RECENT ADVANCES IN STROKE MANAGEMENT DR. PRIYADARSHEE PATEL M.B.B.S
STROKE • World Health Organization defines stroke as 'a clinical syndrome consisting of rapidly developing clinical signs of focal (or global in case of coma) disturbance of cerebral function lasting more than 24 hours or leading to death with no apparent cause other than a vascular origin • 800000 people have stroke in a year in USA • 3rd most common cause of death • Leading cause of disability • Divided in 2 major types- IschemicHaemorrhagic
ISCHEMIC STROKE • 87% • Caused by a clot blocks a vessel supplying blood to the brain • Treatment goal- Bust or remove the clot AND Reperfuse the circuit
HAEMORRHAGIC STROKE • 13% • Caused by a rupture in a blood vessel within the brain • Treatment goal- to stop further bleeding AND manage intracranial pressure
RECOGNISE STROKE (ED) • 'Recognition Of Stroke In the Emergency Room' (ROSIER) tool. The ROSIER tool helps for a more detailed assessment including blood sugar measurement, visual field assessment and documentation of a history of seizures or loss of consciousness, and also focal neurological weakness and speech disturbance.
CT SCAN-HEAD NON CONTRAST • A noncontrast head CT may identify the early signs of stroke, but most importantly will exclude intracerebral hemorrhage and lesions that might mimic acute ischemic stroke such as tumor or intracerebral hemorrhage. • CT manifestations of stroke: Acute (less than 24 hours) cytotoxic edema, It is intracellular edema and causes loss of the normal gray/white matter interface and effacement of the cortical sulci. A thrombus in the acute phase appears as hyperattenuation. Subacute (24 hours to 5 days) vasogenic edema, with greater mass effect, hypoattenuation and well-defined margins. Mass effect and risk of herniation is greatest at this stage. Chronic (weeks) Loss of brain tissue and are hypoattenuating.
MRI HEAD • High signal intensity may be seen on T2WI and proton density–weighted images beginning approximately 8 hours after onset corresponding to a vascular distribution. T1WI may take significantly longer to demonstrate low signal. • FLAIR images demonstrate abnormal signal sooner than T2WI and have been shown to be useful in detecting infarcts within 3 hours after onset of acute stroke. FLAIR images may also demonstrate intra-arterial signal that is hyperintense or isointense to gray matter. This is believed to occur immediately after occlusion • Acutely ischemic lesions demonstrate high signal of DWI and low signal on ADC maps within minutes. Abnormal signal of DWI has been reported to normalize in as little as 14 days.
EEG • ECHO • MRA or CTA • CAROTID ULTRASOUND
COMMON LABS • Routine blood tests • Full blood count • Clotting screen • U+E • Glucose • Lipid profile • ESR/CRP • Thyroid function tests • Vasculitis screen • Thrombophilia screen (Protein C, Protein S, antithrombin III, factor V Leiden, antiphospholipid antibodies) • Toxicology screen • Homocysteine • Serum lactate
The thrombolytics- urokinase, prourokinase, streptokinase, alteplase, and reteplase. • In general, the nonfibrin-selective drugs (e.g., urokinase and streptokinase) can result in systemic hypofibrinogenemia, whereas the fibrin-selective agents (e.g., alteplase and r-prourokinase) are theoretically mostly active at the site of thrombosis.
Intravenous r-TPA (0.9 mg/kg, maximum 90 mg) with 10% of the dose given as a bolus followed by an infusion lasting 60 minutes is recommended treatment within 3 hours of onset of ischemic stroke • If CT demonstrates early changes of a recent major infarction such as sulcal effacement, mass effect, edema, or possible hemorrhage, thrombolytic therapy should be avoided • Thrombolytic therapy should not be given unless the emergent ancillary care and the facilities to handle bleeding complications are readily available • If the patient’s neurologic status declines during tPA infusion- Stop the infusion Page the Stroke Neurologist Draw and send PT/PTT, D-Dimer and fibrinogen Prepare for emergent CT
CONTRAINDICATIONS • CT scan findings of intracranial hemorrhage or major acute infarct • Suspicion of subarachnoid hemorrhage • Significant head trauma or prior stroke in previous 3 months • Recent intracranial or intra-spinal surgery • History of previous intracranial hemorrhage or brain aneurysm, vascular malformation or brain tumor • Arterial puncture at non-compressible site in previous 7 days • Known bleeding diathesis • Current use of oral anticoagulants with INR > 1.7 or PT and > 15 seconds • Use of heparin within 48 hours prolonged PTT • Platelets < 100,000 • Active internal hemorrhage • Persistent systolic BP >185 mm Hg or diastolic BP > 110 mm Hg despite treatment. • Blood glucose concentration < 50 mg/dl
Coil retrievers • The coil retrievers are composed of Nitinol shape-memory wire and delivered through a microcatheter across the target clot. As the device is extruded from delivery catheter, it immediately reassumes its native coil form. The neurointerventionalist deploys the loops of the coil through the clot to engage the thrombus, and then pulls both coil and clot back into the catheter, like pulling a cork from a wine bottle.
Coil retrievers Merci (Stryker) Differing in helix length, diameter, curvature, and presence of additional cascading filaments
Aspiration devices • Suction thrombectomy devices employ vacuum aspiration to remove occlusive clot in acute ischemic stroke. While manual aspiration of target thrombi can be performed through any microcatheter, progress in developing suction thrombectomy devices required a technical solution to the problem of clogging of aspiration tips, a common occurrence when applying suction through a bore small enough to fit within intracranial arteries.
Aspiration devices • The Penumbra System overcomes this obstacle by adding an in bore separator wire with a bulbous tip that the operator continually advances and retracts, disrupting attached clot and pulling in thrombus ahead of the catheter
Stent retrievers • The stent retrievers are self-expanding stents that are deployed in the occluded vessel within the thrombus, pushing it aside and entangling it within the stent struts. The stent and thrombus are then withdrawn back into the delivery catheter.
Stent retrievers • The first retrievable stent approved in the United States is the Solitaire Flow Restoration Device (Covidien). Trevo (Stryker), Revive (Codman), MindFrame (MindFrame Inc.), ReStore (Reverse Medical), and Pulse (which combines a stent retriever and an aspiration device, Penumbra)
ADVERSE EVENTS • Intracerebral hemorrhage, as with all reperfusion therapies, • Subarachnoid hemorrhage, related to device injury to the vessel wall • Fragmentation of the target thrombus leading to embolization to a new, more distal territory. • Symptomatic intracranial (intracerebral or subarachnoid) hemorrhage (SICH) occurs in ∼10% of patients with first generation devices (Merci and Penumbra), but is substantially lower with the Solitaire stent retriever (2%–4%).
EFFICACY • Coil retrievers were approved based on 2 trials: Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi-MERCI. Multi-MERCI was a single-arm, multicenter study that enrolled 177 patients. Substantial partial or complete recanalization was achieved in 55% of patients with the coil retrievers alone and 69% with rescue use of additional endovascular therapies. • The Penumbra suction thrombectomy system was cleared based on results from a prospective single-arm multicenter trial that tested the safety and efficacy of the device in 125 patients. Partial or better recanalization was reported in 82% and complete recanalization in 23% of patients • The first stent retriever to be cleared by the Food and Drug Administration, the SOLITAIRE FR, was authorized based on the SOLITAIRE FR with the Intention for Thrombectomy (SWIFT) study. In this multicenter, randomized trial, Solitaire was compared to the Merci Retriever as the initial device intervention in 113 acute ischemic stroke patients. The primary efficacy outcome, successful recanalization without SICH, was achieved more often in SOLITAIRE vs MERCI patients, 60.7% vs 24.1% (p = 0.0001). Good neurologic outcome at 90 days was more frequent (58% vs 33%, p = 0.02) and mortality rates lower (17% vs 38%, p = 0.02) when the stent rather than the coil retriever was employed.
LIMITATIONS • LARGE PROXIMAL ARTERIES- Mechanical thrombectomy devices work well in large, proximal arteries, rapidly debulking large clot burdens that are resistant to chemical fibrinolysis. Not well suited for distal arterial branches (hard to navigate to and device diameters too large) and are not options for penetrator occlusions, while chemical fibrinolysis works well on those targets. • CARDIAC OR ARTERIAL EMBOLI- Mechanical thrombectomy devices work well when the target intracranial occlusion is an embolus that has arisen from the heart or a proximal aortocervical arterial source and landed in a relatively normal recipient artery. When the occlusive lesion is an in situ intracranial atherosclerotic plaque with supervening thrombosis, retrieval devices may catch on the plaque and aspiration devices are effective only for the thrombus component. In situ atherothrombi are probably better treated with balloon angioplasty and stenting, which accomplish controlled cracking and dissection of the underlying atherosclerotic lesions.
Faster, faster, faster: Speed is of the essence in treating large artery cerebral ischemia, as 2 million more nerve cells are lost every minute in which reperfusion does not occur. All sites performing mechanical thrombectomy should have vigorous continuous quality improvement programs, targeting door to arterial puncture times of less than 90 minutes. Since IV fibrinolysis can be started sooner than endovascular therapy and does not increase the risk of endovascular therapy,2–4 patients who are candidates for IV tPA should receive standard dose (0.9 mg/kg) IV tPA on their way to the neurocath lab. • Imaging selection beyond 3 hours: In the first 3 hours after a large artery vascular occlusion, virtually every patient still harbors at least some salvageable penumbral tissue and may benefit from intervention. Multimodal CT or MRI may assist in identifying the patients in the 3- to 14-hour window who may still benefit from reperfusion. Most likely to benefit are patients with a small core (<20 cc) of irreversibly infarcted tissue and a large penumbral, salvageable region (>20 cc). Highly unlikely to benefit are patients with large cores (>90 cc) and patients with no penumbra.
INTENSIVE CARE AND MONITORING • Do not perform for 24 hours post THROMBECTOMY unless procedure is life-saving: Arterial or central venous punctures/lines, IM injections, nasogastric tubes, Foley catheters • Place the patient on anticoagulation precautions until 24 hours after the infusion • Do not give any antithrombotic drugs (including heparin, warfarin, aspirin, clopidogrel, dipyridamole, ticlopidine, or NSAIDS) x 24 hrs • Treat systolic BP if it rises >180 mm Hg or diastolic BP >105 mm Hg for more than 15 minutes Pause infusion while BP is being controlled. • Avoid BP decrease < 160/ 85 mm Hg
GENERAL TRETMENT • Aspirin and anti-platelet therapy: Once Primary cerebral haemorrhage excluded by imaging, all patients should be given aspirin 300 mg orally (rectally/nasogastrically if dysphagic) as soon as possible and definitely within 24 h. AIS patients receiving thrombolysis should have aspirin withheld for 24 h after thrombolysis. Patient already on Aspirin, add Dipyridamole or switch to Clopidogrel
Statin some controversy surrounds the immediate prescription of statins post AIS, as increased rates of haemorrhagic transformation have been reported, but clear evidence points to their long-term benefit in reducing future AIS risks. All patients should thus be considered for treatment with statin therapy after 48 h. • Avoidance of aspiration pneumonia, SALT assessments • Assessment of nutritional status and supplemental hydration and nutrition, nasogastric feeding in those unable to take adequate oral nutrition within 24 hr • Hypotonic fluids should be avoided as they may worsen cerebral oedema
Temperature Control and Cooling: It is noticed that quarter of patients may be hyperthermic in the initial 6 h after AIS, suggesting an association between high body temperature and poor outcome. The use of therapeutic hypothermia in acute stroke offers potential for combination therapy with aspirin and rt-PA, by attenuating blood–brain barrier permeability and the endogenous inflammatory CNS response after AIS. The fact that hypothermia also lowers metabolic and energy demands may also have implications for extending the window for thrombolysis. • Hemicraniectomy Malignant MCA infarction is a devastating form of ischaemic stroke, which accounts for between 1 and 10% of supratentorial infarction and which carries an 80% mortality. Decompressive hemicraniectomy is a potentially life-saving treatment for the condition, acting by normalizing intracranial pressure, restoring penumbral and adjacent vascular territory blood flow and preventing herniation
Blood Sugar Control: management of an elevated blood glucose level after stroke should be similar to that of other acutely ill patients who have hyperglycaemia. NICE consensus recommends maintaining blood glucose between 4 and 11 mmol litre, although overly aggressive treatment can result in fluid shifts and electrolyte abnormalities including hypoglycaemia detrimental to the brain. • Blood Pressure Control: should be controlled to ≤185/110 mm Hg in patients who may be appropriate for thrombolysis Patients whose blood pressure is >220 mm Hg systolic or >120 mm Hg diastolic on repeat measurements, should be given NO to reduce blood preesure ≤185/110 mm Hg The rationale for treatment is to lower the risk of haemorrhagic transformation, although aggressive blood pressure reductions may adversely affect cerebral perfusion, especially in the penumbra, thus exacerbating ischaemic damage.
First tier intervention: Give IV labetalol 10 mg over 1 to 2 minutes. Labetalol may be repeated up to 3 doses every 10 to 20 minutes then consider drip) • For heart rate <60/minute, use hydralazine 5-20mg intravenous over 1-2 minutes every 20-30 minutes. After second bolus, consider second line intervention. • Second tier intervention: If 3 doses of labetalol or hydralazine bolus or 30 minutes pass without sufficient BP control, the next step should be a nicardipine drip. • Third tier intervention: If nicardipine drip fails, then the next step should be a labetalol drip.
Rehabilitation is probably one of the most important phases of recovery for many stroke survivors. • The effects of stroke may mean that you must change, relearn or redefine how you live. Stroke rehabilitation helps you return to independent living. • Self-care skills such as feeding, grooming, bathing, toileting and dressing • Mobility skills such as transferring, walking or self-propelling a wheelchair • Communication skills in speech and language • Cognitive skills such as memory or problem solving • Social skills for interacting with other people
To test the safety and tolerability of injecting neural stem cells into the brains of ischemic stroke patients, • The stem cell trial started in 2010, with one stroke patient, was injected with ReN001 cells developed by ReNeuron Group plc, at the • Trial center- Southern General Hospital in Glasgow, UK. • By 2012, there were six patients on the small trial, and an early set of results presented that five of the six patients were showing some improvement and there had been no adverse side effects. • The trial is controversial because the stem cell line originated nearly ten years ago, from the tissue of a 12-week fetus. • ReN001 is a genetically engineered line of adult stem cells that are described as "committed, not pluripotent". That is they are not capable of turning into any type of cell in the body: they are already part way down the track of becoming neurons or brain cells.
DERIVED MESENCHYMAL STEM CELLS IN STROKESTANDFORD UNIVERSITY, CA