Abstract
Cerebral hyperperfusion syndrome (CHS) may occur as a severe complication following surgical treatment of carotid stenosis. However, the mechanism inducing neurological symptoms in CHS remains unknown. We describe a patient with CHS presenting with seizures 24 h following carotid endarterectomy. Imaging demonstrated early ipsilateral blood–brain barrier (BBB) breakdown with electroencephalographic evidence of cortical dysfunction preceding brain edema. Using in vitro experiments on rat cortical tissue, we show that direct exposure of isolated brain slices to a serum-like medium induces spontaneous epileptiform activity, and that neuronal dysfunction is triggered by albumin. We propose BBB breakdown and subsequent albumin extravasation as a novel pathogenic mechanism underlying CHS and a potential target for therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53
Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M, Heinemann U, Friedman A, Kaufer D (2009) Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci 29:8927–8935
David Y, Flores LP, Ivens S, Heinemann U, Kaufer D, Friedman A (2009) Astrocytic dysfunction in epileptogenesis: consequences of altered potassium and glutamate buffering? J Neurosci 29:10588–10599
Friedman A, Kaufer D, Heinemann U (2009) Blood–brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. Epilepsy Res 85:142–149
Gutnick MJ, Connors BW, Prince DA (1982) Mechanisms of neocortical epileptogenesis in vitro. J Neurophysiol 48:1321–1335
Hjort N, Wu O, Ashkanian M, Solling C, Mouridsen K, Christensen S, Gyldensted C, Andersen G, Ostergaard L (2008) MRI detection of early blood–brain barrier disruption: parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis. Stroke 39:1025–1028
Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A (2007) TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130:535–547
Kim JH, Im KC, Kim JS, Lee SA, Lee JK, Khang SK, Kang JK (2007) Ictal hyperperfusion patterns in relation to ictal scalp EEG patterns in patients with unilateral hippocampal sclerosis: a SPECT study. Epilepsia 48:270–277
Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A (2005) Focal cortical dysfunction and blood–brain barrier disruption in patients with Postconcussion syndrome. J Clin Neurophysiol 22:1–9
Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I, Janigro D (2007) Seizure-promoting effect of blood–brain barrier disruption. Epilepsia 48:732–742
Moulakakis KG, Mylonas SN, Sfyroeras GS, Andrikopoulos V (2009) Hyperperfusion syndrome after carotid revascularization. J Vasc Surg 49(4):1060–1068
Naylor AR, Evans J, Thompson MM, London NJ, Abbott RJ, Cherryman G, Bell PR (2003) Seizures after carotid endarterectomy: hyperperfusion, dysautoregulation or hypertensive encephalopathy? Eur J Vasc Endovasc Surg 26:39–44
Nelissen N, Van PW, Baete K, Van LK, Palmini A, Van BH, Dupont P (2006) Correlations of interictal FDG-PET metabolism and ictal SPECT perfusion changes in human temporal lobe epilepsy with hippocampal sclerosis. Neuroimage 32:684–695
Neuwelt EA (2004) Mechanisms of disease: the blood–brain barrier. Neurosurgery 54:131–140
Ogasawara K, Inoue T, Kobayashi M, Endo H, Yoshida K, Fukuda T, Terasaki K, Ogawa A (2005) Cerebral hyperperfusion following carotid endarterectomy: diagnostic utility of intraoperative transcranial Doppler ultrasonography compared with single-photon emission computed tomography study. AJNR Am J Neuroradiol 26:252–257
Ogasawara K, Mikami C, Inoue T, Ogawa A (2004) Delayed cerebral hyperperfusion syndrome caused by prolonged impairment of cerebrovascular autoregulation after carotid endarterectomy: case report. Neurosurgery 54:1258–1261
Pascual-Marqui RD (2002) Standardized low-resolution brain electromagnetic tomography (sLORETA): technical details. Methods Find Exp Clin Pharmacol 24(Suppl D):5–12
Prince DA, Futamachi KJ (1968) Intracellular recordings in chronic focal epilepsy. Brain Res 11:681–684
Sakaki T, Tsujimoto S, Nishitani M, Ishida Y, Morimoto T (1992) Perfusion pressure breakthrough threshold of cerebral autoregulation in the chronically ischemic brain: an experimental study in cats. J Neurosurg 76:478–485
Schwartz RB (2002) Hyperperfusion encephalopathies: hypertensive encephalopathy and related conditions. Neurologist 8:22–34
Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A (2004) Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 24:7829–7836
Tomkins O, Friedman O, Ivens S, Reiffurth C, Major S, Dreier JP, Heinemann U, Friedman A (2007) Blood–brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. Neurobiol Dis 25:367–377
Tomkins O, Kaufer D, Korn A, Shelef I, Golan H, Reichenthal E, Soreq H, Friedman A (2001) Frequent blood–brain barrier disruption in the human cerebral cortex. Cell Mol Neurobiol 21:675–691
Tomkins O, Shelef I, Kaizerman I, Eliushin A, Afawi Z, Misk A, Gidon M, Cohen A, Zumsteg D, Friedman A (2008) Blood–brain barrier disruption in post-traumatic epilepsy. J Neurol Neurosurg Psychiatry 79:774–777
van Mook WN, Rennenberg RJ, Schurink GW, van Oostenbrugge RJ, Mess WH, Hofman PA, de Leeuw PW (2005) Cerebral hyperperfusion syndrome. Lancet Neurol 4:877–888
van Vliet EA, da Costa AS, Redeker S, van Schaik R, Aronica E, Gorter JA (2007) Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521–534
Zumsteg D, Friedman A, Wennberg RA, Wieser HG (2005) Source localization of mesial temporal interictal epileptiform discharges: correlation with intracranial foramen ovale electrode recordings. Clin Neurophysiol 116:2810–2818
Acknowledgments
The authors would like to thank Asaf Krah for technical assistance. This study was supported by the Israeli Science Foundation (566/07), the Israel-USA Binational Science foundation and the Sonderforschungsbereich TR3 (C8).
Author information
Authors and Affiliations
Corresponding author
Additional information
A. Friedman and I. Shelef are equally contributing senior authors.
Rights and permissions
About this article
Cite this article
Ivens, S., Gabriel, S., Greenberg, G. et al. Blood–brain barrier breakdown as a novel mechanism underlying cerebral hyperperfusion syndrome. J Neurol 257, 615–620 (2010). https://doi.org/10.1007/s00415-009-5384-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-009-5384-z