Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs)

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Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs) Facteurs pronostiques EEG chez les patients en post-arrêt cardiaque et particularités des aspects de GPEDs (décharges périodiques épileptiformes généralisées) P. Milani a,b, I. Malissin c, Y.R. Tran-Dinh a,b, N. Deye c,d, F. Baud a,c,d, B.I. Lévy a,b,e, N. Kubis a,b,∗,e a

Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France Service de physiologie clinique, hôpital Lariboisière, AP—HP, 2, rue Ambroise-Paré, 75010 Paris, France c Service de réanimation médicale et toxicologique, hôpital Lariboisière, AP—HP, 75010 Paris, France d Inserm U942, hôpital Lariboisière, 75010 Paris, France e Inserm U965, hôpital Lariboisière, 75010 Paris, France b

Received 13 March 2013; accepted 17 November 2013

KEYWORDS Anoxic encephalopathy; Cardiac arrest; Myoclonus status epilepticus; Generalized Periodic Epileptiform Discharges; Therapeutic hypothermia

Summary Study aims. — We assessed clinical and early electrophysiological characteristics, in particular Generalized Periodic Epileptiform Discharges (GPEDs) patterns, of consecutive patients during a 1-year period, hospitalized in the Intensive Care Unit (ICU) after resuscitation following cardiac arrest (CA). Patients and methods. — Consecutive patients resuscitated from cardiac arrest (CA) with first EEG recordings within 48 hours were included. Clinical data were collected from hospital records, in particular therapeutic hypothermia. Electroencephalograms (EEGs) were reanalyzed retrospectively. Results. — Sixty-two patients were included. Forty-two patients (68%) were treated with therapeutic hypothermia according to international guidelines. Global mortality was 74% but not significantly different between patients who benefited from therapeutic hypothermia compared to those who did not. All the patients who did not have an initial background activity

Abbreviations: CPC, Cerebral Performance Category; ICU, Intensive Care Unit; GPEDs, Generalized Periodic Epileptiform Discharges; GSC, Glasgow Coma Scale; ROSC, Return of spontaneous circulation; TH, Therapeutic hypothermia; BZD, Benzodiazepines. ∗ Corresponding author. E-mail address: [email protected] (N. Kubis). 0987-7053/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.neucli.2013.11.002

Please cite this article in press as: Milani P, et al. Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs). Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2013.11.002

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P. Milani et al. (36/62; 58%) died. By contrast, initial background activity was present in 26/62 (42%) and among these patients, 16/26 (61%) survived. Electroencephalography demonstrated GPEDs patterns in 5 patients, all treated by therapeutic hypothermia and antiepileptic drugs. One of these survived and showed persistent background activity with responsiveness to benzodiazepine intravenous injection. Conclusion. — Patients presenting suppressed background activity, even when treated by hypothermia, have a high probability of poor outcome. Thorough analysis of EEG patterns might help to identify patients with a better chance of survival. © 2014 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Encéphalopathie anoxique ; Arrêt cardiaque ; État de mal épileptique myoclonique ; Décharges généralisées épileptiformes périodiques ; Hypothermie thérapeutique

Résumé But de l’étude. — Les caractéristiques cliniques et électrophysiologiques précoces d’une cohorte de patients hospitalisés dans une réanimation médicale après arrêt cardiaque ont été colligées pendant une année, avec l’analyse particulière d’un sous-groupe de patients ayant un aspect de GPEDs à l’électroencéphalogramme (décharges périodiques épileptiformes généralisées). Patients et méthodes. — Tous les patients ayant un électroencéphalogramme (EEG) réalisé dans les 48 premières heures suivant leur arrêt cardiaque ont été inclus de manière consécutive dans l’étude. Les données cliniques ont été recueillies à partir des dossiers d’observation, en particulier la réalisation d’une hypothermie thérapeutique. Les EEG ont été réinterprétés rétrospectivement. Résultats. — Soixante-deux patients ont été inclus. Quarante-deux patients (68 %) ont été traités par hypothermie thérapeutique selon les recommandations internationales. La mortalité était de 74 % mais n’était pas significativement différente entre les patients traités par hypothermie et ceux qui ne l’étaient pas. Tous les patients qui n’avaient pas d’activité de fond initiale (36/62) (58 %) sont décédés. En revanche, l’activité de fond initiale était présente chez 26/62 patients (42 %) et parmi eux, 16/26 (61 %) ont survécu. Des aspects de GPEDs étaient retrouvés chez 5 patients, tous traités par hypothermie thérapeutique et médicaments antiépileptiques. Un seul patient a survécu et avait une activité de fond persistante et une réactivité à l’administration intraveineuse de benzodiazépines. Conclusion. — Les patients ne présentant pas d’activité de fond, y compris les patients ayant un aspect de GPEDs, même quand ils sont traités par hypothermie, sont tous décédés. L’analyse précoce de l’EEG pourrait aider à identifier le sous-groupe de patients survivants. © 2014 Elsevier Masson SAS. Tous droits réservés.

Introduction The extent of cerebral injury following cardiac arrest (CA) depends on the degree of initial global ischemia, related hypoxemia and subsequent damage resulting from the ischemia-reperfusion syndrome [20]. Anoxia duration, time to return of spontaneous circulation (ROSC), duration of cardiopulmonary resuscitation (CPR) and absence of bystander CPR, cause of cardiac arrest, initial non-shockable rhythm, percutaneous coronary intervention if necessary, and acute post-hypoxic myoclonic status epilepticus (SE) have all been related to poor outcome [20]. However, none of these variables alone can accurately discriminate between patients who nevertheless will have better outcome [32]. To date, neuroprotective strategies such as therapeutic hypothermia (TH) after CA seem to have a favorable effect, but require further large clinical trials to be confirmed [11]. Electroencephalography (EEG) has been studied extensively as a tool for evaluating depth of coma, extent of damage and prognosis after CA. Generalized suppression (<50 ␮V/cm on digital EEG), burst suppression, alpha coma and Generalized Periodic Epileptiform Discharges (GPEDs) activity patterns have been associated with poor functional outcome [6,27]. However to our knowledge, therapeutic hypothermia has only once been systematically taken into

account [6]. The interpretation of GPEDs is still a matter of debate. It has been suggested that GPEDs can occur at a late stage of status epilepticus (SE) and therefore should be treated aggressively [13,31] or that GPEDs are the hallmark of severe brain injury and unlikely to respond to aggressive antiepileptic drug treatment [6,14]. In postCA patients, GPED are usually treated as a hallmark of post-anoxic status epilepticus. However, the prognosis of post-anoxic SE is still not clear: in patients treated with hypothermia in addition to antiepileptic drugs, post-anoxic SE has been independently correlated to death among postCA patients [6,24], or in contrast to a better prognosis in 6 post-anoxic SE patients [25]. Interestingly, these last patients had preserved somatosensory evoked potentials (SSEP) and electroencephalography (EEG) reactivity, suggesting that relevant electrophysiological markers of anoxic encephalopathy must be taken into consideration. Electrophysiological pattern of GPEDs among post-CA patients is usually poorly described in the literature, with no systematic information on background activity, responsiveness to stimulation or intravenous antiepileptic drugs, or clinical evolution. We report here a series of 62 patients with EEG recording within 48 hours after CA. We identified a subgroup of 5 (8%) patients with GPEDs, all of whom were treated by

Please cite this article in press as: Milani P, et al. Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs). Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2013.11.002

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Generalized periodic pileptiform discharges after cardiac arrest hypothermia. We show that persistent EEG background activity was significantly more frequent in survivors, in the whole group of 62 patients and in the only GPEDs patient who survived, and discuss relationship to myoclonus and seizures.

Methods Patients Consecutive patients from January 1st, 2009 to December 31st, 2009, successfully resuscitated after CA and with at least one EEG recording within the first 48 hours, were included in the study. EEG is routinely used in our hospital to help assess prognosis. Clinical data were collected from hospital medical records. Patients with brain damage documented by cerebral CT scan (trauma brain injury, intracranial or subarachnoid hemorrhage, hematoma and stroke) were excluded. Clinical and electrophysiological data were collected and analyzed retrospectively.

Clinical data Data were collected according to the Utstein method by the emergency team during hospitalization: • age, sex, past medical history; • presumed etiology, categorized into non-cardiac, cardiac and undetermined; • shockable rhythm as primary origin of the cardiac arrest versus non-shockable rhythm; • Glasgow Coma Scale (GCS) at admission; • brainstem reflexes at admission; • time from collapse (CA) to return of spontaneous circulation (ROSC) dichotomized into ≤25 or >25 minutes, this being the known time threshold associated with differing outcome [22]; • interval from the time of collapse (presumed time of cardiac arrest) to basic and/or advanced life support, defined as no-flow duration, and the interval from the beginning of life support until the return of spontaneous circulation or termination of resuscitative efforts, termed low-flow duration, in minutes; • therapeutic hypothermia (TH) (target 33 ◦ C; started immediately after admission in ICU or the cardiac catheter lab with ice packs and cold fluid infusions, and maintained for 12 to 24 hours using either external or endovascular methods followed by slow rewarming <0.5 ◦ C/h); • myoclonus, referring to sudden, shock-like, involuntary movements, was categorized as focal if a few adjacent muscles were involved; multifocal or diffuse, if many muscles jerks were observed asynchronously; or generalized if most of the muscles of the body were involved in a synchronized fashion [3,8,10]. Only, when myoclonus persisted for more than 30 minutes, it was considered as ‘‘myoclonic status’’ (status epilepticus or SE); • neurological status at ICU discharge was assessed using the 5-grade Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale (Table 1) [7]. A CPC score of 1—2 was considered as a good outcome and a CPC of 3—5 as a poor outcome;

3 Table 1 The 5-grade Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale. CPC grade CPC 1 CPC 2 CPC 3 CPC 4 CPC 5

Conscious, alert and oriented with normal cognitive functions Conscious and alert with moderate cerebral disability Conscious with severe disability Comatose or in persistent vegetative state Certified brain death or dead by traditional criteria

• SAPS II (New Simplified Acute Physiology Score) and APACHE II score (Acute Physiology and Chronic Health Evaluation) were systematically calculated within the first 24 hours after admission, a higher score corresponding to more severe disease and higher risk of death; • duration of hospitalization; • mortality in the ICU (CPC = 5).

Electrophysiological data Electrophysiological data were retrospectively re-analyzed by the neurophysiology team. Cortical somatosensory evoked potentials Cortical somatosensory evoked potentials (SSEP) were recorded in selected patients, by stimulation of both median nerves. Digital electroencephalography Digital electroencephalography (EEG) recordings were performed in all patients for at least 20 minutes with 24 scalp electrodes positioned according to the standard 10—20 system placement, reformatted to both bipolar and off-head referential montages, with filter settings at 0.3 and 70 Hz. Repetitive bilateral auditory and painful stimulations were systematically performed. The EEG of each patient was classified according to five major grades based on an accepted severity scale for ‘‘anoxic encephalopathy’’ (Hockaday’s scale) [12]. GPEDs patterns were defined as the occurrence of periodic or near-periodic complexes of spikes, spike waves or sharp waves, occupying at least 50% of a standard 20-minute EEG over both hemispheres in a symmetric, diffuse and synchronized manner [4,17]. EEG data were correlated with cortical somatosensory evoked potentials when performed, clinical data and prognosis.

Statistical analyses Results are expressed as median and interquartile range (IQR 25—75%). Statistical analyses were performed with Prism 5 software (Prism 5.03, GraphPad, San Diego, USA). Comparison of frequencies in each group was analyzed by the Fisher’s exact test. A value of P < 0.05 was considered statistically significant.

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P. Milani et al. Table 2 Comparison of clinical, cortical somatosensory evoked potentials (SSEP) data and EEG patterns between non-GPEDs (−) patients and GPEDs (+) patients. GPEDs− (n = 57)

GPEDs+ (n = 5)

Age (years, median [IQR 25—75%])

54 [40—66]

58 [55—70]

Male, n (%)

38 (67)

3 (60)

Diabetes, n (%)

9 (16)

0 (0)

14 (25)

3 (60)

Shockable rhythm , n (%)

21 (40)

3 (60)

No-flow (minutes, median [IQR 25—75%])

2 [0—7]

8 [7—11]

Low-flow (minutes, median [IQR 25—75%])

20 [10—55]

10 [10—35]

Time to ROSC (≤25 minutes), n (%)

23 (40)

2 (40)

GCS on admission/15 = 3, n (%)

52 (91)

5 (100)

Myoclonus, n (%)

13 (23)

4 (80)

SAPS II score

63 [54—77]

59 [48—78]

APACHE II score

29 [27—38]

31 [30—35]

Therapeutic hypothermia, n (%)

34 (60)

5 (100)

Unfavorable outcome at discharge (CPC 3—5), n (%)

49 (86)

5 (100)

Favorable outcome at discharge (CPC 1—2), n (%)

8 (14)

0 (0)

Non-Survivors

42 (74)

4 (80)

Survivors

15 (26)

1 (20)

Duration of hospitalization (days, median [IQR 25—75%])

5 [3—10]

6 [5—11]

SSEP (N20 +/n performed)

2/8 (25%)

2/3 (75%)

EEG patterns Grade I: predominant alpha with some theta Grade II: predominant theta with some alpha Grade III: predominant theta Grade IV: delta activity Generalized epileptiform periodic activity (GPEDs) Grade V: electrocerebral silence Burst suppression patterns

5 (9%) 1 (2%) 17 (30%) 7 (12%) 0 16 (28%) 11 (19%)

0 0 0 0 5 (100%) 0 0

Previous hypertension, n (%) a

GPED: Generalized Periodic Epileptiform Discharges; No-flow: delay between collapse and first cardiac arrest; low-flow: delay between first cardiac arrest and return of spontaneous circulation; ROSC: resumption of spontaneous circulation; GCS: Glasgow Coma Score; CPC: Cerebral Performance Category; SAPS II: New Simplified Acute Physiology Score; APACHE II score: Acute Physiology and Chronic Health Evaluation; EEG patterns: according to the five major grades of severity scale for brain injury. a As the first documented rhythm (5 missing data in GPED-group).

Results

Clinical characteristics

From 1st January until 31st December 2009, 582 patients were admitted to the ICU. Cardiac arrest was the main cause of hospitalization for 150 of these. Among 117 outof-hospital cardiac arrests, etiology was toxic for 17 and non-toxic for 100; 23 benefited from extracorporeal life support. Among the 33 in-hospital cardiac arrests, etiology was toxic for 3 and non-toxic for 30; three patients benefited from extracorporeal life support. Seventy-five patients died within the first 48 hours. Only 62 of the 150 cardiac arrest patients had at least one EEG documented in the first 48 hours.

Whole group Sixty-two patients were included, 44 after experiencing outof-hospital CA and 18 after in-hospital CA. Forty patients were male (65%). Median age was 55 years (32—69). Fortythree patients (69%) had a medical history of cardiovascular pathology and/or chronic respiratory disease; among those 43 patients, 17 (39%) had hypertension, 9 (21%) atrial fibrillation, 8 (19%) ischemic cardiomyopathy, 9 (21%) diabetes, 8 (19%) respiratory disease (asthma, nocturnal apnea or chronic obstructive pulmonary disease), 7 (16%) chronic alcoholism, and 3 (7%) were obese. Three patients had a

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Generalized periodic pileptiform discharges after cardiac arrest medical history of epilepsy (5%). Fifteen patients had no significant medical history and no information was available for 4 of the 62 patients. Presumed cardiac origin of the CA was found in 35 (56%) patients, non-cardiac etiology in 21 (34%) and undetermined etiology in 6 (10%). Shockable rhythm was found in 24 (39%) (Table 2). The large majority of patients had a GCS value of 3 at admission in the ICU, all except 5 (8%) who had GCS score 5 to 9. SPAS2 was 63 (53—78) and APACHE II score was 30 (27—37). Median no-flow was 3 minutes (0—8) and undetermined for 7 patients, and median low-flow was 20 minutes (10—45). Time from collapse to ROSC was ≤25 minutes for 25 (40%) patients and >25 minutes for 30 (48%). Only 6 (20%) of the 30 patients with time to ROSC >25 minutes survived compared to 14 (56%) of the 25 patients with time to ROSC ≤25 minutes. Myoclonus was observed in 17 (27%) patients at different times of evolution after ICU admission: at admission, that disappeared once sedation was established in 3 patients (1 with truncal axial myoclonus, 1 with bilateral upper limb and mouth myoclonus and 1 with diffuse myoclonus of all four limbs); intermittent and spontaneous or elicited by tactile stimulation or pain after interruption of sedation until death for 10 (trunk and face-eyelids, lips, chin and tongue myoclonus in 5, involving only the face in 1, generalized tonic-clonic seizures in 2 and myoclonic SE in 3); at admission that lasted during hospitalization in the ICU for 2 patients (intense axial and face myoclonus for 1 and with additional choreiform upper limb movements for 1); and after interruption of sedation for 2 although information of duration and localization were not available. These patients were treated in the ICU by valproate, midazolam and/or clonazepam, sometimes in combination with phenytoin, fentanyl or propofol according to the choice of the treating physician (Table 2). Seven of the 17 patients with myoclonus survived. Global mortality in the ICU was 74% (46/62 patients). Outcome of the 16 surviving patients after ICU discharge was as follows: CPC = 1 (n = 2), CPC = 2 (n = 6), CPC = 3 (n = 9). Duration of hospitalization was 5 days (3—10). Therapeutic hypothermia (TH) was performed in 39 (63%) patients; 10 of these (25%) survived, while 6/23 (26%) of the non-TH treated patients survived. This difference was not significant. GPEDs group Five patients (8%) (62 ± 8, 52—73 years; 3 males and 2 females) presented GPEDs activity on EEG recorded at day 1—2, e.g. the first 48 hours after CA. All patients, except one, had a medical history of cardiovascular disease but none was epileptic. Presumed origin of CA was cardiac for all 5 patients and first documented rhythm was ventricular fibrillation for all except for patient 5 (asystole). In 2/5 patients, the time to ROSC was ≤25 minutes. At ICU admission, all 5 patients had presented a GCS value of 3 without persistent brainstem reflexes and with mydriasis for 2. TH was performed in all patients. Only one survived with CPC 3 at ICU discharge. Four of the GPEDs patients presented myoclonus: sporadic focal and subtle myoclonus involving face or proximal musculature for 2 and myoclonic status for 2. One patient never developed myoclonus during evolution. Only 1 out of the 5 patients (20%) survived with a final CPC 3 at 18 months after hospitalization discharge (Table 3).

5

Electroencephalographic patterns In all 62 patients, EEGs were recorded within 48 hours after CA. In patients who benefited from therapeutic hypothermia, if the first EEG was performed within the first 24 hours, the 2nd EEG was performed the next day, once normothermia was achieved; if possible this was carried out in the absence of sedative agents in order to better appreciate the level of consciousness of the patient. This second EEG was used for subsequent analyses. However, three patients had only a single EEG at 24 hours performed during hypothermia, showing depressed background activity, because they died before the second control at 48 hours. The distribution of EEG patterns is shown in Table 2, according to the five major grades of severity scale for brain injury. Persistent background activity was present in 26/62 (42%) and depression or suppression in 36/62 (56%). All patients who did not have initial persistent background activity died, while 16/26 (61%) of the patients who had persistent initial background activity survived (P < 10−6 ). The GPEDs pattern consisted of: • in one patient (patient 1), clusters of generalized, nearperiodic bi-triphasic potentials of short duration with periods of suppressed background activity (Fig. 1); • in 3 patients (patients 2, 3 and 5), periodic generalized, monotonous sharp waves, or sharp spikes and polyspikes with suppressed background activity on evolution or from first recording; • in the last patient who survived (patient 4), small near-periodic spikes and polyspikes, generalized but predominant in central and parietal regions, with poorly organized theta background activity (Fig. 2). Electrical activity of initial EEGs was unresponsive to auditory, tactile and painful stimulation for all 5 patients (Table 3). Intravenous injection of benzodiazepines (BZD) (1 mg clonazepam) was administered as an antiepileptic diagnostic test. This was considered reliable if sustained electrophysiological and clinical improvement was induced [23,30]. Except for patient 4, BZD administration was ineffective or induced widening of the GPEDs, increased or decreased inter-GPEDs duration, depending on the patient or on the day this test was performed in the same patient. Spontaneously during evolution or after sedative administration as the coma deepened, amplitude of GPEDs decreased and the inter-GPEDs duration increased in the patients who died. In the only surviving patient (patient 4), GPEDs disappeared after a test dose of benzodiazepine and antiepileptic drugs at day 3 (Fig. 2). During follow-up, background activity normalized and became responsive to sensory stimulation. Cortical SSEP were performed in 11 patients, 8 in the non-GPEDs patients and 3 in the GPEDs patients. N20 wave was present in 2/8 non-GPEDs patients (CPC 3 and CPC 5) and in 2/3 GPEDs patients (Tables 2 and 3).

Discussion Despite potentially beneficial therapeutic interventions such as therapeutic hypothermia, the outcome of anoxic

Please cite this article in press as: Milani P, et al. Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs). Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2013.11.002

Patient (age, years)

Sex

Time to ROSC (min)

1 (70)

Male

50

Female 40

Motor signs

CPC

3/absent/intermediary

Focal myoclonus

5

3/absent/myosis

Myoclonic Status

5

N20 (SSEP)

Temperature (◦ C) at the time of EEG

Sedation

EEG pattern/day refers to the day after cardiac arrest when EEG was performed

ND

37.5

0

38 37.2

0 Valproate

36.8

Valproate

37.1

Phenytoin + valproate

Day 2: clusters of generalized near-periodic bi- or triphasic potentials of short duration with depressed background activity; IV injection of BZD widens potentials and decreases transiently the interwave interval Day 5: same pattern Day 7: same pattern; IV BZD induces a burst suppression pattern Day 8: inter-GPEDs duration increases with suppressed background activity Day 9: suppressed background activity periods are longer between GPEDs

32.4

Midazolam + fentanyl

36

0

36.5

Valproate

(+)

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2 (55)

GCS/brainstem’s reflexes/ pupillary diameter at admission at the ICU

Day 1: near-periodic generalized monotonous sharp waves unresponsive to nociceptive stimulation with low background activity Day 4: near-periodic generalized monotone sharp spikes and polyspikes of higher frequency (2 to 3 Hz) with suppressed background activity, unresponsive to IV BZD Day 5: near-periodic generalized monotone sharp spikes and polyspikes of higher amplitude and lower frequency (0.5 Hz) with increased interval duration, suppressed background activity and unresponsive to IV BZD

Male

15

3/absent/myosis

Focal Myoclonus

5

(-)

32.2 37.8

Midazolam Propofol + valproate

Day 1: burst suppression pattern Day 2: near-periodic irregular generalized monotonous sharp waves with discontinuous low background activity, unresponsive to IV BZD

4 (52)

Male

23

3/absent/mydriasis

Myoclonic Status

3

(+)

38

0

Day 2: small amplitude near-periodic spikes and polyspikes with theta background activity

P. Milani et al.

3 (58)

+Model

Detailed clinical and neurophysiological data of Generalized Periodic Epileptiform Discharges (GPEDs) patients.

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Table 3

Time to ROSC (min)

GCS/brainstem’s reflexes/ Motor signs CPC N20 Temperature Sedation pupillary diameter at (SSEP) (◦ C) at the admission at the ICU time of EEG

37.5 37.6 37.2

37 5 (73)

Female 48

3/absent/mydriasis

Absent

5

ND

35.6

0

Day 3: small amplitude near-periodic spikes and polyspikes on theta background activity; suppression of GPEDs for 5 minutes after an IV bolus of BZD and valproate administration during EEG Valproate Day 6: same pattern Valproate Day 7: same pattern and sensitivity to IV BZD Valproate + clonazepam Day 8: decreased amplitude of GPEDs with increased background activity amplitude and frequency (5—7 Hz) Valproate + clonazepam Day 10: GPEDs are more rare; theta background activity Fentanyl

Day 2: 1 Hz periodic generalized single monotonous sharp waves with suppressed background activity; IV BZD decreases amplitude and slightly increases interval duration

GPED: Generalized Periodic Epileptiform Discharges; ROSC: resumption of spontaneous circulation; GCS: Glasgow Coma Score; CPC: Cerebral Performance Category; SSEP: somatosensory evoked potentials; (+): present; (−): absent bilaterally; ND: not done; D1 is the next day after cardiac arrest. All patients were treated by hypothermia the first 12 hours after cardiac arrest. First EEG was performed during hypothermia (patients 2, 3 and 5) or after the rewarming procedure (patients 1 and 4): IV: intravenous; BZD: benzodiazepines: EEGs were all unresponsive to nociceptive stimulation.

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EEG pattern/day refers to the day after cardiac arrest when EEG was performed

+Model

Sex

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Patient (age, years)

Generalized periodic pileptiform discharges after cardiac arrest

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Table 3 (Continued)

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Figure 1 Patient 1. Generalized, near-periodic, bi-triphasic potentials with short interval and depressed background activity at day 2 (A). Intravenous injection of benzodiazepines decreased the interval between discharges with widening of the bi-triphasic potentials (B).

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Generalized periodic pileptiform discharges after cardiac arrest

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Figure 2 Patient 4. Fluctuating theta background activity (5 Hz) with generalized, irregular small spikes, polyspikes, more ample in central and parietal regions, unresponsive to nociceptive stimulation at day 3 (vertical line) (A). Intravenous injection of benzodiazepines suppressed the spikes and polyspikes (B).

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10 encephalopathy after cardiac arrest remains generally very poor. In our series, the mortality was 74%, which is within the range reported in larger epidemiological studies (65—72%) [15,21,28]. We could not evidence any significant difference between the percentages of surviving patients treated with hypothermia (25%) compared with those who were not (26%). Persistent background activity on EEG was significantly more frequent in the patients who survived (P < 10−6 ), including the only surviving GPEDs patient. Indeed, among the 26 patients who had initial background activity, 16 survived (62%) and depressed background activity was observed in 100% of the patients who finally died. Background reactivity has also been associated with better outcome [6,26]. In our series, reactivity in survivors (6/16) was also higher than in non-survivors (3/10), but the low number of patients did not allow statistical analysis. GPEDs may be encountered in various pathologies, but as an uncommon EEG feature, are rarely analyzed in the specific subgroup of comatose survivors of cardiac arrest. They are generally correlated to poor outcome. In the study by Yemisci et al., describing 37 GPEDs patients [33], overall mortality was 48% but etiologies were mixed (infectious, Creutzfeldt-Jakob disease, anoxic encephalopathy). Hussain et al. [13] reported 10 GPEDs in patients with anoxic or toxic/metabolic encephalopathy with a 90% mortality rate. However, prognosis might differ according to the etiology of GPEDs. Indeed, San-Juan et al. [27] identified, over an 8-year period, 6 cases of GPEDs and 8 of biPLEDs in patients with hypoxic encephalopathy with 100% mortality. Moreover, GPEDs definition varies according to different authors, or is not described [6]. Foreman et al. [9] describe 200 (4.5%) GPEDs patients, selected from more than 3,000 consecutive patients who benefited from continuous EEG in the ICU. Of these GPEDs patients, 14.5% were admitted after cardiac arrest and their in-hospital mortality was 65.5%. However, the authors included periodic triphasic wave morphology in their definition of GPEDs and may have included pure metabolic encephalopathies in their cohort, which might explain the relatively better outcome. Conversely, Yemisci et al. [33] included burst suppression, which might be expected to worsen the overall prognosis. We excluded these two patterns, according to the definition given by Brenner and Schaul [4] and Kuroiwa and Celesia [17]. Standardization of EEG terminology would help in future studies since some patterns used throughout the studies may have a better inherent prognosis (such as triphasic waves). Detailed information on the EEG of these patients, in particular on persistent background activity, nociceptive reactivity, or responsiveness to intravenous administration of benzodiazepines is often not provided, and therapeutic hypothermia not specifically considered in the outcome analysis. In our 5 patients, we identified 3 different GPEDs aspects:

• clusters of generalized, near-periodic bi-triphasic potentials of short duration with periods of suppressed background activity in patient 1 (Fig. 1); • continuous bilateral periodic or near-periodic monotonous sharp waves or sharp spikes or polyspikes,

P. Milani et al. unresponsive to IV benzodiazepines (BZD) and progressive total background activity suppression in 3 patients; • irregular spikes and polyspikes with continuous theta background activity, unresponsive to nociceptive stimulation, but responsive to IV BZD injection in the patient who survived (patient 4) (Fig. 2). A single or repeated bolus of intravenous benzodiazepines or propofol was used as a diagnostic test. Although our survivor presented mydriasis and absent brainstem reflexes at ICU admission, IV BZD could suppress periodic activity for more than 5 minutes. In the other patients, IV BZD increased or decreased the GPEDs interval duration and lowered amplitude without extinction of GPEDs, or produced a burst suppression pattern. Whether patient 4 should be considered as myoclonic status epilepticus or post-CA myoclonic status cannot be concluded here. This patient could not be clinically distinguished from the others and from patient 2 in particular, who had also myoclonic status but did not respond to antiepileptic drugs. The near-periodic spikes and polyspikes were consistent with the definition of GPEDs given by others [4,17]: however the complexes were less monotonous, had a less diffuse distribution compared to the others, were sharper, presented persistent background activity, although unresponsive to nociceptive stimulation. The patient still presented diffuse myoclonus at hospital discharge one year and a half after CA. We can hypothesize that status epilepticus complicated initial anoxic encephalopathy (there was EEG responsiveness to IV BZD and slow consciousness improvement over several days), but that ultimately, the patient was left with post-anoxic myoclonus. Seizures following brain ischemia are a classical complication in patients resuscitated from CA and range from 10 to 40% according to clinical and/or electroencephalographic criteria [16,19,29,33,34]. When determined on continuous EEG monitoring, seizures typically start within 24 hours and may occur during the targeted temperature management phase [1,18] and be recurrent up to 2 weeks after CA [29]. Single seizures and sporadic focal myoclonus are not predictors of poor outcome [1,2,18,29,34]. By contrast, myoclonus SE in comatose patients is constantly associated with inhospital death or poor outcome [32]. Myoclonus can be very subtle and masked by sedatives and neuromuscular blockade, especially in patients treated by TH. Whether GPEDs represent an epileptic phenomenon occurring during evolution of anoxic encephalopathy and deserve a specific treatment, or are a marker of brain anoxic injury severity, is still debated. Indeed, the same EEG pattern has been described as the fourth grade of severity scale for anoxic encephalopathy [12], and as last three grades of untreated or insufficiently treated generalized convulsive SE (grade III, continuous ictal activity; grade IV, continuous ictal activity punctuated by low voltage ‘flat periods’; grade V, periodic epileptiform discharges on a ‘flat’ background) [31]. In comatose patients, GPEDs are more often associated with myoclonus [5]: four (80%) of our GPEDs patients presented myoclonus (2 with focal myoclonus and 2 with myoclonic status) and all were treated by hypothermia and systematic antiepileptic drugs, without prejudging the mechanism. Only one of our patients survived (20%) despite myoclonic status, with a CPC of 3 at ICU discharge which

Please cite this article in press as: Milani P, et al. Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs). Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2013.11.002

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Generalized periodic pileptiform discharges after cardiac arrest did not improve at hospital discharge 1 year and a half later (Table 2). In Yemisci et al.’s study [33], motor signs considered to be epileptic seizures were present in 89% of their 37 GPEDs patients. In their series, overall mortality was 48% but all etiologies were mixed (infectious, Creutzfeldt-Jakob disease, anoxic encephalopathy). Hussain et al. [13] reported 10 GPEDs in patients with anoxic or toxic/metabolic encephalopathy and describe status epilepticus in 30% (3/10) patients with a 90% mortality rate. However, prognosis might differ according to the etiology of GPEDs. Indeed, San-Juan et al. [27] identified over an 8-year period 6 GPEDs and 8 biPLEDs in patients with hypoxic encephalopathy: 29% (4/14) developed tonicoclonic seizures (2/6 GPEDs patients) and all patients died despite systematic antiepileptic drugs administration. Crepeau et al. [6] identified 13 out of 18 GPEDs patients (72%) who presented myoclonus. Among these patients, 4 had additional electrographic seizures. Despite high-dose midazolam, all these patients died. Foreman et al. [9] identified 46% of non-convulsive seizures associated with GPEDs in patients who benefited of continuous EEG monitoring in the ICU. If there seems to be a strong association with GPEDs, myoclonus and non-convulsive seizures, overall mortality remains high in those studies, even though antiepileptic agents were administered and therapeutic hypothermia was sometimes used. Our study presents, as do most previously published studies, several limitations, typically associated with the retrospective nature of the data collection. Only 62 of 150 patients benefited from early EEG and indeed, when prognosis seemed favorable or very unfavorable, early EEG was not systematically performed. Influence of anaesthetic agents, antiepileptic drugs and no systematic EEG within the first 48 hours for all patients hospitalized after resuscitation of cardiac arrest, may have potential confounding effects. Choice of treatment, dose regimen and duration were adjusted for each patient in order to ensure optimal hemodynamics and ventilation, and could not be protocoled. However, although this is a retrospective study and clinicians in charge of the patients were not blind to the EEG results, the end-of-life limitations were protocoled and followed usual recommendations [11]. In the future, whether patients presenting GPEDs without convulsive seizures should be treated with antiepileptic drugs needs to be determined in the specific setting of CA, after unified terminology, in multi-center trials. Combined electrophysiological predictors should be better used in order to assess the positive predictive value of these markers.

Conclusion In this series, we show that prognosis is correlated with persistent background activity in the first 48 hours after resuscitation of cardiac arrest, and that hypothermia does not influence final outcome. GPEDs pattern, even in patients treated with hypothermia and by antiepileptic drugs, is evenly correlated to bad outcome when this has a monotonous structure, associated with suppressed background activity, and is unresponsive to IV benzodiazepines. Conversely, near-periodic sharp small spikes and polyspikes

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with persistent background activity and responsiveness to IV BZD could indicate a better prognosis in the specific setting of anoxic encephalopathy. However, our cohort size is not sufficient to allow valid assessment of this.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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Please cite this article in press as: Milani P, et al. Prognostic EEG patterns in patients resuscitated from cardiac arrest with particular focus on Generalized Periodic Epileptiform Discharges (GPEDs). Neurophysiologie Clinique/Clinical Neurophysiology (2014), http://dx.doi.org/10.1016/j.neucli.2013.11.002