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, SpS(K), SpKJ : Guru Besar Emeritus Ilmu Penyakit Saraf FK UNAIR Surabaya : Kawin dengan 4 anak
Riwayat profesi 1961 : Dokter di FK UNAIR Surabaya 1966! : Ahli Ilmu Penyakit Saraf dan Kesehatan Jiwa FK UNAIR Surabaya 1982 : Clinical Neurophysiologist, Department of Clinical Neurophysiology, Institute of Neurology, St.Radboud University Hospital, Nijmegen, The Netherlands 1982 : Neuromorphologist, Neuromorphological Laboratory, St.Radboud University Hospital, Nijmegen,The Netherlands 1983 : Acupuncturist, The Dutch Physician's Association of Acupuncture, Santpoort, The Netherlands 1991 : Ph.D. in Neurology, Catholic University of Nijmegen, The Netherlands 1994 : Guru Besar Ilmu Penyakit Saraf FK UNAIR Surabaya
DJOENAIDI WIDJAJA
DEPARTMENT OF NEUROLOGY, AIRLANGGA UNIVERSITY, FACULTY OF MEDICINE, DR SOETOMO HOSPITAL
SURABAYA
INTRODUCTION
-! Stroke is a leading cause of death in the US, with >140, 000 deaths per year. -! The lifetime risk of stroke is estimated to be 1 in 5 for middle-aged women & 1 in 6 for men (Framingham Study). - Ischemic stroke 85%, hemorrhagic stroke 15% of all strokes. - The key strategies for the treatment of acute ischemic stroke are: 1)Reperfusion 2)Antithrombotic therapy 3) Neuroprotection 4)Supportive care (Kasner AAN 2012).
C- (Cerebral Perfusion Pressure) (control ICP if elevated) Class II D- DVT prevention with compression devices-Class I, until bleeding
stops, then consider SQ UFH or LMWH-Class II
E- Early mobilization Class I F- Fever - work & aggressive treatment to normothermia-Class I G- Glucose > 140 185mg/dL, use insulin PRN;
hypoglycemia is harmful & should be rapidly corrected, Class I
! Maintained pulse oximetry > 92-95% if hypoxemia documented by finger oximetry or bld gas (Freeman AAN 2012). ! Hyperthermia > 37.5 C ! antipyretic/cooling blankets; identify source. Therapeutic hypothermia must undergo more investigation (Kasner AAN 2012). ! Hyperglycemia > 140-180 mg% ! SC sliding scale insulin.
CAUTION: Intensive Insulin Trial improved glucose control in the 1st 24 hrs of stroke but was associated with larger infarct growths. Intensive insulin not recommended in AIS. (INSULIN-INFARCT TRIAL 2012)
ANTIHYPERTENSIVE THERAPY(1)
! Lower BP < 185/110 mm Hg during rt-PA thrombolysis, acute myocardial ischemia, aortic dissection, acute renal failure, early hemorrhagic transformation / hypertensive encephalopathy. Candidates for thrombolysis should be treated only with modest measures (e.g., topical nitropaste or IV low-dose labetalol or nicardipine) to maintain BP < 185/110 mm Hg. ! The optimal BP management for NON-rt-PA AIS is not known (Khatri AAN 2012). ! Do not lower BP in non-rtPA within the 1st week of AIS (Jeffrey ISC 2011; SCAST TRIAL Lancet 2011).
A multihit hypothesis for development of brain ischemia after ICH (Prabhkaran 2012)
Prabhakaran S , Naidech A M Stroke 2012;43:2258-2263
In ICH remote ischemic lesions are found in 25% of patients. Be careful not to lower BP aggressively in ICH. (Wait INTERACT II TRIAL)
ANTI-THROMBOTIC THERAPY
- ASPIRIN (80 (160) to 325 mg/day) administered within 48 hrs of AIS is recommended as initial therapy for AIS, reduce the risk of recurrent stroke during the 1st 2 wks & possibly, improve outcome at 6 mos, one recurrent stroke will be prevented for every 100 patients treated with ASA acutely (IST-3 1997 & CAST 1997). Patients intolerable to ASA, give clopidogrel 375 loading dose, although unproven alternatives (Saver JL AAN 2009). Clopidogrel + ASA is not recommended (New, Class III level C, AHA 2007). - CILOSTAZOL: a selective antagonist of phosphodiesterase 3, inhibits platelet aggregation; is more effective than ASA for sec. prevention of stroke (Alberts 2011, Shinohara 2010) . Patients treated with ASA (1x 300 mg) + cilostazol (2 x 100 mg) during the acute phase of non-cardioembolic stroke had less neurological deterioration & more favorable functional status than with ASA alone (Nakamura 2012) (Cilostazol or ASA + cilostasol: FDA not approved). - HEPARIN, LMWH. Acute full-dose anticoagulation (heparin, LMWH) not recommended offers no overall benefit to AIS patients. The small benefit provided by anticoagulation is cancelled by a comparable risk of hemorrhagic transformation of the acute infarction.
Inhibitor of P2Y12
PAR-1 Integrilin
(PAR-1=Protease Activated Receptor)
("II#3 inhibitor)
2 1 3 membrane modulator
- Magnesium inhibit presynaptic release of excitatory neurotransmitters, noncompetitively block NMDA receptor, presynaptically potentiate adenosine, block Ca channels, suppress cortical spreading depression & anoxic depolarizations, relax vascular smooth muscle ! vasodilation of large & small vascular beds & increased CBF, antagonize endothelin-1 & other vasoconstrictors. - FAST-MAG (Field Administration of Stroke Therapy- Magnesium) phase 3 trial. Start date 1 Jan. 2005, completion 1 June 2013 (Jeffrey 2005). - MgSO4 4 g over 15 minutes & then 16 g over the next 24 hrs, is useful as neuroprotective agent in AIS <12 hrs & lacunar stroke ( Afshari 2012). -!Larger MgSO4 trial showed no benefit (Muir 1995, Muir 1998, Lampi 2001; Muir 2004). Serious adverse events, eg bradycardia & hypotension, at serum Mg concentrations > 2 mmol/L (van Norden 2005). - NEUROAID (Danqi Pianta Jiaonang) (neuroproliferative, neuroprotective, neuroplasticity) 3 x 4 caps for 3 mo (S pore July 2006)
MAGNESIUM SULFATE
NMDA-R blocker
MgSO4
(peroxynitrite)
K+
Extracellular solution
Mg2+ K+ K+ K+
Mg2+ K+
-80 mV -30 mV
K+
Intracellular Solution
Stage
Typical Settings
Prehospital, Hyperacute emergency (02 hrs) department Primary stroke center, emergency department, intensive care unit Comprehensi ve stroke center Stroke unit
Rapid CT
Reperfuse rapidly
IV thrombolysis (rt-PA)
Endovascular recanalization (mechanical thrombectomy) Reperfusion injury cocktail Antithrombotics Secondary prevention Nerve growth factors and choline precursors (citicoline 2012 ?) Stem cells Transcranial magnetic stimulation. Neural prosthetics (brain-machine interface)
Subacute
Rehabilitation unit
3-4.5 HOURS AFTER AIS ONSET: (IV rt-PA) ! ! 3 hrs of symptom onset (FDA approved 1996) ! ! 4.5 hrs symptom onset: (EFNS; ECASS 1, ECASS 2,
ATLANTIS A, ATLANTIS B) (AHA approved 2012; FDA not approved 2012). Some patients might benefit up to 6 hr after stroke (Wardlaw Lancet 2012). Selection of patients for rt-PA is now based on physiological imaging (PWI-DWI mismatch) rather than time ! (Lawrence 2012) BRIDGING THERAPY (COMBINED IV/ IA THROMBOLYSIS) (Mazighi 2012) (FDA not yet approved) 1. Rescue bridging therapy (failure of IV rt-PA) 2. Direct bridging therapy (independently of clinical status after IV rt-PA). IV rtPA (0.6-09 mg/kg/bw) + IA rtPA (0.3 mg/kg/bw) or or IA urokinase (< 7.500.000U - < 100.000 U). CLEAR-ER STROKE TRIAL 2012 : IV rt-PA (0.6 mg/kg total) + IV eptifibatide (integrilin) (bolus 135 mcg/kg & 2 hr infusion at 0.75
mcg/kg/min)
! Within 6 hrs of symptom onset (Nguyen AAN 2012) IA THROMBOLYTIC (FDA not yet approved) - PROACT II TRIAL (Prolyse in Acute Cerebral Thromboembolism) - MELT TRIAL (Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial ) - AUSTRALIAN UROKINASE STROKE TRIAL ! Within 8 hrs of symptom onset (Nguyen AAN 2012) MECHANICAL THROMBECTOMY (FDA not yet approved) - MERCI (Mechanical Embolus Removal in Cerebral Ischemia) retriever. FDA 2004) - Penumbra System (Alameda, CA), FDA Jan. 2008. - Solitaire device retrievable stent-on-a-wire (EV3) may be left in the vessel as a conventional stent. FDA 2010. - Trevo Device approved in Europe & Canada Feb.2010, FDA March 2012
NINDS IV rt-PA in acute ischemic stroke (Nguyen AAN 2012) Bridging therapy (combined IV and IA thrombolysis (Mazighi 2012)
Modality NIHSS Recanaliz base ation rate line 14 30-50% SICH risk % 6.4 mRS!2 Mortalit at 1 or 3 y 1-3 mo mos (%) (%) Advanta ges Disadvantages
69.6
7.9 8.6
The efficacy of IV rt-PA is limited: The greatest benefit is moderate strokes (NIHSS < 20), age < 75 yrs, & earlier therapy. 50% remain disabled Recanalization: 30 -50%. Reocclusion : 20%.
PROACT II IV heparin, 6 hrs MCA PROACT II IA prourokinase, 9 mg over 2 hrs MELT IA UK, 6 hrs MCA, n=57 MELT control n=57 Post. circ. stroke,IA UK, n=8
17 17
14
74% (mechanical disruption in 39/57 patients n/a Available in 7 pts Complete recanalization in 2 pts; partial recanalization in 5 n/a
49
High
14 23
2 n/a
39 50
n/a High
18
n/a
25
50(1 mo)
n/a
n/a
20 20 19
30 28,3
41 45 42 60 (30 d) 45
SWIFT
200
113, stopped
8-30
2010-2011
1. Thrombus disruption. 2. Stents :immediate flow restoration with selfexpandable stents (SES). 3. Mechanical thrombectomy.
Ad 1. Thrombus Disruption
a. Probing the thrombus with the microwire and/or advancing the microcatheter into or beyond the thrombus. b. Percutaneous balloon angioplasty at increasing the thrombus surface and achieving recanalization. c. Low-pressure percutaneous balloon angioplasty. Risk of distal emboli d. Intraluminal clot disruption devices apply ultrasound. (EKOS, Bothell, WA) uses a 2.5-Fr microcatheter (MicroLysUS infusion catheter) with a 2.1-MHz piezoelectric sonography element at its distal tip. e. Laser-based technology is used by the EPAR system (EPAR; Endovasix, Belmont, CA), which aims to emulsify the clot by the application of microcavitation bubbles at the tip of the microcatheter.
Ad 2. Stenting
ADVANTAGE: - Stenting promises immediate flow restoration without thrombolytic drugs; without repetitive passing & retrieval attempts. DISADVANTAGES: % Compressed thrombus causes permanent side branch & perforator occlusion. % Short-term complications eg in-stent thrombosis & reocclusion of the vessel, requiring antiplatelet medication ! ! risk of sICH in the stroke population. % Restenosis 32% reported for bare metal stents at intracranial stenosis in a 9-month follow-up period .
Ad 3. Mechanical Thrombectomy
(Gralla 2012)
3 major groups according to where they apply force on the thrombus. ! 1. Proximal devices apply force to proximal base of the thrombus; e.g. Penumbra system ! 2. Distal devices approach the thrombus proximally, past the thrombus & applied force to the distal base of the thrombus; The Merci devices FDA approved 2004. Vasospasm & vessel wall damage frequently described in distal devices. During retrieval, the loose engagement of the clot is prone to cause thromboembolic events. Therefore, proximal balloon occlusion & aspiration from the guide catheter (flow reversal) during retrieval are recommended. ! 3. Stent retriever. Stent-like devices that are placed across the occlusion side, deployed within the thrombus, & then retrieved; eg TREVO, Concentric Medical, Mountain View, CA; & the Solitaire FR (ev3, Irvine, CA).
Two versions of the Merci retriever consisting of a flexible nitinol wire that can be threatened in the thrombus (A); additional microfilaments aim to ensnare the thrombus (B).
microcatheter dinaik turunkan utk melepas thrombus microcatheter dihubungkan dng pompa aspirasi
PENUMBRA SYSTEM DEVICE FOR TREATMENT OF AIS (Nogueira AAN 2009) 4A. Complete occlusion of the proximal M1 segment L.MCA 4B. Posttreatment : near complete reperfusion of the L.MCA. 4C. 3 different sizes of penumbra device: Aspirate thrombus by connecting the microcatheter (white arrow) to an aspiration pump. The separator (black arrow) is advanced in & out of the microcatheter to unclog any obstructive thrombus.
SOLITAIRE FR DEVICE
(FDA approved 2010)
STENT
GUIDEWIRE TUBE
(A) Acute MCA occlusion. (B) Immediate flow restoration after Stent Retriever placement. (C) Complete recanalization after retrieval; (D) The thrombus is encaged in the SOLITAIRE FR.
DIFFERENT KINDS OF INTRA-ARTERIAL AND/OR IV CHEMICAL THROMBOLYSIS (Nguyen AAN 2012) - First generation: streptokinase & urokinase is not fibrin specific, thus systemic hypofibrinogenemia may occur. The rate of ICH is increased with streptokinase, hence withdrawn from the market. - Second generation agents: alteplase & pro-urokinase are fibrin specific & not antigenic. Alteplase or rtPA has neurotoxic properties including activation of metalloproteinases! increased BBB permeability ! ICH & edema. Pro-urokinase precursor of urokinase has a half life of 7 minutes. - Third generation: Reteplase & tenecteplase, are modified forms of alteplase, have greater thrombolytic potency & and longer half-lives compared to alteplase. - New generation : Desmoteplase in vampire saliva desmodus rotundus. More selective for fibrin-bound plasminogen than any other known plasminogen activator.
CT-BASED SELECTION - Classical non-contrast CT (NCCT) - Alberta Stroke Program Early CT Score (ASPECTS) - CT Angiography Source Imaging (CTA-SI) - CT Perfusion (CT-P)
I. At level of thalamus & basal ganglia (7 areas) II. Just rostral to basal ganglia (3 areas)
I
I
ANTERIOR CIRCULATION
II
POSTERIOR CIRCULATION
ASPECTS STUDY FORM (Barber 2000) C=caudate; L=lentiform; IC=internal capsule; I=insular ribbon; M1=ant. MCA cortex; M2=MCA cortex lateral to insular ribbon; M3=posterior MCA cortex; M4, M5, and M6 are anterior, lateral, & posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia.
M4 M1 M5 M2
I
I I
I
M2
C
L
! NCCT ASPECTS may not fully reflect the core ischemia. ! Newer multislice CT scanners better than NCCT ASPECTS: % CTA-SI (blood-pool analysis) % CT perfusion studies ! accurately identify core & penumbra compare with conventional NCCT (Demchuk 2005).
! CTA-SI (SOURCE IMAGE): 1.25-MM SLICE THICKNESS AT 0.625-MM INTERVALS (CTA : 2.5-MM SLICE THICKNESS AT 2.5 MM INTERVAL) (Coutts 2004).
NCCT
NCCT
CTA-SI
CTA-SI
NCCT
(follow-up)
NCCT
(follow-up)
CT PERFUSION
! CBV = the volume of blood per unit of brain tissue ! CBF= the volume of blood flow per unit of brain tissue per minute ! MTT = Mean transit time : the time difference between the arterial inflow and venous outflow ! TTP = Time to peak : The time from the beginning of contrast material injection to the maximum concentration of contrast material within a region of interest (ROI).
CT PERFUSION
Infarct Penumbra
NCCT
Hypoattenuation
CTP
CTP
CBV
CBF
Summary map
Early CT changes
Acute stroke (2.5 hrs evolution)
Penumbra
(bad prognosis)
Core
NCCT
CTP
CTP
MTT R. fr-temp
CBV R.fr.temp
B SUMMARY MAP
Early CT changes
Acute stroke (6 hrs evolution) & 46 yrs , L.hemiplegia A.NCCT: Dot sign in R.MCA, loss of R.sided gray-white matter differentiation, obscuration basal ganglia. E. CTP: Summary map: small core+ large Penumbra
PCT
CBF R.fr-temp
(good prognosis)
MRI
PWI CT PERFUSION
core
DWI
CBV
CBF
Penumbra Penumbra in (A) MRI (mismatch in PWI/DWI) and (B) CT perfusion (difference in decreased CBF in core and penumbra and increased CBV in penumbra) (Alexandrov 2009)
CTP IS MORE EASILY QUANTIFIED THAN MRP (MRI PERFUSION) (AHA 2009)
A.! L. MCA infarct in diffusion MRI B.! More widespread reduction in CT-CBF CT-perfusion (peri-ventridue to periventricular cular leuco-airaiosis) leuco-araiosis C. Time-to-peak (TTP) > 4 seconds (white outline) D. True-positive low CBF (green)
Time-to-peak in CTP (white outline)
CT-SCAN
- Widespread available - No contraindication - Highly sensitive for exclusion or confirmation of hemorrhage - CBV-perfusion & CTA-SI correlate with DWI - NCCT; CTA-SI; CT-perfusion as sensitive than MRI - Mismatch CBF-CBV = penumbra - Higher radiation dose
CT- PERFUSION MORE EASILY QUANTIFIED THAN MRI PERFUSION (AHA 2009).
A Pragmatic Approach Using FLAIR to estimate AIS of Unknown Onset. A SIR < 1.15 on FLAIR yields an estimate of stroke onset within 4.5 hrs. SIR = ratio of the average ipsilat. voxel intensity to that of the contralat. Hemisphere. Song S S et al. Stroke 2012;43:2331-2335
(WITH CONTRAST) A fast 212-minute ASL perfusion scan may be adequate for screening patients with acute stroke with contraindications to gadolinium-based contrast agents (Bokkers; Stroke. 2012;43:1290-1294.) .
(WITHOUT CONTRAST)
- FLAIR= fluid-attenuated inversion recovery; - DWI= diffusion weighted imaging; - DSC= dynamic susceptibility contrast; - ASL=arterial spin labeling.
ARTERIAL SPIN LABELING PERFUSION MRI, WITH CONTRAINDICATION TO CONTRAST AGENTS (Bokkers; Stroke 2012;43:1290-1294)
Unfractionated heparin diberikan berupa flushing pada awal DSA dilanjutkan dengan continuous (heparinized saline). Dosis heparin 3000-5000 U (40-60 U/kg). Heparin + integrilin diberikan dalam keadaan sangat khusus (acute stroke iskemik ?) (Tempo 30/9/2011). Heparin dapat diberikan bersamaan dng integrilin (Wikipedia) EPTIFIBATIDE (Integrilin)
Is an antiplatelet drug of the glycoprotein IIb/IIIa inhibitor ("IIb#3 inhibitor) , derived from a protein found in the venom of the southeastern pygmy rattlesnake. The drug is usually applied together with ASA or clopidogrel or LMWH or heparin. Side effect severe bleeding (4.4% PURSUIT study) (Wikipedia). To prevent this CLEAR-ER (NIH/NINDS phase 3 2012) advised eptifibatide = integrilin (bolus 135 mcg/kg & 2 hr infusion at 0.75 mcg/kg/min) + medium dose rt-PA (0.6 mg/kg total) for AIS.
MRI: old L. parieto occ infarct 4 th yl + recent lacunar infarct pd ke 2 hemisfer (hipoperfusi ke 2 hemisfer) ! DSA + heparin 5000 IU ! 6 jam & 3 bln post BS peningkatan perfusi pd ke 2 hemisfer (lihat gmbr)! klinis perbaikan + kognisi membaik (KIRIMAN SpS Senior Jkta.)
ACUTE STROKE
-! " 85 tahun coma + hemipar. D., kesadaran ", 2 jam poststroke di BS (integrilin?) ! hasil memuaskan, coma hilang, paresis hilang.
CHRONIC STROKE
- ' 52 th. dari Freeport. 17 hari poststroke, hemiparesis dextra ringan +afasia motorik, DM+; hipertensi ringan terkontrol. Dilakukan BS (DSA + heparin 5000 IU). Post BS no improvement. -!dr. M (SpM) ' 59 thn (suami SpS senior). Paresis N III kiri mendadak, + vertigo. DM sejak 1996; diberi Nicholin 2 X 250 mg + Alinamin F + Lapibal (methycobal dari Lapi) ! agak baik sedikit. Seminggu setelah attack di BS ( DSA + heparin 5000 IU ) ! perbaikan sedikit, sebelumnya tak dapat setir mobil, setelah BS dapat stir mobil. MRI: penyempitan segmen M3 kanan + segmen T1 PCA kiri. Flair: stenosis art. basilaris; trombosis sinus sigmoid & sinus tranversus kanan & kiri; stenosis v. Galen.
Heparin potentiate thrombin inhibition (Goodman & Gilman 2011) Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin.
Abxicimab
Integrilin
Tirofiban
ASA
Fibrinolysis
Fibrinolysis. Endothelial cells secrete tissue plasminogen activator (t-PA) at sites of injury. t-PA binds to fibrin and converts plasminogen to plasmin, which digests fibrin.
Integrilin IV (135 g/kg+0.75 g 2hr inf)+rtPA IV (06 mg/kg) (AIS $ 3 hr CLEAR-ER 2012) DSA: Integrilin IA cath (10 mg) + heparin IA cath (5000IU) (< 6 hr AIS) (dr.TAP, dr. HP) DSA: Heparin IA cath 5000 IU (2wk-3 mo AIS) (dr. TAP , dr HP)
rt-PA
IV heparin 6 hrs MCA (PROACT II) : NIHSS 17; recanalization:18%; sICH: 2%; mRS ( 2 at 3 mo: 25%; ) at 3 mo: 27% (Nguyen AAN 2012).
BIAYA NEUROINTERVENSI
Cerebral DSA ; 6-8 jt / 9 - 12 jt Spinal DSA ; 8-10 jt / 12 - 15 jt IA thrombolysis ; 15-22 jt / 18 - 25 jt Thrombectomy ; 30 - 40 jt / 45-60 jt Carotid stent ; 60 - 70 jt / 75-90 jt Vertebral stent ; 50-65 jt / 65 - 80 jt Intracranial stent ; 70-80 jt / 85 - 100 jt Balon angioplasty ; 30 - 40 jt / 45 - 60 jt Embolisasi AVM ; 60 - 80 jt / 75 - 85 jt Aneurysma coiling ( termasuk harga 3 coil ) : 70-90 jt / 100 - 140 jt Dr. Fritz Sumantri Usman SpS Sr FINS (2012)