Epilepsy & Behavior 49 (2015) 228–233

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Review

Generalized periodic discharges: Pathophysiology and clinical considerations Michel J.A.M. van Putten a,c,⁎, Jeannette Hofmeijer a,b a b c

Department of Clinical Neurophysiology, MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands Department of Neurology, Rijnstate Ziekenhuis, Arnhem, The Netherlands Dept of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede, The Netherlands

a r t i c l e

i n f o

Article history: Accepted 3 April 2015 Available online 2 May 2015 Keywords: Status epilepticus Generalized periodic discharges Synaptic failure Meanfield model Feedforward inhibition

a b s t r a c t Generalized periodic discharges (GPDs) are commonly encountered in metabolic encephalopathy and cerebral hypoxia/ischemia. The clinical significance of this EEG pattern is indistinct, and it is unclear whether treatment with antiepileptic drugs is beneficial. In this study, we discuss potential pathophysiological mechanisms. Based on the literature, supplemented with simulations in a minimal computational model, we conclude that selective synaptic failure or neuronal damage of inhibitory interneurons, leading to disinhibition of excitatory pyramidal cells, presumably plays a critical role. Reversibility probably depends on the potential for functional recovery of these interneurons. Whether antiepileptic drugs are helpful for regaining function is unclear. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Normal brain function critically depends on sufficient energy supply [1] and maintenance of the right balance between excitation and inhibition [2,3]. Numerous homeostatic control mechanisms keep these processes in a physiological working range. These include regulation of blood pressure, heart rate, oxygen, pH, temperature, ion concentrations, and synaptic strengths [4,5]. As the demands imposed on brain function constantly fluctuate, the brain continuously modulates the excitatory–inhibitory balance for efficient information processing, mainly in the neocortex [3]. This may be accompanied by changes in energy consumption [6] and variations in cerebral blood flow [7]. A particular class of derangement of homeostatic control mechanisms is associated with excessive synchronization of neuronal activity: seizures [8]. In patients with epilepsy, the likelihood of seizures is persistently increased. Typically, both genetic and environmental factors are involved [9], together leading to recurrent changes in the physiological balance between excitation and inhibition [10]. During status epilepticus, seizures last relatively long, or sequential seizures occur without full recovery of consciousness [11]. Recently, the neurocritical care society defined this period as lasting 5 min or longer, because of ⁎ Corresponding author. E-mail addresses: [email protected] (M.J.A.M. van Putten), [email protected] (J. Hofmeijer).

the following reasons: (i) most clinical and electrographic seizures last less than 5 min, and if longer, they often do not stop spontaneously; and (ii) in animal models, permanent neuronal injury and pharmacoresistance have been observed early within the traditionally adopted period of 30 min [12]. Characteristics of electroencephalography (EEG) patterns in seizures and status epilepticus are highly variable [13], and often, the EEG evolves over a timescale of hours. Treiman reported on the characteristics of the EEG that can be observed in the transitional period towards generalized convulsive status epilepticus [14]. These observations were based on human EEGs recorded during episodes of generalized convulsive status epilepticus, and a similar sequence of EEG changes was observed in rats, where status epilepticus was induced. Initially, intermittent, discrete seizures occur, which are reflected in the EEG as recurring epileptiform discharges, with durations from one to several minutes (Treiman I). These may evolve to merging seizures with waxing and waning amplitude (Treiman II). In Treiman III, continuous ictal activity is present, which may change into continuous ictal activity punctuated by low-voltage periods (Treiman IV) and, finally, progress towards periodic epileptiform discharges on a ‘flat’ background (Treiman V). Most likely, in patients with nonconvulsive seizures, similar transitions occur [15]. These observations stress that, in prolonged status epilepticus, the waxing and waning characteristics may disappear and a periodic pattern may remain. Here, we focus on generalized periodic discharges (GPDs). We discuss their incidence, potential mechanisms involved in their generation,

http://dx.doi.org/10.1016/j.yebeh.2015.04.007 1525-5050/© 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

M.J.A.M. van Putten, J. Hofmeijer / Epilepsy & Behavior 49 (2015) 228–233

and clinical dilemmas in whether or not to treat these EEG patterns. We present a computational model that allows simulation of GPDs and assists in the generation of hypotheses regarding the underlying pathophysiology.

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2. Generalized periodic discharges The American Clinical Neurophysiology Society recently published a guideline to standardize EEG terminology [16]. Periodic

A

B

Fig. 1. Generalized periodic discharges with a frequency of approximately 2.5 Hz (upper panel) and approximately 0.5 Hz (lower panel). Both recordings are obtained from patients in coma with postanoxic encephalopathy after cardiac arrest. These two EEG examples were also used as illustrations in [57].

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discharges are defined by a “repetition of a waveform with a relatively uniform morphology and duration, with a quantifiable interdischarge interval between consecutive waveforms, and recurrence of the waveform at nearly regular intervals”, where waveforms are characterized by a duration of 0.5 s or less or limited to 3 phases. 2.1. Association with clinical conditions In unselected patients undergoing standard 20-minute EEG testing, the incidence of GPDs is about 1% [17,18]. Otherwise, GPDs occur in up to 20% of patients in coma with severe postanoxic encephalopathy after cardiac arrest, depending on the definition [19–21]. These, typically, are present within the first 12–48 h after resuscitation [22,23]. Other causes are diffuse metabolic encephalopathy [24,25], including sepsis associated encephalopathy [17], and acute brain injury, including stroke [21,26]. Rare intracranial infections, such as subacute sclerosing panencephalitis and Creutzfeldt–Jakob disease, may be associated with GPDs [17]. Two examples of GPDs in patients with postanoxic encephalopathy are shown in Fig. 1. 2.2. Association with structural lesions Several authors studied associations with structural damage on CT or MRI. Structural changes were observed in up to 78% [17,18]. Most found predominance of subcortical lesions, typically in the subcortical gray matter, either alone [17,26] or in combination with cortical lesions [17]. In about 20–25% of patients with GPDs, the absence of MRI abnormalities is reported [17,27]. In a large retrospective study on 162 patients with lateralized or generalized periodic discharges, the authors report on imaging finding in a subgroup of 121, reporting abnormalities in all but one patient [24]. Most had coexistent cortical and subcortical imaging abnormalities (55–65%), and a smaller proportion had isolated cortical (23–30%) or subcortical abnormalities (12–30%). Subcortical damage comprised the subcortical gray matter in most patients, but other studies report that white matter is also affected [28]. Histopathological findings confirm the predominance of coexisting cortical and subcortical pathology, where mainly the subcortical gray matter is involved [29]. In prion diseases, such as Creutzfeldt–Jacob, there is a classical triad of spongiform change, neuronal loss, and gliosis of astrocytes and microglia. The spongiform changes are the most characteristic and affect the deep cortical layers, the cerebellar cortex, or the subcortical gray matter [30]. 2.3. Pathophysiology Regardless of the presence of structural brain damage, most patients with GPDs have actual systemic metabolic derangements [17], cerebral

ischemia [26,31], postanoxic encephalopathy [18,32], or infections [28]. All these conditions readily affect synaptic neurotransmission. Synaptic transmission uses more than 30% of energy consumed by the brain and is the first process to fail if energy supply is limited [33,34]. As a consequence, cerebral ischemia directly affects neurotransmission, which may result in irreversible synaptic damage [35,36]. During other metabolic derangements, changes in neurotransmission are common as well. Mechanisms are divergent and include glucose dysregulation, direct or indirect stimulation of postsynaptic receptors, affected neurotransmitter clearance from the synaptic cleft, endothelial activation, and microglial activation [37]. Consequently, (selective) synaptic failure probably plays a role in the onset or continuation of GPDs. The glutamatergic synapse of excitatory pyramidal cells to inhibitory interneurons is relatively sensitive to hypoxia [38]. This has motivated us to study the effects of changes in the output of inhibitory interneurons in a computational model [32]. In this work, we used a meanfield model of the cortex, comprised of pyramidal cells and inhibitory interneurons [39]. Both neuron types receive input via intracortical synaptic projections as well as nonspecific excitatory input from regions not explicitly incorporated into the model, such as the thalamus. The pyramidal neurons excite both themselves and inhibitory interneurons through glutamate-mediated synapses. Interneurons inhibit both themselves and pyramidal neurons through GABA-mediated synapses (Fig. 2—left). Both cell types, i.e., pyramidal cells and interneurons, receive external input from the same presynaptic source, i.e., the thalamus. Thus, one input to the pyramidal cell is excitatory (direct input from the “thalamus”) and the other is inhibitory (indirect input from the “thalamus” via the inhibitory interneuron). The inhibitory input follows excitatory input after a brief delay resulting from interneuron integration. Such ‘feed-forward’ inhibitory network architecture is ubiquitous in the central nervous system [40] and is important in the control of spike timing in principal cells [41]. With ‘physiological’ parameter values, the model generates rhythms in the alpha band. By selectively changing the synaptic efficacy of the glutamatergic input from the pyramidal cells to the interneurons, 2.5-Hz rhythmic discharges, similar to GPDs, occur (Fig. 2—right). More details are presented in [32]. We emphasize that this model does not differentiate between the potential contributions of various subpopulations of interneurons, as these are lumped into a single population. It is also noted that bilateral synchrony of GPDs cannot be explained by this model, as it is spatially homogeneous. Still, it does present a candidate mechanism involved in the generation of GPDs, i.e., disinhibition of excitatory pyramidal cells, resulting from a change in the feedforward inhibitory network. Feedforward inhibitory networks have been implicated in several types of epilepsies [42]. Selectively impairing Ca2+ channels in neocortical interneurons, resulting in a loss of feedforward inhibition, can produce generalized absence seizures [43]. Some antiepileptic drugs specifically reduce firing in pyramidal cells, but not in the interneurons,

Fig. 2. (Left) Meanfield model used to simulate generalized periodic discharges (GPDs). Pyramidal cells receive both excitatory afferent input and, with a brief delay, inhibitory input from the same presynaptic source (feed-forward inhibition). (Right) Top panel: EEG recording from a patient after cardiac arrest showing GPDs. Bottom panel: simulated EEG showing GPDs. In this simulation, the number of synapses from pyramidal cells to interneurons was selectively reduced to 90%, while the number of other synapses was unchanged. The dominant frequency is similar (~2.5 Hz). Illustration slightly modified from [32].

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restoring or maintaining the physiological balance of feedforward inhibition. The strength of feedforward inhibition accounts for the variation in propagation velocities during seizures [44]. Apart from reduced excitation of inhibitory cells, an intrinsic reduction of the activity of (particular) interneurons may cause disinhibition of excitatory pyramidal cells. This has been observed under experimental conditions of limited energy supply: fast-spiking interneurons were selectively affected [45]. These interneurons are associated with the generation of gamma oscillations, which in turn is associated with memory storage, amongst other cognitive functions [46]. The high energy utilization and the critical position of fast-spiking interneurons in the maintenance of normal cognitive functioning make these neurons important candidates to explain various functional consequences of metabolic and oxidative stress [45]. It is likely that, in patients with hypoxia, energy failure may result in (persistent) loss of (fast-phasic) inhibition of pyramidal cells. Changes in the output of the (fast-spiking) inhibitory interneurons affect the rhythmic activity of pyramidal cells. Although this applies to gamma activity, it supports the hypothesis of selective neuronal dysfunction resulting from restricted energy supply. Relative ischemia or hypoxia may occur during status epilepticus, as the balance between energy supply and demand may be disturbed by increased energy consumption of hyperactive neurons. During recurrent experimentally induced seizures, markers of hypoxia were mainly expressed in interneurons. Similar observations were made in surgical samples from patients with pharmacoresistant epilepsy [47]. This adds further experimental evidence for selective damage of interneurons during energy depletion. 3. Do GPDs reflect seizures or a status epilepticus? Generalized periodic discharges have an association with clinically overt seizures. For instance, in a series of 162 patients with periodic discharges, including lateralized and bilateral independent periodic discharges, seizures (mainly generalized tonic–clonic) occurred in almost 30% of the patients with GPDs [24]. Another study retrospectively analyzed 25 patients with GPDs, where 8 patients were in status epilepticus. In these patients, amplitudes of the periodic discharges were higher, the duration of the discharges was longer, and the inter-GPD amplitude was higher than in patients without status epilepticus [25]. In a retrospective cohort study of 200 critically ill patients with GPDs,

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27% had nonconvulsive seizures and 22% had nonconvulsive status epilepticus [21]. Whether GPDs themselves should be interpreted as seizures or status epilepticus is controversial. Some consider GPDs a reflection of electrographic status epilepticus if present for at least 30 min with a frequency of at least 2.5 Hz. With a lower frequency, they should evolve, i.e. show a change in frequency, morphology or location [16]. Generalized periodic discharges with a frequency of less than 2.5 Hz and without evolution are sometimes classified as interictal [22]. We argue that at least three aspects are relevant in this consideration. First, the energy demand during seizures is increased. For instance, during repetitive seizures in rats, cerebral blood flow rose N200% to meet the enhanced metabolic requirements [48]. Changes in energy demand in patients with various types of GPDs are unknown, but an increased metabolism has been demonstrated with PET and SPECT in some patients with lateralized periodic discharges [49]. Second, seizures may lead to additional neuronal damage. In general, seizures induce various changes in the network architecture, ranging from modulations of synaptic transmission, e.g., resulting from receptor trafficking [50], to neuronal death if energy demands are larger than supplies [47]. Whether synaptic functioning or neuronal integrity during GPDs is compromised is unknown. Finally, with seizures, the underlying brain architecture allows, in principle, the restoration of normal synchronization. As a representation, Fig. 3 shows two possible transitions to seizures, either resulting from a switch in a bistable system (scenario A) [51] or resulting from a change in the landscape (scenario B) [52]. In both situations, the neuronal dynamics (the marble) has moved from the physiological environment to a pathological area. In scenario A, treatment merely needs to restore the physiological equilibrium, whereas in scenario B, reestablishment of the landscape is also needed. Generally, in treating seizures or status epilepticus, we aim to assist in restoring the normal balance, ultimately by the reestablishment of brain architecture. If network architecture is severely disrupted in patients with GPDs, e.g., resulting from massive cell death or irreversible synaptic damage, such as in scenario B, recovery or restoration is probably not possible given current knowledge. 4. Do GPDs warrant treatment? Irrespective of labeling periodic discharges as ictal or not, an important clinical question is whether treatment may eventually improve

Fig. 3. Representation of two possible scenarios involved in seizures or status epilepticus. On the left (scenario A), the system has two equilibria. One reflects physiological function, while the other is associated with seizures. The system may switch between the two states, e.g., resulting from a noisy input, while the landscape remains unchanged. On the right (scenario B), there is a qualitative change in the landscape, eventually resulting in a single equilibrium associated with seizures. The arrow of time has variable durations, from hours to days. The transition towards a very different dynamic behavior (seizures) may be caused by moving to another stable state (left) or may result from a change in control parameters (the shape of the landscape has changed): a ‘bifurcation’ (right). ST: seizure threshold.

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neuronal recovery and clinical outcome [53]. Current literature is not conclusive. Some authors treat GPDs with antiepileptic drugs. However, only a minority of epilepsy experts treat patients with GPDs equally aggressive to those with clinically overt status epilepticus. For most neurologists, the threshold to treat patients with GPDs and myoclonia is lower than for patients with nonconvulsive GPDs. However, in postanoxic encephalopathy, futility of treatment is more likely in patients with myoclonia, given a higher incidence of neuronal necrosis [54] and a larger risk of poor outcome [55]. Some advise treatment if there is evidence of ongoing neuronal injury [21], for instance, an increase in intracranial pressure [56]. In a retrospective analysis in our cohort of patients with postanoxic coma, unstandardized treatment of nonconvulsive seizures, including GPDs, was not associated with a better outcome as compared with no treatment with antiepileptic drugs [57]. Since selective synaptic failure is an important candidate mechanism leading to GPDs, and the EEG reflects synaptic failure and recovery, EEG may provide clues on which patterns can be treated to improve outcome. For example, GPDs on a suppressed background pattern are strongly associated with a poor outcome [58], whereas patients with GPDs on a continuous, normal amplitude background may recover [19]. In 42 patients with postanoxic encephalopathy and GPDs, who were monitored with continuous EEG, we found that earlier appearance, higher periodicity, and absence of accompanying rhythms were associated with a poor outcome. In several patients with a good outcome, GPDs were transient without treatment [23]. The effect of intensive antiepileptic treatment in these patients is currently under investigation in the randomized Treatment of ELectroencephalographic STatus epilepticus After cardiopulmonary Resuscitation (TELSTAR) trial (clinicaltrials.gov, NCT02056236) [59]. 5. Conclusion Generalized periodic discharges result from metabolic derangements or ischemia/hypoxia. The pathophysiology is likely diverse, but selective synaptic failure is a probable common mechanism. Thereby, disinhibition of excitatory pyramidal cells probably plays a critical role. This may result from disturbed excitation of inhibitory interneurons or intrinsic failure of interneurons. Possible reversibility depends on reversibility of synaptic failure and damage to other structures. The effect of an aggressive antiepileptic regimen on patients with GPDs and postanoxic coma is currently being studied in the randomized TELSTAR trial. Conflict of interest Dr. van Putten is a cofounder of clinicalsciencesystems. Dr. Hofmeijer reports no conflicts of interest. References [1] Mergenthaler P, LIndauer U, Dienel GA, Meisel A. NIH public access. Trends Neurosci 2013;36(10):587–97. [2] Siegle JH, Moore CI. Cortical circuits: finding balance in the brain. Curr Biol 2011; 21(23):R956–7. [3] Haider B, McCormick DA. Rapid neocortical dynamics: cellular and network mechanisms. Neuron 2009;62(2):171–89. [4] Somjen GG. Is spreading depression bad for you? Focus on ‘repetitive normoxic spreading depression-like events result in cell damage in juvenile hippocampal slice cultures’. J Neurophysiol 2006;95(1):16–7. [5] Kim JA, Connors BW. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus. Front Cell Neurosci 2012;6(July): 1–12. [6] Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab 2001;21(10):1133–45. [7] Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature 2010;468(7321):232–43. [8] Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE Official Report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–82. [9] Lytton WW. Computer modeling of epilepsy. Biomed Eng (NY) 2009;9(8):626–37.

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Generalized periodic discharges: Pathophysiology and clinical considerations.

Generalized periodic discharges (GPDs) are commonly encountered in metabolic encephalopathy and cerebral hypoxia/ischemia. The clinical significance o...
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