EPIDEMIOLOGY

There are currently 6.6 million stroke survivors in the United States, and stroke is the leading cause of
adult disability.2 Of those free of the diagnosis of stroke or transient ischemic attack (TIA), however,
almost 20% of individuals older than 45 years reported at least one stroke symptom,3 suggesting
rampant underdiagnosing. Owing in part to the need for expensive posthospitalization rehabilitation
and nursing home care, the annual cost of stroke in the United States is estimated to be $33.6 billion.2

Not all groups have benefitted equally from advances in care and prevention of stroke. African
Americans have stroke rates that are twice those of whites, and the difference is exaggerated at
younger ages.2 In addition, geographic disparity in stroke incidence exists, such that many states in the
southeastern United States have stroke mortality rates 40% higher than the national average.2 Lastly,
case fatality due to hemorrhagic stroke has not declined in the past decade, with 30-day rates remaining
around 40%.

Etiology

Stroke can be either ischemic or hemorrhagic (87% and 13%, respectively, of all strokes in the 2015
American Heart Association [AHA] report).2 Hemorrhagic strokes include subarachnoid hemorrhage
(SAH) and intracerebral hemorrhage (ICH). SAH occurs when blood enters the subarachnoid space
(where cerebrospinal fluid is housed) owing to trauma, rupture of an intracranial aneurysm, or rupture
of an arteriovenous malformation (AVM). By contrast, ICH occurs when a blood vessel ruptures within
the brain parenchyma itself, resulting in the formation of a hematoma. These types of hemorrhages very
often are associated with uncontrolled high blood pressure and sometimes antithrombotic or
thrombolytic therapy. Hemorrhagic stroke, although less common, is significantly more lethal than
ischemic stroke, with 30-day case-fatality rates of 46.5% compared to 9% to 23% in ischemic stroke.4

Ischemic strokes are caused either by local thrombus formation or by embolic phenomena, resulting in
occlusion of a cerebral artery. Atherosclerosis, particularly of the cerebral vasculature, is a causative
factor in most cases of ischemic stroke, although 30% are cryptogenic. Emboli can arise from either

http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&secti...

2 of 26 22/12/2016 10:19 ‫ﻡ‬

intracranial or extracranial arteries (including the aortic arch) or, as is the case in 20% of all ischemic
strokes, the heart. Cardiogenic embolism is presumed to have occurred if the patient has concomitant
atrial fibrillation, valvular heart disease, or any other condition of the heart that can lead to clot
formation.2 Distinguishing between cardiogenic embolism and other causes of ischemic stroke is
important in determining long-term pharmacotherapy in a given patient.

Stroke dapat berupa iskemik atau hemoragik (masing-masing 87% dan 13%, dari semua stroke dalam
laporan American Heart Association [AHA] 2015) .2 Stroke hemoragik termasuk perdarahan subaraknoid
(SAH) dan perdarahan intraserebral (ICH). SAH terjadi ketika darah memasuki ruang subarachnoid
(tempat cairan serebrospinal disimpan) karena trauma, pecahnya aneurisma intrakranial, atau pecahnya
malformasi arteriovenosa (AVM). Sebaliknya, ICH terjadi ketika pembuluh darah pecah di dalam
parenkim otak itu sendiri, menghasilkan pembentukan hematoma. Jenis perdarahan ini sangat sering
dikaitkan dengan tekanan darah tinggi yang tidak terkontrol dan kadang-kadang terapi antitrombotik
atau trombolitik. Stroke hemoragik, walaupun lebih jarang, secara signifikan lebih mematikan daripada
stroke iskemik, dengan tingkat fatalitas kasus 30 hari sebesar 46,5% dibandingkan dengan 9% hingga
23% pada stroke iskemik.

Stroke iskemik disebabkan oleh pembentukan trombus lokal atau oleh fenomena embolik, yang
mengakibatkan penyumbatan arteri serebral. Aterosklerosis, khususnya pembuluh darah serebral,
merupakan faktor penyebab pada sebagian besar kasus stroke iskemik, walaupun 30% bersifat
kriptogenik. Emboli dapat timbul dari arteri intrakranial atau ekstrakranial (termasuk lengkung aorta)
atau, seperti halnya pada 20% dari semua stroke iskemik, jantung. Emboli kardiogenik diduga telah
terjadi jika pasien memiliki fibrilasi atrium yang bersamaan, penyakit jantung valvular, atau kondisi
jantung lainnya yang dapat menyebabkan pembentukan bekuan darah. Membedakan antara emboli
kardiogenik dan penyebab lain dari stroke iskemik penting dalam menentukan jangka panjang. istilah
farmakoterapi pada pasien tertentu.
Ischemic stroke results from an occlusion of a cerebral artery, leading to a reduction in cerebral blood
flow. The pathophysiologic mechanisms of ischemic stroke are given in Fig. 20-1. Normal cerebral blood
flow averages 50 mL/100 g per minute, and this is maintained over a wide range of blood pressures
(mean arterial pressures of 50-150 mm Hg) by a process called cerebral autoregulation. Cerebral blood
vessels dilate and constrict in response to changes in blood pressure, but this process can be impaired
by atherosclerosis, chronic hypertension, and acute injury, such as stroke. Arterial occlusion leads to
severe reductions in cerebral blood flow leading to infarction. Tissue that is ischemic but maintains
membrane integrity is referred to as the ischemic penumbra because it usually surrounds the infarct
core.6 This penumbra is potentially salvageable through therapeutic intervention and is assessed
urgently prior to endovascular intervention with a stent retriever.
Stroke iskemik terjadi akibat oklusi arteri serebri, yang menyebabkan berkurangnya aliran darah otak.
Mekanisme patofisiologis stroke iskemik diberikan pada Gambar. 20-1. Aliran darah otak normal rata-
rata 50 mL / 100 g per menit, dan ini dipertahankan pada berbagai tekanan darah (tekanan arteri rata-
rata 50-150 mm Hg) dengan proses yang disebut autoregulasi otak. Pembuluh darah otak melebar dan
menyempit sebagai respons terhadap perubahan tekanan darah, tetapi proses ini dapat terganggu oleh
aterosklerosis, hipertensi kronis, dan cedera akut, seperti stroke. Oklusi arteri menyebabkan penurunan
parah dalam aliran darah otak yang mengarah ke infark. Jaringan yang iskemik tetapi mempertahankan
integritas membran disebut sebagai isumbemik penumbra karena biasanya mengelilingi inti infark.
Penumbra ini berpotensi diselamatkan melalui intervensi terapeutik dan dinilai segera sebelum
intervensi endovaskular dengan stent retriever.

FIGURE 20-1

Pathophysiology of ischemic stroke. Diagram illustrating the three major mechanisms underlying
ischemic stroke including occlusion of an intracranial vessel by an embolus that arises from a distant site
(eg, cardiogenic embolus), in situ thrombosis of an intracranial vessel, typically affecting the small
penetrating arteries, and hypoperfusion caused by flow-limiting stenosis of a major extracranial artery.
(Reproduced with permission from Chapter 370. Cerebrovascular Diseases. In: Longo DL, Fauci AS,
Kasper DL, et al. Harrison’s Principals and Practice of Internal Medicine, 18th ed. New York: McGraw-Hill,
2012.)

Patofisiologi stroke iskemik. Diagram yang menggambarkan tiga mekanisme utama yang mendasari
stroke iskemik termasuk penyumbatan pembuluh intrakranial oleh embolus yang timbul dari tempat
yang jauh (misalnya, kardiogenik embolus), trombosis in situ pembuluh intrakranial, biasanya
mempengaruhi arteri penetrasi kecil, dan hipoperfusi yang disebabkan oleh stenosis pembatas aliran
dari arteri ekstrakranial utama. (Direproduksi dengan izin dari Bab 370. Penyakit Serebrovaskular.
Dalam: Longo DL, Fauci AS, Kasper DL, dkk. Prinsip dan Praktik Kedokteran Harrison, edisi ke-18. New
York: McGraw-Hill, 2012.)

Reduction in the provision of nutrients to the ischemic cell eventually leads to depletion of the high-
energy phosphates (eg, adenosine triphosphate [ATP]) and accumulation of extracellular potassium,
intracellular sodium, and water, leading to cell swelling and eventual lysis. The increase in intracellular
calcium that follows results in the activation of lipases, proteases, and endonucleases and the release of
free fatty acids from membrane phospholipids. In addition, there is a release of excitatory amino acids,
such as glutamate and aspartate, which perpetuate the neuronal damage and the accumulation of free
fatty acids, including arachidonic acid, and result in the formation of prostaglandins, leukotrienes, and
free radicals. In ischemia, the magnitude of free radical production overwhelms normal scavenging
systems, leaving these reactive molecules to attack cell membranes and contribute to the mounting
intracellular acidosis. All these events occur within 2 to 3 hours of the onset of ischemia and contribute
to the ultimate cell death.6
Later targets for intervention in the pathophysiologic process involved after cerebral ischemia include
inflammation and apoptosis, or programmed cell death, occurring many hours after the acute insult and
can interfere with recovery and repair of brain tissue.6

Pengurangan dalam pemberian nutrisi ke sel iskemik pada akhirnya menyebabkan penipisan fosfat
berenergi tinggi (misalnya, adenosin trifosfat [ATP]) dan akumulasi kalium ekstraseluler, natrium
intraseluler, dan air, yang menyebabkan pembengkakan sel dan akhirnya terjadi lisis. Peningkatan
kalsium intraseluler yang mengikuti hasil dalam aktivasi lipase, protease, dan endonuklease dan
pelepasan asam lemak bebas dari fosfolipid membran. Selain itu, ada rilis asam amino perangsang,
seperti glutamat dan aspartat, yang melanggengkan kerusakan neuron dan akumulasi asam lemak
bebas, termasuk asam arakidonat, dan menghasilkan pembentukan prostaglandin, leukotrien, dan
radikal bebas. Pada iskemia, besarnya produksi radikal bebas melebihi sistem pemulungan normal,
meninggalkan molekul-molekul reaktif ini untuk menyerang membran sel dan berkontribusi pada
asidosis intraseluler yang meningkat. Semua peristiwa ini terjadi dalam 2 hingga 3 jam dari awal iskemia
dan berkontribusi pada kematian sel pamungkas

Target selanjutnya untuk intervensi dalam proses patofisiologis yang terlibat setelah iskemia serebral
termasuk peradangan dan apoptosis, atau kematian sel yang terprogram, terjadi beberapa jam setelah
penghinaan akut dan dapat mengganggu pemulihan dan perbaikan jaringan otak.