the epileptic event per se, such as prolonged postictal coma, but in these cases, coma is transient, and recovery can be expected. Comatose-NCSE cannot be diagnosed without EEG, which reveals ictal patterns, epileptiform discharges, or rhythmic discharges. The NCSE contributes to the burden of dysfunction in addition to the cause of coma, which can be structural, metabolic, toxic, or a combination of these (Fig. 2). The degree to which treatment of comatose-NCSE improves outcome is unclear, but retrospective studies recognized nonconvulsive seizures and NCSE as robust predictors of a poorer outcome in patients with critical illness, irrespective of the cause. Nonevolving generalized periodic discharges and burst suppression pattern represent the borderland of NCSE, while other EEG patterns in coma are clearly not reflecting ictal activity, such as low output EEG, or alpha or theta coma (Fig. 14). Non-voluntary movements in coma are poorly understood and may lead to an erroneous diagnosis of NCSE. New EEG criteria for diagnosis of NCSE have been proposed, and first results suggest an excellent clinical utility. However, several patterns remain unclear, such as periodic pattern with triphasic morphology in metabolic coma, diffuse polymorphic delta activity, and alpha coma. New insights might derive from intracranial recordings, which can be correlated with the traditional patterns on surface EEG in comatose patients. The most important question, however, is whether treatment of NCSE in coma improves outcome of these patients or not. A randomized controlled study of treatment of patients with hypoxic brain injury and generalized periodic discharges is on the way [
      • Ruijter B.J.
      • van Putten M.J.
      • Horn J.
      • Blans M.J.
      • Beishuizen A.
      • van Rootselaar A.F.
      • et al.
      Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): study protocol for a randomized controlled trial.
      ], and results can be expected in a few years from now. Further validation of the proposed EEG criteria is needed to achieve a solid basis for future studies of the treatment of comatose-NCSE.
      Figure thumbnail gr14
      Fig. 14The relationship of seizures/status epilepticus, ictal EEG patterns, and EEG patterns in coma.

      Acknowledgments

      The authors would like to thank Prof. Gerhard Bauer, Medical University Innsbruck, for his continuous support and valuable input. We would also like to thank Prof. Bauer for providing us with Fig. 4, Fig. 6, which have also been used in several EEG courses of the Austrian Society of Clinical Neurophysiology.
      Disclosures
      E Trinka has acted as a paid consultant for Eisai, Ever Neuropharma, Biogen Idec, Medtronics, Bial, Takeda, and UCB. He has received research funding from UCB, Biogen Idec, Sanofi-Aventis, FWF, Jubiläumsfond der Österreichischen Nationalbank, and Red Bull. He has received speakers' honoraria from Bial, Eisai, GL Lannacher, GlaxoSmithKline, Böhringer, Viropharma, Actavis, and UCB and is the CEO of Neurocunsult Ges. m.b.H.
      M Leitinger has received a travel grant by Medtronic.

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