Repetitive cortical spreading depolarizations in a case of severe brain trauma Jed A. Hartings*, Marinella Gugliotta{, Charlotte Gilman{, Anthony J. Strong{, Frank C. Tortella* and M. Ross Bullock{ *Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD, USA { Division of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA { Department of Neurosurgery, King’s College Hospital, London, UK Objective and importance: Cortical spreading depolarizations (CSD) are waves of mass tissue depolarization that mediate progressive development of cortical infarction in animal models and occur in ,50% of patients with acute brain injury. Here we performed multi-modal cerebral monitoring to investigate pathologies associated with CSD occurrence in a case of severe traumatic brain injury. Clinical presentation: A 20 years old male suffering severe traumatic brain injury from a fall had extensive frontal subdural and intraparenchymal hemorrhage with mass effect. Craniectomy was performed for hematoma evacuation and decompression. Intervention: During surgery, a subdural electrocorticography (ECoG) electrode strip, along with microdialysis and PtiO2 probes, was placed beside injured cortex for CSD monitoring. Within 13–81 hours post-injury, 34 CSD occurred. CSD incidence increased during spontaneous hyperthermia and decreased during induced normothermia. Periods of CSD activity were also associated with low brain glucose (,0.10 mmol/l), elevated glutamate (.40 mmol/l) and lactate/pyruvate (.40), and PtiO2,10 mmHg. CSD caused progressive deterioration of ECoG activity only in regions with infarction at follow-up on day 27. Conclusion: Repetitive mass tissue depolarizations accompanied a negative course of hemorrhagic lesion progression in the presence of ischemic conditions after traumatic brain injury. Whether as cause or effect, CSD may represent an inherent component of progressive metabolic failure leading to tissue death, and temperature appears to be an important factor influencing their occurrence. Continuous ECoG is a valuable tool for monitoring subclinical events such as CSD and seizures and for translational research in acute brain injury mechanisms and therapeutics. [Neurol Res 2008; 30: 876–882] Keywords: Spreading cortical depression; seizure; traumatic brain injury; microdialysis; electroencephalography; critical care INTRODUCTION Cortical spreading depolarizations (CSD) are waves of mass neuronal/astroglial depolarization that propagate through gray matter at 1–5 mm/min and like seizures, can arise spontaneously in the context of acute cerebral pathology. CSD are manifested as depressions of spontaneous electrocorticographic (ECoG) activity and a hallmark drop in the extracellular DC potential of 10– 20 mV1,2. Experimentally, repeated episodes of CSD occur spontaneously in border zones of cerebral ischemia, causing depletion of high energy phosphates3,4, tissue acidification4–6, decreased oxygen tension7, and further reduction of cerebral blood flow8,9. CSD thus play a causative role in the progressive expansion of infarcted tissue4,10,11. This Correspondence and reprint requests to: Jed A. Hartings, PhD, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910, USA. [jed.hartings@na.amedd.army.mil] Accepted for publication August 2007. 876 Neurological Research, 2008, Volume 30, October process of metabolic deterioration is reflected in the ECoG as progressive amplitude decrements and prolongation of CSD depression periods7,12,13. Microdialysate signatures include glucose depletion and lactate accumulation, since recovery of ion homeostasis after CSD is dependent on glycolytic metabolism14,15. Recent neurophysiology studies have shown that CSD is also a common sequela of acute brain injury in humans, with an incidence of ,50% in operative cases of trauma and spontaneous intracerebral hemorrhage16–18. In major aneurysmal subarachnoid hemorrhage (aSAH) requiring surgery, where the incidence is even higher (72%), a sequence of recurrent CSD is temporally correlated to the development of delayed ischemic neurological deficits19. Furthermore, aSAH patients who developed delayed CT-proven infarcts show deterioration of ECoG activity specifically in those regions, with CSD depression periods lasting .60 minutes19. Thus, it would appear that CSD are a component of progressive ischemic damage in man as well as animals. # 2008 W. S. Maney & Son Ltd 10.1179/174313208X309739 Repetitive CSD in a case of severe brain trauma: J. A. Hartings et al. In contrast, the consequences of CSD in the context of traumatic lesions have not been well characterized. The existing experimental data are conflicting20,21, and it is even possible that CSD may be beneficial if ischemia is absent. In the healthy brain, CSD elicit a transient, .100% increase in blood flow and do not cause injury22. Moreover, pre-conditioning the intact brain with CSD, which down-regulates cerebral metabolism, can reduce damage caused by subsequent ischemia23. Nonetheless, ischemic damage is frequently evident in autopsy studies of brain trauma in man24, and imaging and PtiO2 monitoring confirm ischemic conditions in severe traumatic brain injury (TBI)25,26. Here we present a trauma case study in which repetitive CSD are associated with ischemia near an intraparenchymal hemorrhage and appear to adversely affect the course of lesion evolution. METHODS AND CASE PRESENTATION A healthy 20 years old male under alcohol intoxication struck his head on a concrete floor. He was GCS 5 at the scene, subsequently improved to GCS 8, and was then intubated upon transfer from a regional medical center to Virginia Commonwealth University. At admission 5 hours post-injury, he had normal temperature (36.2uC), 100% oxygen saturation and BP 119/57. Pupils were normal. After propofol sedation, initial CT scan revealed a right frontal subdural hemorrhage extending from the inferior frontal lobe to the vertex with a large amount of subarachnoid blood, 6 mm of midline shift and mass effect (Figure 1A,B). There was mild effacement of the frontal horns, right frontal intraparenchymal hemorrhage, and extensive skull base fracture. Upon placement of an intraparenchymal ICP probe and obtaining a value of 42 mmHg, it was determined that neurosurgery was required and informed consent was obtained for ECoG monitoring. The research protocol was approved by the Institutional Review Boards at VCU and WRAIR. Twelve hours post-injury, a right fronto-temporo-parietal craniectomy, duraplasty, subdural hematoma evacuation, ventriculostomy, and partial frontal lobectomy were performed. An intraparenchymal microdialysis probe (10 mm membrane length; CMA 20, CMA Microdialysis, Acton, MA, USA) and Licox brain tissue oxygenation (PtiO2) probe (0.8 mm diameter; Integra NeuroSciences, Plainsboro, NJ, USA) were inserted into the frontal lobe just superior to the area of contusion, separated by 1–2 cm alongside an electrode strip placed on the cortex. The electrode strip extended from the inferior frontal gyrus to inferior parietal cortex (Figure 1D). After surgery, the patient was transferred to the Neuroscience ICU and continuous monitoring was initiated. There were no complications related to the probes or electrode strip. During post-operative monitoring, the patient was maintained on synchronized intermittent mandatory ventilation at FiO2 0.35–0.50. He was given 3–6 mg intravenous morphine hourly and 5–15 mg intravenous vecuronium hourly until hour 66 post-injury. Intravenous phenytoin was administered at 200 mg twice daily for 7 days for seizure prophylaxis. Mannitol (intravenous 50–100 g), ventricular drainage and body cooling (Arctic Sun 2000, Medivance Inc., Louisville, KY, USA) were used to control ICP, and intravenous fluids and phenylephrine were used to increase MAP. Body temperature was measured rectally. Plasma glucose was measured every 4 hours, ranged 114– 178 mg/dl over 53 hours post-injury, and insulin was given sub-cutaneously beginning 71 hours post-injury when glucose reached 212 mg/dl. ECoG recordings were made from a linear subdural strip consisting of six platinum electrodes with 10 mm spacing between electrodes (Wyler, Ad-Tech Medical, Racine, WI, USA). Data were acquired continuously in four active channels (A–D) from electrodes 2–6, which were connected in sequential bipolar fashion to two Dual Bioamp amplifiers (ADInstruments, Castle Hill, NSW, Australia). Ground was provided by electrode 1. Band-pass cutoffs for the alternating current amplifiers were set to 0.02 and 100 Hz. Data were sampled at 200 Hz and recorded and reviewed with the use of a Powerlab 16/SP analog-to-digital converter and Chart 5 software (ADInstruments). CSD were identified according to methods described previously in detail17. Briefly, 0.5–2.0 mV shifts in the slow potential were observed that could be attributed to individual electrodes by observing phase reversals on adjacent bipolar channels (Figure 2A). These slow potential changes (SPCs) correspond to DC shifts, the signature of mass tissue depolarization, and propagate along the electrode strip at the rate of CSD (1–5 mm/min). Propagating depressions of fast (0.5–100 Hz) activity amplitude occurred simultaneously with SPCs (Figure 2B). The microdialysis probe was perfused with sterile 0.9% saline at a flow rate of 2 ml/min. After 1 hour stabilization, microdialysate samples were collected every 60 minutes into sealed glass vials and refrigerated at 4uC. Cerebral concentrations of glucose, lactate, pyruvate, glutamate and glycerol were analysed by enzymatic fluorometric assays on a CMA 600 Microdialysis Analyser (CMA Microdialysis, Solna, Sweden). All data are presented as concentrations measured in the microdialysate, without corrections for probe recovery rates. RESULTS At the start of monitoring 13 hours post-injury, peak-topeak ECoG amplitudes were 500–700 mV in channels A–D. Channel A (the nearest injured tissue; electrodes 2 and 3) showed recurrent sharp/slow waves at 1– 2 seconds intervals on a flat background, whereas channels B–D showed continuous delta activity. In hours 13–19, the patient was mildly hyperthermic (.38uC), CPP fell below 60 mmHg, and ICP increased from 9 to 20 mmHg. Brain dialysate glucose was initially low (0.69 mmol/l) and fell to ,0.10 by hour 16. In this context, 11 CSD occurred, beginning at the start of monitoring (hour 13) and continuing at intervals of 12–152 minutes through hour 23. The first five CSD propagated from electrode 2 to 3, while the next six Neurological Research, 2008, Volume 30, October 877 Repetitive CSD in a case of severe brain trauma: J. A. Hartings et al. Figure 1: CT scans of brain pathology. (A and B) Extensive subdural and intraparenchymal hemorrhage with mass effect 5 hours post-trauma. (C and E) The same slice as in A shows the progression of intraparenchymal hemorrhage and surrounding edema. (D) The positions of electrodes 1–6 are shown beside the hemorrhage. (F) CT scan at day 27 shows encephalomalacia in areas that were underlying electrodes 2 and 3 (channel A) 878 Neurological Research, 2008, Volume 30, October Repetitive CSD in a case of severe brain trauma: J. A. Hartings et al. Figure 2: CSD propagating from electrodes 3–5. (A) ECoG recordings in channels A–D were low-pass filtered at 0.5 Hz to reveal slow potential changes (SPCs). In the sequential bipolar chain, phase reversals on adjacent channels identify the common electrode as the active site of depolarization. SPCs propagate from electrodes 3–5 at 4.0–4.5 mm/min. Negative down. (B) The same recordings were high-pass filtered at 0.5 Hz to identify spreading depression of spontaneous ECoG activity. Scale bars apply to all traces in A and B, respectively were at electrode 3 only. Throughout this period, PtiO2 values dropped from .20 to 8–10 mmHg, dialysate glutamate (40–80 mmol/l) and lactate (3–7 mmol/l) were elevated, and L/P was .40. After the last CSD of this cluster, whole body cooling was initiated to control ICP and core body temperature decreased to ,35.5uC by hour 30. During this time, brain dialysate lactate values normalized (1.3– 2.1 mmol/l), L/P fell to ,40, glutamate decreased to 8–16 mmol/l, and glucose recovered to .0.3 mmol/l. CPP was .60 mmHg and ICP was maintained at 20 mmHg. ECoG improved likewise: no CSD occurred during this 7 hour period, and recurrent slow/sharp wave activity on channel A was gradually attenuated, being replaced by continuous delta. Rhythmic 2 Hz delta activity then evolved and developed at hour 29.5 to a 60 second seizure of 0.5–1.5 Hz rhythmic polyspike complexes. Beginning 30 minutes later, over hours 30–32.5, after brain dialysate glucose dropped again to ,0.1 mmol/l, three additional CSD occurred at electrode 3. No further CSD were observed through hour 38, when recordings in channels A and B were interrupted. CT scan at this time revealed significant expansion of intraparenchymal hemorrhage to 3.8 6 2.1 cm (Figure 1C). For the next 24 hours, and as previously, no CSD appeared in channel C or D (electrodes 4–6). At hour 59, CT scan revealed further slight increase in the intraparenchymal hemorrhage and surrounding edema (Figure 1E). Physiologic and microdialysate values remained constant, though PtiO2 had dropped to 6– 8 mmHg when recordings were again initiated in channels A and B at hour 62. In the next 19 hours (hours 62–81), a series of 20 CSD were recorded, with intervals ranging 18–172 minutes. Throughout the first 13 CSD, which occurred on electrodes 2 and/or 3 only, spontaneous ECoG activity in channel A progressively deteriorated in a stepwise fashion with each CSD until peak-to-peak amplitude was ,200 mV (Figure 3, see also Figure 2). At the start of this series, core temperature remained near 35uC, but began increasing 2 hours later when cooling was terminated. In hours 68–70, there was a rebound hyperthermic period (37.9–38.3uC) that corresponded to the densest clustering of six CSD occurring at 20–30 minute intervals (filled circles, Figure 3). From hours 71 to 81, when recordings were terminated, a final seven CSD occurred that mainly propagated from electrodes 3 to 6 (e.g. Figure 2), and L/P again rose above 40 (range: 44–122) where it persisted until microdialysis ended at hour 92. Brain dialysate glucose remained at ,0.10 mmol/l throughout this series of 20 CSD and thereafter. At hour 92, the electrode strip and intraparenchymal probes were removed and the patient was weaned from sedation. At GCS 14 (E3, V5 and M6) on the same day, he was transferred to inpatient brain injury rehabilitation and was discharged 8 days later. CT scan on day 27 post-injury showed significant encephalomalacia in the right frontal cortex including areas that were underlying electrodes of channel A (electrodes 2 and 3) (compare panels D and F, Figure 1). On follow-up after 3 months, the patient’s extended Glasgow outcome score was upper moderate. After 6 months, he had improved to upper good recovery and returned to his college curriculum. There was no evidence of seizures or complaint of headaches after 3 or 6 months. DISCUSSION We have presented a case of severe TBI in which multiparametric monitoring of cerebral tissue was performed. ECoG revealed a preponderance of spontaneous spreading depolarizations in the acute phase of neurocritical care. There are three principal findings. First, patterns of ECoG activity correlated spatially and temporally with lesion development and served as a real-time indicator of lesion progression and functional state of cerebral cortex. At the beginning of recordings, the baseline pattern of recurrent sharp/slow waves in channel A reflected a more injured state on electrodes 2 and 3, located closest to the injury. Similarly, the first 26 of 34 CSD occurred only at electrodes 2 and 3. When CSD later propagated to adjacent electrodes, the predominant direction of propagation (3R6) was consistent with CSD being provoked near the injury site. Finally, only channel A showed progressive stepwise deterioration of ECoG through a series of repetitive CSD, and accordingly, CT scan on day 27 revealed necrotic tissue where electrodes 2–3 had been Neurological Research, 2008, Volume 30, October 879 Repetitive CSD in a case of severe brain trauma: J. A. Hartings et al. Figure 3: Progressive deterioration of cortical activity mediated by a series of CSD. Upper: ECoG power in 0.5–100 Hz band denotes a paroxysmal burst of 1 Hz rhythmic delta that was integrated with a 60 second decay time constant in channel A. occurred in channels A and B. Lower: 0.5 Hz low-pass filter of channel A shows the SPCs accompanying progressive ECoG depressions. Circles denote CSD; other spikes in the trace are artifacts. Filled circles denote the dense clustering of CSDs during the period of hyperthermia in hours 68–70. * indicates the CSD illustrated in Figure 2 located. These correlations of ECoG activity, electrode location and tissue outcome are similar to those reported in aSAH19. A handful of TBI patients with multiple episodes of CSD have also been reported previously, and in some cases, CSD similarly provoked prolonged ECoG depression eventually lasting several hours17,27. Second, the rate of CSD occurrence appeared to be strongly influenced by core body temperature. In the first 10 hours of recording, mean hourly temperature was 38.2uC, and CSD occurred at a rate of 1.1/h. In a subsequent 10 hour period as mild hypothermia was induced, mean temperature was 35.7uC and CSD occurred at a rate of only 0.3/h. Similarly, 1 day later, CSD occurred at 1.25/h while temperature was ,35uC, but escalated to 3.0/h when the patient was rewarmed (mean: 38.1uC). These trends are consistent with data from experimental stroke showing that induced hyperand hypothermia have strong effects to modulate the rate of spontaneous depolarizations and lesion volume28. Hypothermia is widely accepted as a useful therapeutic option for brain injury29, despite conflicting results from clinical trials in TBI30–33. Hypothermia reduces cellular metabolism and decreases microdialysate levels of excitatory amino acids, glucose and lactate34, as observed here. The present data suggest that controlled normothermia may be an effective means to inhibit CSD, and that, conversely, inhibition 880 Neurological Research, 2008, Volume 30, October of CSD may be a mechanism whereby cooling contributes to an improved course of cerebral neurochemistry. Third, we found that repetitive series of CSD and the progressive deterioration of ECoG amplitude were associated with tissue hypoxia and ischemia. During the first cluster of CSDs at hours 13–23, dialysate L/P was often .40 and glucose was undetectable (,0.1 mmol/l). Interestingly, glucose recovered when CSD ceased for the next 7 hours, but then fell again to ,0.1 mmol/l during the subsequent three CSD, thus evidencing a cause–effect, and possibly recursive, relationship. Plasma glucose levels have been shown to modulate the occurrence of CSD35–37, and conversely, CSD cause progressive depletion of brain dialysate glucose3,15. L/P ratios rose again to persistently .40 during the second cluster of CSD over 62–81 hours post-injury, and glucose remained undetectable. Throughout monitoring, PtiO2 was frequently ,10 mmHg. Persistently low glucose38 and low cerebral oxygen tension26,39 have been shown to correlate with poor outcome after severe TBI. Vespa and colleagues found that low glucose (,0.2 mmol/l) is common after TBI, but occurs with unknown causes in 72% of cases38. Similarly they found that metabolic crisis, as evidenced by L/P.40, also occurs frequently with unknown, nonischemic etiology40. Elevated L/P reflects impaired oxidative metabolism and low glucose results from the Repetitive CSD in a case of severe brain trauma: J. A. Hartings et al. compensatory shift to glycolysis during acute periods of increased energy demand40,41. We suggest the possibility that repeated series of CSD may partly underlie this metabolic crisis after TBI, since CSD occurs in a high proportion of patients (57%)18 and recovery from depolarizations is metabolically demanding, relying mainly on glycolysis and causing glucose depletion and lactate accumulation14,15. In the present patient, microdialysate and PtiO2 values were at ischemic levels, and it is therefore not possible to determine to what degree CSDs may have been triggered by, or may have precipitated, these conditions. Rapid-sample microdialysis would provide temporal information that may be useful to distinguish cause and effect42. The illustrated case provides the first evidence that CSD can occur in ischemic cortex after TBI with the hallmark characteristics of adverse effects established in experimental stroke and aSAH in man: (1) repeated occurrence in tight temporal clusters; (2) progressive stepwise deterioration of ECoG activity; (3) death of underlying cortical tissue. It is important to reemphasize, however, that it is unproven in man whether these CSD play a causal etiologic role or are an epiphenomenon or marker of other injury processes. Furthermore, whether these characteristics of CSD are present under non-ischemic conditions after TBI, and whether CSD are innocuous or even neuroprotective in other conditions of TBI pathology, remain questions for future studies. 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