Perfusi otak bergantung pada metabolisme otak secara local dan secara mandiri memiliki

sistem tekanan darah tersendiri kecuali pada tekanan darah yang sangat tinggi atau sangat
rendah, hal ini disebut autoregulasi otak.
Proses yang mengikuti stroke akut iskemi yaitu hilangnya autoregulasi. Disautoregulasi
tersebut biasanya berakhir pada beberapa minggu. Dalam pandangan di atas, hal tersebut
umumnya meningkatkan tekanan darah yang akan mengkompensasi perfusi, sehingga secara
potensial menghasilkan penurunan tekanan darah yang mengurangi perfusi dan dengan
demikian dapat memperburuk keadaan. In view of the above, it is commonly held that
raising blood pressure will improve perfusion, and therefore potentially improve
outcome, and lowering blood pressure will reduce it, thereby possibly worsening
outcome. Sayangnya, pandangan ini sederhana dan tidak mempertimbangkan banyak faktor,
termasuk respon patofisiologis untuk meningkatkan tekanan darah, perubahan besar dan laju
tekanan darah, arus darah dan agen darah yang terlibat. Faktor komorbid yang mengubah
fungsi hemodinamik juga penting sebagaimana termasuk di antaranya yaitu cardiac output,
fibrilasi atrial, diabetes mellitus, dan pireksia. Terdapat pula bukti bahwa memungkinkan
untuk menurunkan tekanan darah tanpa membahayakan arus darah otak pada stroke akut
iskemi maupun hemoragik.
Otak memediasi dan mengintegrasikan semua aktivitas kognitif, pengalaman terkait emosi,
hingga perilaku. Stroke adalah sindrom klinis yang dikarakteristikkan sebagai kehilangan
akut dari fungsi serebri fokal dengan gejala yang berakhir lebih dari 24 jam.
Stroke akut memiliki pengaruh yang dalam pada perilaku penderita. Pada topik ini membahas
lesi iskemi akut, karena hal-hal tersebut lebih terkait pada perilaku stereotip dan memenuhi
hubungan anatomiklinis yang lebih tepat. Pada bahasan ini yang dimaksud fase akut
merupakan 2 minggu awal dari onset. Selama interval, area inti dari infark dan zona
hipoperfusi mungkin merupakan faktor yang lebih terkait dengan tanda-tanda perilaku. Pada
fase lebih lanjut, selama proses penyembuhan, jaringan (gliosis) dan perubahan fungsional
(plastisitas) lebih lanjut berkontribusi terhadap gejala perilaku. Dalam fase keduanya,
variabel lain dibandingkan letak lesi mungkin berperan (kepribadian premorbid, kondisi
kejiwaan yang sudah ada dan penyakit neurologis, faktor epidemiologis dan genetik, reaksi
psikologis terhadap kerusakan), menghasilkan keberagaman individu yang besar.
In acute stroke, cognitive syndromes such as aphasia or neglect are easily recognized and
classified, but emotional, mood, and behavioral changes (psychosis, depressive reactions,
anxiety, mania, apathy) are less well defined in their phenomenology, pathogenesis, and

linkage to regional brain dysfunction. On many occasions they are also undiagnosed. In this
period, behavioral changes are often transitory and fluctuating.
Nevertheless, acute stroke undoubtedly remains a privileged disease for behavioral studies. It
has a high incidence, and recent advances in high-resolution magnetic resonance imaging
(MRI) techniques and functional neuroimaging allow precise lesion localization1 as well as
on-line visualization of cerebral areas and networks activity.
Mekanisme cedera otak pada iskemi
A thorough understanding of the mechanism of brain injury is central to any neuroprotective
strategy. Our level of understanding has greatly improved since the first observations of
Astrup and colleagues, who demonstrated that reductions in cerebral blood flow led first to
loss of electrical activity and then to failure of intracellular energy mechanisms leading to
membrane disruption and ultimately cell death. The important interaction between the extent
of ischemia and its duration has provided the premise for much of the neuroprotective clinical
work that has been undertaken. The idea that there is penumbral tissue which is destined for
infarction without any intervention and yet which may be salvageable during the early hours
of the process supported a wealth of laboratory research. The processes were mostly studied
in small animal species.

The problems with time window have also prompted exploration of other processes involved
in ischemic injury. While cell necrosis has been the primary concern after an ischemic insult,
the initiation of apoptosis, programmed cell death, has also attracted enthusiastic study,
though so far no strategy for limiting this process has reached large clinical trials. Either
ischaemia per se or free radical injury seems capable of prompting cells to enter a selfdestructive process which causes penumbral cells to succumb unnecessarily to an ischemic
insult. These cells can be recognized by histologic features that are distinct from necrosis.
Apoptosis may be reduced by caffeine and calcium channel blockers; conversely,
theophylline and nitric oxide both seem capable of increasing apoptosis.
Although infarct damage appears to reach a peak within 13 days of the ischemic insult in
rats, there is evidence that some continuing damage may occur for several weeks. Partly, this
may be due to apoptosis but delayed neuronal degeneration may be seen in selected cell
types, perhaps due to loss of growth factors or neuronal activity. The other process which
occurs relatively later in the timescale of injury is the inflammatory response. Leukocytes

begin to accumulate in the infarct zone within 30 min of ischemia, peaking between 24 and
48 hours later. While some of the inflammatory response is undoubtedly a mopping-up
exercise to remove dead tissue, the invasion of inflammatory cells at least in the early stages
may further restrict perfusion through the capillary bed and contribute to free radical induced
injury. There is laboratory evidence to suggest that anti-inflammatory approaches may reduce
infarct volume and improve outcome. There is some evidence that broadly acting antiinflammatory drugs such as the calcineurin inhibitor, tacrolimus, may be neuroprotective.
Conversely, clinical trials with both general (corticosteroids) and with specific (enlimomab)
anti-inflammatory agents have been unsuccessful. These trials have their flaws, however,
and it has been argued that clinical use of anti-inflammatory strategies remains inadequately
tested. On the one hand, redundancy and overlap of the effects of individual inflammatory
mediators cast doubt around the chances of successful intervention using agents acting at
single sites; on the other hand, without optimal timing of the intervention, carefully judged
duration of action, and suitable formulations, broad suppression of the inflammatory response
could clearly be deleterious.
Atherosclerosis and its complications are beyond the scope of this review. Briefly,
atherosclerosis is currently viewed as an inflammatory reaction in response to injury. The
multifocal nature of atherosclerosis across several vascular beds was underscored by the trials
of antiplatelet agents in secondary prevention. These studies showed that the onset of
symptomatic illness, irrespective of the involved territory, increases the risk of vascular
death, myocardial infarction, or stroke.
Atherosclerotic plaque disruption exposes the flowing blood to the thrombogenic stimulus of
subendothelial matrix (e.g., collagen, fibronectin, laminin, and von Willebrand factor) and
plaque contents (e.g., tissue factor, lipid core). Thrombosis arises from the parallel activation
of platelets and coagulation, culminating to thrombin generation and formation of a plateletfibrin lattice. Over the ensuing hours, the platelet-fibrin lattice becomes more resistant to
plasmin degradation, in part owing to the phenomena of fibrin cross-linking and clot
retraction.
Trombus adalah pembentukan bekuan platelet atau fibrin di dalam darah yang dapat
menyumbat pembuluh vena atau arteri dan menyebabkan iskemia dan nekrosis jaringan lokal.
Trombus ini bisa terlepas dari dinding pembuluh darah dan disebut tromboemboli. Trombosis
dan tromboemboli memegang peranan penting dalam patogenesis stroke iskemik. Lokasi
trombosis sangat menentukan jenis gangguan yang ditimbulkannya, misalnya trombosis arteri

dapat mengakibatkan infark jantung, stroke, maupun claudicatio intermitten, sedangkan

trombosis vena dapat menyebabkan emboli paru. Trombosis merupakan hasil perubahan dari
satu atau lebih komponen utama hemostasis yang meliputi faktor koagulasi, protein plasma,
aliran darah, permukaan vaskuler, dan konstituen seluler, terutama platelet dan sel endotel.
Trombosis arteri merupakan komplikasi dari aterosklerosis yang terjadi karena adanya plak
aterosklerosis yang pecah.
Kematian sel neuron pada kejadian iskemik
Pada daerah dimana pasokan oksigen berkurang , konsumsi ATP yang berlanjut meski
kekurangan sintesisnya, menyebebkan jumlah ATP total jatuh dan terjadi asidosis laktat
dengan hilangnya homeostasis ion pada neuron secara bersamaan.

Hal ini mengawali

terjadinya proses iskemik yang melibatkan mekanisme multisel.

Iskemi otak berat menyebabkan hilangnya cadangan energi yang kemudian menyebabkan
ketidak seimbangan ion dan pelepasan neurotransmitter serta inhibisi reuptake. Khususnya
bagi glutamat (neurotransmitter utama eksitotoksik).
Glutamate berikatan dengan ionotropic N-Methyl-D-aspartate (NMDA) dan -amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs), memicu influks
kalsium dalam jumlah besar. Kalsium yang berlebih memicu fosfolipase dan protease yang
mendegradasi membrane dan protein esensial. Selain itu, reseptor glutamate memulai influk
Na dan air yang berlebih dengan penelanan sel secara bersamaan, edema dan penyusutan
ruang ekstraselular.
Influk kalsium yang besar-besaran mengaktivasi proses katabolic yang dimediasi
protease, lipase dan nuclease. (Pada percobaan, blokade GluRs mengurangi volume infark
dengan tiga cara: pertama, mengurangi influk Ca dan terkait aktivasi protease, kedua,
melemahkan cortical spreading depressions (CSDs), ketiga memicu neuron dari dubfamili
metabotropik mGluRs terhadap sinyal prosurvival atau prodeath. Konsep eksitotoksisitas
glutamate ini meningkatkan harapan besar bagi terapi stroke yang baru.
Tingkat Ca, Na, dan ADP tinggi dalam sel iskemik memicu produksi oksigen radikal
mitokondrial yang berlebih dengan sumber lain dari produksi radikal bebas misal sintesis
prostaglandin dan degradasi hipoksantin. Reactive oxygen species (ROS) secara langsung
merusak lipid, protein, asam nukleat dan karbohidrat yang pada dasarnya toksik bagi sel

(enzim antioksidan terlalu lambat mengimbangi kerugian produksi ROS). Lebih lanjut, ROS
dan nitrogen reaktif juga berpotensi memodifikasi fungsi endogen, yang mungkin
neuroprotektif. Dengan begini, beberapa kaskade menghasilkan proses campuran yang
kompleks di antaranya penekanan kematian neuronal, nekrosis nekrosis, apoptosis, dan
autofagi.