Journal Pre-proof Ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation Sheshali Wanchoo (Data curation) (Writing - original draft), Shahab Khazanehdari (Data curation) (Writing - original draft), Arpan Patel (Conceptualization) (Writing - original draft), Amanda Lin (Data curation) (Writing - review and editing), Tania Rebeiz (Supervision) (Writing - review and editing), Celine DeMatteo (Supervision) (Writing - review and editing), Jamie Ullman (Conceptualization) (Supervision) (Writing - review and editing), David Ledoux (Visualization) (Supervision) (Writing - review and editing) PII: S0303-8467(20)30661-2 DOI: https://doi.org/10.1016/j.clineuro.2020.106318 Reference: CLINEU 106318 To appear in: Clinical Neurology and Neurosurgery Received Date: 22 August 2020 Revised Date: 10 October 2020 Accepted Date: 13 October 2020 Please cite this article as: { doi: https://doi.org/ This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier. Ketamine for empiric treatment of cortical spreading depolarization after subdural hematoma evacuation Sheshali Wanchoo, DO, MS1, Shahab Khazanehdari, MD1, Arpan Patel, MBBS2, Amanda Lin, PharmD3, Tania Rebeiz, MD1, Celine DeMatteo, MD1, Jamie Ullman, MD1 and David Ledoux, MD1. ro of 1. Department of Neurosurgery, Northwell Health, Manhasset, NY 11030, USA 2. Department of Neurology, Northwell Health, Manhasset, NY 11030, USA 3. Department of Pharmacology, Northwell Health, Manhasset, NY 11030, USA Corresponding Author’s name and current institution: David Ledoux, Northwell Health re -p Corresponding Author’s Email: DLeDoux@northwell.edu. Highlights Some patients surgically treated for subdural hematoma (SDH) experience neurologic deficits not clearly explained by the acute brain injury or known sequelae like seizures.  There is increasing evidence that cortical spreading depolarization (CSD) may be the cause of such neurological deterioration post SDH evacuation.  We report cases of patients with subdural hematoma (SDH) not undergoing ECoG in whom CSD was suspected to be the cause of their neurologic deficits post evacuation, after extensive workup for neurological deficits was negative. These patients were empirically treated with ketamine infusion, and had resultant neurological recovery.  Cortical spreading depression should be considered as an etiology for neurologic deficits not otherwise explained post SDH evacuation. Empiric treatment with ketamine, perampanel or other agents known to treat CSD may be helpful in such cases. Jo ur na lP  ABSTRACT Background: It is widely known that some patients surgically treated for subdural hematoma (SDH) experience neurologic deficits not clearly explained by the acute brain injury or known sequelae like seizures. There is increasing evidence that cortical spreading depolarization (CSD) may be the cause. A recent article demonstrated that CSD occurred at a rate of 15% and was associated with neurological deterioration in a subset of patients following chronic subdural hematoma evacuation. Furthermore, CSD can lead to ischemia leading to worsening neurologic deficits. CSD is usually detected on electrocorticography (ECoG) and needs cortical strip electrode placement with equipment and expertise that may not be readily available. of Case Description: We report three cases of patients with subdural hematoma (SDH) not undergoing ECoG in whom CSD was suspected to be the cause of their neurologic deficits post evacuation. Extensive workup including neuroimaging and electroencephalography (EEG) were inconclusive. Patients were subsequently treated with ketamine infusion and had resultant neurological recovery. -p ro Conclusions: Ketamine infusion can help reverse neurologic deficits in patients with SDH in whom the deficits are not explained by neuroimaging or electrographic seizure. CSD is a known phenomenon that can result in neurological injury and must remain in the differential diagnosis of such patients. Though only limited cases are discussed (n = 3), this small case series provides the basis for conducting clinical trials evaluating the efficacy of ketamine in improving functional outcome in brain-injured patients demonstrating evidence of CSD. INTRODUCTION: lP re Keywords: Cortical spreading depression, subdural hematoma, ketamine, empiric treatment Jo ur na Cortical spreading depolarization (CSD) is a slow spreading electrical activity across the cortical surface. It induces a disruption in the ionic gradient across the neuronal membrane and causes a mismatch between the energy demand and supply [1]. It has been known to occur in patients with subdural hematoma [2, 3]. A recent article demonstrated that CSD occurred at a rate of 15% and was associated with neurological deterioration in a subset of patients following chronic subdural hematoma evacuation [4]. Another recent study reported the same phenomenon - EEG negative transient neurological symptoms, that were potentially caused by cortical spreading depolarization, but called the phenomenon as NESIS (Nonepileptic, Stereotypical, and Intermittent Symptoms) [5]. There is evidence that CSD plays a major role in the pathogenesis of secondary brain injury through disruption of the blood brain barrier, paradoxical hypoperfusion leading to spreading ischemia and neuronal injury and loss of astrocytic function [6]. Studies have shown that spreading ischemic can lead to cortical necrosis [7] and is associated with brain energy failure [8]. Inhibiting CSD could prevent secondary brain injury and improve prognosis. Ketamine infusion has been shown to suppress CSD on electrocorticography (ECoG)in patients with acute brain injury [8-10]. We report three cases not undergoing ECoG with subdural hematoma (SDH) in whom CSD was suspected to be the cause of their neurologic deficits post evacuation. Extensive workup including neuroimaging and electroencephalography (EEG) were inconclusive. Patients were subsequently treated with ketamine infusion, and had resultant neurological recovery. Ketamine was chosen to treat suspected CSD since CSD involves activation of NMDA receptors, and ketamine is a known NMDA antagonist [11]. CASE PRESENTATIONS: Jo ur na lP re -p ro of Case 1: A 57-year-old right-handed male with past medical history notable for end stage renal disease (ESRD) on hemodialysis (HD), history of previous right sided stroke with residual left sided weakness, type 2 diabetes mellitus, and hypertension presented to Emergency Department (ED) with slurred speech during dialysis. CT scan of the brain showed left sided mixed density subdural hematoma (SDH) measuring 11mm at its max diameter, with minimal shift. Of significance, patient was on aspirin 81mg daily, which was reversed with desmopressin (DDAVP) and platelet transfusion. On presentation, his neurologic exam was alert, oriented to person, place, time, and situation (x4), left facial palsy and residual left upper extremity weakness from previous stroke. Patient was started on seizure prophylaxis with levetiracetam 500 mg twice/day per brain trauma guidelines (Guidelines for the Management of Severe TBI, 4th Ed.). On the third day of hospitalization, his exam worsened, and he developed severe dysarthria. An emergent CT scan showed increased SDH. He was taken to the OR emergently, and underwent left craniotomy for SDH evacuation. Post op CT showed adequate/near complete SDH evacuation and no infarcts. However, his neurologic exam did not improve, and he became globally aphasic, but with no change in motor strength. Structural and metabolic causes including infections, electrolyte abnormalities, myocardial infarction were ruled out. Forty-eight hours of continuous video EEG (v-EEG) monitoring showed moderate background slowing (more persistent over left hemisphere) and maximal intermittent lateralized periodic discharges (LPDs) in the left temporal region, yet no seizures were detected (see table 4). Post-operative day 2, he developed spasticity of left upper extremity with minimal movement to noxious stimuli, and triple flexion of the left lower extremity. Repeat CT scan did not show any worsening of SDH since evacuation. As neuroimaging and electrographic monitoring did not explain the decline in motor exam, transcranial dopplers (TCDs) were ordered to evaluate for the presence of cerebral vasospasm, which can be a complication of traumatic brain injury [12]. The TCDs demonstrated normal velocities in anterior and posterior circulations. Given no explanation for his neurological deterioration or evidence of electrographic seizures, empiric ketamine infusion was initiated, treating presumed CSD. Rate was initiated at 0.25 mg/kg/hr and titrated up to 0.75 mg/kg/hr by next day. Table 1 discusses the duration, and titration of the drip since this has not been discussed in literature before. Within one day of initiating ketamine infusion, he began moving all his extremities spontaneously but remained globally aphasic. On day 2 of ketamine infusion, he started following commands. He was subsequently prescribed perampanel (see discussion) 6mg daily and titrated off the ketamine drip. The perampanel was stopped after five days. He was discharged to an acute rehabilitation facility thirteen days after SDH evacuation. His neurologic exam at the time of discharge was close to his baseline examination, except for mild expressive aphasia. ur na lP re -p ro of Case 2: 85-year-old female with past medical history of left posterior cerebral artery (PCA) infarct in 2016 (with residual right sided homonymous hemianopsia), on aspirin and clopidogrel presented to the ED in January 2020 with left arm weakness and confusion. CT scan of the head revealed acute right holohemispheric subdural hemorrhage measuring 1.1 cm in diameter with 8 mm midline shift. There was no history of fall or trauma. Her admission physical examination was notable for right homonymous hemianopsia (baseline), right gaze preference, left hemiparesis (left upper extremity 3/5, left lower extremity 4/5) and left sided extinction. She was given DDAVP and platelets for reversal of her antiplatelet agents. Family initially declined neurosurgical intervention, and patient was monitored in the NeuroICU till her SDH was stable. Further during her hospital course, however, patient was noted to have fluctuating left sided weakness (0/5 to 4/5). Given the fluctuations, levetiracetam started initially at the dose of 500 mg twice daily was increased to 1000 mg twice daily. Repeat CT scan showed an interval increase in size of the right sided SDH and demonstrated chronic components of the SDH. She was started on Dexamethasone 4mg every 6 hours, and monitored for seizures with v-EEG. EEG monitoring for three days did not show epileptiform discharges or seizures (table 4). Given fluctuating exam and negative EEG recording, family agreed to surgical intervention and patient was taken for right craniotomy for SDH evacuation. Post operatively, her left arm weakness improved to 4+/5. However, her exam continued to fluctuate and became nearly monoplegic. Repeat CTH was stable (Figure 1 shows pre- and post-op imaging) and v-EEG was negative for electrographic seizures. Metabolic work-up performed to explain the neurologic exam was inconclusive. She was subsequently transferred to the NeuroICU on post-op day 7 for empiric ketamine infusion for presumed CSD. Ketamine was started at an initial rate of 0.5 mg/kg/hr and titrated up to 1.5 mg/kg/hr. Table 2 discusses the duration and titration of ketamine for this patient. During titration, patient’s gabapentin (home medication) was discontinued since it could contribute to patient’s somnolence. v-EEG monitoring while on ketamine infusion revealed background suppression. Due to sedation, ketamine was rapidly tapered off. A few hours later, she was more alert and was able to move antigravity, improving to 4/5 strength subsequently. Patient was transferred to the floor the next day and discharged to rehab 2 days later with stable exam. Jo Case 3: 68 year-old male with past medical history of DM2 presented to the ED with son and wife, who reported that patient was becoming more steadily confused for the past several days (increased agitation, confusion). Family could not rule out trauma but did not recall a traumatic event. They denied any anticoagulant or antiplatelet usage. Since the SDH could be potentially traumatic, patient was started on levetiracetam 500 mg twice/day for seizure prophylaxis. His exam upon presentation was A&Ox3, extra ocular muscles intact, no facial, following commands on all extremities - 5/5 throughout, no drift; and sensation intact to light touch. A CT head obtained to work up the confusion showed acute on chronic bilateral subdural hematomas (2.1 cm on left, 1.2 cm on right; with a 7mm left to right midline shift). He was taken emergently to the OR the next day when his exam progressed to severe agitation. He underwent left minicraniotomy and right burrhole x 2 for evacuation of SDH. Post procedure, he was somnolent but opening eyes to physical touch and moving all extremities spontaneously and purposefully, but not following commands. CT head on post-op day # 1 showed good subdural evacuation with ur na DISCUSSION: lP re -p ro of decreased left to right midline shift, and the presence of bilateral subdural drainage catheters. He was noted to be agitated, flailing around in bed, and moving all extremities but significantly weaker on the right side (~2/5); which then progressed to right upper extremity monoplegia by evening. Given agitation, patient’s antiepileptic was changed to valproic acid to assist with mood stabilizing. Workup for the right upper extremity monoplegia included a CT head, which was unchanged. There were no metabolic derangements, or febrile episodes to explain his acute neurological change. The patient was then placed on v-EEG monitoring. When bedside read for EEG was negative, patient was started on ketamine at 0.5 mg/kg/hr. The final EEG read, by epileptologist the next day, confirmed that patient had no focal or epileptiform abnormalities, and demonstrated severe diffuse cerebral dysfunction (Table 4). The subsequent day (post-op day 2), he was intubated 2/2 to hypoxia, which was initially attributed to ketamine. The ketamine was discontinued. His examination on post-operative day # 2 was eye opening (EO) to noxious stimuli, localizing on left upper extremity, withdrawing on right upper extremity, and withdrawals on bilateral lower extremities (left > right). His right upper extremity exam continued to improve throughout the day, and he was noted to be moving all extremities strongly by night. His surgical drains were removed on post-operative day # 3, and he was extubated on post-operative day #4. He continued to have episodes of respiratory distress subsequently, which was found to be due to upper airway obstruction, and a nasal trumpet was placed. He also continued to be agitated and required antipsychotics during the hospital stay. He was transferred to the floor on post-operative day # 6. His exam at the time of transfer out of the ICU was that he was oriented x 3, following simple commands, moving all extremities strongly. He was discharged to acute rehab on post-operative day # 14, intact, and with no agitation issues. It is widely known that some patients surgically treated for SDH experience neurologic deficits not clearly explained by the acute brain injury or known sequelae like seizures. There is increasing evidence that CSD may be the cause [2, 3]. Mohammad et al 2020 performed a prospective observational study with placement of a subdural strip and found that 6/40 patients had CSD and experienced neurological deterioration [4]. Jo CSD was first described by Leão in 1944, has been since observed in human brain in various conditions like TBI, stroke, SAH, SDH, migraines and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) [11]. Electrocortigraphically, it has been described as “sequential onset in adjacent channels of propagating slow potential change” [13] or “rapidly developing reduction of the power of ECog amplitude by at least 50% in subsequent electrodes” [14]. On a molecular level, elevation of extracellular potassium and glutamate have been demonstrated to begin the cascade [11, 15]. The voltage-sensitive Mg2+ block of the Nmethyl--aspartate (NMDA) receptor is deactivated by change in membrane potentials and the glutamate binding to the NMDA receptor opens the channel allowing for influx of Na+ and Clwith efflux of K+. These electrolytes changes lead to neuronal swelling and energy failure state [due to excessive use of adenosine triphosphates (ATPs) following depolarization wave of cortical spreading depression] and prolonged phase of neuronal inactivation. Additionally, glutamate binding to the NMDA receptor triggers further K+ and glutamate release, thus continuing the propagation of depolarization wave to neighboring cerebral regions [11, 16, 17]. Furthermore, response to this process is different in healthy brain vs injured brains – while CSD causes hyperemia in healthy brain, significant decrease in cerebral blood flow is seen in injured brain [18]. Therefore, we attempted the use of NMDA receptor antagonist to pharmacologically halt this potential cascade. ro of Ketamine, a glutamate receptor antagonist, is known to be an effective agent against CSD in animal models as well as humans [9, 10, 19, 20]. However, the mechanism of action of ketamine is complex, and includes numerous processes in addition to blockade of NMDA channels, depending upon the concentration used [21]. One of the ways in which ketamine disrupts the NMDA receptor is via the “trapping block” in which ketamine remains trapped in the closed ion channel, disrupting the pathological as well as physiological function of the receptor [21]. Jo ur na lP re -p Dosage of ketamine generally used to treat and/or suppress CSD is 2-4 mg/Kg/hr [9, 19] and 1mg/kg/hr for procedural sedation [22]. In case 1, our patient had poorly controlled hypertension, and hence we decided to start on lower dose and uptitrate slowly. However, the patient had a near complete return to neurological baseline with a maximum dose of 0.75 mg/kg/hr. Elevation in blood pressure was noted in case 1 and required up titration of patient’s medications. Given the previous success, in case two, we started the patient on 0.5 mg/kg/hr and were able to uptitrate the dose to 1.5mg/kg/hr. In case 2, it was noted that high dose of ketamine made the patient encephalopathic but suppressed the CSD; when ketamine was discontinued, she became more alert. The resolution of her left sided hemiplegia was attributed to suppression of CSD via ketamine, since no other concomitant intervention was utilized. Similar effect was noted in case 3, where right upper extremity plegia resolved with ketamine administration (0.5 1 mg/kg/hr), and his exam continued to improve despite discontinuation of ketamine. Ketamine was discontinued early secondary to concerns that it was causing respiratory insufficiency (although it is generally thought to be protective of respiratory drive). However, the respiratory distress issues continued despite discontinuation of ketamine, and were attributed to upper airway obstruction. Of note, we are aware of research that has shown no effect of ketamine on CSD at doses of 0.55mg/kg/hr [10] and that doses > 1.15 mg/kg/hr were required to suppress CSD [10]. However, we noted neurological recovery at doses ranging from 0.75 mg/kg/hr - 1.5 mg/kg/hr. The duration of treatment has also varied from patient to patient and was based on clinician discretion. See tables 1, 2 and 3 for ketamine dosing and titration used in these patients. Usage of ketamine is not without risks. Some of the adverse effects of ketamine include: anaphylaxis, arrhythmias, bradycardia, hypertension (more common), hypotension (rare), urological toxicity (dose related and can be irreversible), hepatotoxicity, spasms/tonic-clonic movements, seizures, psychomimetic side-effects and emergence reactions, laryngospasm and respiratory depression (rare) [22, 23] . Ketamine generally maintains normal pharyngeal and laryngeal reflexes but transient laryngeal spasm and airway obstruction has been reported, as well as, apnea around the time of injection [22]. We monitored the patients for these symptoms. We were also cautious with ketamine use due to its stimulatory effect on sympathetic system. The most frequent noted side effect in our patients receiving ketamine were sedation, delirium, and elevation in blood pressure. Of note, all the patients were monitored in NeuroICU for the duration of their treatment, sometimes longer. All three patients had outpatient follow-up post discharge and were doing well, with no re-emergence of their symptoms. of In case 1, we added oral perampanel to prevent CSD while attempting to titrate off the ketamine. Perampanel is a newer anti-epileptic drug which acts through blockage of AMPA receptor. AMPA receptor are different from NMDA receptor in structure, however both NMDA and AMPA receptors are present at glutaminergic synapses and activated by glutamate [24]. Although theoretically perampanel can prevent glutamate hyperexcitation of NMDA receptors, similar to the action of ketamine, it has not been previously reported for treatment of cortical spreading depression. Other agents that have been used include topiramate, and magnesium in animal models and in individual case report [2, 25, 26]. Carbamazepine and levetiracetam have not been proven effective [27]. lP re -p ro Limitations of this paper include no definitive evidence of CSD as being the cause, though all other causes of neurological deterioration were ruled out. It has been shown that CSD is the cause of neurological deterioration in 15% of patients post chronic subdural hematoma evacuation [4]. Additionally, ketamine is known to treat seizures, and therefore, neurologic deterioration could also have been due to EEG-negative seizures. Also, two out of the three patients had evidence of prior strokes. Whether this identifies a patient population that is more susceptible to this phenomenon remains unknown and needs further research, because Mohammad et. al., 2020 did not find any difference in baseline and SDH characteristics between patients who developed CSD and those who did not [4]. Another drawback is that this is a small case series (n =3), and therefore, further studies are needed. Jo ur na Though CSD was a diagnosis of exclusion in our series, we demonstrated recovery of neurological deficits after ketamine infusion, arguing for empiric treatment of these deficits, especially when confirmatory ECoG is not available. The equipment and expertise to diagnose CSD via ECoG may not be routinely or readily available and non-invasive methods, such as EEG, are not reliable to fully detect this phenomenon [28]. Unless ECoG is part of an institution’s protocol for managing subdural hematomas and other conditions harboring the threat of ischemic, secondary neuronal injury, unexplained new neurological deficits related to CSD in patients without such monitoring may, ultimately, go untreated, potentially having an adverse effect on recovery and functional outcome. It is essential that CSD becomes part of the differential diagnosis in such patients in order to guide therapy. CONCLUSION: Cortical spreading depression should be considered as an etiology for neurologic deficits not otherwise explained post SDH evacuation. Empiric treatment with ketamine, perampanel or other agents known to treat CSD may be helpful in such cases. Diagnosing and treating CSD needs further study, particularly with confirmatory ECoG, and with an opportunity to study other novel agents such as perampanel. We agree with Carlson et al., 2018 that determination of the optimal patient population, ideal pharmacologic agent, delivery method and timing of administration also needs to be studied and determined [10]. Ketamine-CSD Credit Author Statement Sheshali Wanchoo, DO, MS: Data curation, Writing – Original draft Shahan Khazanehdari, MD: Data curation, Writing – Original draft Arpan Patel, MBBS: Conceptualization, Writing – Original draft Amanda Lin, PharmD: Data curation, Writing – Review & Editing Celine DeMatteo, MD: Supervision, Writing – Review & Editing of Tania Rebeiz, MD: Supervision, Writing – Review & Editing ro Jamie Ullman, MD: Conceptualization, Supervision, Writing – Review & Editing -p David LeDoux, MD: Visualization, Supervision, Writing – Review & Editing re REFERENCES: Jo ur na lP [1] N. Carney, A.M. Totten, C. 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Sleigh, M. Harvey, L. Voss, B. Denny, Ketamine – More mechanisms of action than just NMDA blockade, Trends in Anaesthesia and Critical Care 4(2-3), 76–81 (2014). [22] R.J. Strayer, L.S. Nelson, Adverse events associated with ketamine for procedural sedation in adults, Am J Emerg Med 26(9) (2008) 985-1028. [23] B. Short, J. Fong, V. Galvez, W. Shelker, C.K. Loo, Side-effects associated with ketamine use in depression: a systematic review, Lancet Psychiatry 5(1) (2018) 65-78. [24] M.A. Rogawski, Revisiting AMPA receptors as an antiepileptic drug target, Epilepsy Curr 11(2) (2011) 56-63. [25] S. Akerman, P.J. Goadsby, Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura, Neuroreport 16(12) (2005) 1383-7. [26] W.S. van der Hel, W.M. van den Bergh, K. Nicolay, K.A. Tulleken, R.M. Dijkhuizen, Suppression of cortical spreading depressions after magnesium treatment in the rat, Neuroreport 9(10) (1998) 2179-82. [27] C. Costa, A. Tozzi, I. Rainero, L.M. Cupini, P. Calabresi, C. Ayata, P. Sarchielli, Cortical spreading depression as a target for anti-migraine agents, J Headache Pain 14 (2013) 62. [28] J. Hofmeijer, C.R. van Kaam, B. van de Werff, S.E. Vermeer, M.C. Tjepkema-Cloostermans, M.J.A.M. van Putten, Detecting Cortical Spreading Depolarization with Full Band Scalp Electroencephalography: An Illusion?, Front Neurol 9 (2018) 17. Jo ur na lP re -p ro of Figure 1: Figure 1 demonstrates pre- and pos-op imaging for patient described in case #2. Image on the left shows acute right sided subdural hematoma with 0.8 cm midline shift (pre-op). Image on the right is CT scan obtained on post-op day 2 after subdural hematoma evacuation, and demonstrated adequate evacuation of blood, with resolution of the midline shift. Ketamine Administration Time Line and Events during Therapy Table 1: Events During Ketamine Therapy 0.5 mg/kg/h 19:44 patient obtunded, not following commands, grunting, VEEG showed no seizures. Ketamine continued at same rate. Day 2 00:00 – 6:59 0.25 mg/kg/h At 22:38 patient grunting, making gurgling oral noises, coughing thick clear/white sputum, required suctioning every 30 minutes. Ketamine rate decreased. Day 2 07:00 – 11:59 Day 2 12:00 – 12:59 Day 2 13:00 – Day 3 11:59 0.5 mg/kg/h Day 3 12:00 – 22:27 0.25 mg/kg/h Jo ro -p 0.5 mg/kg/h Patient drowsy, not fully alert but has sustained awakening. Ketamine dose was reduced re 0.75 mg/kg/h ur na Day 1 15:00 – 16:29 Day 1 16:30 – 23:59 of Rate 0.25 mg/kg/h lP Date and Time After cessation of ketamine, oral preampanel was administered for the next 5 days. On day 5 patient was noted to be sedated and preampanel was discontinued Table 2: Rate 0.5mg/kg/h Day 2 10:00 – 11:59 1mg/kg/h Day 2 12:00 –15:30 1.5 mg/kg/h Day 2 15:30 – 16:00 Day 2 16:00 – 16:30 1 mg/kg/h 0.5 mg/kg/h Events During Ketamine Therapy No change in patient response. Patient was noticed to be overly sedated after addition of gabapentin and ketamine was discontinued. No change in patient’s response. Gabapentin was discontinued and ketamine was restarted Patient was obtunded, background suppression on video-EEG. Due to concern of sedation and no change in patient response observed, ketamine was rapidly tapered off. Jo ur na lP re -p ro of Date and Time Day 1 20:00 - Day 2 1:00 Table 3: Date and Time Day 1 23:00 – Day 2 01:00 Events During Ketamine Therapy 1 mg/kg/hr Order discontinued due to respiratory insufficiency, incorrectly attributed to ketamine at that time; later attributed to airway obstruction. Jo ur na lP re -p ro of Day 2 01:01 - 7:00 am Rate 0.5 mg/kg/hr Table 4: EEG findings prior to, during and post ketamine infusion for all three patients are discussed in the following table. EEG findings (preketamine infusion) EEG findings (during ketamine infusion) EEG findings (post ketamine infusion) Case # 1 The background was continuous, spontaneously variable and reactive. During wakefulness, the posterior dominant rhythm was poorly modulated with more diffuse 6Hz activity. There was more diffuse irregular theta and delta activity present, though persistently more prominent and higher amplitudes over the left frontotemporal region. At times semirhythmic and sharply contoured near 1.5 Hz max P7. (T7 maximal intermittent LPDs). No seizures seen. The background was continuous, spontaneously variable and reactive. During wakefulness, the posterior dominant rhythm was poorly modulated with more diffuse 6Hz activity. There was more diffuse irregular theta and delta activity present, though persistently more prominent and higher amplitudes over the left frontotemporal region and semirhythmic near 2Hz. Periodic and sharply contoured near 1.5 Hz max P7-T7, improved overnight. (P7 T7 maximal intermittent LPDs, improved overnight). No seizures seen. The background was continuous, spontaneously variable and reactive. No posterior dominant rhythm seen. Diffuse theta and polymorphic delta slowing. No interictal epileptiform activity. No seizures. ro -p re lP Jo ur na EEG Impression: Moderate multifocal cerebral dysfunction, persistently worse in the left hemisphere and risk of seizures from the left mid-temporal region. of Case EEG Impression: Moderate multifocal cerebral dysfunction, persistently worse in the left hemisphere. Focal cortical irritability and risk of focal onset seizures from the left midposterior temporal region. LPDs less frequent overnight. EEG Impression: Moderate nonspecific diffuse or multifocal cerebral dysfunction. No epileptiform pattern or seizure seen. Subtle evidence for skull defect in the left hemisphere. N/A of The background was continuous, spontaneously variable and reactive. During maximally recorded wakefulness, the posterior dominant rhythm consisted of symmetric, poorlymodulated 7.5 Hz activity, with amplitude to 20 µV. Excessive diffuse polymorphic delta slowing. Near continuous theta/delta slowing in the right frontotemporal region (Fp2/F4/F8 > T8). Breach effect in max in EEG Impression: Mild nonspecific left frontal region diffuse or multifocal characterized by higher cerebral dysfunction. amplitude, sharply No epileptiform pattern contoured waves and or seizure seen. fast activities. No interictal epileptiform discharges. No seizures. EEG Impression: Structural or functional abnormality in the right frontotemporal region. Mild to moderate nonspecific diffuse or multifocal cerebral dysfunction. No epileptiform pattern or seizure seen. Skull defect max in the left frontal region. [Same as during The background ketamine infusion. Did predominantly not wait for formal consisted of theta and read; when bedside delta activities. No read of EEG screen per posterior dominant neurointensivist was rhythm seen. Diffuse negative, patient was polymorphic delta started on ketamine slowing. Decreased infusion] underlying faster activities over left hemisphere. No clear ro The background was continuous, spontaneously variable and reactive. During wakefulness, the posterior dominant rhythm consisted of symmetric, wellmodulated 7.5 Hz activity, with amplitude to 30 µV, that attenuated to eye opening. Diffuse theta and polymorphic delta slowing. No interictal epileptiform discharges. No seizures. Jo ur na lP re -p Case # 2 Case # 3 The background was spontaneously variable and predominantly consisted of periods of theta and admixed frontally predominant rhythmic delta activities (GRDA). These periods were alternating with periods of mainly Jo ur na lP re -p ro EEG Impression: No epileptiform abnormalities. Severe, nonspecific diffuse or multifocal cerebral dysfunction; left worse than right. alpha and theta activities during more awake appearing epochs, where there was also occasional diffuse beta. No posterior dominant rhythm seen. No clear reactivity to environmental stimuli. Diffuse polymorphic delta slowing. Decreased underlying faster activities over the left hemisphere. Higher amplitude and more sharply contoured activity over F4 and C4 suggested a breach rhythm. No interictal epileptiform activity. No seizures. of reactivity to environmental stimuli. No interictal epileptiform discharges. No seizures. EEG Impression: No epileptiform abnormalities recorded. Severe nonspecific diffuse or multifocal cerebral dysfunction; left worse than right. Possible skull lesion over the right.