Dr Jatinder S. Minhas, Department of Cardiovascular Sciences, University of Leicester and University Hospitals of Leicester NHS Trust.

This brief clinical review was prompted following a recent study by Matsubara et al. Stroke 2018.

Epidemiology

Early seizures (ES) are defined as seizures occurring within 7-14 days post-acute stroke and those occurring after this window as late1. Stroke pathologies are the leading cause of symptomatic epilepsy with registry data suggesting an incidence of at least 5%2,3. Furthermore, seizures occur more commonly in acute intracerebral haemorrhage (ICH) than acute ischaemic stroke (AIS)3. Seizures have been identified as the presenting feature in up to 30% of ICH patients2. Therefore, ES are a common but fortunately treatable phenomenon. Such seizures should respond well to antiepileptic drugs (AEDs) though recognition and assessment of treatment effectiveness remain areas of importance4. The difficulties in recognition are typified by data from a recent prospective observational study highlighting the alarming frequency (8.8%) of nonconvulsive status epilepticus (NCSE) in acute ICH patients and independently associated factors5.

Pathophysiology of ES in Acute ICH

The pathophysiology remains unclear, potential explanations include haemosiderin deposition itself causing focal cerebral irritation and hence focal seizures6. Others have suggested thrombin exerts an effect on neuronal excitability and voltage-gated sodium channels causing seizures6. Lastly, increased extracellular glutamate and down regulation in GABA and potassium channels have been associated with post stroke seizures7. Unfortunately, there is a paucity of animal studies and limited data to support these hypotheses.

Predicting Likelihood of Seizures

Lobar locations are considered to be the most epileptogenic in acute ICH4. Case series have identified highest seizure incidence with haemorrhage associated with lobar cortical structures and lowest with thalamic haemorrhage8. Involvement of the caudate nucleus predicted seizures as did temporal or parietal involvement1,8. Also worth reminding ourselves that haemorrhage due to cerebral venous sinus thrombosis commonly presents with seizure activity.

The 2017 European Stroke Organisation guidelines for the management of post-stroke seizures and epilepsy highlight that a “substantial portion of stroke patients have electrographic seizures without a clinical correlate”9. Besides, several other electrophysiological disturbances are also often noted in this group of patients, whose clinical significance remains unclear, and in centres with continuous EEG monitoring post-stroke, there is likely to be differing approaches to management.

Non-convulsive status epilepticus (NCSE) is a key differential in stroke patients with a disturbance of consciousness not in keeping with burden of acute stroke disease10. NCSE is associated with a poor outcome in ICU datasets though, until recently, data did not exist on ICH associated NCSE5,10.

Diagnostic Criteria for NCSE

The modified Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus is suggested for use in all patients with qualitative or quantitative disturbance of consciousness and suspicion of NCSE10. The diagnosis of NCSE requires the combination of EEG and clinical data.

The Role of the EEG

The Neurocritical Care Society, 2012 Guidelines for the Evaluation and Management of Status Epilepticus suggest Class I, Level B evidence for continuous EEG monitoring being initiated within an hour of status epilepticus onset if ongoing seizures suspected (particularly as frequency of non-convulsive seizures is 20-35%)11. The 2015 AHA/AMA guidelines advise “continuous EEG monitoring is probably indicated in ICH patients with depressed mental status that is out of proportion to the degree of brain injury”, Class IIa, Level C evidence12. Ultimately, an EEG is mandatory where NCSE is suspected, though in instances where NCSE follows a convulsive seizure, this should be treated as a convulsive seizure and emergency treatment should begin without EEG confirmation.

Management Guidelines

Clinical seizures should be treated with AEDs, Class I, Level A evidence. Importantly, the 2015 AHA/AMA guidelines advise “patients with a change in mental status who are found to have electrographic seizures on EEG should be treated with AEDs”, Class I, Level C evidence12. Prophylactic AEDs are not recommended, Class III, Level B evidence. Ultimately, the clinical importance of subclinical seizures detected on EEG is unclear12. In the instance of refractory NCSE or less common subtypes, more aggressive treatment may be indicated including the use of anaesthetic agents following specialist input.

Prognostic Implications of Seizures

Epilepsy occurs in up to 10% of young patients (18-50) with ICH13. Risk factors for epilepsy post ICH include initial stroke severity, cortical location of haematoma and delayed initial seizures13. Currently no data exists suggesting early use of AEDs will prevent lesion-related epilepsy. Encouragingly, patients with NCSE, although they had higher modified Rankin Scale (mRS) scores at discharge, NCSE was not independently associated after adjustment for confounders with poor functional outcomes (mRS 4-5) or mortality5.

Conclusion

Seizures commonly occur after ICH and may be nonconvulsive in presentation. In patients for whom a disturbance of consciousness not in keeping with burden of acute stroke disease is present, consider NCSE.

References

(1) Silverman IE, Restrepo L, Mathews GC. Poststroke seizures. Arch Neurol . 2002;59:195-201.

(2) Sung CY, Chu NS. Epileptic seizures in intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 1989;52:1273-1276.

(3) Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Cote R, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol. 2000;57:1617-1622.

(4) Zelano J. Poststroke epilepsy: update and future directions. Ther Adv Neurol Disord. 2016;9:424-435.

(5) Matsubara S, Sato S, Kodama T, Egawa S, Nakamoto H, Toyoda K, et al. Nonconvulsive Status Epilepticus in Acute Intracerebral Hemorrhage. Stroke. 2018.

(6) Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53-63.

(7) Lu A, Tang Y, Ran R, Ardizzone TL, Wagner KR, Sharp FR. Brain genomics of intracerebral hemorrhage. J Cereb Blood Flow Metab. 2006;26:230-252.

(8) Faught E, Peters D, Bartolucci A, Moore L, Miller PC. Seizures after primary intracerebral hemorrhage. Neurology. 1989;39:1089-1093.

(9) Holtkamp M, Beghi E, Benninger F, Kalvainen R, Rocamora R, Christensen H for European Stroke Organisation. Eur Stroke J. 2017;2:103-115.

(10) Leitinger M, Beniczky S, Rohracher A, Gardella E, Kalss G, Qerama E, et al. Salzburg Consensus Criteria for Non-Convulsive Status Epilepticus–approach to clinical application. Epilepsy Behav. 2015;49:158-163.

(11) Brophy GM, Bell R, Claassen J, Alldredge B, Bleck TP, Glauser T, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17:3-23.

(12) Hemphill JC,3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-2060.

(13) Arntz R, Rutten-Jacobs L, Maaijwee N, Schoonderwaldt H, Dorresteijn L, van Dijk E, et al. Post-stroke epilepsy in young adults: a long-term follow-up study. PLoS One. 2013;8:e55498.