VASCULAR NEUROLOGY: ACUTE ISCHEMIC STROKE (AIS) PATIENT MANAGEMENT

• Critical factors to consider: last known well (LKW) time, timing of symptoms, previous history of strokes (which may indicate recrudescence), baseline deficits, degree of disability, and associated risk factors.
• Must document the NIHSS score for all patients upon admission; consult a senior team member if unsure about this process.

STEP-BY-STEP APPROACH AT UCMC

• Once page is received, the primary team should leave immediately for the patient's room.
• While en route, check Qgenda to identify the on-call stroke and neuro-intervention team.
• Upon arrival, gather pertinent information from the response team, including a brief history, vital signs (BP, blood glucose), kidney function, recent medication administrations (blood thinners and sedatives), bleeding history, and family contact information.
  *Request stat orders for a CT Head and CT Angiography of the head and neck ± wake-up MRI if applicable.
• Risk Factor Assessment: Assess the patient for risk factors such as HTN, A-fib, diabetes, hyperlipidemia, CHF, valvular disease, a hypercoagulable state, recent trauma, tobacco use, and drug use.
• NIHSS:Immediately after gathering information, complete the NIHSS, order rainbow labs, and document the times of LKW, symptom discovery, and page stroke team.
• Imaging: Transport patient to imaging right after completing the NIHSS. During transport, complete the tNK and thrombectomy exclusion criteria checklist:
  
  
  1. Bleeding diathesis (with an INR cutoff of 1.7)
  2. Recent gastrointestinal or genitourinary bleeding
  3. Severe head trauma or intracranial/spinal surgery within the last three months
  4. Severe uncontrolled hypertension (BP > 185/110)
  5. Positive pregnancy test
  6. Any history of oral anticoagulants (INR cutoff of 1.7)
  7. Consider situations such as major surgery in the past two weeks or recent ICH within the last three months.
• CT Imaging: confirm no bleed and make a preliminary ± LVO determination
• Wake-Up MRI: confirm order, and bring patient immediately after CT.
• Call the Stroke Team to present the case, review imaging and lab results, which should typically return by the time the first imaging sequences are available. Decisions regarding tNK and intervention will be made via phone. (see below)
• Place patient flat until thrombectomy if they are a candidate and awaiting activation of the intervention team.
• Calculate ASPECTS Score: . (see below)
• Critical Documentation: Initial NIHSS, follow-up NIHSS (if performed), LKW time, symptom onset time, door time, NIHSS completion time, imaging acquisition time, tNK bolus time, groin puncture time, stent deployment time, and revascularization time. Initial note should also include recommendations for antiplatelet therapy, high-dose statins, and physical/occupational/speech therapy, and ABCD2 score (for stroke risk after TIA.)

TREATMENT PROTOCOLS BASED ON SYMPTOM ONSET

Symptoms with LKW less than 4.5 hours:

• If there are no contraindications, administer tNK after consulting with the stroke team.
• CTA of the head and neck:
  • If negative for LVO, admit the patient to the ICU for post-tPA monitoring
  • If positive for LVO, proceed with angiography and thrombectomy.

Symptoms with LKW greater than 4.5 hours:

• Outside tNK window
• If within 6 hours: 
  • Perform CTA H/N; if LVO is present, proceed with thrombectomy.
• If > 6 hours but < 24 hours: 
  • Perform CTA H/N + CT perfusion:
    • If no LVO is found, no further action is necessary.
    • If LVO is present (distal ICA/M1), evaluate CTP:
      • Is mismatch present (penumbra > core)? = thrombectomy.
      • Penumbra has decreased CBF (so dose core), but what makes it different than core is unchanged/increased CBV (due to vasodilation in that area trying to increase perfusion)
    • On CTP: "CBF < 30%" = core, and "tmax > 6" = penumbra.
  • If cannot get CT perfusion (due to contrast load) ➔ can use CT head to calculate ASPECTS score
    • 8 regions, MCA distribution assessment. M1, M2, M3, insula, internal capsule,
    • If ASPECTS > 7 and patient young/healthy and has large vessel occlusion -➔ could still consider thrombectomy

• Final Considerations

  • Confirm whether the patient will be transferred back upstairs or requires neurointerventional care.
  • Contact the neurointerventional team to confirm necessity and arrange transport to the holding area or interventional radiology suite.

EXTENDING THE TREATMENT WINDOW

MRI – tNK

• WAKE trial used timing ofc imaging to determine if the patient is still within the treatment window for tNK:
• DWI - indicates cytotoxic edema.
• FLAIR - indicates vasogenic edema, 4.5 hrs away/6 hrs away
• EXTEND trial - Perfusion imaging – Stopped early. Not useful anymore.
• Physiology, not time. Ratios of penumbra to core to say if there is benefit
• Core = blood flow <30% of the healthy side of the brain.
• Penumbra = Tmax > 6 seconds.
• A mismatch ratio >1.2, volume >10cc, and Core <70cc

Thrombectomy Trials

• MR CLEAN, EXTENDED IA, SWIFT PRIME, REVASCAT, and ESCAPE
• require CTA, included LVO, good DTN time within 6 hours, with a NNT of 4.
• Guideline- ASPECT > 6, reported within 6 hours
• DAWN and DIFFUSE 3
• Used imaging software to give core and penumbra directly to phone. Used mismatch of >1.8.
• Allowed to extend window from 6 to 16-24 hours.

GENERAL MANAGEMENT OF ISCHEMIC STROKE

Non-tNK Candidate: 

• Goal BP < 220/120 mmHg.
• PRN labetalol 10-20 mg Q1H PRN for SBP >220/110
• Ensure euvolemia.
• If symptoms fluctuate, consider the use of pressors and repeat CT scan.

Post-tNK Management: 

• tNK patients must be admitted to the NSICU.
• Goal BP < 180/105 mmHg.
  BP Options:
  • IV labetalol 10mg ➔ 20mg push
  • IV nicardipine gtt, 5mg/hr, inc by 2.5 mg/hr every 5 min
  • IV clevidipine 1-2mg/hr, double every 90 sec until closer to goal and then slow down (very titratable)
• Repeat CT head 24 hours after tNK
• No antiplatelet/anticoagulant for 24hr post-tNK + neg CTA repeat CT of the head should be performed 24 hours after tNK.
• No antiplatelet or anticoagulant therapies should be administered for 24 hours post-tNK if the CT is negative.
• If evidence of ICH, contact the ICU fellow and stroke physician at 513-584-8282.
  • Suspect if headache, acute htn, seizure, N/V
  • Stop alteplase, get CBC, PT INR, APT, fibrinogen, type cross, CTH
  • Sryoprecipitate 10u infusion over 10-30min (onset in 1hr, peaks 12hr) administer additional dose for fibrinogen level <200 mg/dl
  • Tranexamic acid 1000mg infused over 10 min or Aminocaproic acid 4-5 g over 1 hour followed by 1 g IV until bleeding controlled (peak onset in 3 hours)
  • reduce rapidly target <140 if bleed
  • 1% Angioedema assoc with tNK(tongue, lip, larynx, oropharynx within 30 min)
  • Dc tNK, hold ACEi, administer IV methylpred 125mg.

Post-Thrombectomy Management: 

• Must be admitted to NSICU
• Maintain SBP is variable
• BEST-2 Trial- patients with TICI2b or better target <140 vs <160 vs <180- (results pending from trial)
• Groin and pulse checks per protocol
• Hold ASA 24 hours post-procedure
• Continuous cardiac monitoring

ROUTINE STROKE WORKUP

• Risk stratification labs: INR, aPTT, lipid panel, hgb a1c, TSH, LFTs, UA, UDS
• Studies: 12-lead EKG, CXR, TTE with agitated saline study (consider TEE for high-risk, i.e. suspected endocarditis, or with cryptogenic stroke), repeat stroke protocol CT or MR imaging if indicated
• Nursing:
  • Neurochecks as clinically indicated
  • Bedside swallow: For every patient at admission. Document results in chart
• Medications for every non-TPA patient:
  • Antiplatelet agent (ASA 81mg or plavix 75mg, both if NIHSS <3)
  • High-dose statin – typically atorvastatin 80mg
  • Lovenox 40mg SC daily (use heparin alternative if renal failure)
  • GI prophylaxis if NPO - H2 blocker or PPI
  • For tNK patients, hold anti-platelets and DVT ppx for 24h.
• Further Testing (per stroke attending or fellow discretion): TCD, carotid ultrasound, CTA.

COMPLICATIONS OF STROKE

Complication of Ischemic Stroke

1. Extension of ischemia: due to progressive thrombosis or collateral failure. Consider endovascular recanalization, collateral support (increase IVF, start albumin, add pressors), change in antithrombotic.
2. Hemorrhagic conversion: risk factors include older age, large infarct (>5 cm), severe hypertension, & coagulopathy. Antiplatelets should be held, blood pressure lowered, and coagulopathy corrected.
3. Edema: Increased risk with large infarcts and younger age (peaks at 3-5 days). Obtain serial imaging to assess for edema & midline shift. Acutely manage with HOB elevation to 30 degrees, ICU transfer for hyperventilation, and hypertonic (3%) saline or mannitol administration. Consult neurosurgery for hemicraniectomy if indicated.

Hemorrhagic Stroke Complications of ischemic stroke

• In acute focal stroke syndrome patients, MRI is more sensitive to ischemia and equally or more sensitive to intraparenchymal hemorrhage as CT. Accordingly, emergent MR should be ordered in acute patients unless they have a contraindication to MRI (e.g. pacemaker, cardiorpulmonary instability) or MR scanner unavailability within 20 minutes of scan order. 
• For patients going to CT, a CTA of the neck and head should be obtained at the time of the brain CT and CT perfusion.
• Carotid duplex and TCD: For patients with contraindications to MR (e.g. pacemaker) and to CT contrast (e.g. renal failure), carotid duplex ultrasound of the neck arteries and standard transcranial Doppler of the cerebral arteries should be obtained.
• Special consideration in patients undergoing acute endovascular recanalization:
  • MRA: Initial MRA of the neck requires repositioning of the patient with a neck coil. When this will unduly delay patient transfer to the angiography suite for endovascular intervention, neck MRA should NOT be obtained –cervical imaging can be acquired via catheter angiography.
  • CTA: To avoid high contrast load in both CT and angio suites, request a reduced contrast dose CT. In patients with moderate to severe renal compromise, consider skipping CT angiography altogether if patient is a clear endovascular candidate – arterial imaging can be acquired via catheter angiography.

RISK FACTOR MANAGEMENT

Key risk factors:

• HTN – management HCTZ, ACE, ARB with Goal SBP < 140, DBP < 90
• Exercise – 10 minute mod 4x a week, or 20 minutes vigorous exercise 2x a week
• Nutrition – Mediterranean- type diet, plant based, fish consumption
• OSA – sleep smart study
• Smoking – counseling, NRT, oral cessation
• Alcohol – heavy (reduce), J shaped curve, may benefit from 1 drink a day. (Not for hemorrhage)
• HLD – Mainstay is LDL lowering and statins IF LDL >100 -atorvastatin 80. (Goal LDL<70 by 4 month or 90-110) could add ezetimibe or PCSK9 inhibitors(not as much evidence) to get to goal. Randomized trial showed benefit.
  • SPARCL - 5 year ARR in major CV was 3.5%, or RR f 20%.
• Hypertriglyceride – (fasting 135-499) give IPE, Icosa-pent ethyl
• Antithrombotic – If < 70kg- give ASA 81mg, if >70kg- 325mg ASA

SPECIFIC MANAGEMENT BY STROKE TYPE

Toast Classifications of Subtypes of AIS: AIS mechanisms can be classified into several subtypes:

1. Large vessel occlusion (LVO) due to embolus or thrombosis
2. Cardioembolic (high vs. moderate risk)
3. Small-vessel (lacunar) strokes
4. Strokes of other determined etiology
5. Strokes of undetermined etiology.

TIA/MINOR STROKE

• POINT/CHANCE trial - NIHSS <3 or ABCD2 >4 for 3 weeks start patients within 12-24 hr of stroke on DAPT- clopidogrel with load 600(3hrs) vs 300mg(6hours). Should do within at least 7 days. Meta-analysis showed peak benefit at 21 days duration and limits bleeding sequelae
• THALES trial - ASA vs ASA+ticagrelor - inclusion of NIH < 5, ABCD2 > 6 (stroke risk after TIA) or stenosis >30%.
  • Ticagrelor load 180 mg f/b 90 mg BID (loads faster than clopidogrel) (takes 90 min)
  • Ticagrelor is 2x a day and has major bleeding associated.

SMALL VESSEL STROKE

• 20% of ischemic strokes, often resulting from atheroma and lipohyalinosis in deep penetrating small vessels of deep penetrating small vessels causing infarct <15-20mm in the brainstem, deep gray matter or internal capsule.
• Clinically presents as 5 classic Lacunar syndromes that spare cortical functions (aphasia/neglect), often with stereotypic TIAs in preceding week or a stuttering onset.
  The five classic syndromes include:
  1. Pure Motor Hemiparesis: Associated with lesions in the corona radiata, internal capsule, pons, or medullary pyramid.
  2. Pure Sensory Stroke: Linked to the ventral posterior thalamus.
  3. Sensorimotor Stroke: Involves the corona radiata or thalamus and internal capsule.
  4. Ataxic Hemiparesis: Results from lesions in the pons, middle cerebellar peduncle (MCP), internal capsule, or corona radiata.
  5. Dysarthria-Clumsy Hand Syndrome: Related to the anterior limb of the internal capsule, pons, or corona radiata.
• Diagnosis of small vessel etiology is typically one of exclusion, supported by lesion location, evidence of extensive leukoaraiosis, and the presence of risk factors such as hypertension, diabetes mellitus, hyperlipidemia, smoking, and age.
• Concurrent intracranial atherosclerosis is common.
• Secondary prevention: single or dual antiplatelet therapy, high-dose statins, and comprehensive risk factor management.
• Use of cilostazol, a PDE3 inhibitor, is still under investigation for lacunar interventions
  • PDE 3 inhibitor- cilostazol- for MI and intermittent claudication. Reduces recurrent stroke 30% (2022). ICH, death and bleeding. Good compared to aspiring, clop, or placebo. Good for lacunar strokes. Better over extended periods of time. Causes headaches and palpitations

LARGE VESSEL DISEASE AND STROKE

• 20% of ischemic strokes, can arise from intracranial atherosclerosis, extracranial vertebrobasilar disease, or carotid stenosis.
• Strokes are often preceded by TIAs, characterized by monocular blindness, and occur within a single vascular territory.

Intracranial Atherosclerotic Stenosis or Extracranial Vertebrobasilar Disease:

Management dual AP, statin w. LDL goal <70, aggressive management of HTN and other risk factors, stent only if failed MM

• SAMMPRIS trial- stenting vs Rx for intracranial athero. Only post-stroke. - give DAPT for 90 days. Don’t give if they have Afib. Avoid triple therapy. Given within 30 days.
  • Major 50-70% stenosis ASA 325 recommended (B-R),
  • Sever 70-99% stenosis- ASA 325 + clopidogrel- (B-NR)...do not stent unless 2x stroke while on or after Rx therapy completed
• CAPTIVA study- ASA + plavix vs ASA + ticagrelor vs Rivaroxaban- Pending results

Extracranial atherosclerotic disease

• CEA vs CAS: CREST 2010. CAS with more periop stroke, CEA w. more MI. Pt >70 had more strokes with CAS, and better outcome w. CEA. Female and DM higher rates of restenosis. Periprocedure outcomes trended CAS better for pt <70, CEA better for Pt >70. Trial Included symptomatic (>70% CT/MR or 50% angio) and asymptomatic (>80% CT/MR, 60% angio) and overall no difference in composite stroke, MI, death.
• Symptomatic Severe Carotid Stenosis: If symptomatic (w/in 6 mo) tx with Carotid Endarterectomy (CEA) or Carotid Artery Stenting. For CEA: NASCET, 1991: 16% ARR for 70-99% stenosis; in ECST, 1991: 14% ARR for 70-99% stenosis.
  • if 70-99%- anti platelet + get CEA or >70% with symptoms. No stent.
• Symptomatic Moderate Carotid Stenosis: Med Management vs CEA. NASCET had 6.5% ARR, ESCT w/o benefit. Overall risk of procedure ~7% for stroke or death w/in 30 days. More benefit in men, age >75, and tx w/in 2 wks symptoms.
• Asymptomatic Carotid Stenosis: Medical management vs CEA. Studies showed benefit but medical management often did not include aggressive lipid lowering tx. ACAS 1995: Stenosis >60%: Med tx w ASA: 11% 5yr stroke risk. CEA 5%. NNT=5. ACST 2004: Stenosis >60%: Med tx 11% 5yr stroke risk. CEA 3.8%. Perioperative risk 3%. NNT=14. Presence of microemboli on TCDs increases 1yr stroke risk from 1% to 15%
  • CREST 2 study - enrolling

Vasculitis - Immediate steroids

• ESR, ANA, RF, SS-A, SS-B, ANCAs, RPR, Hepatitis Abs, SPEP/UPEP, Cryoglobulins (C3, C4, cryocrit), VZV, HSV Abs, Immune complex labs. If strong suspicion LP.

CARDIOEMBOLIC STROKE

• May account for 40-50% of ischemic stroke. Suspect when evidence of concurrent systemic embolism, multiple strokes of different ages in right and left anterior or posterior circulation. Imaging with distal, cortical, wedge-shaped infarcts. Clinically may have full hemispheric syndrome that rapidly improves due to recanalization and distal embolization.
• Risk factors include afib, cardiomyopathy, prior MI, systemic infection (septic emboli).
• Mechansims include nonvalvular afib (equivalent to atrial thrombus), LV thrombus, cardiac deviecs/valves, aortic plaque, paradoxical emboli via PFO, valvular vegetations (bacterial or rheumatic aka murantic vegetations).
• Additional Workup:
  • TCD w. emboli detection and bubble (TCD more sensitive than TTE to detect shunt)
  • TTE+definity contrast (if low EF)
  • TEE
  • LE dopplers (if +PFO)
  • Prolonged cardiac monitoring: Implantable loop recorder > ziopatch > holter. Longer recording = higher yield up to 11% in Embolic stoke of unknown source (ESUS)

Atrial Fibrillation Management

For patients with AFib, the cHADS2VASC score should be calculated, considering factors such as congestive heart failure (CHF), hypertension, age over 75, diabetes mellitus (DM), prior embolism, vascular disease, and sex.

• Non-valvular AF Stroke or TIA:
  • The ACTIVE-W trial:
  • Warfarin Vs ASA + Plavix 40% RR Vs Aspirin: 37% RR. Oral ACTIVE-W -
  • Warfarin: 2° prevention 64% RR, bleed risk 0.3-2%. NNT=12; (1° prevent, NNT=37)
  • ASA alone: 2° prevention:19% RR, NNT=40; 1° prevention: NNT=125
  • Rec DOAC (apixiban, dabigatran, rivaroxaban, warfarin) to reduce stroke risk
  • If no mitral stenosis or mechanical valve- no warfarin
• Valvular Heart Disease: 
  • IF Afib - Mitral stenosis or mechanical - give warfarin
  • IF afib no mitral stenosis or mechanical- give apix or rivarox
  • IF Sinus Non-rheumatic, AVD, MV prosthesis- Class 1 antiplatelet
  • IF sinus Mechanical valve- Warfarin
• Watchman device, Atrial appendage closure (lariat), ablation procedures: none have been shown to reduce stroke risk, pt should c/w AC

Endocarditis – No ASA

Cardiomyopathy + stroke in sinus rhythm

• Risk of stroke increases by 18% per 5% decline in EF (SAVE trial).
• In WARCEF (2012) Pt with EF<35%, warfarin reduced stroke risk (RR 0.52), but >2x bleeding vs ASA.
• If no e/o afib or thrombus, bleed risk > stroke risk. But if EF <15% can consider AC 3.
• IF LV or LA thrombus – warfarin
• If LVAD- ASA + Warfarin
• AC resumption- AHA guidelines( -14 days), EHRA-ESC (1-3-6-12 rule)
• Pending ELAN, OPTIMAS, TIMING

Embolic Stroke of Unknown Source (AKA cryptogenic stroke)

• No benefit from NOAC versus DAPT
• ARCADIA trial, which aimed to identify atrial cardiopathy, yielded negative results. ☹

Patent Foramen Ovale (PFO)

• 25% of the population
• No evidence for closure in trials due to low stroke recurrence rate
• Found in 50% of cryptogenic stroke if < 60 yr old, Consider closure for recurrent stroke in young
• RoPE score- suggestions of risk paradoxysmal emboli from PFO
• PASCAL scoring system- combines the RoPE score with the presence or absence of high-risk PFO features
• Get BLE Doppler
• Also consider anticoagulation, ideally as part of trial for cryptogenic stroke:
  • RESPECT-ESUS (pradaxa); ATTICUS (Eliquis); NAVIGATE ESUS (xarelto)
  • Spencer Grading for R>L Shunt via TCD based on #emboli detected:
    Grade I [1-10]; II [11-30]; III [1-100]; IV [101-300], Grade V [>300

Proximal Aortic Plaque

• Large (>4-5mm) and complex (ulcerated, protruding, mobile) plaques significantly increase stroke risk (by 4-15 times).
• Treatment options include statins, dual antiplatelet therapy, or anticoagulation if the plaques are large and mobile.

Septic Emboli and Dissection – Treat infection

Dissection

• CADISS 2023- antiplatelet or anticoagulant for 3 months. Needs a larger population.
• Antiplatelet vs Dual Antiplatelet vs Anticoagulation. NOACs are safe. TPA is safe, although may not be effective if e/o vessel occlusion.
• CADISS Trial 2015: Antiplatelet (28%) /Dual Antiplatelet (23%) vs Anticoagulation (48%). N= 250. Very low rate of recurrent stroke. (recurrent strokes typically within first 2 weeks, often prior to randomization) No benefit of AC vs AP. No significant bleeding difference. However calculated power to find a difference was N=9752.
• In favor of AC: TCD w. emboli despite AP, vessel occlusion/pseudo-occlusion,multiple TIAs/strokes, visualized floating thrombus
• In favor of AP: Severe clinical deficit / large volume stroke, intracranial dissection, local compression syndrome without ischemic event, high bleeding risk

Hypercoagulability

• Work up for <55 yo w/ stroke
• Arterial Thrombosis: DRVVT (Lupus Anticoagulant), Anticardiolipin Antibody, Beta-2 Glycoprotein 1 Antibodies, Homocysteine
• Venous Thrombosis: Protein C &S Functional Activity, Activated Protein C Resistance (Factor V Leiden if abnormal), Antithrombin III, DRVVT (Lupus Anticoagulant), Anticardiolipin Antibody, Beta-2 Glycoprotein 1 Antibodies, Homocysteine, Prothrombin Gene Mutation 20210A , Factor VIII Level, Fibrinogen, Alpha-galactosidase activity assay – if suspicious of metabolic disorder in adult
• Treatment:
  • Antiphospholipid- Warfarin, INR2-3’. If only antibody- antiplatelet (no rivaroxaban)
  • Homocysteinemia (B vitamins dont help but we do it anyway)
  • Neoplastic hypercoagulability- DOACs
  • Sickle cell- goal HgbS < 30% or hydroxuyria if transfusion therapy isn’t an option
• Anticoag for secondary stroke prevention.
  • Warfarin- LV thrombus, prosthetic valve, antiphospholipid, high risk for GI bleed - half life 40hrs, lasts 2-5 days
  • DOACs- AFIB, probably venous sinus thrombosis, probably malignancy- related hypercoag. Half life 12 hrs.
  • TEACH2 trial LMWH vs DOACS

UNCOMMON ETIOLOGIES IN STROKE AND RELATED CONDITIONS

Cervical Artery Dissection:

• Presents with neck pain, HA, partial horners (ptosis/miosis), and TIA or stroke
• Most common cause of stroke in young patients (10-25%)
• Risks: smoking, HLD, HTN, trauma/neck manipulation, collagen vascular disorders, infections eg VZV
• Imaging: DWI will have embolic appearing watershed territory or posterior circulation infarcts. CTA>MRA, MRI neck (T1 fat sat, T2 or FLAIR), DSA if unclear. May see thickened vessel wall with mural hematoma (crescent sign).
• Treatment: Antiplatelet vs Dual Antiplatelet vs Anticoagulation. NOACs are safe. TPA is safe, although may not be effective if e/o vessel occlusion.
• CADISS Trial 2015: Antiplatelet (28%) /Dual Antiplatelet (23%) vs Anticoagulation (48%). N= 250. Very low rate of recurrent stroke. (recurrent strokes typically within first 2 weeks, often prior to randomization) No benefit of AC vs AP. No significant bleeding difference. However calculated power to find a difference was N=9752
• In favor of AC: TCD w. emboli despite AP, vessel occlusion/pseudo-occlusion, multiple TIAs/strokes, visualized floating thrombus
• In favor of AP: Severe clinical deficit / large volume stroke, intracranial dissection, local compression syndrome without ischemic event, high bleeding risk

Posterior Reversible Encephalopathy Syndrome (PRES)

Despite the name, this entity can be seen outside of posterior regions, may not always be reversible, and may occur without encephalopathy. It may present with strokes or intraparenchymal hemorrhage. It can also be associated with RCVS. Pathophysiology is presumed to be disruption of the blood brain barrier or autoregulatory failure, which is more likely to occur in the posterior circulation for unclear reasons.

If you don't think about this diagnosis, you won't make it until after the MRI, at which time it may be too late (ie development of hemorrhage)

• Common Settings: Severe Hypertension , Pre- or post-partum (Eclampsia=PRES) , Immunosuppression (esp calcineurin inhib – tacro, sirolimus, cyclosporine)
• Symptoms: Altered mental status, Visual complaints (field cut, floaters, auras, hallucinations, cortical blindness), Headache, Seizures
• Exam: Fundoscopic – papilledema, exudates, flame hemorrhages
• Differential Diagnosis: Tip of the basilar occlusion, Venous sinus thrombosis, Demyelinating pathology, Vasculitis,Encephalitis
• MRI Findings: (Standard MRI and MRV w/o gad)
  Bilateral, asymmetric, confluent FLAIR hyperintensities (often in the posterior parietal and occipital lobes, occasionally in the posterior frontal lobes), DWI hypo- or isointense (due to vasogenic edema), punctate hemorrhages
• Treatment: Etiology-dependent
  • Hypertension: Treat as HTN Emergency, decrease 25% within 2 hrs
  • Eclampsia: Mg load (4-6g over 15min) then 2-3g/hr maintenance, deliver baby
  • Immunosuppressants: Check levels, adjust dosing, supportive care
• Long-term: MRI findings can reverse in about 3 months. Antiepileptics are recommended for at least 6 months duration. Long-term AEDs unnecessary as seizures do not recur unless disease recurs.

Reversible Cerebral Vasoconstriction (aka Call-Fleming syndrome)

• Severe thunderclap headache ± seizure and focal neuro deficit 2/2 segmental cerebral artery vasoconstriction, with peak constriction at 2-3 weeks, resolving in 1-3 months.
• Causes ischemic or hemorrhagic strokes
• Mean age 45, female predominance
• 60% Triggered, post-partum usually within first week of pregnancy or 2/2 vasoactive.
  Substances: SSRI/SNRI, alpha-sympathomimetics, nasal decongestants, Triptans, bromocriptine/methergine (used to tx postpartum hemorrhage), Nicotine patches, diet pills, herbal meds, Ginseng, cannabis, spice (synthetic marijuana), MDMA, LSD, cocaine, amphetamines or other stimulants, SIVIG, transfusions, Interferon alpha, pheochromocytoma or carcinoid tumors.
• MRA/CTA ~80% sensitive
• DSA may be negative within 4-5 days of symptom onset, but will later become positive. RCVS is an angiographic diagnosis showing vessel irregularities that are often bilateral and diffuse.
• Diagnostic criteria:
  • Acute and severe headache +/- focal neuro deficit or seizure, with monophasic course
  • Segmental vasoconstriction on imaging without SAH, with normalization by 12 weeks
  • Normal/near normal csf (protein wnl, wbc <15) (abnl suggest primary CNS angiitis)
• Treatment: Stop offending agents, AEDs, nimodipine 60mg q4-8h for 4-12weeks

CNS Vasculitis:

Primary or Secondary (to systemic rheumatologic disease or infection) Usually pw long prodromal period, insidious headache (60%), progressive encephalopathy ± seizure. Suspect in young patients without identifiable stroke risk factors. ESR may be normal in primary CNS vasculitis. Diagnose with CSF with mild lymphocytic pleocytosis (in 80-90%), elevated protein ± oligoclonal bands. MRI with multiple cortical and subcortical infarcts and angio may have segmental narrowing (“beading”) of medium to small vessels (60% sensitive), and can be repeated after weeks. Biopsy is gold standard.

Cerebral Venous Thrombosis:

• Presents with band-like headache ± neurologic deficits, often with papilledema.
• May have ischemic strokes 2/2 vasogenic edema, or lobar hemorrhages.
• Imaging: CTV, MRV, or T1-post contrast w. “delta sign”, filling defect in sagittal sinus, or flow void in venous system. MRI with vasogenic edema or stroke.
• Consider CVT in unusual stroke locations: biparietal, bithalamic.
• Triggered by infection, thrombophilia, OCPs.
• Treatment with anticoagulation, consider thrombectomy.

Cerebral Fat Embolism

• Cerebral fat embolism can occur following post-traumatic or post-surgical fractures, leading to fat embolization. This condition presents with altered mental status, which can progress to coma, hypoxia due to pulmonary emboli, fever, and a petechial rash. The cerebral manifestations are often associated with a patent foramen ovale (PFO).
• Imaging via MRI typically reveals numerous embolic infarcts characterized by a "starfield" pattern, along with microbleeds and vasogenic edema. Echocardiography with Doppler or transcranial Doppler (TCD) may show continuous emboli.
• Treatment involves the repair of the fracture, respiratory support, and consideration of corticosteroids or hyperbaric oxygen therapy.

Moya Moya Disease

• Moya Moya is a progressive large vessel vasculopathy that can be classified as either primary or secondary, the latter often linked to conditions such as diabetes mellitus, renal dysfunction, sickle cell disease, radiation exposure, or thyroid disease. The epidemiology shows a female-to-male ratio of 1.8:1, with the highest incidence reported in Japan and East Asia.
• Genetics: Moya Moya is associated with the RNF213 gene located on chromosome 17q25.3.
• Imaging: studies typically reveal narrowed supraclinoid internal carotid arteries (ICAs) and proximal middle cerebral arteries (MCAs), which are accompanied by collateral circulation, often described as a "puff of smoke" on angiography. Infarcts usually present in a borderzone distribution.
• Treatment strategies include the use of aspirin, supporting cerebral perfusion, and considering external carotid-internal carotid bypass (EDAS).

Cerebral Amyloid Angiopathy (CAA)

• Early dementia, high risk for stroke and lobar hemorrhages. Requires post-mortem exam for definitive dx
• May have TIA-like episodes or migraine-equivalents due to cortical convexity subarachnoid blood (superficial siderosis)
• MRI with subcortical ischemic WM disease sparing U-fibers, subcortical microbleeds, superficial cortical siderosis (subarachnoid blood), and old hemorrhages
• Treatment: avoidance of antithrombotics, blood pressure control, management of risk factors
• Boston criteria for CAA diagnosis: CAA-Related Inflammation
  1. Definite CAA: post mortem exam with lobar, cortical, or corticosubcortical hemorrhage; Severe CAA with vasculopathy; absence of other diagnostic lesion
  2. Probable CAA with supporting pathology: Clinical data and path with Lobar, cortical, or corticosubcortical hemorrhage; some degree of CAA in specimen, absence of other diagnostic lesion
  3. Probable CAA: Clinical and MRI/CT data demonstrating: Mulitple hemorrhages restricted to lobar, cortical, or corticosubcortical regions (incl cerebellar hemorrhage); Age > 55 years; absence of other cause of hemorrhage
  4. Possible CAA: Clinical data and MRI/CT demonstrate: Single lobar, cortical or corticosubcortical hemorrhage; Age > 55 yrs; Absence of other cause.

CAA-Related Inflammation:

• Rare presentation of CAA that pw acute/subacute headaches, encephalopathy, ±seizures and ± focal neuro deficits.
• MRI with asymmetric, extensive patchy or confluent FLAIR WM hyperintensities, and microbleeds, may have leptomeningeal enhancement.
• CSF may have elevated protein.
• Biopsy with vascular amyloid deposition and perivascular inflammatory changes.
• Treatment with immunosuppressive therapy: corticosteroids, Cytoxan, methotrexate, cellcept.

INFECTIOUS CAUSES OF STROKE

Subacute Infective Endocarditis:

May have an indolent course. Suspect in stroke with fever, with very elevated ESR, small multifocal embolic appearing strokes and microbleeds on MRI. Septic emboli are more likely to have hemorrhagic transformation.

• Vessel imaging: may show mycotic aneurysms. Suspect fungal etiology in immunocompromised patients.
• Exam: may have hypopnion, subconjunctival petechiae, roth spots, osler nodes, petechiae, splinter hemorrhages, janeway lesions. EKG: may have PR prolongation 2/2 perivalvular abcess. See Duke Criteria for diagnosis.
• Risk factors: include age, injection drug use, poor dentition, structural, congential, or valvular heart disease, intracardiac hardware, hemodialysis and HIV
• Organisms: Staph A. (31%), Viridns Group A strept (17%), Coag neg staph (11%), strept bovis (7%), other strept (5%), gram neg (2%), Fungi (2%), HACEK organisms (2%), enterococcus, or culture negative (8%)

Infective Vasculopathy:

• Varicella can have an indolent course with progressive encephalopathy. Imaging shows multifocal strokes, vasculopathy of small and large vessels, aneurysms, SAH or ICH. CSF with mononuclear pleocytosis, elevated RBC, VZV PCR ~30% sensitive, VZV IgG or IgM ~93% sensitive. Tx IV acyclovir 10-15mg/kg TID x14 days PLUS oral prednisone 1mg/kg x5 days. If immunosuppressed continue oral acyclovir 1-2mo after.
• HIV, or CMV (usually in setting of HIV) and very rarely HSV can also cause vasculitis/Vasculopathy. Hepatitis C can cause a post-infectious vasculitis associatd with cyroglobulinemia. Hep B can be associated with Polyarteritis Nodosa.
• Syphillis causes an obliterative endarteritis of medium to large vessels and can predispose to cervical artery dissections. CSF may have mild lymphocytic pleocytosis, elevated protein, IgG and oligoclonal bands. Rarely, Lyme and rickettsia can have similar presentations. Brucellosis and Typhus are associated with small vesssel cerebral vasculitis.
• Tuberculous meningitis can cause ischemic stroke in 60% due to inflammatory exudate in the subarachnoid space and direct invasion affecting small and medium vessels. Strokes typically found in the caudate heads, anteriomedial thalami, and anterior limbs and genu of the internal capsule due to proximity to the basilar meningitis.

Parasites

1. Chagas is the most common parasitic cause of stroke because it causes dilated cardiomyopathy and cardiac conduction abnormalities leading to embolic events.
2. Neurocystercercosis can cause stroke during active infections due to a local inflammatory arteriopathy of the small vessels, or direct compression of vessels due to cyst enlargement

GENETIC CAUSES OF STROKE

• Fabry Disease: X-linked inherited, multisystemic disease causing early onset small vessel strokes, particularly of the vertebrobasilar system. May account for 1-4% of cryptogenic stroke in the young. Caused by mutations in alpha-galactosidase A gene (GAL), resulting in deficient lysosomal activity and accumulation of glycosphingolipids in the vascular endothelium, smooth muscle, and dorsal root ganglia. MRI may show T1 hyperintensity in the pulvinar region. Alpha-galactosidase A activity can be measured and is 100% sensitive and specific in men, ~50% in women. Other manifestations include hearing loss, vertigo, neuropsychiatric symptoms, hypohidrosis, intestinal dysmotility and small fiber peripheral neuropathy with painful acroparasthesias, angiokeratomas, corneal dystrophy, renal impairment, and cardiac conduction problems.
• CADASIL (Cerebral Autosomal dominant Arteriopathy with subcortical infarcts and Leukoencephalopathy): Causes migraine with aura, depression/apathy, early dementia and subcortical lacunar strokes. Most common cause of inherited stroke and dementia in adults. MRI with subcortical small vessel strokes, particularly at the bilateral anterior temporal lobes. Diagnose with NOTCH3 genetic testing.
• CARASIL (Cerebral Autosomal recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy): similar to CADASIL but earlier in life, may have early alopecia and back pain, but typically without migraine. MRI with microbleeds, progressive leukoariosis with involvement of external capsule, pons, frontal white matter, and 'arc sing' – hyperintese lesion from pons to middle cerebellar peduncles. Diagnose with HTRA1 gene on chromosome 10q.
• Retinal Vasculopathy with Cerebral Leukodystrophy (TREX1): Presents with vision loss, early dementia, and stroke-like episodes. MRI with multifocal WMH, and may have enhancing tumor-like lesion with cortical sparing that may spontaneously regress. The retinopathy may respond to avastin.
• COL4A1-related cerebral small vessel disease (autosomal dominant): Early-onset cerebral vessel disease, microbleeds, and lacunar strokes, with high risk for subcortical ICH. May have infantile hemiparesis, congenital porencephaly, cerebral aneurysms, migraine w. aura. Additional manifestations in eyes, kidney and muscle

Miscellaneous

In some instances, a patient may require a heparin drip or low-molecular-weight heparin. Due to risk of hemorrhagic conversion, stroke patients receive a lower dose than the standard medicine doses for DVT or ACS (see heparin protocol)

THROMBECTOMY OVERVIEW

Thrombectomy - especially in large vessels benefits people on the GRADE scale- Mainstays of tx are aspiration or stent retriever

• We do a combo of adapt and penumbra--- solumbra.
• Since there are risk and benefits of each it really depends on the situation
• Place head of bed flat, 0 degrees while waiting for OR/thrombectomy per ZODIAC Excluding CHF, COPD. Limitations (terminated early, selection bias)

SCALES and TESTING

Thrombolysis in Cerebral Infarction (TICI) Scale: The TICI scale is used to evaluate immediate outcomes following thrombolysis in cerebral infarction:

• TICI 0: No reperfusion
• TICI 1: Open vessel but no reperfusion
• TICI 2a: Less than half of reperfusion return
• TICI 2b: More than half but not complete reperfusion
• TICI 3: Full reperfusion

Modified Rankin Scale (mRS): The Modified Rankin Scale is assessed 90 days post-stroke to determine functional independence:

• MRS Scale:
  • mRS 0: No symptoms at all
  • mRS 1: No significant disability; able to carry out usual duties
  • mRS 2: Slight disability; unable to carry out all previous activities but can manage own affairs
  • mRS 3: Moderate disability; requires some help but can walk independently
  • mRS 4: Moderately severe disability; unable to walk or attend to bodily needs without assistance
  • mRS 5: Severe disability; bedridden, incontinent, requiring constant care
  • mRS 6: Deceased
• Goal is to achieve an mRS score of 0-2 at 90 days = functional independence (doesn’t need help walking)
  • HERMES trial - Highly effective reperfusion evaluated in multiple endovascular stroke trials
• 46% returned to mRS 0-2 with thrombectomy
• 26% return to mRS 0-2 with tNK and medical therapy

Factors Influencing Endovascular Therapy (EVT)

1. Timing: odds ratio of returning to mRS 0-2 = we stop when the bottom 95% no longer benefit= 6 hours. (most conservative)
• There are still patients who benefit after 7 hours
• If good collaterals, reflect salvageable brain= seen on CT scan= usually seen with MCA on the other side.
• CTP techniques - observing dynamic flow as contrast washes in and out.
  • Gives us a map of CBV, CBF, TMax
2. Mismatch present (prenumbra > core)? -->thrombectomy
3. Penumbra has decreased CBF (so dose core), but what makes it different than core is unchanged/increased CBV (due to vasodilation in that area trying to increase perfusion)
4. On CTP:
   • "CBF < 30%" = core “already dead”
   • "tmax > 6"sec = penumbra “will die if we don’t do anything”
   • Extending the time window
   • DAWN - NIHSS> 10 6-24 hours, NIHSS 6
5. Deficits: The ENDOLOW trial evaluated immediate EVT versus initial maximal medical therapy for patients with an NIHSS score of ≤ 5
6. Extent of Infarct (ASPECTS)
7. Pre-morbid level of functioning  >>>>>age
   • HERMES sub-group analysis= no reason to hold thrombectomy soley on the basis of age
8. Lesion location/accessibility - Should we reperfuse more-distal lesions?
   • Superior M2, inferior M2- there is variability, sometimes, there are anterior temporal arteries, sometimes equal M2s, sometimes dominants or duplications
   • M2s are less disabling, riskier, and have smaller clots that work with tPA
   • M2s can still be disabling, stent retrievers designed for M2s
   • Half of patients with M2 will have mRS 3-6
9. Devices for the distal occlusion - Not yet developed