BRIEF COMMUNICATION
Drug-induced EEG pattern predicts effectiveness of ketamine in treating refractory status epilepticus Maysaa M. Basha, Abdulradha Alqallaf, and Aashit K. Shah Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
SUMMARY
Dr. Basha is an adult epileptologist and Assistant Professor of Neurology at Wayne State University.
Refractory status epilepticus (RSE) can lack overt clinical manifestation and is usually treated with continuous infusion of intravenous anesthetic drugs (IVADs), where the use of continuous electroencephalography (cEEG) is imperative. Ketamine has recently been shown to be effective in the treatment of RSE. We retrospectively review a cohort of 11 patients receiving ketamine as part of their treatment regimen for RSE. We report on the presence of a characteristic EEG rhythm consisting of a generalized archiform theta to beta rhythms (7–20 Hz) appearing after ketamine administration. This pattern was seen in five patients, four of whom achieved successful resolution of RSE. Ketamine-induced EEG pattern may serve as a biomarker predictive of successful treatment outcome in RSE. KEY WORDS: Continuous EEG, Intravenous anesthetic drugs, Status epilepticus treatment.
EEG “biomarker” that can predict success in controlling RSE. Ketamine has been reported recently to be an efficacious anesthetic in the treatment of RSE.4–6 It has attractive properties in N-methyl-D-aspartate (NMDA) blockade, has been associated with less hemodynamic complications, and is considered protective in concomitant traumatic brain injury.7,8 These unique characteristics make it useful in the treatment of RSE. In this study we provide evidence of ketamine efficacy and also describe characteristic EEG patterns seen with its use in RSE that may serve as a biomarker for lasting success.
Refractory status epilepticus (RSE) is defined by failure to respond to two antiepileptic medications and often requires induction of anesthesia.1 Status epilepticus is estimated to be refractory in about 30% of cases and is associated with increased morbidity and mortality.2 Treatment of RSE with intravenous anesthetic drugs (IVADs) has its own limitations and risks. Long-term ventilation and immobilization and individual anesthetic side effects can lead to several complications including hypotension, cardiac arrhythmias, and infection.3 Furthermore, continuous electroencephalography (cEEG) monitoring is often required to guide treatment and titration of anesthetics. In many instances, RSE recurs upon withdrawal of IVADs. Factors associated with permanent termination of SE such as the type and dose of IVADs, the duration of IVAD administration, and the desirable EEG pattern (seizure freedom vs. burst suppression) are unknown. In this critically ill population, it is desirable if one can choose an agent based on an
Methods Retrospective review of patients with status epilepticus requiring continuous EEG monitoring between July 2011 and February 2013 was done and 11 patients were identified as having received intravenous ketamine as part of a treatment regimen. Local institutional review board approval for the project was obtained. A detailed chart review of these 11 patients was performed and all relevant information including results of history taking, physical
Accepted January 22, 2015. Department of Neurology, Detroit Medical Center, Wayne State University, Detroit, Michigan, U.S.A. Address correspondence to Maysaa M. Basha, 4201 St Antoine, 8C UHC, Detroit, MI 48201, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 M. M. Basha et al. examination, laboratory testing, and neuroimaging were recorded in a systemic fashion. In addition, electronic medication records were reviewed for time of ketamine initiation, total dosage, and concomitant use of other anesthetics and antiepileptic drugs. Continuous video-EEG monitoring tracings were also reviewed for any immediate electrographic effects after initiation of ketamine and for control of SE. Response to ketamine was defined as control of SE when ketamine was the last drug added, resulting in cessation of clinical and/or electrographic seizures without recurrence of SE during the same hospitalization. Additional clinical outcomes were measured at discharge, and mortality and adverse events were considered.
Results Eleven adult patients (six female) aged 33–68 years (mean 54 years) with RSE and cEEG received intravenous (IV) ketamine. The underlying etiology, SE clinical classification, and SE EEG patterns were varied (see Table 1). Ketamine was initiated within 24 h and up to 11 days after the diagnosis of SE (mean 5.4 days, standard deviation [SD] 4.0). Ketamine was initiated via IV bolus administration in four patients (patients 3 and 10, 1.1 mg/kg; patient 4, 3 mg/ kg; and patient 1, 4 mg/kg). Those without a bolus were started at 1 mg/kg/h and were arbitrarily titrated to higher doses. Ketamine was maintained for 2–27 days on maximum continuous infusions ranging from 1–5 mg/kg/h (mean = 3.5 mg/kg/h). Prior to initiation of ketamine, at least one or more IVADs along with antiepileptic medications (1–5 agents) were used unsuccessfully. Concomitant administration of anesthetics included midazolam, propofol, and pentobarbital. Ketamine was successful in terminating RSE in 4 (36%) of 11 patients treated. All of these patients demonstrated a characteristic EEG rhythm described as generalized frontally predominant archiform theta to beta rhythms (7–20 Hz) of 25–35 lV in amplitude after ketamine initiation and was present throughout drug administration (Fig. 1). This was achieved at both low and high doses of ketamine regardless of coadministration of other anesthetics. The appearance of ketamine EEG effect was within minutes to hours of ketamine initiation, and further dose escalation and maintenance was undertaken to achieve seizure control (Table 1). One additional patient demonstrated this characteristic rhythm during the time of ketamine infusion at a maximum infusion rate of 1.2 mg/kg/h. Ketamine was not titrated further and did not result in SE control. Status epilepticus was later aborted by midazolam alone in this particular patient. Overall, SE was controlled in 73% of patients, three of which were discharged home or to acute rehabilitation and five of which were discharged to subacute rehabilitation Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
or nursing home. Death resulted from brainstem herniation due to worsening intracranial hemorrhage (n = 1), treatment with palliative care with progression of underlying disease (n = 1), and cardiac arrest (n = 1). Of the eight survivors, one patient with successful termination of SE had recurrence of SE, and palliative treatment was elected in subsequent hospitalization. Another patient also had recurrence of SE and surgical intervention was undertaken. Ketamine-specific adverse events were not identified. Major adverse events including end-organ damage or severe sepsis did not increase after ketamine administration (Table 1).
Discussion Ketamine’s success in aborting SE has been well described in several case reports and case series in the literature.4–6,9–11 However, there is little information as to the effect of ketamine on EEG rhythms. We retrospectively report characteristic EEG findings induced by ketamine in patients with SE, the presence of which proved to be a biomarker for RSE response. A diffuse pattern of medium voltage fast theta and alpha rhythms appeared on EEG after administration of ketamine. The appearance of these changes was attributed to ketamine based on temporal appearance of the EEG pattern subsequent to medication administration. No other medication changes were made during this time. Morphologic ketamine-related changes have been described previously. A sequential change of (1) loss of alpha rhythm, (2) appearance of persistent rhythmic theta activity, and (3) development of polymorphic delta activity was seen in normal subjects who were monitored using four-lead quantitative EEG analysis.12 Theta and delta activity were seen superimposed by a faster beta rhythm (14–20 Hz). Ketamine has been shown to similarly induce an increase in EEG fast activity and less low frequency activity than propofol in normal test subjects, which may be consistent with a different mechanism of achieving deep anesthetic levels.13,14 With 56% of neurologist in the United States aiming for burst-suppression (BS) pattern when treating SE,15 it is important to note, that patients in our cohort did not achieve BS pattern with administration of ketamine. Instead, the appearance of the characteristic rhythms was associated with the disappearance of the ictal EEG pattern in some patients; suggesting that achieving BS pattern is not always needed for successful treatment of RSE. A recent report of ketamine use in six patients did demonstrate BS pattern.4 These patients, however, appeared to have coadministration of midazolam and phenobarbital, which may be contributory to BS pattern. The overall response of RSE to AED and IVAD was 73% in our cohort. This is similar to what is reported in the overall RSE literature, which includes the use of the more common IVADs midazolam, propofol, or barbituates.1 The
48F
62M
60M
65M
68M
56M
50F
42F
57F
52F
33F
Pt
1
2
3
4
5
6
7
8
9
10
11
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
Prior epilepsy
Autoimmune intractable epilepsy
Rt medial temporal sclerosis
Rt frontotemporal epidural and intraparenchymal hematoma
Unknown
Metastatic brain lesions Unknown
Mucocele
Encephalomalacia, sepsis Medication noncompliance
Anoxic brain injury
Intra-parenchymal hemorrhage
Etiology
CPSE, SG
CPSE, SG
CPSE, SG
CPSE
CPSE, SG
SG
SG
CPSE, SG
SPSE, CPSE
NCSE
SPSE, CPSE
SE semiology
Lt temporal parietal sz
Rt temp PLEDs, Lt posterior sz
Rt frontotemporal sz and PLEDs
Independent Lt and Rt frontal sz Left temporal PLEDs
Rt frontotemporal sz
Independent Lt and Rt posterior sz Lt frontal sz
Lt frontal sz
GPED
Lt temporal PLEDs
Ictal EEG findings
2
11
5
4
1.1 (26 h)
11
8
5
10
0.7 (16 h)
1.1 (27 h)
1.0 mg/ kg/h
1.1 mg/ kg bolus
1.1 mg/ kg/h
1.0 mg/ kg/h
1.0 mg/ kg/h 1.0 mg/ kg/h 1.0 mg/ kg/h
1.1 mg/ kg bolus 3 mg/ kg bolus
1.0 mg/ kg/h
4 mg/ kg bolus
KA bolus/ infusion rate
4.0
3.0
3.5
1.5
4.0
5.0
1.0
5.0
1.2
5.0
5.0
Maximum KA infusion rate (mg/kg/h)
3
26
14
4
2
3
4
3.5
4
2
3
Days on KA
Yes/ 10–15 m
Yes/ 5–10 m
No
Yes/ 35 m
Yes/ 5–10 m No
No
Yes/ 2 h 45 m No
No
No
KA EEG effect and latency to effect
Yes
Yes
No
Yes
No
Yes
No
No
No
No
No
Status response to KA
Propofol
Midazolam
Propofol pentobarbital
Propofol Midazolam
Midazolam propofol
Midazolam
Midazolam
Midazolam pentobarbital
Midazolam
Midazolam
Midazolam pentobarbital
Concomitant anesthetics
None
Inpatient rehabilitation
Pneumoniabk, Renal failurebk Cardiac failurebk, ak, ↑ICPbk hepatic failureak Pneumoniaak, sepsisak
Recurrence of SE, hospice Recurrence of SE, epilepsy surgery, NH
Death, (cardiac arrest)
Home
Nursing home Home
Death, (brain stem herniation) Death (withdrawal of care) Subacute facility Subacute facility
Patient outcome
Hepatic failurebk
None
None
None
Sepsisbk, cardiac failurebk Sepsisbk
Pneumoniabk, ↑ICPak
Major adverse events
SPSE, simple partial status epilepticus; CPSE, complex partial status epilepticus; NCSE, nonconvulsive status epilepticus; SG, secondary generalization; Lt, left; Rt, right; PLED, periodic lateralized epileptiform discharge; GPED, generalized periodic epileptiform discharge; sz, seizures; KA, ketamine; AED, antiepileptic drug; IVAD, intravenous anesthetic drug; ICP, intracranial pressure; rehab, rehabilitation center; bk, before ketamine; ak, after ketamine; h, hours; m, minutes.
Age/ sex
Latency to KA initiation (days)
Table 1. Demographics and clinical data. Major adverse effects include major end organ damage, increased intracranial pressure, and septic shock
3
Ketamine Pattern Predicts RSE Response
Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
4 M. M. Basha et al. A
B
C
D
Figure 1. Ketamine-induced EEG characteristic in patient 8 (A, B) and patient 11 (C, D). (A) EEG demonstrating periodic lateralizing epileptiform activity (PLED) associated with clinical picture of complex partial status epilepticus. (B) EEG after the addition of ketamine showing the resolution of PLEDs and appearance of characteristic generalized theta (6–8 Hz) activity without burst suppression. (C) EEG demonstrating left posterior quadrant seizure. (D) EEG after addition of ketamine showing the resolution of seizure activity and appearance of characteristic generalized beta (10–12 Hz) activity without burst suppression. Scale: 1 s 9 100 lV. Epilepsia ILAE
response attributed to ketamine administration specifically was 36%, which is also similar to a large ketamine cohort, where 32% of the patients were reported to achieve permanent control of RSE with ketamine.6 Higher rates of success with ketamine have been reported at 63% and 73%.4,5 The patient population in these studies had a history of prior epilepsy and lower incidence of acute brain injury or new-onset refractory status epilepticus (NORSE). Three of our patients had acute brain injury and two had NORSE. These subgroups are typically more difficult to treat. Four of our patients had established prior epilepsy. There was high variability in terms of number of AED and IVAD coadministered as well as variability in ketamine infusion rates. This speaks to the limitation of retrospective review studies of SE where protocols are not well defined and physician preference plays a significant role. However, we did find that infusion rates up to 5 mg/kg/h and durations as long as 26 days did not increase adverse events when compared to that of prior to ketamine initiation. It has been reported that when ketamine is introduced early, response rate tends to be higher6; however, our cohort did not match these findings. The three patients with early ketamine introduction (within 27 h of diagnosis of SE) did not result in appearance of EEG characteristics nor in the abortion of RSE. In contrast, one patient with ketamine introduction as late as 11 days resulted in both the Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
appearance of ketamine EEG characteristics and abortion of RSE. This supports the use of ketamine in prolonged SE, where enhancement of glutamatergic excitation has been demonstrated in animal models and where NMDA receptor blockade may prove to be more effective.16 Overall, ketamine was found to be safe in our cohort. Three deaths occurred, all related to underlying etiology, which included one patient who had increased intracranial pressure and herniation due to worsening intraparenchymal hemorrhage. Adverse events of end-organ damage resulted from cardiac failure in two, hepatic failure in two, and renal failure in one. Pneumonia and sepsis occurred in 36% of patients. Use of ketamine was likely aborted due to lack of efficacy or other unknown factors, since in some cases high doses were not achieved. This is a retrospective study limited by variability in dosage of ketamine, administration of other drugs, timing of drug administration, and underlying etiology. Data collection in this setting is dependent on review of documentation of health care professionals and review of available pruned EEG data. All of these factors impact the perceived success and failure of ketamine administration in the SE population. Nonetheless, we are able to report on efficacy and tolerability of ketamine as well as the presence of an EEG pattern that may serve as a biomarker guiding its utility.
5 Ketamine Pattern Predicts RSE Response
Conclusion The use of anesthetic agents to stop RSE is guided by cEEG. Ketamine is an effective treatment option for treatment of RSE. The early appearance of the characteristic EEG rhythm in response to ketamine administration may be indicative of successful treatment response and ultimately good outcome. The role of these rhythms and use of KA will need to be investigated further in a larger cohort and with a standardized treatment algorithm in a prospective study.
Acknowledgment Funding and support is provided by the Department of Neurology.
Conflict of Interest Dr. Shah has received an investigator-initiated study grant from UCB Pharma, Inc. He also serves on the speaker’s bureau for UCB Pharma, Sunovion Pharmaceuticals, Inc, and Lundbeck Pharmaceuticals Services. Drs. Shah and Basha are conducting clinical trials sponsored by UCB Pharma, Pfizer, and Sunovion. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References 1. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802–2818. 2. Mayer SA, Claassen J, Lokin J, et al. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59:205–210.
3. Wijdicks EF. The multifaceted care of status epilepticus. Epilepsia 2013;54 (Suppl. 6):61–63. 4. Rosati A, L’Erario M, Ilvento L, et al. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology 2012;79:2355– 2358. 5. Synowiec AS, Singh DS, Yenugadhati V, et al. Ketamine use in the treatment of refractory status epilepticus. Epilepsy Res 2013;105:183– 188. 6. Gaspard N, Foreman B, Judd LM, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia 2013;54:1498–1503. 7. White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology 1982;56:119–136. 8. Zeiler FA, Teitelbaum J, West M, et al. The ketamine effect on ICP in traumatic brain injury. Neurocrit Care 2014;21:163–173. 9. Sheth RD, Gidal BE. Refractory status epilepticus: response to ketamine. Neurology 1998;51:1765–1766. 10. Pruss H, Holtkamp M. Ketamine successfully terminates malignant status epilepticus. Epilepsy Res 2008;82:219–222. 11. Yeh PS, Shen HN, Chen TY. Oral ketamine controlled refractory nonconvulsive status epilepticus in an elderly patient. Seizure 2011;20:723–726. 12. Schuttler J, Stanski DR, White PF, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm 1987;15:241–253. 13. Hering W, Geisslinger G, Kamp HD, et al. Changes in the EEG power spectrum after midazolam anaesthesia combined with racemic or S- (+) ketamine. Acta Anaesthesiol Scand 1994;38:719– 723. 14. Maksimow A, Sarkela M, Langsjo JW, et al. Increase in high frequency EEG activity explains the poor performance of EEG spectral entropy monitor during S-ketamine anesthesia. Clin Neurophysiol 2006;117:1660–1668. 15. Claassen J, Hirsch LJ, Mayer SA. Treatment of status epilepticus: a survey of neurologists. J Neurol Sci 2003;211:37–41. 16. Wasterlain CG, Naylor DE, Liu H, et al. Trafficking of NMDA receptors during status epilepticus: therapeutic implications. Epilepsia 2013;54 (Suppl. 6):78–80.
Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
Drug-induced EEG pattern predicts effectiveness of ketamine in treating refractory status epilepticus Maysaa M. Basha, Abdulradha Alqallaf, and Aashit K. Shah Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
SUMMARY
Dr. Basha is an adult epileptologist and Assistant Professor of Neurology at Wayne State University.
Refractory status epilepticus (RSE) can lack overt clinical manifestation and is usually treated with continuous infusion of intravenous anesthetic drugs (IVADs), where the use of continuous electroencephalography (cEEG) is imperative. Ketamine has recently been shown to be effective in the treatment of RSE. We retrospectively review a cohort of 11 patients receiving ketamine as part of their treatment regimen for RSE. We report on the presence of a characteristic EEG rhythm consisting of a generalized archiform theta to beta rhythms (7–20 Hz) appearing after ketamine administration. This pattern was seen in five patients, four of whom achieved successful resolution of RSE. Ketamine-induced EEG pattern may serve as a biomarker predictive of successful treatment outcome in RSE. KEY WORDS: Continuous EEG, Intravenous anesthetic drugs, Status epilepticus treatment.
EEG “biomarker” that can predict success in controlling RSE. Ketamine has been reported recently to be an efficacious anesthetic in the treatment of RSE.4–6 It has attractive properties in N-methyl-D-aspartate (NMDA) blockade, has been associated with less hemodynamic complications, and is considered protective in concomitant traumatic brain injury.7,8 These unique characteristics make it useful in the treatment of RSE. In this study we provide evidence of ketamine efficacy and also describe characteristic EEG patterns seen with its use in RSE that may serve as a biomarker for lasting success.
Refractory status epilepticus (RSE) is defined by failure to respond to two antiepileptic medications and often requires induction of anesthesia.1 Status epilepticus is estimated to be refractory in about 30% of cases and is associated with increased morbidity and mortality.2 Treatment of RSE with intravenous anesthetic drugs (IVADs) has its own limitations and risks. Long-term ventilation and immobilization and individual anesthetic side effects can lead to several complications including hypotension, cardiac arrhythmias, and infection.3 Furthermore, continuous electroencephalography (cEEG) monitoring is often required to guide treatment and titration of anesthetics. In many instances, RSE recurs upon withdrawal of IVADs. Factors associated with permanent termination of SE such as the type and dose of IVADs, the duration of IVAD administration, and the desirable EEG pattern (seizure freedom vs. burst suppression) are unknown. In this critically ill population, it is desirable if one can choose an agent based on an
Methods Retrospective review of patients with status epilepticus requiring continuous EEG monitoring between July 2011 and February 2013 was done and 11 patients were identified as having received intravenous ketamine as part of a treatment regimen. Local institutional review board approval for the project was obtained. A detailed chart review of these 11 patients was performed and all relevant information including results of history taking, physical
Accepted January 22, 2015. Department of Neurology, Detroit Medical Center, Wayne State University, Detroit, Michigan, U.S.A. Address correspondence to Maysaa M. Basha, 4201 St Antoine, 8C UHC, Detroit, MI 48201, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
1
2 M. M. Basha et al. examination, laboratory testing, and neuroimaging were recorded in a systemic fashion. In addition, electronic medication records were reviewed for time of ketamine initiation, total dosage, and concomitant use of other anesthetics and antiepileptic drugs. Continuous video-EEG monitoring tracings were also reviewed for any immediate electrographic effects after initiation of ketamine and for control of SE. Response to ketamine was defined as control of SE when ketamine was the last drug added, resulting in cessation of clinical and/or electrographic seizures without recurrence of SE during the same hospitalization. Additional clinical outcomes were measured at discharge, and mortality and adverse events were considered.
Results Eleven adult patients (six female) aged 33–68 years (mean 54 years) with RSE and cEEG received intravenous (IV) ketamine. The underlying etiology, SE clinical classification, and SE EEG patterns were varied (see Table 1). Ketamine was initiated within 24 h and up to 11 days after the diagnosis of SE (mean 5.4 days, standard deviation [SD] 4.0). Ketamine was initiated via IV bolus administration in four patients (patients 3 and 10, 1.1 mg/kg; patient 4, 3 mg/ kg; and patient 1, 4 mg/kg). Those without a bolus were started at 1 mg/kg/h and were arbitrarily titrated to higher doses. Ketamine was maintained for 2–27 days on maximum continuous infusions ranging from 1–5 mg/kg/h (mean = 3.5 mg/kg/h). Prior to initiation of ketamine, at least one or more IVADs along with antiepileptic medications (1–5 agents) were used unsuccessfully. Concomitant administration of anesthetics included midazolam, propofol, and pentobarbital. Ketamine was successful in terminating RSE in 4 (36%) of 11 patients treated. All of these patients demonstrated a characteristic EEG rhythm described as generalized frontally predominant archiform theta to beta rhythms (7–20 Hz) of 25–35 lV in amplitude after ketamine initiation and was present throughout drug administration (Fig. 1). This was achieved at both low and high doses of ketamine regardless of coadministration of other anesthetics. The appearance of ketamine EEG effect was within minutes to hours of ketamine initiation, and further dose escalation and maintenance was undertaken to achieve seizure control (Table 1). One additional patient demonstrated this characteristic rhythm during the time of ketamine infusion at a maximum infusion rate of 1.2 mg/kg/h. Ketamine was not titrated further and did not result in SE control. Status epilepticus was later aborted by midazolam alone in this particular patient. Overall, SE was controlled in 73% of patients, three of which were discharged home or to acute rehabilitation and five of which were discharged to subacute rehabilitation Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
or nursing home. Death resulted from brainstem herniation due to worsening intracranial hemorrhage (n = 1), treatment with palliative care with progression of underlying disease (n = 1), and cardiac arrest (n = 1). Of the eight survivors, one patient with successful termination of SE had recurrence of SE, and palliative treatment was elected in subsequent hospitalization. Another patient also had recurrence of SE and surgical intervention was undertaken. Ketamine-specific adverse events were not identified. Major adverse events including end-organ damage or severe sepsis did not increase after ketamine administration (Table 1).
Discussion Ketamine’s success in aborting SE has been well described in several case reports and case series in the literature.4–6,9–11 However, there is little information as to the effect of ketamine on EEG rhythms. We retrospectively report characteristic EEG findings induced by ketamine in patients with SE, the presence of which proved to be a biomarker for RSE response. A diffuse pattern of medium voltage fast theta and alpha rhythms appeared on EEG after administration of ketamine. The appearance of these changes was attributed to ketamine based on temporal appearance of the EEG pattern subsequent to medication administration. No other medication changes were made during this time. Morphologic ketamine-related changes have been described previously. A sequential change of (1) loss of alpha rhythm, (2) appearance of persistent rhythmic theta activity, and (3) development of polymorphic delta activity was seen in normal subjects who were monitored using four-lead quantitative EEG analysis.12 Theta and delta activity were seen superimposed by a faster beta rhythm (14–20 Hz). Ketamine has been shown to similarly induce an increase in EEG fast activity and less low frequency activity than propofol in normal test subjects, which may be consistent with a different mechanism of achieving deep anesthetic levels.13,14 With 56% of neurologist in the United States aiming for burst-suppression (BS) pattern when treating SE,15 it is important to note, that patients in our cohort did not achieve BS pattern with administration of ketamine. Instead, the appearance of the characteristic rhythms was associated with the disappearance of the ictal EEG pattern in some patients; suggesting that achieving BS pattern is not always needed for successful treatment of RSE. A recent report of ketamine use in six patients did demonstrate BS pattern.4 These patients, however, appeared to have coadministration of midazolam and phenobarbital, which may be contributory to BS pattern. The overall response of RSE to AED and IVAD was 73% in our cohort. This is similar to what is reported in the overall RSE literature, which includes the use of the more common IVADs midazolam, propofol, or barbituates.1 The
48F
62M
60M
65M
68M
56M
50F
42F
57F
52F
33F
Pt
1
2
3
4
5
6
7
8
9
10
11
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
Prior epilepsy
Autoimmune intractable epilepsy
Rt medial temporal sclerosis
Rt frontotemporal epidural and intraparenchymal hematoma
Unknown
Metastatic brain lesions Unknown
Mucocele
Encephalomalacia, sepsis Medication noncompliance
Anoxic brain injury
Intra-parenchymal hemorrhage
Etiology
CPSE, SG
CPSE, SG
CPSE, SG
CPSE
CPSE, SG
SG
SG
CPSE, SG
SPSE, CPSE
NCSE
SPSE, CPSE
SE semiology
Lt temporal parietal sz
Rt temp PLEDs, Lt posterior sz
Rt frontotemporal sz and PLEDs
Independent Lt and Rt frontal sz Left temporal PLEDs
Rt frontotemporal sz
Independent Lt and Rt posterior sz Lt frontal sz
Lt frontal sz
GPED
Lt temporal PLEDs
Ictal EEG findings
2
11
5
4
1.1 (26 h)
11
8
5
10
0.7 (16 h)
1.1 (27 h)
1.0 mg/ kg/h
1.1 mg/ kg bolus
1.1 mg/ kg/h
1.0 mg/ kg/h
1.0 mg/ kg/h 1.0 mg/ kg/h 1.0 mg/ kg/h
1.1 mg/ kg bolus 3 mg/ kg bolus
1.0 mg/ kg/h
4 mg/ kg bolus
KA bolus/ infusion rate
4.0
3.0
3.5
1.5
4.0
5.0
1.0
5.0
1.2
5.0
5.0
Maximum KA infusion rate (mg/kg/h)
3
26
14
4
2
3
4
3.5
4
2
3
Days on KA
Yes/ 10–15 m
Yes/ 5–10 m
No
Yes/ 35 m
Yes/ 5–10 m No
No
Yes/ 2 h 45 m No
No
No
KA EEG effect and latency to effect
Yes
Yes
No
Yes
No
Yes
No
No
No
No
No
Status response to KA
Propofol
Midazolam
Propofol pentobarbital
Propofol Midazolam
Midazolam propofol
Midazolam
Midazolam
Midazolam pentobarbital
Midazolam
Midazolam
Midazolam pentobarbital
Concomitant anesthetics
None
Inpatient rehabilitation
Pneumoniabk, Renal failurebk Cardiac failurebk, ak, ↑ICPbk hepatic failureak Pneumoniaak, sepsisak
Recurrence of SE, hospice Recurrence of SE, epilepsy surgery, NH
Death, (cardiac arrest)
Home
Nursing home Home
Death, (brain stem herniation) Death (withdrawal of care) Subacute facility Subacute facility
Patient outcome
Hepatic failurebk
None
None
None
Sepsisbk, cardiac failurebk Sepsisbk
Pneumoniabk, ↑ICPak
Major adverse events
SPSE, simple partial status epilepticus; CPSE, complex partial status epilepticus; NCSE, nonconvulsive status epilepticus; SG, secondary generalization; Lt, left; Rt, right; PLED, periodic lateralized epileptiform discharge; GPED, generalized periodic epileptiform discharge; sz, seizures; KA, ketamine; AED, antiepileptic drug; IVAD, intravenous anesthetic drug; ICP, intracranial pressure; rehab, rehabilitation center; bk, before ketamine; ak, after ketamine; h, hours; m, minutes.
Age/ sex
Latency to KA initiation (days)
Table 1. Demographics and clinical data. Major adverse effects include major end organ damage, increased intracranial pressure, and septic shock
3
Ketamine Pattern Predicts RSE Response
Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
4 M. M. Basha et al. A
B
C
D
Figure 1. Ketamine-induced EEG characteristic in patient 8 (A, B) and patient 11 (C, D). (A) EEG demonstrating periodic lateralizing epileptiform activity (PLED) associated with clinical picture of complex partial status epilepticus. (B) EEG after the addition of ketamine showing the resolution of PLEDs and appearance of characteristic generalized theta (6–8 Hz) activity without burst suppression. (C) EEG demonstrating left posterior quadrant seizure. (D) EEG after addition of ketamine showing the resolution of seizure activity and appearance of characteristic generalized beta (10–12 Hz) activity without burst suppression. Scale: 1 s 9 100 lV. Epilepsia ILAE
response attributed to ketamine administration specifically was 36%, which is also similar to a large ketamine cohort, where 32% of the patients were reported to achieve permanent control of RSE with ketamine.6 Higher rates of success with ketamine have been reported at 63% and 73%.4,5 The patient population in these studies had a history of prior epilepsy and lower incidence of acute brain injury or new-onset refractory status epilepticus (NORSE). Three of our patients had acute brain injury and two had NORSE. These subgroups are typically more difficult to treat. Four of our patients had established prior epilepsy. There was high variability in terms of number of AED and IVAD coadministered as well as variability in ketamine infusion rates. This speaks to the limitation of retrospective review studies of SE where protocols are not well defined and physician preference plays a significant role. However, we did find that infusion rates up to 5 mg/kg/h and durations as long as 26 days did not increase adverse events when compared to that of prior to ketamine initiation. It has been reported that when ketamine is introduced early, response rate tends to be higher6; however, our cohort did not match these findings. The three patients with early ketamine introduction (within 27 h of diagnosis of SE) did not result in appearance of EEG characteristics nor in the abortion of RSE. In contrast, one patient with ketamine introduction as late as 11 days resulted in both the Epilepsia, **(*):1–5, 2015 doi: 10.1111/epi.12947
appearance of ketamine EEG characteristics and abortion of RSE. This supports the use of ketamine in prolonged SE, where enhancement of glutamatergic excitation has been demonstrated in animal models and where NMDA receptor blockade may prove to be more effective.16 Overall, ketamine was found to be safe in our cohort. Three deaths occurred, all related to underlying etiology, which included one patient who had increased intracranial pressure and herniation due to worsening intraparenchymal hemorrhage. Adverse events of end-organ damage resulted from cardiac failure in two, hepatic failure in two, and renal failure in one. Pneumonia and sepsis occurred in 36% of patients. Use of ketamine was likely aborted due to lack of efficacy or other unknown factors, since in some cases high doses were not achieved. This is a retrospective study limited by variability in dosage of ketamine, administration of other drugs, timing of drug administration, and underlying etiology. Data collection in this setting is dependent on review of documentation of health care professionals and review of available pruned EEG data. All of these factors impact the perceived success and failure of ketamine administration in the SE population. Nonetheless, we are able to report on efficacy and tolerability of ketamine as well as the presence of an EEG pattern that may serve as a biomarker guiding its utility.
5 Ketamine Pattern Predicts RSE Response
Conclusion The use of anesthetic agents to stop RSE is guided by cEEG. Ketamine is an effective treatment option for treatment of RSE. The early appearance of the characteristic EEG rhythm in response to ketamine administration may be indicative of successful treatment response and ultimately good outcome. The role of these rhythms and use of KA will need to be investigated further in a larger cohort and with a standardized treatment algorithm in a prospective study.
Acknowledgment Funding and support is provided by the Department of Neurology.
Conflict of Interest Dr. Shah has received an investigator-initiated study grant from UCB Pharma, Inc. He also serves on the speaker’s bureau for UCB Pharma, Sunovion Pharmaceuticals, Inc, and Lundbeck Pharmaceuticals Services. Drs. Shah and Basha are conducting clinical trials sponsored by UCB Pharma, Pfizer, and Sunovion. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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