Association of seizures with cortical spreading depression and peri-infarct depolarisations in the acutely injured human brain

Abstract

Objective: To test the co-occurrence and interrelation of ictal activity and cortical spreading depressions (CSDs) - including the related periinfarct depolarisations in acute brain injury caused by trauma, and spontaneous subarachnoid and/or intracerebral haemorrhage.

Methods: 63 patients underwent craniotomy and electrocorticographic (ECoG) recordings were taken near foci of damaged cortical tissue for up to 10 days.

Results: 32 of 63 patients exhibited CSDs (5-75 episodes) and 11 had ECoGraphic seizure activity (1-81 episodes). Occurrence of seizures was significantly associated with CSD, as 10 of 11 patients with seizures also had CSD (p=0.007, 2-tailed Fishers exact test). Clinically overt seizures were only observed in one patient. Each patient with CSD and seizures displayed one of four different patterns of interaction between CSD and seizures. In four patients CSD was immediately preceded by prolonged seizure activity. In three patients the two phenomena were separated in time: multiple CSDs were replaced by ictal activity. In one patient seizures appeared to trigger repeated CSDs at the adjacent electrode. In 2 patients ongoing repeated seizures were interrupted each time CSD occurred.

Conclusions: Seizure activity occurs in association with CSD in the injured human brain.

Significance: ECoG recordings in brain injury patients provide insight into pathophysiological mechanisms, which are not accessible by scalp EEG recordings.

Figure 1

Schematic drawing of four different patterns of the time relation between cortical spreading depression (CSD) and seizure activity as encountered in patients 1-10 for selected times. The number of hours indicated for each pattern gives the duration of the recording time, which is illustrated. Pattern I: Close interaction of ictal activity and CSD: At one or several electrodes, the slow potential change and depression of cortical activity was preceded by ictal activity for 1-2 minutes. In patients 1 and 2, this ictal activity started at the time when the approaching CSD reached the neighbouring electrode (upper line in the drawing) (Fig 2). In patient 3 and 4, seizure activity of a few minutes duration spread at a slow rate to the next electrodes immediately followed by CSD (lower two lines in the drawing). The seizure activity subsequently stopped as CSD reached each electrode. Pattern II: Segregation of CSD and seizures in time: a) Frequent CSD episodes recurred for ~24 hours without any seizure activity. After spontaneous arrest of CSDs, frequent seizures (pt.5) or periodic epileptiform discharges (PEDs) (pt.6) were noted for the next 24-31 hours. b) Frequent CSDs stopped when patient was cooled. After 7 hours a single seizure occurred and 30 minutes later CSD activity resumed (pt.7). Pattern III: Temporary blocking of seizures by CSD: Frequent seizures were interrupted by CSDs at the same electrode, each time causing a temporary block of seizure activity. Pattern IV: Segregation of CSD and seizures in space + triggering of CSD by seizures Frequent brief seizures and CSDs coexisted, but at separate electrodes (see also Fig 6). Most CSDs were preceded by timelocked seizure activity suggesting triggering. When seizures were blocked by phenytoin (arrowhead), the incidence of CSD episodes decreased as well.

Figure 2. Ictal delta activity in front of approaching CSD

Pt.1, a 22 year old male sustained a depressed skull fracture with left frontal and parietal contusions, and subsequent diffuse brain swelling. Phenytoin was administered for anticonvulsant prophylaxis. Two days later the contusion was evacuated. The subdural ECoG electrode strip was placed along left middle frontal gyrus. Over the initial 64 hours, 9 episodes of CSD occurred at 1.2 to 18.6 hour intervals. Seizure activity of ~ 2 min duration and characterized by trains of sharp 1-1.5 Hz rhythmic slow waves occurred only in relation to CSD episodes. At 8 month follow up, he was quite severely disabled and post traumatic generalized tonic-clonic seizures were well-controlled on carbamazepine. (a) Upper traces: Time compressed traces of the raw ECoG signal (analogue frequency limits 0.02-100 Hz) showing the spread of a CSD from channel A to channels B and C. Lower traces: The amplitude integral of the same ECoG signal, enhancing very low frequencies. Each depression in the upper traces was accompanied by a stereotyped baseline change reflecting a slow potential change. Electrode numbers are indicated (black arrows) to mark the onset of depolarisation at that particular electrode as evidenced by phase reversal. In electrode 4 the seizure activity (c) started ~2 min before onset of the slow potential change and thereby onset of CSD. Grey arrows above channel A indicate time points for the detailed traces (b and c, same filtering as upper traces). (b) Baseline activity before the CSD episode. ECoG activity showed irregular delta activity of 2-400 μV amplitude and short periods of flattening in channels A, B, and C. (c) 1-1.5 Hz seizure activity in channels B and C at the time point indicated by the right grey arrow in (a). Seizure activity started at the same time in channel B and C, i.e. at electrode number 4. 70 sec later the pattern changed into complete depression of the ECoG (not shown in detail).

Figure 3. Multiple CSDs replaced by PEDs

Pt. 6, a 40 year old male struck by a car, developed severe and diffuse bilateral contusions, scattered intracerebral hemmorhages, acute subdural hematoma, and diffuse sub-arachnoid hemorrhage. Bilateral craniectomy was performed 13 hr after injury. ECoG was recorded from the partietal lobe for 5 days. 200 mg phenytoin was administered twice daily. Initially ECoG showed flattening and pseudoperiodic 1-2 Hz activity at 2-5 s intervals. During the first 34.5 hours of recording, 73 episodes of CSD occurred at 10-40 minutes interval. After the last CSD, a continuous pattern of dynamically fluctuating PEDs with prominent spikes occurred at 1-4 seconds intervals to resolve gradually only after 25.5 hours. Patient died after 19 days. (a): Highly compressed recording, analogue frequency limits 0.02-100 Hz. Upper four traces show an 0.5 Hz high pass digitally filtered trace while the lower four traces show the same recording after 0.05 Hz low pass digital filtering. 13 episodes of CSD are evidenced by loss of local ECoG activity accompanied by a quite stereotyped slow potential change spreading between electrodes at a rate of 2-6 mm/min as indicated by boxes. Arrows indicate time points for 0.5 Hz high pass filtered traces (b): two small double arrows and (c): big double arrow. (b): A CSD has just started in channel A, but not reached channel B and C, while channel D persistently has little or no locally generated ECoG activity. (c): Continuous PED activity in channel A, B, and C.

Figure 4. Comparison of seizure- and cortical spreading depression (CSD)-induced changes as recorded in a single bipolar electrode

Pt. 7, a 20 year old male who suffered a closed head injury and was operated for a frontal sub-dural hemorrhage, extensive sub-arachnoid blood, and right frontal intraparenchymal hemorrhage. The electrode strip extended from the inferior frontal gyrus to inferior parietal cortex. 200 mg phenytoin was administered twice daily. 6 month recovery was good. (a) Upper traces: low pass digital filter (< 0.05 Hz) lower traces: same channel, high pass digital filter (> 0.5 Hz), all traces analogue frequency limits 0.02-100 Hz. At the left, a 220 s lasting spike/polyspike-and-wave seizure augments to a 1.8 mV amplitude then stops abruptly followed by a 1 minute lasting post seizure depression. No significant changes are detected in the low pass filtered curve (note: the recording is bipolar, electrodes 1 cm apart). At the right, 38 minutes later, a CSD evidenced by a slow potential change of 2.5 mV amplitude and lasting 2 minutes is accompanied by a gradual loss of amplitude lasting 4.5 minutes. The slow potential change spread to the neighbouring channels at a speed of 3.4 mm/min (not shown). Both episodes were followed by a gradual recovery of an irregular, but continuous 1.5-3 Hz ECoG activity. (b): 2 × 13 s recording (same electrode) from the onset and from the end of the seizure shown in (a, lower trace) as indicated by arrows.

Figure 5. Prolonged blockade of ECoG seizure activity by CSD

Pt 8, a 68 year-old woman, suffered a head injury after falling down a staircase. After evacuation of an acute right subdural haematoma, the electrode strip was placed over the pre-central gyrus. At 10 - 30 hours after start of recording we observed 5 episodes of CSD. A total of 61 seizure episodes were recorded at 24 to 32 hours. Most of the time, the seizures recurred approximately every 5 minutes. Corresponding to the 3 CSDs occurring in this period, seizure activity was blocked for 19, 17, and 72 min. respectively, while ECoG was fully depressed for 8, 4, and 10 min. 6 month recovery was good. (a) In the middle of the traces (analogue frequency limits 0.5-70 Hz), a CSD spreads from channel A–D with a velocity of 1-1.8 mm/min (duration of depression 5.5 – 11 min). Rates and ECoG recovery times were comparable to CSD {Leao, 1944 6242 /id}. Arrows depict 16 episodes of seizure activity in channel A and B occurring before and after, but not during the CSD. The grey arrow above channel A marks the seizure shown in detail in (b): Ictal pattern of rhythmic 5 Hz activity with spikes.

Figure 6. Seizure activity at one electrode preceding CSD at neighbouring electrodes

Pt.10, a 21 year old male, had sudden onset of severe headache whilst weight-lifting, and developed dense paresis of the left arm. He was operated for a large right posterior frontal intracerebral haematoma and a small right frontal arteriovenous malformation. The electrode strip was placed anteriorly over the frontal convexity. A loading dose phenytoin was administered. During the first 34 hours, 34 episodes of CSD and 81 seizure episodes were recorded. Seizure frequency gradually decreased from 12 per hour to 1-2 per hour. CSD frequency remained stable at approximately 1.6 CSD episodes per hour during the first 15 hours of recording at which time clinically overt seizure activity was noticed and the patient was restarted on phenytoin. This abolished seizure activity altogether, and the incidence of CSD declined to 0.6 episodes per hour. At 6 month the paresis persisted and there were repeated focal seizures affecting the right arm. (a) Time compressed recording (analogue frequency limits 0.02-100 Hz, high pass digital filter 0.5 Hz) showing 3 episodes of CSD spreading from channel C to A with a velocity of 3.3 - 5 mm per min. An amplitude reduction of 50-75% evolved over 20-60s, and lasted for 3-6 min. Duration of suppression was longest in channel C, which was closest to the electrode in which seizure activity was observed. 4 episodes of seizure activity recorded in electrode D are marked by arrows. The seizures lasted for 64–128 s. Note the constant time interval between seizure activity in channel D and the ECoG suppression in electrodes A-C. The grey arrow in channel D depicts the seizure shown in (b): an ictal pattern of rhythmic 1-2 Hz activity with spikes. Channel A-C show irregular 1-3 Hz activity.

Figure 7. Time lock between ECoG seizure episodes and CSD in pt. 10 may suggest causal link between cortical seizure activity and CSD

The figure shows for the initial 24 CSD episodes the incidence and timing of seizure episodes (■) within10 min before and after onset of the CSD (○) arranged in a top-down sequence. Seizures were of 1-2 minutes duration. 15 CSD episodes were preceded at 5-7 minutes by a seizure, suggesting that in these instances the seizure triggered the CSD.