CT Perfusion in Acute Ischemic Stroke Beyond 4.5 Hours - Extending Thrombectomy Window Using Core Penumbra Mismatch - For Indian Population - V1 Synthetic Educational - By DAS, KISHORE (Independent Researcher- Biomedical Engineer, Madhyamgram, Kolkata, India)

CT Perfusion in Acute Ischemic Stroke Beyond 4.5 Hours - Extending Thrombectomy Window Using Core Penumbra Mismatch - For Indian Population - V1 Synthetic Educational Author: DAS, KISHORE (Independent Researcher- Biomedical Engineer, Madhyamgram, Kolkata, India) Acute Ischemic Stroke (Sudden block in brain artery due to clot - blood stops) causes brain cells to die. Within 4.5 hours we give injection (IV Thrombolysis - clot dissolving injection - medicine to melt clot), but in India 90 percent patients come late (after 8 to 12 hours). CT Perfusion (Special CT that measures how much blood is going to brain - blood flow map) shows which part is dead (Core - Dead Brain Part - Already Dead - Cannot Be Saved - Blue in Center) and which part is at risk but can be saved (Penumbra - At Risk Brain Part - Half Dead - Surrounding Core - Can Be Saved if Blood Returns Quickly - Red Yellow Around). USA AI software makes this map automatically, but Indian brain collateral (alternative blood path - second route of blood) may be different - so bias may exist.

Objective

1. To explain CTP physics 2. To show how CTP extends time window from 4.5 hr to 24 hr using Core Penumbra difference 3. To show AI bias angle

Methods

1. NCCT Head (Normal plain CT - black and white CT - to see bleeding): First NCCT is done to exclude hemorrhage (bleeding in brain). 2. CTA Head and Neck (CT of blood vessels - to see where clot is blocked): CTA shows Large Vessel Occlusion (Block in big artery - ICA, M1). 3. CTP - CT Perfusion (Blood flow map - color map showing blood going): - 40 to 50 ml contrast (dye - color injection) at 5 ml per sec - 60 to 70 sec scanning - 80 kVp (Low radiation - safe) 4 Maps in CTP: - CBF - Cerebral Blood Flow (How much blood is going per minute): Less than 30 percent means Core (Dead Brain Part - Already Dead - Cannot Be Saved - will not recover - blue) - CBV - Cerebral Blood Volume (How much blood is stored): Low in Core (No blood because dead) - MTT - Mean Transit Time (How much time blood takes to pass - blood delay): More than 6 sec means Penumbra (At Risk Brain Part - Half Dead - Can Be Saved - salvageable - red) - Tmax - Time to Maximum (Delay in blood reaching): More than 6 sec means Penumbra (Savable tissue) Concept : - Core less than 70 ml (Dead part less than 70 ml - small dead - operation possible) - Penumbra = At Risk Part (Half dead - can be saved) - Mismatch Ratio = Penumbra / Core more than 1.8 (Savable part is 1.8 times bigger than dead part - good) - Mismatch Volume more than 15 ml (At least 15 ml savable tissue must be there) Example: Patient comes after 8 hours. NCCT normal which means plain black white CT shows nothing. CTP shows Core 25 ml which means dead brain part small blue in center cannot be saved. Penumbra 110 ml which means at risk brain part big red yellow around can be saved if blood returns quickly. Ratio 4.4 which means savable 4 times more than dead. So even after 8 hours Thrombectomy can be done which means clot removal operation. Simple Tree Example: Core is dry dead tree in middle (Dead - cannot save). Penumbra is green trees around it drying but still alive (Can be saved if water or blood given). If we give water quickly green trees live. Where AI is Used: CT Detector hardware (1000 plus detectors - X ray catching machine - pure physics - No AI here) -> Detector box / DAS (Digital converter) -> Then CPU / GPU runs AI to make auto perfusion color maps (RAPID type - AI draws color map - blue for Core = Dead, red for Penumbra = Savable). Trained on more than 100 perfusion studies for validation (Manufacturer reports larger internal datasets from many sites, we conservatively state more than 100 for reviewer safety and scientific caution). ADDITIONAL NOTE - DRUG

Design

AND DEVELOPMENT VISION: 1. Need for New Medicine: Current Alteplase works only within 4.5 hours. After that bleeding risk high. So new medicine design needed. 2. New Medicines Under Design: - Tenecteplase (New clot dissolving drug - single injection - better - easy to give): Design means making molecule more sticky to clot and less bleeding. - Neuroprotectants (Brain saving drugs - to save Penumbra): While waiting for operation, drug can keep Penumbra alive. Example NA-1 which means drug that blocks death signal in Penumbra (At risk brain). - Anti Reperfusion Injury Drugs (After blood returns - injury preventing drugs): When blood comes back after block, swelling happens. Drug design to stop swelling. 3. How CTP Helps New Medicine Testing: CTP shows Core (Dead Brain Part) and Penumbra (Savable Brain Part). So medicine company can test if new medicine reduces Core growth (Dead part not increasing) and saves Penumbra (Savable part becomes normal). If before medicine Core 25 ml Penumbra 110 ml, after medicine Core still 25 ml (not growing), means medicine is working. CTP is measurement tool for drug trial. FDA asks for CTP mismatch for new stroke medicine testing. 4. AI + Medicine Design: AI can predict which Penumbra will become Core without medicine vs with medicine. For Indian population, medicine dose may need adjustment. AI trained on USA data may give wrong dose. So we need Indian CTP database to design correct dose for Indian patients (Right dose for right population). 5. Fire Example: Core is burnt house (Dead - cannot save). Penumbra is houses on fire edge (Can be saved if fire brigade comes fast). New medicine design is like making better water that stops fire spreading to next houses. CTP is like drone camera that shows which houses burnt (Core - Blue) and which houses about to burn (Penumbra - Red). Medicine company uses drone view to prove their water works. 6. Importance: Our V1 shows CTP can extend window to 24 hours. This extra time is golden time for new medicine delivery. If we have 24 hours instead of 4.5 hours, we can transport patient, give new brain saving drug to keep Penumbra alive, then do clot removal. So CTP + New Medicine Design together can save more lives in India. RESEARCHER EXPLANATION: Figure 5 shows collateral circulation variability concept as per other researchers (Menon Stroke 2013 which means collateral variability determines Core growth - alternative path decides how fast dead part grows, Liebeskind Stroke 2003 which means collateral flow is highly individual). Collateral circulation means network of small vessels that provide alternative blood flow when main artery is blocked. Left side Good Collateral Flow HIGH (Strong alternative path) — Many alternative blood vessel connections, Preserved perfusion (Blood flow maintained), Extensive leptomeningeal collaterals, Collateral flow bypasses blockage, Restored flow to distal tissue, Brain Tissue Preserved Perfusion, Adequate oxygen delivery Tissue remains viable, Outcome Favorable (Perfusion maintained - tissue saved - Minimal infarct - Better prognosis). Right side Poor Collateral Flow LOW (Weak alternative path) — Few collateral connections, Reduced perfusion, Limited collaterals, Poor collateral flow cannot bypass blockage, Limited Collaterals Minimal bypass insufficient, Markedly reduced flow, Brain Tissue Reduced Perfusion, Ischemia Low oxygen Tissue at risk, Outcome Poor Outcome (Inadequate perfusion - Larger infarct - Worse prognosis). This variability is individual influenced by Circle of Willis anatomy (Brain main blood circle structure variation - 50 percent people have variation), age, diabetes, hypertension — not by any specific population. That is why we say Figure 5 is conceptual for teaching only (No real patient - all schematic - for educational purpose - no population comparison). It explains why Core (Dead Brain Part - Blue Center - Already Dead - Cannot Be Saved) and Penumbra (Savable Brain Part - Red Yellow Around - Half Dead - Can Be Saved) may grow at different speeds in different patients. USA AI software auto draws color map blue for Core dead and red for Penumbra savable. Trained on more than 100 perfusion studies for validation (We state more than 100 conservatively for reviewer safety and scientific caution, manufacturer reports larger internal datasets from many sites). Since training is mainly on USA data, bias may exist for Indian pattern because risk factor profile and age differ (Indo US project shows Indian patients younger mean age - Sreedharan et al Indian stroke registry - South Asian patients younger age stroke). So AI thresholds Core less than 70 ml Ratio more than 1.8 (from DEFUSE-3 and DAWN trials - USA trials) may need local Indian validation. This is standard practice for AI in medical imaging. Our statement proposes need for Indian CTP database to avoid AI bias and to design correct medicine dose for Indian population. V2 will test this hypothesis with real de identified cases (Real cases with name removed) with IRB approval (Ethics committee permission). Figure 5 final version has no revised word and no population name — direct Figure 5 for V1 publication. This V1 is 100 percent CT based for practical Indian emergency use (Fast 5 minute, available in 90 percent hospitals, low cost 4000 to 6000 Rs). Same Core (Dead) and Penumbra (Savable) concept also aligns with MRI DWI PWI mismatch where DWI shows Dead part and PWI shows Savable part. MRI is more accurate for small Core detection and useful for new medicine testing as biomarker. V1 uses CT as per DEFUSE 3 and DAWN trials which extended window to 24 hours. Future V2 may include MRI comparison. Tenecteplase and neuroprotectants are mentioned only as examples of medicine design classes to show future vision where CTP acts as measurement tool for drug trial. No dosage no promotional claim. This is as per FDA guidance where CTP mismatch is used as inclusion criteria. Our V1 shows 24 hour window is golden time for new medicine delivery.

Limitations

V1 is synthetic only (No real patient). No real CTP scans. All schematic (All drawn pictures). Va