CAVERNOUS SINUS SYNDROME

PENDAHULUAN^1,2

                Sinus cavernous adalah sebuah rongga di pusat yang terletak di dasar otak sebelah tulang temporal dan tulang sphenoid. Rongga ini berisi arteri karotis internal dan beberapa saraf penting termasuk saraf oculomotor, saraf troklearis, saraf mata, saraf rahang atas, dan saraf abducens. Arteri karotis interna dan saraf abducens berjalan secara horizontal melalui sinus cavernous sementara saraf sisanya berjalan secara vertikal. Ada dua sinus cavernous, satu untuk masing-masing belahan otak. Kelenjar pituitari duduk diantara dua sinus cavernous.

Anatomi sinus cavernous adalah unik karena merupakan satu-satunya tempat dalam tubuh manusia di mana arteri bergerak sepenuhnya melalui struktur vena. Dalam kasus ini, arteri karotis interna bergerak darah dari otak dan wajah kembali ke jantung akan oksigen.

Sindrom sinus cavernous didefinisikan dengan tanda dan gejala yang berupa ophthalmoplegia, chemosis, proptosis, sindrom Horner, atau kehilangan sensori trigeminus. Proses inflamasi, pembuluh darah, trauma, dan neoplastik adalah penyebab utama dari sindrom sinus cavernous ini. Contoh tertentu yang dapat mengakibatkan sindrom sinus cavernous banyak sekali dan mencakup aneurisma arteri karotis, fistula karotis-cavernous (CC fistula), tumor, dan Tolosa-Hunt syndrome, adalah beberapa nama yang sering dibahas.

ANATOMI^2,3,4,5

                Sinus cavernous terletak di dalam kepala manusia adalah kumpulan besar dari vena berdinding tipis yang menciptakan rongga berbatasan dengan tulang temporal dari tengkorak dan tulang sphenoid, dan berada dilateral sela tursika.

                Sinus cavernous menerima darah melalui vena oftalmik melalui fisura orbital superior dan vena kortikal superfisial dan terhubung ke pleksus pembuluh darah basilar posterior. Arteri karotis interna, dan saraf kranial III, IV, V1, V2 dan VI semua melewati ruang ini. Infeksi dari wajah dapat mencapai sinus cavernous melalui banyak koneksi anastomosisnya, dengan konsekuensi yang berat. Sinus cavernous mengalir oleh dua saluran, sinus petrosus superior dan inferior, akhirnya menjadi vena jugularis interna.

Setiap sinus cavernous (satu untuk masing-masing belahan otak) berisi sebagai berikut :

-          Secara vertikal, dari superior inferior (dalam dinding lateral sinus)

o   Nervus oculomotorius (N III)

o   Nervus Troklearis (N IV)

o   Nervus Abducens (N VI)

o   Nervus Trigeminus cabang saraf oftalmik (N V1)

o   Nervus Trigeminus cabang saraf maxilaris (N V2)

-          Secara horizontal, dari medial ke lateral

o   Arteri karotis interna (dan pleksus simpatis).

Saraf optik terletak tepat di atas dan di luar sinus gua, superior dan lateral kelenjar hipofisis di setiap sisi, dan memasuki puncak orbit melalui kanal optik.

Gambar anatomi sinus cavernous

DEFINISI^1,6

                Sindrom sinus cavernous adalah kumpulan gejala yang menyebabkan ophthalmoplegia (akibat dari kompresi saraf oculomotor, saraf troklearis, dan saraf abducens), hilangnya sensorik mata (akibat dari kompresi saraf mata), dan kehilangan sensorik maksila (akibat dari kompresi saraf rahang atas). Sebuah lesi komplit dari sinus cavernous dapat mengganggu saraf kranial III, IV, dan VI, dan dapat menyebabkan ophthalmoplegia total, biasanya disertai dengan pupil yang tetap melebar. Keterlibatan saraf kranial V1 dan V2 menyebabkan hilangnya sensorik dalam divisi saraf trigeminal. Sindrom Horner juga dapat terjadi karena keterlibatan okular karotis sympathetic.

ETIOLOGI^1,4

                Penyebab utama dari sindrom sinus cavernous ini adalah dapat berupa metastatik tumor yang berasal dari Payudara, Prostat atau paru-paru, Penyebaran tumor lokal yang dapat berasal dari Nasofaring dan kelenjar di bawah otak, Tumor intrakranial primer seperti Meningioma, Neurofibroma ataupun Chondroma (kurang umum).

Selain itu sindrom sinus cavernous ini dapat juga disebabkan oleh karena trauma (termasuk pascaoperasi), Aneurisma karotis-cavernous, fistula karotis-cavernous, trombosis sinus cavernous, inflamasi lainnya seperti Herpes zoster, Tolosa-Hunt syndrome, dan Sarkoidosis.

PATOFISIOLOGI¹

                Sinus cavernous terdapat sepasang pada setiap manusia, struktur vena terletak di kedua sisi sela tursika. Vena tersebut menerima cabang dari pembuluh vena orbital superior dan inferior dan mengalir ke sinus petrosus superior dan inferior. Sinus cavernous berisi arteri karotis (pleksus simpatik), dan saraf oculomotor (ketiga, saraf kranial keempat, dan keenam). Selain itu, cabang oftalmik dan kadang-kadang cabang dari nervus kelima maksilaris melintasi sinus cavernous. Saraf melewati dinding sinus sementara arteri karotid melewati sinus itu sendiri.

TUMOR SINUS CAVERNOUS

                                                Tumor sinus cavernous adalah penyebab paling umum dari sindrom sinus cavernous. Tumor dapat bersifat primer atau mungkin timbul dari penyebaran lokal atau sebagai metastasis. Contoh tumor primer termasuk meningioma atau Neurofibroma. Contoh penyebaran lokal dapat berupa dari tumor karsinoma nasofaring atau tumor hipofisis. Lesi metastatik paling sering berasal dari payudara, prostat, atau paru-paru. Radioterapi mungkin dapat memberikan bantuan sementara, khususnya pada kanker nasofaring. Perpanjangan lateral tumor hipofisis dapat diobati dengan reseksi bedah dan agonis dopamin dalam kasus prolaktinoma.

ANEURISMA SINUS CAVERNOUS

Tidak seperti aneurisma intrakranial di lokasi anatomi lainnya, aneurisma sinus cavernous tidak melibatkan risiko utama yaitu berupa perdarahan subarachnoid. Namun, mereka pecah sehingga dapat mengakibatkan fistula karotis-cavernous, yang dapat menyebabkan pendarahan pada otak. Aneurisma ini, yang lebih sering terjadi pada orang yang lanjut usia, dan hadir dengan indolen ophthalmoplegia.

FISTULA KAROTIS-CAVERNOUS

Fistula kqrotis-cavernous terdiri dari 2 jenis yaitu langsung dan tidak langsung. Fistula langsung terjadi jika arteri karotis dan sinus cavernous dalam kontinuitas. Mereka mewujudkan dengan onset mendadak proptosis, chemosis, kehilangan penglihatan, dan ophthalmoplegia. Fistula tidak langsung terjadi akibat adanya komunikasi antara sinus cavernous dan cabang-cabang dari arteri karotis interna, arteri karotis eksternal, atau keduanya. Fistula tidak langsung memiliki presentasi yang lebih berbahaya daripada fistula langsung, sering dengan resolusi spontan. Trauma atau ruptur aneurisma adalah penyebab umum dari fistula karotis-kavernosa. Intervensi radiolog berhasil dapat mengobati semua jenis fistula dengan teknik oklusi endovascular. Kadang-kadang, pengobatan bedah dengan ligasi karotid diperlukan.

GEJALA KLINIS^1,4

                Tanda-tanda dan gejala yang sering ditemukan pada pasien dengan lesi sinus cavernous termasuk kehilangan penglihatan, proptosis, kongesti okular dan konjungtiva, meningkatnya tekanan okular, ophthalmoplegia, dan nyeri. Berbagai kombinasi gejala-gejala ini mungkin terjadi, yang umumnya bersifat unilateral, namun dapat terjadi secara bilateral dengan proses neoplastik. Gejala dapat bersifat akut atau progresif lambat. Tumor primer adalah neoplasma yang paling sering bertanggung jawab untuk sindrom sinus cavernous.

Lesi pada sinus cavernous ditandai oleh tanda-tanda sebagai berikut :

-          Kelumpuhan saraf kranial ketiga, keempat, atau keenam

-          Ophthalmoplegia

-          Proptosis atau exophthalmos yang berdenyut menunjukkan fistula karotis-cavernous langsung

-          Bruit okular dan kranial

-          Kongesti pada konjungtiva

-          Hipertensi okular

-          Edema atau pucatnya diskus optik, perdarahan retina

-          Penurunan sensasi nyeri di oftalmik dari saraf trigeminal (N V1) atau refleks kornea yang menurun atau tidak ada dan mungkin juga terjadi penurunan sensasi nyeri di cabang maksilaris (N V2)

-          Pupil dalam keadaan midposition dan reaktif jika kedua sympathetics dan parasympathetics dari saraf kranial ketiga ikut terkena.

TUMOR SINUS CAVERNOUS

-          Lesi metastatik dapat menyebabkan ophthalmoplegia, ophthalmoplegia yang menyakitkan, anestesi pada saraf oftalmik

-          Tumor hipofisis dapat menyebabkan ophthalmoplegia, tanda-tanda endokrin seperti acromegaly, galaktorea, dan defek bidang visual yang unitemporal atau bitemporal

-          Tumor intrakranial primer dapat menyebabkan ophthalmoplegia dan regenerasi primer dari saraf kranial ketiga

ANEURISMA SINUS CAVERNOUS

-          Ophthalmoplegia, atau opthalmoplegia yang disertai dengan rasa nyeri

-          Penurunan sensasi nyeri di saraf oftalmik (N V1)

FISTULA KAROTIS-CAVERNOUS

-          Langsung - proptosis masif unilateral, exophthalmos yang berdenyut, kongesti konjungtiva, chemosis konjungtiva, kongesti orbital, hipertensi okular, kehilangan penglihatan, neuropati optik, optik disk edema, perdarahan retina, kongesti vena retina, dan okular yang keras dan bruit kranial

-          Tidak langsung - kadang-kadang, ophthalmoplegia, terutama jika fistula saluran posterior.

TROMBOSIS SINUS CAVERNOUS

-          Secara umum prosesnya dikarenakan infeksi primer yang melibatkan sinus paranasal dan / atau selulitis orbital

-           Selain tanda-tanda lokal dan sistemik dari infeksi, tanda-tandanya adalah sebagai berikut :

o   Ophthalmoplegia atau ophthalmoplegia yang disertai dengan rasa nyeri

o   Kongesti orbital, chemosis konjungtiva, proptosis

o   Kehilangan penglihatan, edema disk optik (unilateral)

o   Tanda-tanda iritasi meningeal.

GEJALA LAIN DARI LESI SINUS CAVERNOUS

-          Tolosa-Hunt syndrome - ophthalmoplegia yang menyakitkan

-           Herpes zoster - Akut zoster ophthalmicus, lesi kulit yang khas, dan keratitis

-          Sarkoidosis - tanda-tanda sistemik, uveitis, ophthalmoplegia, diplegia wajah.

DIAGNOSIS¹

                Pasien yang lesi sinus cavernous diduga harus menjalani bagian pencitraan multiplanar dari daerah orbit dan sellar / parasellar. Precontrast dan postcontrast scan yang biasanya dianjurkan. CT scan menawarkan visualisasi yang lebih baik pada tulang dan kalsium. Namun, MRI dapat memberikan detail yang lebih baik dari semua jaringan lunak yang terdapat didalam sinus serta hubungannya dengan struktur sekitar. Sehingga dengan kedua pemeriksaan tersebut dapat mengetahui penyebab dari sindrom sinus cavernous ini.

PENATALAKSANAAN^1,4

                Penatalaksanaan dari penyakit ini tergantung dari penyebabnya.

TUMOR SINUS CEVERNOSUS

-          Lesi metastatik

o   Radioterapi dapat menawarkan perbaikan sementara.

o    Karsinoma nasofaring mungkin sangat radiosensitive.

-          Tumor hipofisis

o   Prolaktinoma diatasi dengan pemberian agonis dopamin oral, atau mungkin memerlukan reseksi.

o    Pisau gamma bisa menjadi pengobatan tambahan untuk sisa tumor atau berulang pasca operasi tumor, dan mungkin memiliki peran sebagai alternatif untuk perawatan bedah.

-          Sinus cavernous meningioma

o   Lesi ini merupakan tantangan besar untuk dilakukannya reseksi bedah, terutama karena aksesibilitas yang miskin dan dibungkus dengan arteri karotid cavernous.

o   Karena tumor ini lambat tumbuh dan sulit untuk direseksi, pasien tua atau orang dengan gejala minor mungkin harus diamati tanpa pengobatan khusus.

o   Radioterapi dapat ditawarkan untuk beberapa pasien, dan menunjukkan beberapa perbaikan fungsi saraf kranial setelah perawatan gamma pisau.

ANEURISMA SINUS CAVERNOUS

-          Aneurisma sinus cavernous dapata diatasi dengan oklusi balon endovascular.

FISTULA KAROTIS-CAVERNOUS

-          Pengobatan idealnya terdiri dari obliterasi endovascular fistula dengan kumparan, meskipun beberapa sinus dural cavernous fistula AV mungkin dikelola secara observasional.

-           Akses ke fistula dapat transarterial, namun pendekatan transvenous telah menjadi andalan pengobatan, dalam beberapa kasus pendekatan bedah / endovascular gabungan dapat digunakan dengan paparan bedah vena oftalmik diikuti dengan embolisasi fistula. Beberapa pendekatan vena telah digunakan, termasuk pendekatan transfemoral yang paling aman. Namun, jika ini tidak layak, puncture vena orbital superior atau transorbital perkutan ke sinus cavernous dapat digunakan.

-          Diseksi vena supraorbital dengan penempatan kateter untuk mengakses sinus cavernous telah berhasil dilakukan.

-          Akses perkutan transorbital ke sinus cavernous diikuti oleh embolisasi.

-          Fistula karotis-cavernous tidak langsung dapat menutup jalan baik secara spontan atau setelah angiografi diagnostik. Jika tanda-tanda klinis yang ringan, pertimbangkan pemantauan secara cermat.

-          Jika tekanan intraokular meninggi, antiglaucoma mungkin diperlukan.

TROMBOSIS SINUS CAVERNOUS

-          Terapi antibiotik dosis tinggi harus diarahkan terhadap bakteri patogen yang paling umum, seperti Staphylococcus S dan S. Pneumoniae, serta gram batang negatof dan anaerob.

-           Antikoagulan dalam trombosis sinus cavernous adalah kontroversial, tetapi dapat mempercepat laju pemulihan.

-          Drainase dari setiap situs utama infeksi (misalnya, abses, sinusitis) disarankan.

-          Kortikosteroid tidak dianjurkan.

SINDROM INFLAMASI YANG LAINNYA

-          Sindrom inflamasi sinus cavernous dapat merespon dengan baik pengobatan peradangan sistemik tertentu.

-          Tolosa-Hunt syndrome merespons yang baik dengan 3 – untuk 6-bulan saja dari terapi steroid dosis tinggi yang kemudian dosisnya diturunkan secara perlahan.

DAFTAR PUSTAKA

1.       Kattah, J. Cavernous Sinus Syndrome. Available from : www.emedicine.net. Update : Januari 2009.

2.       Wikipedia. Cavernous Sinus. Available from : http://en.wikipedia.org.

3.       Cavernous Sinus. Available from : www.wisegeek.com

4.       Cavernous Sinus Syndrome. Available from : www.ehow.com.

5.       Snell, R, S. Neuroanatomi Klinik Edisi 2. Jakarta. EGC. Hal 529.

6.       Cavernous Sinus Syndrome Definition. Available from : www.medicinenet.com.

Hypertension A Harbinger of Stroke and Dementia

1. Giuseppe Faraco, 
2. Costantino Iadecola

+Author Affiliations

1. From the Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY.

1. Correspondence to Costantino Iadecola, Brain and Mind Research Institute, Weill Cornell Medical College, 407 E 61st St, RR-303, New York, NY 10065. E-mailcoi2001@med.cornell.edu

 

Next Section

Introduction

Despite remarkable successes in prevention and treatment, hypertension (HTN) remains a major cause of morbidity and mortality worldwide.¹ The brain is one of the preeminent target organs in which high blood pressure is particularly damaging, contributing significantly to its burden of disease.¹ HTN is the biggest risk factor for stroke, the second cause of death worldwide and a major cause of long-term disability.² HTN is also a leading risk factor for vascular cognitive impairment (VCI),³ as well as Alzheimer disease (AD), the most common cause of dementia in the elderly.³ Therefore, HTN is involved in the pathogenesis of 2 major brain diseases: stroke and dementia. In this brief review, we first examine the role of HTN in the alterations in cerebrovascular structure and function underlying the pathological effects of HTN on the brain. Then, we examine the pathophysiological bases of these alterations, focusing on how high blood pressure promotes stroke and cognitive impairment. Finally, we discuss the impact of preventive and therapeutic approaches to mitigate the deleterious effects of HTN on the brain.

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Alterations in Cerebrovascular Structure Induced by HTN

Adaptive Changes: Hypertrophy and Remodeling

Sustained elevations in blood pressure have profound effects on the structure of cerebral blood vessels, inducing adaptive changes aimed at reducing the mechanical stress on the arterial wall and protecting microvessels from pulsatile stress.⁴ In hypertrophic remodeling, the media thickens to encroach into the lumen, resulting in increased media cross-sectional area and media/lumen ratio (Figure 1). The size of vascular smooth muscle cells increases, and there is accumulation of extracellular matrix proteins, such as collagen and fibronectin, in the vessel wall.⁵ In eutrophic remodeling, smooth muscle cells undergo a rearrangement that leads to a reduction in the outer and inner diameters, whereas media/lumen ratio is increased and cross-sectional area is unaltered (Figure 1). In this case, the change in vascular smooth muscle cells size is negligible, and the reduction in lumen is attributable to a reorganization of cellular and acellular material in the vascular wall, accompanied by enhanced apoptosis in the outer regions of the blood vessel.⁵ Remodeling is damaging because it reduces the vessels’ lumen and increases vascular resistance, and has emerged as a potential risk factor for cardiovascular events and cerebrovascular disease.⁶

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Figure 1.

Effect of hypertension (HTN) on cerebral blood vessels. HTN induces profound alterations of critical regulatory mechanisms of the cerebral circulation, which, in concert with the structural alterations, compromise the blood supply to the brain and increase the risk for stroke and dementia. BBB indicates blood–brain barrier; CBF, cerebral blood flow; and ROS, reactive oxygen species.

Longstanding HTN induces deposition of collagen and fibronectin and elastin fragmentation, leading to an increase in the stiffness of the wall of large arteries. Arterial stiffening is a good predictor of stroke and cognitive decline, and is associated with clinically silent brain lesions in patients with hypertension.^3,7

Atherosclerosis and Small Vessel Disease

HTN is a leading risk factor for atherosclerosis. A 10-mm Hg increase in arterial pressure increases by 43% the odds of complex aortic atherosclerosis (protruding atheroma, ulcerated plaques, mobiles debris), highly predictive of ischemic strokes.⁸ Atherosclerotic lesions are also observed at sites of turbulent flow, such as the carotid bifurcation and the vertebrobasilar system, and less frequently in intracranial arteries (Figure 2). A potential mechanism is related to vascular shear stress at those sites leading to expression of innate immunity receptors on macrophages/monocytes and inflammation.⁹ Atherosclerotic plaques can cause stroke by releasing fragments and leading to artery-to-artery embolism, or by rupture and hemorrhage, resulting in acute cerebrovascular occlusions (Figure 2).

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Figure 2.

Ischemic brain lesions associated with hypertension (HTN). HTN induces atherosclerosis of major extracranial and intracranial arteries, which could lead to major infarcts. HTN causes both microbleeds and macrobleeds and is the main pathogenetic factor for small vessel disease responsible for lacunar infarcts, white matter lesions (leukoaraiosis), and microinfarcts. The subcortical white matter at the boundary between different vascular territories (middle cerebral artery [MCA] and anterior cerebral artery [ACA]) is particularly susceptible to damage.

HTN also promotes highly distinctive alterations in small arteries and arterioles supplying the deep hemispheric white matter and basal ganglia, resulting in a condition known as small vessel disease (SVD; Figure 2). The susceptibility of these vessels to SVD may be related to their short linear path from larger vessels at the base of the brain, rendering them more vulnerable to the mechanical stresses imposed by HTN.¹⁰ The most common pathological substrates of SVD related to HTN is arteriolosclerosis.¹¹ The pathological features of arteriolosclerosis include loss of smooth muscle cells from the tunica media, deposits of fibro-hyaline material, narrowing of the lumen, and thickening of the vessel wall (lipohyalinosis¹¹; Figures 1 and 2). In more advanced lesions, fibrinoid necrosis of the vessel wall facilitates the rupture of the vessel resulting in microscopic hemorrhages or large hemorrhages typically in basal ganglia or thalamus (Figure 2). In addition, HTN induced capillary rarefaction, which may also contribute to the associated brain lesions in the periventricular white matter.

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Alterations in Cerebrovascular Function Induced by HTN

The brain is highly dependent on an adequate delivery of oxygen and glucose from the circulation, and cerebral blood flow (CBF) reductions impair neuronal function and, if protracted, induce brain damage.¹² Consequently, cerebrovascular control mechanisms assure that the delivery of oxygen and glucose is well matched to the energy demands of the cellular constituents of the brain. HTN induces profound alterations of these regulatory mechanisms, which, in concert with the structural changes described above, compromise the blood supply to the brain. Next, we examine the major mechanisms regulating the cerebral circulation and their perturbation by HTN.

Cerebrovascular Autoregulation

Cerebrovascular autoregulation buffers the cerebrovascular effects of the wide fluctuations in arterial pressure that occur during the activities of daily living. Autoregulation allows the brain to maintain a steady blood flow between 60 and 150 mm Hg of mean arterial pressure.¹³ Within this range, blood pressure increases result in constriction, and blood pressure decreases result in dilatation of cerebral resistance vessels, maintaining CBF relatively constant. Cerebral autoregulation depends on the intrinsic ability of vascular smooth muscle cells to constrict when transmural pressure increases (myogenic tone). Myogenic tone depends on the concerted action of ion channels on the vascular smooth muscle cells membrane, as well as stretch activated receptors, resulting in increases in intracellular Ca²⁺ or increases in the Ca²⁺ sensitivity of the contractile apparatus, ultimately leading to phosphorylation of contractile proteins and constriction.¹³

Regulation by Endothelial Cells

Cerebral endothelial cells have powerful effects on vascular tone and regulate CBF by releasing vasodilators (NO, prostacyclin, bradykinin, etc) and vasoconstrictors (endothelin-1 [ET-1], endothelium-derived constrictor factor, etc).¹⁴Endothelium-derived vasoactive factors participate in the maintenance of resting CBF and may play a role in coordinating the vasodilatation of intraparenchymal arterioles with that of upstream pial arteries, and in local adjustments of flow in response to mechanical forces.¹² Another important aspect of endothelial cell function is the regulation of the blood–brain barrier (BBB). Cerebral endothelial cells have a low vesicular transport and are linked to each other by tight junctions, which prevent the entry of hydrophilic substances into the brain.¹⁵ Specialized transport proteins on the endothelial cell membrane regulate the bidirectional transfer of substances into and from the brain parenchyma.¹⁵ The integrity of the BBB is vitally important to maintain the homeostasis of the cerebral microenvironments, which is a prerequisite for normal brain function.

Functional Hyperemia

Functional hyperemia is a homeostatic mechanism by which the vascular delivery of oxygen and glucose and the removal of metabolites produced by brain activity are coupled to the energy requirements of neurons and glia.¹² Therefore, CBF is dynamically related to the level of neural activity of the different brain regions. A growing body of evidence indicates that neurons, glia, and cerebrovascular cells, acting as an integrated unit, mediate the increase in CBF produced by neural activity.^12,16 Neural activity induces the release of vasoactive mediators such as NO, prostanoids, carbon monoxide, cytochrome p450 metabolites, H⁺, and K⁺ions that act at different levels of the cerebral vasculature to mediate the hemodynamic changes underlying the CBF increase.¹² Vasodilation of arterioles at the site of activation is accompanied by vasodilation of upstream pial arteries that supply the activated area, and this coordinated response is essential for increasing CBF efficiently.¹²

HTN and Cerebrovascular Dysfunction

HTN has profound effects on all aspects of the regulation of CBF (Figure 1). HTN alters cerebrovascular autoregulation, leading to a shift of the pressure–flow relationship to the right, such that higher pressures are needed to maintain the same level of cerebral perfusion (Figure 1). The lateral shift may be also associated with a reduction in resting CBF, resulting in a downward displacement of the curve¹⁷ (Figure 1). These alterations reduce cerebral perfusion at each level of blood pressure, compromising the ability of the brain to maintain adequate CBF in the face of hypotension or arterial occlusion. The mechanisms of the effects of HTN on autoregulation are not completely understood, but are likely to include a combination of effects on myogenic tone and on the changes in the mechanical characteristics of cerebral blood vessels induced by remodeling and stiffening.^4,13These changes in autoregulation are particularly damaging to the periventricular white matter, which is located at the boundary between different arterial territories¹⁸ and, as such, is most susceptible to hypoperfusion (Figure 2). Accordingly, the magnitude of autoregulatory dysfunction induced by HTN correlates with the severity of periventricular white matter injury.¹⁹ The HTN-induced autoregulatory impairment also leads to more severe brain damage after arterial occlusion in stroke models, which may underlie the increased susceptibility to large artery stroke.

HTN also alters functional hyperemia and endothelial function. Attenuations in cerebrovascular responses to endothelium-dependent vasodilators have been reported in rodent models of chronic HTN.^20–22 Similarly, functional hyperemia, produced in the somatosensory cortex by activation of the facial whiskers, is attenuated in mice treated with slow-pressor doses of angiotensin II (Ang II) and in spontaneously hypertensive rats.^22,23 The cerebrovascular dysfunction precedes the HTN induced by slow-pressor Ang II infusion and persists beyond the elevation in blood pressure at the end of the infusion.²¹ Furthermore, doses of Ang II that do not elevate blood pressure produce cerebrovascular alterations comparable with those observed with slow-pressor or pressor doses,^21,24,25suggesting that the cerebrovascular actions of Ang II are independent of the elevation in blood pressure.

Consistent with findings in animal models, the increase in CBF induced by brain activation is attenuated in patients with chronic HTN, and the cerebrovascular dysfunction correlates with cognitive deficits.²⁶ Furthermore, the increase in retinal blood flow produced by light flickering, a model of function hyperemia, is blunted in individuals with hypertension.²⁷ Direct evidence of altered cerebrovascular endothelial responses in humans with HTN is lacking. But the NO synthase inhibitor L-NAME (N^G-nitro-L-arginine methyl ester) does not reduce retinal blood flow in patients with HTN, a finding consistent with NO-dependent endothelial dysfunction.²⁷ These observations, collectively, indicate that HTN disrupts key cerebrovascular control mechanisms aimed at maintaining the energy homeostasis of the brain, which act in concert with the structural alterations of cerebral blood vessels described earlier to produce brain dysfunction and damage.

Key Role of Oxidative Stress in the Cerebrovascular Effects of HTN

Several lines of evidence suggest that reactive oxygen species (ROS) are key mediators of the cerebrovascular damage produced by HTN. HTN promotes ROS production in cerebral blood vessels and ROS scavenger counteracts the effects of HTN on functional hyperemia and endothelial dysfunction, including alterations of the BBB.^21,24,25,28 In models of Ang II HTN, ROS production is elevated in brain regions regulating cardiovascular function.²² Suppression of ROS in one of these regions, the subfornical organ, prevents the alterations in functional hyperemia and endothelium-dependent responses induced by slow-pressor administration of Ang II.²² In this model, the cerebrovascular dysfunction involves, in addition to direct vascular effects of circulating Ang II, also activation of neurohumoral mechanisms leading to vasopressin release and upregulation of ET-1 in cerebral blood vessels.²² ET-1, in turn, leads to vascular ROS production through activation of ET type A receptors.²² In contrast, the cerebrovascular alterations induced by acute administration of pressor Ang II doses are entirely depended on a direct action of Ang II on cerebral blood vessels leading to oxidative and nitrosative stress.^24,25 Cerebrovascular ET-1, via ET type A receptor and ROS, is also involved in the cerebrovascular effects of the HTN induced by chronic intermittent hypoxia, a model of obstructive sleep apnea.²⁹ Oxidative stress has also been implicated in other vascular effects of HTN including vascular remodeling and inflammation.³⁰ The evidence for a role of ROS in the white matter damage produced by SVD is suggestive but limited. Increased markers of oxidative stress have been described in white matter lesions in autopsy studies.³¹Furthermore, reduced circulating levels of NO metabolites, possibly reflecting increased oxidative stress, have been reported in patients with white matter lesions detected by MRI.³² More studies are clearly needed.

Among the potential sources of ROS in cerebral blood vessels,⁶ the enzyme nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase has emerged as a major contributor in the cerebrovascular effects of HTN.³³ Importantly, cerebral blood vessels have a greater capacity to produce NADPH oxidase–derived ROS than systemic vessels.³⁴ The cerebrovascular dysfunction induced by Ang II is not observed in mice lacking Nox2, and NADPH inhibition abrogates the alterations in endothelium-dependent vasodilation and functional hyperemia induced by Ang II.^24,25 Nox2-derived radicals are also involved in the cerebrovascular remodeling induced by Ang II HTN.³⁰

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Brain Lesions Underlying VCI

VCI includes a wide spectrum of cognitive alterations caused by cerebrovascular factors, ranging from mild cognitive impairment affecting a single cognitive domain, such as executive function, to full blown vascular dementia affecting multiple domains and impairing the activities of daily living.³ Stroke is a major cause of cognitive impairment. Up to one third of patients with stroke have cognitive impairment within 3 months, and having a stroke doubles the risk of dementia (poststroke dementia).³ Furthermore, the risk of VCI is increased in patients with no history of stroke in which imaging shows brain infarcts (silent infarcts).³ A single stroke affecting a region important for cognition, like the thalamus or the frontal lobe, can lead to cognitive impairment (strategic-infarct dementia).³ VCI and dementia can also result from multiple strokes destroying large amounts of brain tissue (multi-infarct dementia).³ However, SVD remains a major cause of VCI contributing up to 45% of dementia cases.³ Next, we examine the neuropathological alterations caused by cerebral SVD that have been linked to VCI.

Lacunar Infarcts

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 They have been attributed to acute occlusion of small perforating cerebral arteries (40–200 µm diameter) because of SVD pathology or, less likely, embolism from upstream vessels.³⁶ More recently, evidence of white matter BBB disruption has been provided in patients with lacunes, raising the possibility that BBB alterations are early pathogenic events that could lead to secondary ischemia and inflammation.³⁶ Therefore, multiple factors are likely to be involved in the pathogenesis of lacunar infarcts.

Diffuse White Matter Damage

Another manifestation of SVD is diffuse white matter damage or leukoaraiosis, indicating a reduction in white matter density.^3,11 High systolic blood pressure precedes the development of leukoaraiosis, and blood pressure lowering slows down its progression.³⁷ Often present in the periventricular white matter, leukoaraiosis could result from hypoxia-hypoperfusion. The periventricular white matter is thought to be more susceptible to hypoperfusion because it is located at the boundary between separate arterial territories¹⁸ (Figure 2). Supporting this hypothesis, CBF is reduced in normal appearing periventricular white matter of patients with leukoaraiosis,³⁸ and hypoxia inducible genes are expressed in white matter lesions.³⁹ Endothelial dysfunction and BBB alterations produced by HTN could cause leakage of plasma proteins, leading to oxidative stress, inflammation, and edema, which compresses the tissue and contributes to hypoperfusion and demyelination.³⁶ Hypoxia could induce production of metalloproteases in oligodendrocyte precursors contributing to the BBB opening.^31,40,41

Microinfarcts

SVD is also associated with ischemic lesions not visible to the naked eyes (microinfarcts).⁴² Cerebral microinfarcts are small infarcts (<1 although="" be="" because="" challenging="" common="" detection="" diameter="" elderly="" in="" is="" mm="" of="" size.="" small="" style="border: 0px; font-family: inherit; font-size: 0.85em; font-style: inherit; line-height: 0; margin: 0px; outline-style: none; padding: 0px; position: relative; text-align: inherit; top: -2px; word-wrap: break-word;" sup="" the="" their="" thought="" to="" very="" vivo="">42

 It is estimated that 1 or 2 microinfarcts in routine postmortem examination suggest the presence of hundreds of microinfarcts throughout the brain.⁴³ Microinfarcts are common in patients with vascular or mixed dementia but are an independent predictor of VCI.⁴² Number and the location of the microinfarcts are major determinants of cognitive dysfunction, the cortical location being more closely associated with dementia.⁴²

Cerebral Microbleeds and Macrobleeds

SVD also produces hemorrhagic manifestations. Cerebral microbleeds are small perivascular hemorrages (2–10 mm) that can be detected histologically at autopsy or in vivo using iron-sensitive MRI sequences.⁴⁴ Microbleeds, which are observed in 10% to 20% of the elderly often in association with other SVD pathologies, are an independent predictor of cognitive decline.⁴⁴ HTN is a major risk factor of microbleeds, which in this condition are typically located in the basal ganglia, thalamus, brain stem, and cerebellum.⁴⁵ Microbleeds are frequently associated also with cerebral amyloid angiopathy, but in this case they tend to have a lobar distribution.⁴⁴ HTN is well known to cause large cerebral hemorrhages, typically in the basal ganglia or thalamus (Figure 2). The relationship between microbleeds and cerebral hemorrhages is not entirely clear, but microbleeds are associated with an increased risk of brain hemorrhage.⁴⁶

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HTN and AD

AD and VCI are, respectively, the first and second most common causes of dementia in the elderly.³ Although traditionally considered separate pathologies, increasing evidence indicates that AD and VCI share common pathogenetic mechanisms.¹⁶ Vascular risk factors, such as HTN, smoking, hyperlipidemia, and diabetes mellitus, are also risk factors for AD.¹⁶ In particular, midlife HTN doubles the risk of AD later in life and accelerates the progression of the dementia.⁴⁷ Up to 50% of cases of dementia have mixed pathology featuring both vascular (SVD) and neurodegenerative lesions (amyloid plaques and neurofibrillary tangles).⁴⁸ Several studies have shown that HTN-induced lesions and AD may have an additive or synergistic effect and produce a more severe cognitive impairment than either process alone.¹⁶

Several postmortem studies have also reported more atherosclerosis in cerebral vessels of AD patients compared with nondemented controls, a finding associated with increased amyloid plaques and neurofibrillary tangles.^49,50 Furthermore, an increased amount of amyloid plaques and neurofibrillary tangles have been reported in the brain of patients with hypertension.⁵¹ β-amyloid (Aβ), a peptide involved in the pathogenesis of AD, is elevated in the blood of patients with VCI and could potentially contribute to vascular insufficiency and white matter injury.^52,53 Furthermore, increases in diastolic blood pressure in midlife are linked to an increase in AD risk and to a reduction in plasma Aβ decades later,⁵⁴suggesting that the vascular dysfunction induced by HTN may inhibit the vascular transport of brain Aβ into the plasma. HTN interacts with Apoε4 to promote amyloid deposition in healthy individuals, suggesting an interaction between vascular and genetic factors in increasing the susceptibility to AD.⁵¹ Patients with HTN and elevated AD biomarkers have increased gray matter atrophy, indicating that HTN may exacerbate gray matter damage in AD.⁵⁵

Experimental studies also support an interaction between HTN and Aβ. In mouse models of AD, Aβ attenuates functional hyperemia and endothelium-dependent vasodilatation through mechanisms involving Nox2-derived ROS.^56–58 However, unlike Ang II, the vascular effects of Aβ require the scavenger receptor and Aβ receptor CD36.⁵⁹ It is conceivable that HTN and Aβ have an additive or synergistic pathogenic effect on cerebrovascular function. Consistent with this hypothesis, brain deposition of Aβ is increased in hypertensive mice,⁶⁰ an effect attributed to inhibition of the perivascular and transvascular clearance of Aβ secondary to vascular dysfunction and damage (Figure 3). HTN may also facilitate the transfer of Aβ from blood to brain through the receptor for advanced glycation products (RAGE).⁶¹ Cerebral hypoxia-ischemia, which can occur with HTN, can also facilitate β-secretase–mediated cleavage of Aβ from its precursor protein and increases the brain Aβ burden.^62,63

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Figure 3.

Interaction between hypertension (HTN) and Alzheimer disease. HTN increases the deposition of β-amyloid (Aβ) and might aggravate the cerebrovascular dysfunction induced by Aβ. HTN could impair the vascular clearance of Aβ and increase its cleavage from the amyloid precursor protein (APP). Both of these effects would lead to increased Aβ concentration in the brain parenchyma and blood vessels, aggravating the attendant vascular and synaptic dysfunction.

These observations, collectively, suggest that HTN may promote the development of AD through several mechanisms (Figure 3). First, HTN could impair the vascular clearance of the peptide, enhancing Aβ accumulation in brain and vessels. Second, HTN could increase the cleavage of Aβ from the amyloid precursor protein. Both of these effects would lead to increased Aβ concentration in the brain parenchyma and blood vessels, aggravating the attendant vascular and synaptic dysfunction. Speculations aside, our understanding of human HTN and AD is far from complete and, consequently, the relationship between these 2 conditions is even less well understood. Nevertheless, because the pathological processes underlying AD starts decades before their clinical manifestation,⁶⁴ HTN is likely to exert its effects in the presymptomatic phase of the disease, stressing the need for early diagnosis and blood pressure lowering.

Treatment of HTN and Prevention of Stroke vand Dementia

The National High Blood Pressure Education Program of the National Heart, Lung, and Blood Institute, introduced >40 years ago, has led to remarkable advances in the public awareness and treatment of HTN. This highly successful program is credited with a 70% to 80% reduction in the morbidity attributable to HTN, mainly heart attack and stroke.¹ The effect of HTN control on the incidence of stroke is indeed substantial, and for each 10-mm Hg decrease in systolic blood pressure, there has been a one-third decrease in stroke risk.²

The effects of HTN treatment on VCI have been more difficult to assess,⁶⁵ and there is still a debate as to whether HTN control leads to a better cognitive outcome,^10,65 except for the prevention of poststroke dementia.³ Some studies have shown a cognitive benefit from blood pressure lowering especially in the younger of the old, for example, Perindopril pROtection aGainst REcurrent Stroke (PROGRESS), Hypertension in the Very Elderly (HYVET), Systolic Hypertension in the Elderly (SHEP), Systolic Hypertension in Europe (SYST-EUR), whereas other studies have not, for example, Study on Cognition and Prognosis in the Elderly (SCOPE), Action in Diabetes and Vascular Disease (ADVANCE), and Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS).^10,65 No specific class of antihypertensive agents has been consistently found to be more effective.³Limitations of all these studies have been short follow-up, low rates of incident dementia, lack of accounting for cotreatments, and heterogeneity of the cognitive assessment, among others.^3,65 Despite the controversy, a recent American Heart Association statement strongly recommends blood pressure lowering in patients who have suffered a stroke (Class I, level of evidence level B), and encourages treatment in the younger of the elderly (Class IIa, level of evidence B).³ The degree of blood pressure lowering remains uncertain, but there is evidence that more aggressive lowering may lead to a greater improvement in cerebral perfusion.¹⁷The blood pressure threshold for starting treatment remains to be defined. Data from the Honolulu Heart Program/Honolulu Asian Aging Study suggest that 17% of late-life dementia cases are attributable to midlife systolic pressure levels between 120 and 140 mm Hg.⁶⁶ Similarly, a progressive cognitive decline has been reported for blood pressures between 120 and 140 mm Hg,⁶⁷ arguing for starting treatment at prehypertensive blood pressure levels.

Treatments targeting oxidative stress have long been considered to treat HTN and related complications,⁶⁸ but it has been difficult to develop agents that cross the BBB and effectively reduce oxidative stress in brain.⁶⁹ Similarly, epidemiological studies have not shown a beneficial impact of dietary antioxidants on late-life dementia.⁷⁰ NADPH oxidase inhibitors would be valuable, and there is great interest in developing agents that could be used for cardiovascular and brain diseases.⁶⁹ On the other hand, the link between HTN and AD provides clues to potential therapeutic interventions that could benefit both diseases. Calcium-channel antagonists and inhibitors of the renin–angiotensin system increase Aβ removal from the brain and protect against cognitive dysfunction in mouse models.^71,72 The renin–angiotensin system has been of particular interest in light of the observation that angiotensin-converting enzyme activity is increased in patients with AD, and that this enzyme may degrade Aβ, but there are many unresolved issues.⁷² Nevertheless, these preclinical observations raise the possibility of using specific blood pressure–lowering agents in patients with HTN at risk for AD. Furthermore, dietary interventions and exercise have been shown to be promising, and would also be valuable as a primary or adjuvant therapeutic approach.⁷³

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Conclusions

The evidence reviewed in this article indicates that HTN, despite resounding successes in controlling its impact on morbidity and mortality, remains one of most pervasive and devastating diseases with broad consequences for worldwide health. HTN has profound effects on the brain and contributes in a substantive manner to stroke and dementia, highly prevalent diseases projected to have an even greater public heath impact in decades to come because of population aging. Large and small cerebral vessels are key targets of HTN, resulting in pathological alteration of the vascular wall, impairment of vital hemodynamic responses regulating cerebral perfusion, and disruption of BBB permeability leading to major alterations in the brain microenvironment. Although oxidative stress and inflammation are important factors in the pathogenesis of these events, the cellular and molecular bases of the susceptibility of the white matter to HTN and other cerebrovascular risk factors have not been fully elucidated and represent a fruitful area of future research. The vascular changes induced by HTN not only increase the susceptibility of the brain to ischemic-hypoxic damage in vulnerable white matter regions but also promote the expression of AD neuropathology. The realization that HTN has an impact on AD represents a major departure from traditional views on the pathogenesis of AD, a disease in which vascular factors were thought not to play a role.¹⁶ However, our understanding of the interaction of HTN with AD is rudimentary at best, and much needs to be learned on the vascular biology of their respective effects on the cerebral vasculature and resulting cognitive impact. Although current approaches to treat HTN have dramatically reduced stroke incidence and mortality, the role of blood pressure control in the prevention of late-life dementia has been more difficult to assess. Questions remain on the blood pressure threshold for therapy initiation, length of treatment, and the blood pressure reduction needed to maximize benefits and reduce risks. Whatever the impact on cognition, however, the great benefits for general health afforded by blood pressure control justify early and aggressive intervention. Nonpharmacological strategies based on diet and exercise may be particularly valuable in younger patients facing treatment for a lifetime.

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Sources of Funding

The work was supported by National Institutes of Health grant HL96571 and Alzheimer’s Association grant ZEN-11-202707.

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Disclosures

None.

• Received July 17, 2013.
• Revision received July 22, 2013.
• Accepted August 2, 2013.

• © 2013 American Heart Association, Inc.

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