CURRICULUM VITAE

Nama : Prof. Djoenaidi Widjaja dr. Ph.D., SpS(K), SpKJ Jabatan : Guru Besar Emeritus Ilmu Penyakit Saraf FK UNAIR Surabaya Status : 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) Neuro-protection 4)Supportive care (Kasner AAN 2012).

Initial “Stroke Protocol” Orders for AIS (Freeman AAN 2012)

Exam - Rapid NIH Stroke Scale (NIHSS) exam or Los Angeles Prehospital Stroke Screen Radiology - STAT noncontrast head CT (differentiate AIS vs hemorrhage) ECG - 2 lead- evaluate for ischemia, arrhythmia Laboratory - Complete blood count with differential, & platelets. Prothrombin time (PT) & INR esp. if taking warfarin - aPTT (Activated partial thromboplastin time) - Serum glucose (detect hypoglycemia mimic, hyperglycemia >250mg/dl) - Electrolyes - Serum creatinine (e.g., calculate glomerular filtration rate, GFR) & BUN - Pregnancy test in females of child-bearing years - Drug abuse screen - Troponin for MI (or CK-MB if renal impairment)

“ABCDEFG” of Stroke Management & Complications (Levels of Evidence)

(Freeman AAN 2012)

A- Airway/Aspiration, cardiac monitor at least 24hrs in all patients, O2 for hypoxic patients, intubation/mech ventilation for compromised airway – Class I Evidence B- Blood Pressure Control Specific to Stroke Type– Class II, Hypotension cause should be evaluated & treated- Class I 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 > 37.5º 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) Avoid IV D5 in AIS (Khatri AAN 2012). ■ Maintenance fluids ± 2000-2500 ml/24 hrs (Saver 2009). ■ Passive full-range-of motion movement of paralyzed limbs during the 1st 24 hrs. Prevent decubitus by frequent turning, or alternating pressure mattresses (Saver 2009). ■ Cautiously begin oral intake if they pass a bedside: 3 ounces water swallow test before oral intake (Saver 2009). ■ Prevent DVT intermittent external compression boots / low dose heparin SC / LMWH (Saver 2009)

■ 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).

ANTIHYPERTENSIVE THERAPY(1)

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)

Prabhakaran S , Naidech A M Stroke 2012;43:2258-2263

Example of DWI lesions after ICH.

- 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-cardio-embolic 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.

ANTI-THROMBOTIC THERAPY

Inhibitor of P2Y12

PAR-1

(αIIβ3 inhibitor)

Integrilin

(PAR-1=Protease Activated Receptor)

SITES OF ACTION OF ANTIPLATELET-DRUGS (Goodman & Gilman 2011)

NEUROPROTECTIVE AGENTS IS CURRENTLY NOT RECOMMENDED FOR AIS (AHA 2007; EFNS 2012)

■ CITICOLINE seems not efficacious in the treatment of moderate to-severe AIS - ICTUS trial (24 hours after onset of AIS; dosis 2 x 1000 mg/day IV for 3 days, afterwards 2 x 500 mg oral for 6 weeks) (Dảvalos A, Lancet 2012). Diederich (2012) in experimental rats demonstrate that, citicoline besides its neuroprotective effects in AIS, also Citicoline possesses neuroregenerative potential in animal studies ( Diedrich 2012). Even 24 hrs after onset of ischemia in chronic stroke. ■ Other currently neuroprotectors trials: NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, could reduce ischaemic brain damage in iatrogenic stroke after endovascular aneurysm repair (ENACT): phase 2 trial (Hill, Lancet neurology November 2012). ■ Magnesium sulfate (Afshari 2012, FAST-MAG 2012) ■ Neuroaid (S’pore July 2006)

NEUROPROTECTIVE AGENTS (CITICOLINE)

INTERACTION OF NEUROPROTECTIVE CANDIDATES WITHIN ISCHEMIC PATHOPHYSIOLOGY (Rogalewski 2006)

1 2

3 membrane modulator

(SITE OF ACTION OF CITICOLINE 1,2,3)

- Magnesium inhibit presynaptic release of excitatory neuro- transmitters, 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, neuro-protective, neuroplasticity) 3 x 4 caps for 3 mo (S’pore July 2006)

MAGNESIUM SULFATE

NMDA receptor mediated excitotoxicity (Dawson 2004) NOS=nitric oxide synthase; NO=nitric oxide; AIF=apoptosis inducing factor;

PARP=poly (ADP-ribose) polymerase

(peroxynitrite)

SITE OF ACTION OF MGSO4

MgSO4

NMDA-R blocker

K-Inward Rectifier (Kir) “gating” Ex

trace

llula

r sol

utio

n

Intra

cellu

lar S

olut

ion

-80 mV -30 mV

K+

K+

Mg2+

K+

K+

K+

K+

K+

Mg2+

K+

K+

(C-type slow inactivation)

MG++ BLOCKS NMDA-R

Stage Typical Settings

Diagnostic Steps

Treatment Strategy Treatment Components

Hyperacute (0–2 hrs)

Prehospital, emergency department

Clinical screens

Stabilize penumbra

Neuroprotective cocktail (FAST-MAG ? 2012) (NA-1 ? 2012)

Early acute (1–4.5 hrs)

Primary stroke center, emergency department, intensive care unit

Rapid CT Reperfuse rapidly

IV thrombolysis (rt-PA)

Later acute (2–10 hrs)

Comprehensive stroke center

Multimodal; MRI or CT

Reperfuse definitively

Endovascular recanalization (mechanical thrombectomy) Reperfusion injury cocktail

Early subacute Stroke unit Complete

work-up

Deter reocclusion or recurrence

Antithrombotics Secondary prevention

Subacute Rehabilitation unit

Functional MRI

Enhance neurorepair

Nerve growth factors and choline precursors (citicoline 2012 ?) Stem cells

Transcranial magnetic stimulation. Neural prosthetics (brain-machine interface)

Targeting the Brain: Neuroprotection and Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, Medscape 27-10-2010

-  IV rt-PA(0.9 mg/kg BW, max.90 mg) with 10% given as bolus followed by 60-min infusion, is recommended within 4.5 h of AIS (Cl I, L A). - Multimodal imaging criteria may be useful for patient selection for thrombolysis, but not recommended for routine clinical practice (Cl 3, L C). -  Lower BP of ≥ 185/110 mm/Hg before thrombolysis (Cl 4, GCP). - IV rt-PA may be used in patients with seizures at stroke onset, if the neurological deficit is related to AIS (Cl 4, GCP). - IV rt-PA may be used in selected patients < 18 yrs & > 80 yrs, but outside the current European labelling (Cl 3, L C). - IA treatment of 6-hr MCA AIS is recommended as an option (Cl 2, L B).

EFNS RECOMMENDATION FOR AIS-1 (2012)

- IA thrombolysis is recommended for acute basilar occlusion in selected patients (Cl 3, L B). - ASA (160-325 mg loading dose) is recommended within 48 hr after AIS (Cl 1, L A). - No ASA/other antithrombotic therapy within 24 h IV-rtPA (Cl 4, GCP). - Other antiplatelet (single or combined) is not recommended in AIS. - GP IIb-IIIa inhibitors is not recommended (Cl 1, L A). - Early administration of unfractionated heparin, LMWH, or heparinoid is not recommended in AIS (Cl 1, L A). -Treat AIS with neuro-protectors is currently not recommended (Cl 1, LA ■ Routine BP lowering is not recommended following AIS (Cl 4, GCP). ■ Cautious BP lowering is recommended in extremely high BP (≥ 220/120 mm Hg) on repeated measurement, or with severe cardiac failure; aortic dissection; hypertensive encephalopathy (Cl 4, GCP). ■ It is not recommended abrupt BP lowering (Cl 2, L C).

EFNS RECOMMENDATION FOR AIS-2 (2012)

Modification of antiplatelet therapy (resistent to non-resistent) was associated with significantly increased rates of death, ischemic events, or bleeding compared with no modification. No differences in ischemic events were observed (Depta; Stroke. 2012;43:2376-2381).

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

Exclusion citeria IV rt-PA (AAA-PILGRIMS-GPS) : (Freeman AAN 2012) - Aneurysm or AVM - Anticoagulation (INR >1.7) - Any history suspicious for SAH - Puncture at NC site (or LP) within 1 week - ICH History - Low platelets <100,000 - Glucose < 50 or > 400mg/dL - Rapid resolution or minor neuro deficits - Intracranial neoplasm - Major Surgery or serious bodily trauma < 2 weeks - Stroke or Serious Head Trauma 3 months - GI/GU tract hemorrhage w/in 21 days - Pressure >180/110mmHg - Seizure at stroke onset

Additional Exclusion Criteria: IV rt-PA (ECASS 3)

- > 80 years (2012 NOT VALID*); - Baseline NIHSS >25; -  Oral anticoagulants regardless of INR - Combination previous stroke + DM

* IAT does not increase the risk of mortality of those aged > 80 yrs compared with IV thrombolysis alone. (SPOTRIAS Specialized Program of Translational Research in Acute Stroke )eStroke 2012;43:2369-2375)

Modality NIHSS base line

Recanalization rate

SICH risk %

mRS≤2 at 1 or 3 mos (%)

Mortality 1-3 mo (%)

Advantages

Disadvantages

NINDS IV rt-PA

14 30-50% 6.4 40 (mRS ≤1

17 (3 mo) Widely accessible

Narrow timewindow. Strict eligibility criteria

ECASS III - - 7.9 16 - idem Larger time window

Bridging ther. (IV/IA rt-PA)

- 69.6 8.6 48.9 17.9 - -

NINDS IV rt-PA in acute ischemic stroke (Nguyen AAN 2012) Bridging therapy (combined IV and IA thrombolysis (Mazighi 2012)

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%.

Modality NIHSS

Recanalization SICH risk %

mRS≤2 at 1 -3 mos %

Mortality 1-3 mo %

Advantages recanalization

Disadvantages

PROACT II IV heparin, 6 hrs MCA

17 18% TIMI 2 or 3 2 25 27 (3 mo)

n/a n/a

PROACT II IA prourokinase, 9 mg over 2 hrs

17 66% TIMI 2 or 3 10 40 25 (3 mo)

High n/a

MELT IA UK, 6 hrs MCA, n=57

14 74% (mechanical disruption in 39/57 patients

9 49 5.3 High Urokinase not available

MELT control n=57 14 n/a 2 39 3.5 n/a n/a Post. circ. stroke,IA UK, n=8

23 Available in 7 pts Complete re-canalization in 2 pts; partial reca-nalization in 5

n/a 50 50(1 mo) High Urokinase not available

Post. circ. stroke control, n=8

18 n/a n/a 25 50(1 mo) n/a n/a

Summary IA thrombolytic trials (Nguyen AAN 2012)

Modality No NIHSS basal

Recanali zation

sICH Mortality 90 D %

mRS <2 90 D %

MERCI 141 20 60 8 44 28

MultiMERCI, Smith 2008 164 19 55 10 34 36

Penumbra Pivotal 125 17 82 11 33 25

Penumbra POST, 2009 157 16 87 6.4 20 41

Solitaire, Castano 2010 20 19 90 10 20 45

Solitaire, Miteff 2011 26 96 10 19 42

Revive, Rohde 2011 10 19 100 20 30 60 (30 d)

Trevo, Román 2012 60 18 73.3 11.7 28,3 45

sICH = symptomatic intracerebral hemorrhage; mRS = modified Rankin Scale (outcome)

Outcomes of different FDA approved retrieval devices in mechanical thrombectomy

Román 2012

Modality Goal n Current n NIH Time window h

Randomization Primary outcome

Start, End

IMS 3 900 371 ≥10 3 IVtPA vs IVtPA+IA mRS 3 mo 2006-2014

THRACE 480 pending ≥10 3 Idem Idem 2010-2011

SYNTHESIS EXP

>344 >170 Open 4.5 IVtPA vs IA tPA mRS 0.1,3 mo

2008-2011

MR CLEAN 500 Pending ≥2 6 IA tPA +/or mechanical vs no IA

mRS 90 d 2010-2015

THERAPY 400 Pending 4.5 IV tPA vs IV tPA + IA penumbra, 8 mm clot

2012

DAWN Pending Pending ≥10 Indeter minate

Standard vs IA with CT perfusion

mRS 90 d 2009

CURRENT RANDOMIZED TRIALS (Nguyen AAN 2012)

MR RESCUE

120 120 ≤6 8 Standard vs with MR perfusion

mRS 90 d 2005-2013

SENTIS 515 515 5-18 10 Standard vs aortic balloon Cath

Neurol improvement; serious adverse events 90 d

2008-2011

SWIFT 200 113, stopped

8-30 8 Merci vs solitaire TIMI 2 or 3 flow 2010-2011

RECENTLY COMPLETED TRIALS (Nguyen AAN 2012)

1. Thrombus disruption. 2. Stents :immediate flow restoration with selfexpandable stents (SES). 3. Mechanical thrombectomy.

MECHANICAL THROMBOLYSIS (MT) (Gralla 2012)

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).

FDA approved retrieval devices in mechanical thrombectomy

■ MERCI (Mechanical Embolus Removal in Cerebral Ischemia) retriever (Concentric Medical, Mountain View CA) FDA approved 2004. ■ Penumbra System (Penumbra, Alameda, CA), FDA approved Jan. 2008. ■ Solitaire device is another retrievable stent- on-a-wire (EV3) may be left in the vessel as a conventional stent (Henkes). FDA approved 2010. ■ Trevo Device (Concentric Medical) approved in Europe & Canada, February 2010.

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).

Gralla J et al. Stroke 2012;43:280-285

MERCI RETRIEVER (FDA approved 2004)

MICROFILAMENTS Menjerat trombus

Penumbra system (FDA approved Jan. 2008) (Brooks 2011)

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.

microcatheter dinaik turunkan utk melepas thrombus

microcatheter dihu- bungkan dng pompa aspirasi

SOLITAIRE FR DEVICE

(FDA approved 2010)

STENT

GUIDEWIRE TUBE

Solitaire FR with clot Dávalos A et al. Stroke 2012;43:2699-2705

(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.

Gralla J et al. Stroke 2012;43:280-285

TREVO Pro Retriever (Stryker Neurovascular) (FDA approved May 2012)

TREVO stent-like retriever (Román 2012)

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.

- Classical non-contrast CT (NCCT) - Alberta Stroke Program Early CT Score (ASPECTS) - CT Angiography Source Imaging (CTA-SI) - CT Perfusion (CT-P)

CT-BASED SELECTION

Alberta Stroke Program Early CT Score (ASPECTS) ■ ASPECTS is a 10-point quantitative topographic CT scan score used in MCA stroke patients. ASPECT SCORE = 10 – affected areas

NCCT (non contast CT) ASPECT score - ≤ 7 worse outcome at 3 months as well as

symptomatic hemorrhage. - > 7 good outcome - 10 normal CT - 0 diffuse ischemia thru-out MCA territory.

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.

I. At level of thalamus & basal ganglia (7 areas) II. Just rostral to basal ganglia (3 areas)

I II

7 areas At level thalamus/

basal ganglia

3 areas Just rostral to basal ganglia

I ANTERIOR CIRCULATION

POSTERIOR CIRCULATION

♀ 65 yrs: L. hemiplegia, hemianopia, neglect < 3 hrs AIS. ASPECT SCORE 10-5=5 (POOR) Area affected: M1, M2, insula (I), M4, & M5 (A &B) IV thrombolysis was administered. Followup CT scans (C&D)) Large area of hypoatennuation of MCA territory. Patient was dependent at 3 months. X X

EXAMPLES OF NCCT ASPECTS (Pexman 2001) M1

M2

M4

M5

I

♂ 68 yrs with global aphasia, NIHSS 7 (mild to moderate stroke). ASPECT SCORE 10-2=8 (GOOD) Hypoatennuation : anterior insula (I),+ swelling M2 Follow-up NCCT (C&D): The patient made a full recovery.

I

M2

I

X X

EXAMPLES OF NCCT ASPECTS (Pexman 2001)

I

♀ 79 yrs. L. hemiparesis 2 hrs after AIS. NIHSS 15 (good). ASPECT SCORE 10-2 = 8 (GOOD) Hypoattenuation R.lentiform nucleus (L) & caudate nucleus (C) Follow up NCCT: Patient made a full recovery after thrombolysis.

L

C

X X

EXAMPLES OF NCCT ASPECTS (Pexman 2001)

■ 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).

CTA-SI (blood pool analysis) - REFLECTS BLOOD VOLUME - HYPOPERFUSION MUCH MORE DETECTABLE THAN NCCT. - CTA-SI MORE RELIABLE THAN NCCT & AS GOOD AS DWI FOR THE DETECTION OF LARGE ISCHEMIC REGIONS, BUT LESS EFFECTIVE FOR SMALL LESIONS OR THOSE IN THE POSTERIOR FOSSA (AHA 2009)

♂ 75 yrs: L.hemiplegia & hemineglect syndr. Caused by R.MCA occlusion. 62 minutes after AIS (Coutts 2004). NIHSS 15 (good). A.NCCT ASPECTS: 10-1=9 (good) Possible subtle R. lentiform/sub-insular ischemic density. B. CTA-SI ASPECTS: 10-4=6 (worse). Unequivocal hypocontrast involving caudate nucleus, lentiform nucleus, M2 territory & insula.. C. Follow-up CT ASPECTS 6-5 (worse) Progression to infarction in CTA-SI lesions, despite successful vessel recanalization after IV & IA rt-PA.

NCCT NCCT

CTA-SI CTA-SI

NCCT (follow-up)

NCCT (follow-up)

X X X

X X X

CTA-SI ASPECTS better than NCCT ASPECTS

X X X

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

Wintermark M, Stroke 2006;37:979–985.

MTT = mean transit time

CT Perfusion: Identification of The Ischemic Penumbra

Tissue type CBF CBV MTT Tissue State

Normal tissue Normal

Viable, oligemic ↓ Penumbral

Viable, ischemic ↓ ↑ ↑ Penumbral

Infarcted – bland ↓ ↓ ↑ Infarct Core

Infarcted, reperfused

↑ ↑ ↓ Infarct Core

Wintermark, et.al, Ann Neurol. 2002;51:417-432

Infarct

Penumbra

Early CT changes Acute stroke (2.5 hrs evolution) ♂ 55 yrs, R. hemiplegia: A. NCCT: L fronto-temp hypo- attenuation B-D. Perfusion CT maps: B. CBV perfusion C. CBF perfusion D. Summary map: CBF-CBV reduced mismatch + large infarcted core (bad

prognosis) E. CT scan 24 hrs later: Hemorrhagic transformation after thrombolysis. (Marco de Lucas 2008)

A B C

D E

Hyp

oatte

nuat

ion

CBV CBF

Cor

e

Penumbra

Summary map

NCCT

CT-SCAN 24 HRS LATER

CTP CTP

(bad prognosis)

√

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 (good prognosis)

A B C

D E

Dot sign Loss gray-white diff Obscuration bas.gl

MTT R. fr-temp CBV R.fr.temp

CBF R.fr-temp Core

Penumbra

SUMMARY MAP

NCCT CTP CTP

PCT

(good prognosis)

DEFUSE I trial (MRI based selection): ■ No PWI/DWI mismatch No benefit from reperfusion & risk of ICH. ■ Large PWI/DWI mismatch Benefit from reperfusion & favorable clinical response to thrombolysis . ■ Selection of patients for rt-PA is now based on physiological imaging rather than time (Wechsler; Stroke. 2012;43:2517-2519). ■ Desmoteplase is beneficial in large MMV (Minimum baseline DWI-PWI Mismatch Volume) & ineffective in patients with small MMV. (Warach; Stroke 2012;43 : 2313-2318) ●↑ biomarkers of oxidative stress — F2-isoprostane & total plasma antioxidant capacity were associated with penumbra in AIS. (AAN 2012).

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)

PWI DWI

MRI

CT PERFUSION core

Penumbra

CBV CBF

MRI Perfusion-Diffusion Mismatch vs CT-perfusion Campbell B C et al. Stroke 2012;43:2648-2653

A.  L. MCA infarct in diffusion MRI

B.  More widespread reduction in CT-CBF due to periventricular leuco-araiosis

C. Time-to-peak (TTP) > 4 seconds (white outline)

D. True-positive low CBF (green)

MRI perfusion L.MCA infarct

CT-perfusion (peri-ventri- cular leuco-airaiosis)

Time-to-peak in CTP (white outline)

Low CBF in CTP (green)

MRI vs CT for acute ischemic stroke (Marcus de Lucas 2008)

MRI CT-SCAN - Less widely available - Widespread available - Contraindication: electronic implant

- No contraindication

- Gradient-echo imaging superior to CT for detection of acute H.

- Highly sensitive for exclusion or confirmation of hemorrhage

- DWI more sensitive than NCCT for early detection of AIS

- CBV-perfusion & CTA-SI correlate with DWI

- More sensitive than NCCT for detection of acute stroke

- NCCT; CTA-SI; CT-perfusion as sensitive than MRI

- Mismatch PWI-DWI = penumbra - Mismatch CBF-CBV = penumbra - No radiation dose - 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

A fast 21⁄2-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.) . - FLAIR= fluid-attenuated inversion recovery; - DWI= diffusion weighted imaging; - DSC= dynamic susceptibility contrast; - ASL=arterial spin labeling.

(WITH CONTRAST)

(WITHOUT CONTRAST)

ARTERIAL SPIN LABELING PERFUSION MRI, WITH CONTRA-INDICATION TO CONTRAST AGENTS (Bokkers; Stroke 2012;43:1290-1294)

Severe hemispheric stroke occurs in 10% of stroke patients. ■ First-line options for cerebral edema: Mannitol 1 g/kg IV & repeated every 4–6 hrs; Hypertonic saline 30-mL bolus of 23.4% saline is a standard dose (Kimberly 2011) ■ In progressive malignant infarction, urgent HEMICRANIECTOMY should be offered. - The absolute risk of death is reduced by 40-50% among patients < 60 yrs within 48 hrs of stroke onset (HAMLET, DESTINY & DECIMAL trials) - For every 2 patients : one death was prevented & one fewer patient developed severe disability (mRS > 4; bedridden, incontinent & requiring constant nursing care & attention, or dead). - Among those who survived, there was an increase in moderately severe disability (mRS = 4; unable to walk without assistance & unable to attend to own bodily needs without assistance. (Khatri AAN 2012).

SEVERE CEREBRAL EDEMA IN SEVERE HEMISPHERIC STROKE

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 (αIIbβ3 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.

Pengalaman SpS (senior Jkta) Selama kurang lebih 2 th, telah dilakukan DSA dg terapi BS pada ± 200 pasien, -  5 pasien acute stroke iskemik < 6 jam,diberikan Intergrilin intra kateter, kesemuanya menunjukkan perbaikan klinis (memuaskan). -  Khronik 2mg-3 bln AIS DSA + heparin 5000 IU tidak memuaskan. - Small vessel iskemia (lacunar stroke) DSA + heparin 5000 IU hasilnya sering memuaskan. Kebanyakan pasien datang pada fase Stroke Iskemik Khronis, dilakukan pemeriksaan diagnostik MRI Otak; MRA Otak; MRV Otak; MR Perfusi Otak; serta TMS (pre&post BW), apabila memenuhi kriteria seperti: Perfusi cerebral ↓, adanya small vessel ischemia; trombus vena cerebral; maka dilakukan prosedur DSA dengan pemberian infus Heparin ± 5000 IU.

MRI: old L. parieto occ infarct 4 th yl + recent lacunar infarct pd ke 2 hemi-sfer (hipoperfusi ke 2 hemi-sfer) 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.

LACUNAR (SMALL VESSEL ISCHEMIA) - ♂ 64 tahun vertigo hebat, MRI small vessel ischema hebat. Di BS (DSA + 5000 IU heparin). Post BS lovenox 1 X 0.4 cc. Vertigo hilang, penderita puas. MRI ulangan : small vessel ischemia tetap.

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.

Heparin potentiate thrombin inhibition (Goodman & Gilman 2011)

Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor

-

ASA

-

Abxicimab Integrilin Tirofiban

-

PLATELET ADHESION AND AGGREGATION (Goodman & Gilman 2011)

-

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.

Plasminogen activator inhibitors-1 and -2 (PAI-1, PAI-2) inactivate t-PA;

α2-antiplasmin (α2-AP) inactivates plasmin

SITE OF ACTION OF rt-PA (Goodman & Gilman 2011)

Fibrinolysis

rt-PA

Integrilin Integrilin

rt-PA rt-PA

Heparin potentiate thrombin inhibition

Integrilin IV (135 µg/kg+0.75 µg 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)

IV heparin 6 hrs MCA (PROACT II) : NIHSS 17; recanalization:18%; sICH: 2%; mRS ≤ 2 at 3 mo: 25%; Ť 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)