Late-onset epilepsy (LOE) first occurs after 60 years of age and may be due to occult cerebrovascular disease (CVD) which confers an increased risk of stroke. However, patients with late-onset epilepsy are not currently consistently investigated or treated for cerebrovascular risk factors. We discuss how abnormalities of neurovascular unit function, namely, changes in regional cerebral blood flow and blood brain barrier disruption, may be caused by occult cerebrovascular disease but present clinically as late-onset epilepsy. We describe novel magnetic resonance imaging methods to detect abnormal neurovascular unit function in subjects with LOE and controls. We hypothesise that occult CVD may cause LOE as a result of neurovascular unit dysfunction. 1. Introduction Late-onset epilepsy (LOE) is defined as epilepsy that first occurs after 60 years of age, and is considered by family doctors to be rare [1], despite the fact that it accounts for over a third of all incident epilepsy [2]. LOE occurs in approximately 4% of stroke patients [3], but importantly, LOE can present without a history of overt cerebrovascular disease (CVD), yet LOE confers a subsequent threefold increased risk of stroke [4]. It is widely assumed that LOE is often attributable to otherwise occult CVD. However, at least in the UK, patients with LOE tend to be prescribed anticonvulsant medication, but the opportunity that LOE presents as a marker of increased stroke risk may be lost if a presentation of LOE does not prompt clinicians to screen for other vascular risk factors and initiate appropriate vascular secondary prevention measures, for which there is a strong case [4, 5]. Occult CVD may be detected on brain imaging but by definition does not manifest otherwise clinically. Structural imaging markers of occult CVD are thought to include cortical or subcortical infarcts, white matter hyperintensities, leukoaraiosis (LA), cerebral atrophy, and brain microbleeds (BMBs) which are a marker particularly of cerebral microangiopathy, and strongly associated with hypertension [6]. However, between 72 and 94% of occult infarcts are subcortical, yet epilepsy derives from the cortex. If occult CVD is aetiologically important in LOE then markers of CVD would be expected to have a more diffuse anatomical distribution than described previously. Subcortical lesions in isolation would not be expected to cause the disruption of corticocortical or subcorticocortical circuits that would be a necessary substrate for epileptogenesis. Markers of functional rather than structural integrity may then be
References
[1]
I. Craig and R. C. Tallis, “General practitioner management of adult-onset epilepsyanalysed,” Care Elderly, vol. 3, pp. 69–72, 1991.
[2]
R. Tallis, G. Hall, I. Craig, and A. Dean, “How common are epileptic seizures in old age?” Age and Ageing, vol. 20, no. 6, pp. 442–448, 1991.
[3]
J. Burn, M. Dennis, J. Bamford, P. Sandercock, D. Wade, and C. Warlow, “Epileptic seizures after a first stroke: the Oxfordshire community stroke project,” British Medical Journal, vol. 315, no. 7122, pp. 1582–1587, 1997.
[4]
P. Cleary, S. Shorvon, and R. Tallis, “Late-onset seizures as a predictor of subsequent stroke,” The Lancet, vol. 363, no. 9416, pp. 1184–1186, 2004.
[5]
C. L. M. Sudlow, “Epilepsy and stroke,” The Lancet, vol. 363, no. 9416, pp. 1175–1176, 2004.
[6]
C. Cordonnier, R. Al-Shahi Salman, and J. Wardlaw, “Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting,” Brain, vol. 130, no. 8, pp. 1988–2003, 2007.
[7]
B. R. Reed, J. L. Eberling, D. Mungas, M. Weiner, J. H. Kramer, and W. J. Jagust, “Effects of white matter lesions and lacunes on cortical function,” Archives of Neurology, vol. 61, no. 10, pp. 1545–1550, 2004.
[8]
R. B. Buxton, K. Uluda？, D. J. Dubowitz, and T. T. Liu, “Modeling the hemodynamic response to brain activation,” NeuroImage, vol. 23, supplement 1, pp. S220–S233, 2004.
[9]
L. M. Parkes and P. S. Tofts, “Improved accuracy of human cerebral blood perfusion measurements using arterial spin labeling: accounting for capillary water permeability,” Magnetic Resonance in Medicine, vol. 48, no. 1, pp. 27–41, 2002.
[10]
P. Jezzard and R. B. Buxton, “The clinical potential of functional magnetic resonace imaging,” Journal of Magnetic Resonance Imaging, vol. 23, no. 6, pp. 787–793, 2006.
[11]
S. Kobayashi, K. Okada, and K. Yamashita, “Incidence of silent lacunar lesion in normal adults and its relation to cerebral blood flow and risk factors,” Stroke, vol. 22, no. 11, pp. 1379–1383, 1991.
[12]
H. Nakane, S. Ibayashi, K. Fujii et al., “Cerebral blood flow and metabolism in patients with silent brain infarction: occult misery perfusion in the cerebral cortex,” Journal of Neurology Neurosurgery and Psychiatry, vol. 65, no. 3, pp. 317–321, 1998.
[13]
J. De Reuck, D. Decoo, P. Boon, K. Strijckmans, P. Goethals, and I. Lemahieu, “Late-onset epileptic seizures in patients with leukoaraiosis: a positron emission tomographic study,” European Neurology, vol. 36, no. 1, pp. 20–24, 1996.
[14]
R. A. Trivedi, H. A. L. Green, J. U-King-Im et al., “Cerebral haemodynamic disturbances in patients with moderate carotid artery stenosis,” European Journal of Vascular and Endovascular Surgery, vol. 29, no. 1, pp. 52–57, 2005.
[15]
T. L. Davis, K. K. Kwong, R. M. Weisskoff, and B. R. Rosen, “Calibrated functional MRI: mapping the dynamics of oxidative metabolism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 4, pp. 1834–1839, 1998.
[16]
P. A. Chiarelli, D. P. Bulte, R. Wise, D. Gallichan, and P. Jezzard, “A calibration method for quantitative BOLD fMRI based on hyperoxia,” NeuroImage, vol. 37, no. 3, pp. 808–820, 2007.
[17]
J. A. Goodwin, R. Vidyasagar, G. M. Balanos, D. Bulte, and L. M. Parkes, “Quantitative fMRI using hyperoxia calibration: reproducibility during a cognitive Stroop task,” NeuroImage, vol. 47, no. 2, pp. 573–580, 2009.
[18]
D. P. Bulte, K. Drescher, and P. Jezzard, “Comparison of hypercapnia-based calibration techniques for measurement of cerebral oxygen metabolism with MRI,” Magnetic Resonance in Medicine, vol. 61, no. 2, pp. 391–398, 2009.
[19]
T. H. Schwartz, “Neurovascular coupling and epilepsy: hemodynamic markers forlocalizing and predicting seizure onset,” Epilepsy Current, vol. 7, no. 4, pp. 91–94, 2007.
[20]
C. S. Hawco, A. P. Bagshaw, Y. Lu, F. Dubeau, and J. Gotman, “BOLD changes occur prior to epileptic spikes seen on scalp EEG,” NeuroImage, vol. 35, no. 4, pp. 1450–1458, 2007.
[21]
J. Valmier, J. Touchon, and M. Baldy-Moulinier, “Interictal regional cerebral blood flow during non specific activation test in partial epilepsy,” Journal of Neurology Neurosurgery and Psychiatry, vol. 52, no. 3, pp. 364–371, 1989.
[22]
L. Niehaus, U. C. Wieshmann, and B. U. Meyer, “Changes in cerebral hemodynamics during simple partial motor seizures,” European Neurology, vol. 44, no. 1, pp. 8–11, 2000.
[23]
R. Wiest, F. von Bredow, K. Schindler et al., “Detection of regional blood perfusion changes in epileptic seizures with dynamic brain perfusion CT-A pilot study,” Epilepsy Research, vol. 72, no. 2-3, pp. 102–110, 2006.
[24]
S. Rupprecht, M. Schwab, C. Fitzek, O. W. Witte, C. Terborg, and G. Hagemann, “Hemispheric hypoperfusion in postictal paresis mimics early brain ischemia,” Epilepsy Research, vol. 89, no. 2-3, pp. 355–359, 2010.
[25]
J. De Reuck and G. Van Maele, “Acute ischemic stroke treatment and the occurrence of seizures,” Clinical Neurology and Neurosurgery, vol. 112, no. 4, pp. 328–331, 2010.
[26]
L. H. Rodan, R. I. Aviv, D. J. Sahlas, B. J. Murray, J. P. Gladstone, and D. J. Gladstone, “Seizures during stroke thrombolysis heralding dramatic neurologic recovery,” Neurology, vol. 67, no. 11, pp. 2048–2049, 2006.
[27]
D. A. Sun, S. Sombati, and R. J. DeLorenzo, “Glutamate injury-induced epileptogenesis in hippocampal neurons: an in vitro model of stroke-induced "epilepsy",” Stroke, vol. 32, no. 10, pp. 2344–2350, 2001.
[28]
D. A. Sun, S. Sombati, R. E. Blair, and R. J. DeLorenzo, “Long-lasting alterations in neuronal calcium homeostasis in an in vitro model of stroke-induced epilepsy,” Cell Calcium, vol. 35, no. 2, pp. 155–163, 2004.
[29]
C. Terborg, F. Gora, C. Weiller, and J. R？ther, “Reduced vasomotor reactivity in cerebral microangiopathy: a study with near-infrared spectroscopy and transcranial Doppler sonography,” Stroke, vol. 31, no. 4, pp. 924–929, 2000.
[30]
M. L. Schroeter, S. Cutini, M. M. Wahl, R. Scheid, and D. Yves von Cramon, “Neurovascular coupling is impaired in cerebral microangiopathy—an event-related Stroop study,” NeuroImage, vol. 34, no. 1, pp. 26–34, 2007.
[31]
J. M. Wardlaw, P. A. G. Sandercock, M. S. Dennis, and J. Starr, “Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?” Stroke, vol. 34, no. 3, pp. 806–812, 2003.
[32]
G. Roob and F. Fazekas, “Magnetic resonance imaging of cerebral microbleeds,” Current Opinion in Neurology, vol. 13, no. 1, pp. 69–73, 2000.
[33]
E. Seiffert, J. P. Dreier, S. Ivens et al., “Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex,” Journal of Neuroscience, vol. 24, no. 36, pp. 7829–7836, 2004.
[34]
Y. David, L. P. Cacheaux, S. Ivens et al., “Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?” Journal of Neuroscience, vol. 29, no. 34, pp. 10588–10599, 2009.
[35]
U. Heinemann, S. Gabriel, R. Jauch et al., “Alterations of glial cell function in temporal lobe epilepsy,” Epilepsia, vol. 41, supplement 6, pp. S185–S189, 2000.
[36]
P. A. Armitage, A. J. Farrall, T. K. Carpenter, F. N. Doubal, and J. M. Wardlaw, “Use of dynamic contrast-enhanced MRI to measure subtle blood-brain barrier abnormalities,” Magnetic Resonance Imaging, 2010. Epub ahead of print.
[37]
G. J. Zipfel, H. Han, A. L. Ford, and J. M. Lee, “Cerebral amyloid angiopathy progressive disruption of the neurovascular unit,” Stroke, vol. 40, no. 3, supplement, pp. S16–S19, 2009.
[38]
S. M. Greenberg, J. P. G. Vonsattel, J. W. Stakes, M. Gruber, and S. P. Finklestein, “The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage,” Neurology, vol. 43, no. 10, pp. 2073–2079, 1993.
[39]
K. Karabatsou, B. R. F. Lecky, N. G. Rainov, J. C. Broome, and R. P. White, “Cerebral amyloid angiopathy with symptomatic or occult subarachnoid haemorrhage [1],” European Neurology, vol. 57, no. 2, pp. 103–105, 2007.
[40]
C. Kinnecom, M. H. Lev, L. Wendell et al., “Course of cerebral amyloid angiopathy-related inflammation,” Neurology, vol. 68, no. 17, pp. 1411–1416, 2007.
[41]
L. M. Gibson, L. M. Parkes, and H. C. A. Emsley, “Occult cerebrovascular disease in late-onset epilepsy: a literature review and novel hypothesis,” in Proceedings of the 18th Meeting of the European Neurological Society, Nice, France, June 2008, (poster).
[42]
L. M. Gibson, L. M. Parkes, and H. C. A. Emsley, “Occult cerebrovascular disease in late-onset epilepsy: a literature review and novel hypothesis,” Journal of Neurology, vol. 255, supplement 2, p. 102, 2008.
