Brain Advance Access originally published online on October 25, 2006
Brain 2006 129(12):3224-3237; doi:10.1093/brain/awl297
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Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations
1 Department of Experimental Neurology and Neurology, Charité University Medicine Berlin Berlin 2 Department of Neurosurgery, Charité University Medicine Berlin Berlin 3 Department of Neuroradiology, Charité University Medicine Berlin Berlin 4 Department of Anaesthesiology, Charité University Medicine Berlin Berlin 5 Department of Neurosurgery, University Hospital Mannheim Faculty for Clinical Medicine of the University of Heidelberg, Mannheim 6 Department of Neurosurgery, University of Heidelberg Heidelberg, Germany 7 Department of Clinical Neurophysiology Glostrup Hospital, Copenhagen, Denmark 8 Department of Neurosurgery, University of Copenhagen Glostrup Hospital, Copenhagen, Denmark 9 Department of Neurosurgery, King's College London, UK 10 The Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research Silver Spring, MD, USA
Correspondence to: Jens P. Dreier, Department of Neurology, Campus Charité Mitte, Charité University Medicine Berlin, Schumannstrasse 20-21, 10117 Berlin, Germany E-mail: jens.dreier{at}charite.de
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Progressive ischaemic damage in animals is associated with spreading mass depolarizations of neurons and astrocytes, detected as spreading negative slow voltage variations. Speculation on whether spreading depolarizations occur in human ischaemic stroke has continued for the past 60 years. Therefore, we performed a prospective multicentre study assessing incidence and timing of spreading depolarizations and delayed ischaemic neurological deficit (DIND) in patients with major subarachnoid haemorrhage (SAH) requiring aneurysm surgery. Spreading depolarizations were recorded by electrocorticography with a subdural electrode strip placed on cerebral cortex for up to 10 days. A total of 2110 h recording time was analysed. The clinical state was monitored every 6 h. Delayed infarcts after SAH were verified by serial CT scans and/or MRI. Electrocorticography revealed 298 spreading depolarizations in 13 of the 18 patients (72%). A clinical DIND was observed in seven patients 7.8 days (7.3, 8.2) after SAH. DIND was time-locked to a sequence of recurrent spreading depolarizations in every single case (positive and negative predictive values: 86 and 100%, respectively). In four patients delayed infarcts developed in the recording area. As in the ischaemic penumbra of animals, delayed infarction was preceded by progressive prolongation of the electrocorticographic depression periods associated with spreading depolarizations to >60 min in each case. This study demonstrates that spreading depolarizations have a high incidence in major SAH and occur in ischaemic stroke. Repeated spreading depolarizations with prolonged depression periods are an early indicator of delayed ischaemic brain damage after SAH. In view of experimental evidence and the present clinical results, we suggest that spreading depolarizations with prolonged depressions are a promising target for treatment development in SAH and ischaemic stroke.
Key Words: cortical spreading depression; electrocorticography; ischaemic stroke; spreading ischaemia; subarachnoid haemorrhage
Abbreviations: AD, anoxic depolarization; DIND, delayed ischaemic neurological deficit; DSA, digital subtraction angiography; ICP, intracranial pressure; MCA, middle cerebral artery; SAH, subarachnoid haemorrhage; SD, spreading depression; TCD, transcranial Doppler sonography
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Received April 8, 2006. Revised September 14, 2006. Accepted September 15, 2006.
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In 1944, the Brazilian physiologist Leão
first described the spreading depression (SD) of electrocorticographic activity in rabbit cerebral cortex, and he subsequently reported the large spreading negative slow voltage variation of the extracellular space that accompanies this depression (Leão, 1947). Furthermore, he showed that a similar spreading negative slow voltage variation occurs in the cortex in response to ischaemia induced by bilateral carotid artery occlusion (Leão, 1947), concluding that ‘in the SD of activity, a change of the same nature as one resulting from prolonged interruption of the circulation, occurs in the cerebral cortex’ (authors' emphasis).
The cellular correlate of Leão's spreading negative slow voltage variation is a spreading mass depolarization of neurons and astrocytes (Martins-Ferreira et al., 2000; Somjen, 2001). Under conditions of anoxia and severe ischaemia, spreading depolarization and the corresponding electrocorticographic depression are persistent and referred to as anoxic depolarization (AD), whereas under normal conditions they are transient, and are referred to as SD. AD and SD are similar in their rate of propagation across the cortex, as demonstrated by recordings of the intrinsic optical signal (Jarvis et al., 2001), and also in their associated dramatic changes of intra/extracellular ion concentrations (Kraig and Nicholson, 1978; Hansen and Zeuthen, 1981). The restoration of ion homeostasis, and hence electrocorticographic activity, after a spreading depolarization is energy dependent (Somjen, 2001). During SD, regional cerebral blood flow increases in order to meet this demand, thus preventing neural damage (Lauritzen, 1994). In contrast, when AD is superimposed on preexisting ischaemia, a further decrease of cerebral blood flow occurs (Sonn and Mayevsky, 2000; Shin et al., 2005).
Focal ischaemia is a special condition since there are gradients of perfusion, oxygen, and glucose between the core ischaemic region and the normal tissue where blood flow and energy substrates are unrestricted. Accordingly, direct evidence from microelectrode studies and indirect evidence with laser speckle imaging indicates that the spreading negative slow voltage variation starts in the ischaemic core as persistent AD, becomes a transient depolarization as it spreads through the metabolically compromised penumbra, and traverses the surrounding healthy tissue as SD (Nedergaard and Hansen, 1993; Koroleva and Bures, 1996; Nallet et al., 1999; Shin et al., 2005). Often referred to as peri-infarct or transient ischaemic depolarizations, these intermediate forms of spreading depolarizations in the penumbra typically occur in a temporal cluster of repetitive events (Nedergaard and Hansen, 1993; Koroleva and Bures, 1996; Nallet et al., 1999; Hartings et al., 2003). Peri-infarct depolarizations cause neuronal damage since, like AD, they increase the mismatch between energy demand and supply (Busch et al., 1996; Takano et al., 1996; Strong et al., 1996) and exacerbate ischaemia in the penumbra (Shin et al., 2005). As a consequence, the period of electrocorticographic depression becomes increasingly prolonged with repeated transient depolarizations, evolving to a state of persistent depression with loss of function but preserved ion homeostasis (Back et al., 1994; Ohta et al., 2001; Hartings et al., 2006). Under these conditions, subsequent spreading depolarizations are reflected only in slow negative voltage variations without the opportunity for further depression of electrocorticographic activity.
Spreading depolarization appears to be a highly conserved trait in the phylogenesis of vertebrates (Kraig and Nicholson, 1978; Hansen and Zeuthen, 1981). However, it has been a matter of speculation for the last 60 years whether spreading depolarizations occur in ischaemic stroke in man. Were this to be shown, AD and the intermediate forms of spreading depolarization could be used as a real-time and comprehensive indicator of progressive ischaemic damage, marking metabolic challenge, glutamate release, and toxic calcium entry into neurons (Koroleva and Bures, 1996; Ohta et al., 2001). Moreover, therapy might then target the intermediate forms of spreading depolarizations so as to protect the penumbra against recruitment into the infarct core.
Delayed ischaemic neurological deficit (DIND) after subarachnoid haemorrhage (SAH) is a distinctive syndrome of cerebral ischaemia. Increased headache, meningism and body temperature are typically followed by a fluctuating decline in consciousness and appearance of focal neurological symptoms (Hijdra et al., 1986). The recent multicentre trials of tirilazad mesilate recorded a rate of 33–38% for DIND after SAH and of 10–13% for CT-proven delayed infarcts in the vehicle groups, which comprised a total of over 1000 patients (Haley et al., 1997; Lanzino and Kassell, 1999; Lanzino et al., 1999).
The risk of developing DIND correlates with the amount of blood observed in the initial CT scan (Kistler et al., 1983; Brouwers et al., 1993), and its onset coincides with the time of peak subarachnoid haemolysis in a primate model of SAH (Pluta et al., 1998). This led to the hypothesis that breakdown products of erythrocytes in the subarachnoid space induce DINDs (MacDonald and Weir, 1991). The assumed prime mechanism of DIND is the induction of vasospasm. Proximal vasospasm is visualized with digital subtraction angiography (DSA) or measured with transcranial Doppler sonography (TCD) (Kistler et al., 1983; Vora et al., 1999; Unterberg et al., 2001). However, the positive predictive values of TCD and DSA for the development of DIND are only between 30 and 50% (Vora et al., 1999; Unterberg et al., 2001). Using PET, Minhas et al. (2003) showed that after SAH, TCD in particular was unable to distinguish a state of tissue ischaemia from hyperaemia. These PET findings, similar to those of a study with single-photon emission CT, called for research aimed at the microcirculatory mechanisms underlying DIND (Ohkuma et al., 2000; Minhas et al., 2003). Notably, in animals, spreading depolarization, in the presence of breakdown products of erythrocytes, is the most potent inducer of microarterial spasm currently known, leading to spread across the cortex of virtual disappearance of microcirculation for periods of minutes or even hours. This stimulated the question whether spreading depolarization is involved as both consequence of proximal and cause of distal arterial spasm in the complex sequence of events underlying DIND (Dreier et al., 1998, 2000).
Early treatment of ruptured intracranial aneurysms is performed to reduce the risk of rebleeding. Aneurysms are either treated with endovascular detachable coils or craniotomy and clipping. If craniotomy is indicated for aneurysm occlusion or for surgical evacuation of an intracerebral haematoma, implantation of a subdural electrode strip for electrocorticography is possible. This allows electrocorticographic monitoring for the whole period of ischaemic stroke development, since DINDs have a delayed peak incidence at Day 7 after SAH.
Here, we studied prospectively whether a cluster of spreading depolarizations, with delayed onset following SAH, is associated with DIND. For the first time we show that (i) spreading depolarizations occur in patients with SAH, (ii) a cluster of spreading depolarizations accompanies DIND, and (iii) the evolution of delayed infarcts on CT/MRI is associated with prolonged electrocorticographic depression periods similar to features of spreading depolarizations in the ischaemic penumbra or in the presence of breakdown products of erythrocytes (animal experiments).
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Patient recruitment and clinical care
Patients with major SAH were consecutively recruited by four centres in the Co-Operative Study on Brain Injury Depolarizations (COSBID, see www.cosbid.org). The research protocol was approved by the local ethics committees. Clinical and research consents were obtained after a clinical decision had been taken to offer surgical treatment. SAH was diagnosed by assessment of CT scans. Haemorrhage was graded according to the Fisher scale (Kistler et al., 1983
), and clinical presentation according to the World Federation of Neurological Surgeons (WFNS) scale (Drake et al., 1988). The aneurysm was assessed using four-vessel DSA, or a more restricted study when indicated. The aneurysm was clipped (n = 16), coiled (n = 1) or wrapped (n = 1). A single, linear, 6-contact (platinum) electrocorticography recording strip (Wyler, 5 mm diameter; Ad-Tech Medical, Racine, WI, USA) was placed on cortex accessible through the craniotomy, as previously described (Strong et al., 2002; Fabricius et al., 2006). After surgery, patients were transferred to the intensive care unit. Intracranial pressure (ICP) was monitored via ventricular drainage catheter or ICP transducer (Codman or Camino systems). Glasgow Coma Scale (GCS), blood gases, glucose and electrolytes were documented every 6 h. A thorough neurological examination was performed at least daily. A clinical DIND was defined by either a delayed decrease of consciousness by at least two GCS levels and/or a new focal neurological deficit. Serial CT scans were performed post-operatively, at the time of clinical deterioration and after the monitoring period to screen for delayed infarcts. This was complemented by MRI in selected cases. Vasospasm was defined using DSA as >30% narrowing of the arterial luminal diameter in one of the following arterial segments: A1, A2, M1, M2, and C1–C2 (Unterberg et al., 2001). Magnification errors were corrected by comparing extradural segments of the internal carotid artery (C4–C5). Using TCD, significant vasospasm was defined by a mean velocity >200 cm/s in at least one middle cerebral artery (MCA) and vasospasm was excluded if the MCA mean velocities remained below 120 cm/s throughout the observation period (Vora et al., 1999). Patients with DIND were treated with triple-H therapy (hypertension, hypervolaemia and haemodilution). Triple-H-therapy aimed at a mean arterial pressure of 100–110 mmHg, a haematocrit around 30% and a central venous pressure >10 mmHg. For this purpose hydroxyethyl starch (10%) 250 ml was given four times daily and crystalloids were infused at a rate of 
120 ml/h. Catecholamines, mostly noradrenaline, were administered if fluid therapy alone failed to secure adequate mean arterial pressure (Unterberg et al., 2001; van Gijn and Rinkel, 2001). Oral nimodipine was given prophylactically in 11 patients (i.e. in 3 of 4 centres) (Pickard et al., 1989). The use of a single, narrow linear electrode strip allowed withdrawal at the bedside. No local haemorrhagic or infectious complications of the subdural strip were encountered.
Electrocorticography
Electrocorticographic recordings were acquired continuously in four active channels (A–D) from the 6-electrode (linear array) subdural strips. Electrode 1 served as ground while Electrodes 2–6 (interelectrode distance 1 cm) were connected in sequential bipolar fashion to one GT205 or two Dual Bioamp amplifiers (0.01–100 Hz) (ADInstruments, New South Wales, Australia). Data were sampled at 200 Hz and recorded and reviewed with the use of a Powerlab 16/SP analogue/digital converter and Chart-5 software (ADInstruments, New South Wales, Australia).
Data analysis
Spreading depolarization was defined by the sequential onset in adjacent channels of a propagating, polyphasic slow potential change (Fabricius et al., 2006) that corresponds to the negative slow voltage variation described by Leão (1947) and Hartings et al. (2006). The parallel electrocorticographic depression was defined by a rapidly developing reduction of the power of the electrocorticographic amplitude by at least 50% (Strong et al., 2002; Fabricius et al., 2006). The duration of the depression period of electrocorticographic activity (>0.5 Hz) was used as an indirect indicator of tissue energy supply since restoration of this activity after spreading depolarization is energy dependent (Nedergaard and Hansen, 1993; Back et al., 1994). This duration, used here to assess the spatial and temporal relation between compromised energy supply and the development of brain infarcts, was measured as the interval between depression onset and onset of restoration of activity using the integral of power of the high-pass filtered activity (lower frequency limit, 0.5 Hz; time constant decay, 60 s).
Data are given as median (1st, 3rd quartile). Statistical analysis was performed using Wilcoxon signed rank or Mann–Whitney rank sum test. P < 0.05 was considered statistically significant.
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Illustrative cases
Patient 1
A 44-year-old female with WFNS Grade 2 and Fisher Grade 3 SAH is presented. On Day 1 after SAH, an anterior communicating artery aneurysm was clipped, an external ventricular drain was established, and the electrode strip was placed at the left frontolateral base (Fig. 1A, B, D and E). The patient showed good recovery on Days 2 and 3. On Day 4, some confusion coincided with the occurrence of nine spreading depolarizations with short-lasting depression periods. On Day 5 10:30 h, the patient was again fully orientated, without signs of focal neurological deficits. Around 10:45 h the GCS level decreased from 15 to 7, coinciding with a series of four spreading depolarizations (Fig. 2). TCD detected a significant mean velocity of >200 cm/s in the left MCA suggesting vasospasm. Triple-H therapy was started. A CT scan was normal. Consciousness improved transiently, followed rapidly by a decline during the next series of four spreading depolarizations. Level of consciousness fluctuated over the following 2 days in correlation with repeated spreading depolarizations. The development of a right hemiparesis on Day 7 correlated with two spreading depolarizations characterized by very prolonged electrocorticographic depression periods in channel D (= Electrodes 5–6, duration: 37 and 66 min, Fig. 3). On Day 8, the propagation pattern of the spreading depolarizations changed; spreading depolarizations now propagated along the whole distance from channel D to A (representing Electrodes 6–2, Fig. 4). A CT scan showed sulcal effacement of the left hemisphere (data not shown). On Day 9, channel D showed spreading depolarization without restoration of electrocorticographic activity. While the electrocorticogram was depressed, two more episodes with slow potential changes occurred in channel D. A CT scan on Day 9 showed a large new hypodensity of the left lateral frontal and perisylvian region [compare the CT scan of Day 9 (Fig. 1F) with the scan of Day 8 (Fig. 1C)]. Later, a rapid increase of ICP to 50 mmHg necessitated sedation, intubation and mannitol i.v. Electrical silence in channel D lasted until the end of the recording period on Day 11. In contrast, there was a burst-suppression pattern interrupted by some persisting short-lasting spreading depolarizations at channels A and B (Electrodes 2–4). On Day 20, MRI was performed. Note the impressive MR signal abnormalities in the left lateral frontal and perisylvian cortex in Fig. 1G–L. Such MR-signal abnormalities were previously shown to correspond with the characteristic histological pattern of cortical necrosis in patients after SAH (Birse and Tom, 1960
; Neil-Dwyer et al., 1994; Dreier et al., 2002). Thus, electrophysiological changes at Electrode 6, where the presumed cortical necrosis evolved, consisted of repeated spreading depolarizations displaying progressively increasing electrocorticographic depression periods (compare Fig. 3A and B), whereas fewer spreading depolarizations with only short electrocorticographic depression periods were recorded at Electrodes 2–4, where cortex remained normal. The patient was transferred to a rehabilitation unit with global aphasia and severe right-sided hemiparesis on Day 22.
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Patient 2
This 50-year-old female with WFNS Grade 5 and Fisher Grade 3 SAH (Fig. 5A) had a right-sided ophthalmic artery aneurysm which was coiled. A frontal haematoma was surgically evacuated, extraventricular drainage was established and a subdural electrode strip was placed at the right frontolateral base. Electrodes 4 and 5 of the strip are shown in Fig. 5C and E. Until Day 8 after SAH (20:23 h), a total of 37 spreading depolarizations were observed in this intubated and sedated patient. They appeared to originate from the site of the intracerebral haematoma (Fig. 5A and C) since they all propagated in the direction of Electrode 6–4 (Fig. 5B and D). Initially, these spreading depolarizations were all associated with short-lasting depression periods (Fig. 5B). Starting on Day 5, the depression periods progressively increased (Fig. 5D), coinciding with the advent of vasospasm in the ipsilateral MCA. On Day 8 (20:23 h), for the first time, a spreading depolarization propagated in the opposite direction from Electrode 4–6. At 1:54 h, another spreading depolarization spread in the new direction; depression period was now 93 min. The next spreading depolarization occurred on Day 9 at 4:25 h and was followed by several spreading depolarizations in a row without restoration of electrocorticographic activity for 455 min (Fig. 5F and H). On Day 9 at 15:41 h, CT showed large new infarcts in the ipsilateral anterior cerebral artery (Fig. 5E) and MCA territories, thus providing an explanation for both the change in direction of propagation of the spreading depolarizations (i.e. new anterior source of initiation) and prolongation of the electrocorticographic depression period. The next night, increase of ICP necessitated decompressive hemicraniectomy. The recording area showed gyral swelling but remained relatively well preserved on the MRI on Day 13, consistent with a penumbral region (Fig. 5G). At discharge from the intensive care unit on Day 25 after SAH, the patient had deviation of gaze to the right, left-sided hemiplegia and right leg paresis.
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Incidence of spreading depolarizations in patients with SAH
Patient characteristics are given in the Table 1. In a total electrocorticographic recording time of 2110 h, 298 spreading depolarizations [peak-to-peak amplitude: 1.9 (1.6, 2.6) mV, propagation velocity: 2.0 (1.5, 2.4) mm/min] occurred in 13 of 18 patients (72%). Figure 6 gives the duration of electrocorticographic depression in logarithmic scale for every single spreading depolarization in each patient. This variable is important as patients who developed depression periods lasting >10 min (Patients 1–11) had worse outcome on discharge from the acute unit to the rehabilitation unit than the other patients (Patients 12–18) (modified Rankin scale: 5 (3.5, 5) versus 2 (1.5, 2.5), P = 0.008, Mann–Whitney rank sum test).
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Clusters of spreading depolarizations accompany DIND in SAH
The grey-shaded areas in Fig. 6 indicate the periods of DIND defined by GCS, constituting a delayed decrease from 14 (12, 15) to 9 (8, 11) (Patients 1 and 3–7, P = 0.031, Wilcoxon signed rank test) and/or the finding of a delayed brain infarct (dark grey-shaded areas, Patients 1–4). Clinical DIND began 7.8 days (7.3, 8.2) after SAH and was always time-locked to a new cluster of spreading depolarizations. This was reflected in the statistical analysis: the number of spreading depolarizations per day was significantly higher in patients with DIND and/or delayed brain infarct at Days 7–9 after SAH [5.6 (3.8, 8.4), n = 7 versus 0.0 (0.0, 0.0), n = 4, P = 0.006, Mann–Whitney rank sum test]. The positive predictive value of a new cluster of spreading depolarizations was 86% for a DIND while the negative predictive value if no cluster occurred was 100%. On the day of DIND, none of the core variables changed significantly from the values 1 day before, but ICP [20 (19, 24) mmHg], maximal body temperature in 24 h [38.7 (38.2, 38.7)°C], serum glucose [136 (131, 138) mg/dl], leucocyte count [13.9 (8.8, 15.1)/nl] and C-reactive protein [7.4 (4.0, 8.2) mg/dl] were above the normal range. Haematocrit was slightly diminished [33.8 (30.0; 34.7)%]. Normal values were recorded for cerebral perfusion pressure, arterial oxygen saturation, arterial pH and serum sodium. Epileptic electrocorticographic activity, hydrocephalus, metabolic and pharmacological causes for delayed neurological deterioration were excluded in all cases.
Dense clusters of spreading depolarizations occurred shortly after operation in Patients 8 and 9 and were associated with an acute focal and global neurological deficit (Fig. 6) (Unterberg et al., 2001). This acute deficit was related to a large intracerebral haematoma as a sequel of the aneurysmal haemorrhage in Patient 8 and to the operation in Patient 9. Both patients showed a protracted post-operative recovery.
Spreading depolarizations with prolonged electrocorticographic depression precede delayed cortical infarcts at the recording site
In Patients 1–4, imaging demonstrated delayed brain infarcts in the recording area (compare illustrative cases). While 53% of all spreading depolarizations showed depression periods shorter than ten minutes in all channels, spreading depolarizations with depression periods beyond 60 min in at least one channel were (i) only observed in Patients 1–4 (n = 9 spreading depolarizations), (ii) occurred at 7.8 days (7.2, 9.1) after SAH, and (iii) were always spatially confined to electrocorticography channels of cortical areas showing delayed infarcts on CT/MRI. This was reflected in the statistical analysis: the electrocorticographic depression per day was significantly higher in patients with delayed infarcts at Days 7–9 after SAH [307 (212, 426) min, n = 4 versus 26 (0, 30) min, n = 7, P = 0.006, Mann–Whitney rank sum test; Fig. 7].
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All 11 patients who were electrocorticographically monitored at Days 7–9 had a Fisher Grade 3 haemorrhage, which is typically associated with very high rates of significant vasospasm and DIND (Kistler et al., 1983
). DSA was carried out to assess vasospasm in 8 and daily TCD in 9 of these patients. Only one patient had neither DSA nor TCD. The percentage of significant vasospasm was 90%. |
Discussion |
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Aneurysmal SAH has a 30 day mortality rate of
45% (Broderick et al., 1993) and represents one quarter of haemorrhagic stroke (Nilsson et al., 2000). DIND is a prominent complication of SAH, is a major cause of disability and mortality, is familiar to specialists in neurosurgery, neurology, radiology, anaesthesiology and internal medicine, and is difficult to treat (van Gijn and Rinkel, 2001). One reason for this difficulty is incomplete understanding of the pathophysiology. This paper documents for the first time the occurrence of spreading depolarizations in patients with SAH, similar to previous findings in animals (Hubschmann and Kornhauser, 1980; Busch et al., 1998). In a total recording time of 2110 h, 298 spreading depolarizations were observed in 13 of 18 patients with SAH. It would appear that spreading depolarizations are very frequent after major SAH.
Consistent with animal studies, the evolution of ischaemic stroke, as studied in these patients, was associated with a cluster of spreading depolarizations and increasingly prolonged periods of electrocorticographic depression (Nedergaard and Hansen, 1993; Back et al., 1994; Ohta et al., 2001; Hartings et al., 2006). The progressive prolongation of the depression period of spreading depolarization was locally restricted to areas of new infarct evolution as demonstrated on serial CTs and MRI. Within the limits of a small study, it is suggested that this pattern is an early, sensitive indicator for impending tissue necrosis, as in animals. In addition, only patients with the clinical syndrome of DIND showed a statistically significant delayed increase in the number of spreading depolarizations per day. The presence and absence of a delayed cluster of spreading depolarizations had high positive (86%) and negative predictive values (100%), respectively, for a DIND.
However, our study has certain limitations.
(i) Similar to previous studies (Kistler et al., 1983), we observed a very high rate of significant proximal vasospasm in this patient group. Although this suggests that similar electrocorticographic patterns occur in the pathology of ischaemic stroke, it is possible that our results are more or less specific for DIND after SAH. Strictly speaking, our results apply only to patients with Fisher Grade 3 SAH and a large amount of blood in the subarachnoid space. Only patients with this Fisher grade carry a high risk of developing a DIND, which was a principal inclusion criterion for the study (Kistler et al., 1983).
Consistent with this reservation, it remains possible that the lysing blood, which covers in abundance wide areas of cortex after SAH, has important direct effects on neurons and astrocytes with relevance for spreading depolarization. Indeed, in animals, recurrent spreading depolarizations with prolonged electrocorticographic depressions are found not only in the ischaemic penumbra after MCA occlusion but also when breakdown products of erythrocytes are applied to the subarachnoid space (Dreier et al., 1998, 2000; Windmüller et al., 2005). Whether these different conditions converge on very similar cellular and molecular mechanisms is unresolved (Dreier et al., 1998, 2000; Sonn and Mayevsky, 2000; Shin et al., 2005; Windmüller et al., 2005).
(ii) The use of AC-coupled amplifiers with a 0.01 Hz high-pass cut-off enabled detection of transient voltage negativities associated with SD, but on the other hand pre-cluded recording of sustained negative potentials associated with persistent depolarizations such as AD. Hence, there is potential ambiguity in instances of spreading depolarizations with prolonged depression periods: does tissue remain depolarised throughout the depression, as in AD, or is there rapid repolarization followed by an induced penumbral state of continued electrical silence and preserved ion homeostasis? In many instances in our recordings, spreading negative slow voltage variations recurred while the spontaneous electrocorticographic activity still exhibited a prolonged depression from a previous event (e.g. Case 2). This same phenomenon has been previously reported in focal ischaemia in rats and cats (Back et al., 1994; Ohta et al., 2001; Hartings et al., 2006). This demonstrates that in such instances spreading depolarizations with prolonged depression are in fact transient depolarizations with delayed recovery, since tissue experiencing sustained depolarization during AD cannot generate subsequent negative slow voltage variations.
Other characteristics of AD and SD shed additional light on this ambiguity. First, it is one of the hallmarks of AD in animal experiments that the negative slow voltage variation is preceded by a period of a few minutes with non-spreading cessation of the electrocorticographic activity (Leão, 1947) accompanied by gradual acidification and a slow rise of the extracellular potassium concentration (Obrenovitch et al., 1990; Nedergaard and Hansen, 1993). This non-spreading cessation of spiking activity within seconds of anoxia or severe ischaemia is explained by the high sensitivity of the underlying synaptic processes to energy compromise (Fleidervish et al., 2001). Characteristically, the spreading depolarizations in our human recordings did not show this electrocorticographic pattern typical of AD. Rather, consistent with SD, the depression of electrocorticographic activity began simultaneously with the spreading negative slow voltage variation. Second, in AD, the lag time of the negative slow voltage variation between neighbouring electrodes is often shorter than in SD since AD often initiates at multiple cortical sites (Nedergaard and Hansen, 1993; Jarvis et al., 2001). In our human recordings, in contrast with AD, the lag times of the negative slow voltage variations were not significantly different between spreading depolarizations with short- and long-lasting depressions.
We observed a continuous spectrum of events with depression periods ranging from <10 min to several hours. Rather than two strictly separate types of spreading depolarizations such SD and AD, we suggest that many of these events represent intermediate forms of spreading depolarizations, referred to as peri-infarct or transient ischaemic depolarizations (Nedergaard and Hansen, 1993; Koroleva and Bures, 1996). As mentioned, peri-infarct depolarizations have prolonged depression periods and are associated with expansion of neuronal damage in animal experiments, and these characteristics were observed in the present study. Although the above points argue against the possibility that prolonged depressions reflect AD phenomena, it remains possible that some events with prolonged depression had transient depolarizations that endure longer than typical SD and can occur as a characteristic of peri-infarct depolarization (Nedergaard and Hansen, 1993; Koroleva and Bures, 1996).
Although our study is too small to provide precise numerical values to allow discrimination between SD and intermediate forms of spreading depolarization, it indicates in principle that a cluster of spreading depolarizations with a dynamic change of progressively increasing depression periods carries a high risk for the development of a delayed brain infarct. We believe that our data are sufficient to justify the use of this electrocorticographic pattern as a reliable indication for triple-H therapy (in addition to clinical status, TCD and DSA). Electrocorticography appears to have particular value for sedated and ventilated patients in whom clinical assessment is very limited and the positive predictive values of TCD and DSA alone are insufficient to diagnose delayed ischaemia at an early stage (Vora et al., 1999; Unterberg et al., 2001; Minhas et al., 2003; Rabinstein et al., 2005). This implies that patients with higher WFNS grade will derive greatest benefit from electrocorticographic monitoring.
(iii) The present study is based only on electrocorticographic, clinical and imaging data. Neuroimaging with CT and MRI is the gold standard in the clinics to demonstrate ischaemic lesions and a good correlation exists between neuroimaging and histopathological findings of delayed ischaemia (Birse and Tom, 1960; Neil-Dwyer et al., 1994; Dreier et al., 2002; Rabinstein et al., 2005). However, in future studies, the combination of electrocorticography with microdialysis to monitor metabolism and methods to monitor the tissue oxygen level and cerebral blood flow will further increase our understanding of the precise relations between spreading depolarizations and delayed ischaemic damage in the human brain (Hopwood et al., 2005; Parkin et al., 2005).
(iv) Based on animal studies, it was previously hypothesized that microvascular spasm and spreading ischaemia in response to spreading depolarization causes the characteristic widespread focal laminar cortical infarcts in SAH as seen in Patient 1 (Dreier et al., 1998, 2000, 2002). We are unable to prove or disprove this hypothesis since we did not measure local cerebral blood flow in conjunction with the electrocorticogram. However, the occurrence of abundant spreading depolarizations during the evolution of these distinctive lesions warrants future study of this issue.
(v) Because electrocorticography was performed with a single electrode strip, it is possible that spreading depolari-zations in other regions of the brain escaped detection. With limited spatial sampling, the incidence of spreading depolarizations is likely underestimated and the statistical results influenced accordingly.
(vi) It could be argued that the electrode strip facilitated the spread of depolarizations by acting as a conductor. However, in several studies in which the spread of spreading depolarization has been imaged continuously in the gyrencephalic brain (Strong et al., 1996, 2000; Bowyer et al., 1999), events have never been seen to move immediately from one gyrus to another. Rather, a delay is invariably seen with timing appropriate for propagation around the depth of the sulcus. Thus the pia-arachnoid forms a barrier to the depolarization current, and would prevent short-circuiting by surface electrodes.
(vii) Part of the electrode strip might have been placed on cortex previously retracted during surgery. As recently shown, spreading depolarization can occur as a consequence of brain contusion (Strong et al., 2002; Fabricius et al., 2006) and this was possibly a confounding factor. Experimental experience is that penumbral tissue is highly sensitive to even gentle mechanical disturbance, manifest as easy, inadvertent induction of peri-infarct depolarizations, and neurosurgeons recognise well the risks of ill-timed surgery in SAH. The present findings offer a possible explanation for this clinical observation.
(viii) Based on the fluctuating clinical course, it has been previously suggested that recurrent spreading depolarizations could be the pathophysiological basis of the syndrome of fever, coma and focal neurological deficits in patients with familial hemiplegic migraine (Dreier et al., 2005). In the present study, a correlation of a cluster of spreading depolarizations with decreased level of consciousness has been demonstrated directly for the first time. However, the exact pathophysiological mechanism remains uncertain and needs to be investigated in future studies.
In conclusion, we found overall that spreading depolarizations with electrocorticographic depression of >10 min duration indicated a significantly worse outcome when the patient was discharged from the acute unit. Additionally, clusters of spreading depolarizations, with onset delayed for some days after SAH, correlated with DIND, and the electrocorticographic recovery phases after spreading depolarizations were progressively prolonged during infarct evolution. These data support the notion that in SAH spreading depolarizations with prolonged depression are indicators of the impending and progressive neuronal damage in the human brain.
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Footnotes |
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*These authors contributed equally to this work.
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Acknowledgements |
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We would like to thank the nursing staff of ICU WNCS1-I Campus Charité Virchow Berlin, the Jack Steinberg Intensive Care and Kinnear Wilson High Dependency Units of King's College Hospital, London, and the intensive care units of the Departments of Anaesthesiology and Neurosurgery, University Hospital Mannheim and Glostrup Hospital Copenhagen. The views of the authors do not purport or reflect the position of the United States Department of the Army or the Department of Defense (para 4-3, AR 360-5). The contributions from Dr Vibeke Just Larsen (Department of Radiology, Glostrup Hospital, Copenhagen, Denmark) are gratefully acknowledged. Supported by grants of the Wilhelm Sander foundation (2002.028.1), Deutsche Forschungsgemeinschaft (SFB-507A1, DFG DR 323/2-2), BMBF Berlin Neuroimaging Center (01GI9902/4), Kompetenznetz Schlaganfall to Dr Dreier, donations to King's College Hospital (Dr Strong) from GlaxoSmithKline, HeadFirst and the Rosetrees Trust and to Dr Sakowitz from ZNS Hannelore Kohl Stiftung (#2004006). Funding to pay the Open Access publication charges for this article was provided by DFG-SFB 507 (Dr Dreier).
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