Cerebral infarction refers to ischemic necrosis or softening of restricted brain tissue due to impaired blood circulation in the brain and ischemia and hypoxia. Vascular wall lesions, blood composition and hemodynamic changes are the main causes of cerebral infarction. The incidence of cerebral infarction is 110 per 100,000 population, accounting for about 60% to 80% of all strokes. The diagnosis and treatment of cerebral infarction focuses on staging according to the time of onset, clinical manifestations, etiology and pathology, integrating the systemic status and implementing individualized treatment. It is especially important to take active and reasonable treatment measures in the hyperacute and acute phases.
I. Diagnosis
(A) General diagnosis
1. Clinical features
(1) Most of the cases have acute onset under static conditions; cardiogenic cerebral infarction is more common in dynamic onset, and some cases may have TIA episodes before the onset.
(2) The condition mostly peaks within a few hours or days, and some patients’ symptoms can progressively worsen or fluctuate.
(3) Clinical manifestations are determined by the size and location of the infarct foci, mainly symptoms and signs of focal neurological deficits, such as hemiparesis, hemianesthesia, aphasia, ataxia, etc. Some may have whole-brain symptoms such as headache, vomiting, coma, etc.
2.Auxiliary examination
(1) Blood tests: platelets, coagulation function, blood sugar, etc.
(2) Imaging examination: Imaging examination of brain can visually show the scope, location, vascular distribution, presence of bleeding, old and fresh infarct foci, etc. of cerebral infarction, which helps clinical judgment of whether the tissue is reversible after ischemia, vascular condition, and hemodynamic changes. To help select patients for thrombolysis and assess the degree of risk of secondary bleeding.
① Cranial computed tomography (CT) scan
Cranial CT plain scan is the most commonly used test. However, it is not sensitive to ultra-early ischemic lesions and small cortical or subcortical infarcts, especially brainstem and cerebellar infarcts in the posterior cranial fossa are more difficult to detect.
In the ultra-early stage (within 6 hours of onset), CT can reveal some minor changes: high-density sign in the middle cerebral artery; unclear demarcation of gray and white matter in the cortical margins (especially in the insula) as well as in the region of the nucleus accumbens; and disappearance of the cerebral sulcus. Usually plain scan is sufficient for clinical use. If CT angiography, perfusion imaging, or to exclude tumor, inflammation, etc., contrast injection is required to enhance the image.
② Cranial magnetic resonance imaging (MRI)
Standard MRI sequences (T1, T2 and proton phases) are not sensitive to cerebral infarction within a few hours of onset. Diffusion-weighted imaging (DWI) can show the size and location of ischemic tissue early and can even show small infarct foci in the subcortex, brainstem and cerebellum. The diagnostic sensitivity of early infarction reaches 88% to 100%, and the specificity reaches 95% to 100%.
Perfusion-weighted imaging (PWI) is imaging that shows relative hemodynamic changes in brain tissue after intravenous injection of paramagnetic contrast agent. The area of perfusion-weighted alterations is larger than that of diffusion-weighted alterations, and the area of diffusion-perfusion mismatch is currently considered a semidark band.
(iii) Transcranial Doppler ultrasound (TCD)
is useful in determining the degree of intracranial and extracranial vascular stenosis or occlusion, vasospasm, and establishment of collateral circulation. Recently, it has been applied to the monitoring of thrombolytic therapy and is useful for prognostic judgment.
④ Angiography
Although modern angiography has reached a minimally invasive, low-risk level, it is not necessary to routinely perform angiographic digital subtraction (DSA) for the diagnosis of cerebral infarction. DSA is helpful in performing endovascular interventions, intra-arterial thrombolysis, and determining the effectiveness of treatment, but still carries some risk.
Magnetic resonance angiography (MRA) and CT angiography (CTA) are non-invasive examinations that are helpful in determining the involved vessels and the effect of treatment.
⑤ Others
Positron emission tomography (PET), xenon enhanced CT, single photon emission computed tomography (SPECT), etc., are mostly used for research in units that have the conditions.
(II) Clinical staging (OCSP staging)
Due to the differences in the site and size of cerebral infarction, the compensatory capacity of collateral circulation, and secondary cerebral edema, there can be different clinicopathological types, and their treatment is very different, which requires rapid and accurate staging in the acute phase, especially in the ultra-early stage (within 3-6 h). The Oxfordshire Community Stroke Study Staging (OCSP) does not rely on imaging findings. It allows rapid staging based on clinical presentation before conventional CT and MRI can detect the lesion, and indicates the size and location of the occluded vessel and infarct, which is clinically simple and easy to perform, and is valuable in guiding treatment and assessing prognosis.
OCSP clinical staging criteria.
1, complete anterior circulation infarction (TACI): manifested as a triad, i.e., the manifestation of complete middle cerebral artery (MCA) syndrome: impairment of higher neural activity in the brain (impaired consciousness, aphasia, aphasia, spatial disorientation, etc.); isotropic hemianopia; and more severe motor and/or sensory impairment in three contralateral sites (face, upper limbs and lower limbs). Most of them are proximal trunks of the MCA, and a few are large brain infarcts caused by occlusion of the siphon segment of the internal carotid artery.
2. Partial anterior circulation infarction (PACI): two of the above triad signs are present, or only higher neural activity impairment, or sensory-motor deficits are more limited than TACI. It is suggested that the infarct is a small or medium-sized infarct caused by occlusion of the distal trunk of MCA, branches at all levels or ACA and branches.
3. Posterior circulation infarction (POCI): manifests as various degrees of vertebral-basilar artery syndrome: it can manifest as ipsilateral cerebral nerve palsy and contralateral sensorimotor deficits; bilateral sensorimotor deficits; binocular synergistic activity and cerebellar dysfunction without long bundle sign or visual field deficits, etc. Brainstem and cerebellar infarcts of varying sizes caused by occlusion of vertebral-basilar arteries and branches.
4. Lacunar infarction (LACI): manifests as lacunar syndrome, such as pure motor light hemiparesis, pure sensory stroke, ataxic light hemiparesis, clumsy hand – poor dysarthria syndrome, etc. Most of them are small cavernous foci caused by lesions in the basal ganglia or small penetrating branches of the pons.
II. Treatment
The treatment of cerebral infarction cannot be generalized, and highly targeted treatment plans should be determined according to different etiologies, pathogenesis, clinical types and time of onset, etc., and individualized treatment with the core of typing and staging should be implemented. On the basis of general medical support treatment, measures such as improving cerebral circulation, cerebral protection, anti-cerebral edema and lowering cranial pressure can be used as appropriate. Usually, the disease can be divided into acute phase (1 month), recovery phase (2-6 months) and sequelae phase (after 6 months) according to the course of the disease. The focus is on the fractionated treatment in the acute phase. Dehydration is not recommended for lacunar cerebral infarction, mainly to improve circulation; large and medium infarcts should be actively anti-cerebral edema to lower cranial pressure and prevent brain herniation formation. Thrombolytic therapy is feasible for those with indications within the time window of less than 6 hours.
(i) Comprehensive medical support therapy: special attention should be paid to blood pressure regulation
(ii) Anti-cerebral edema and lowering cranial hypertension
(C) Improvement of cerebral blood circulation
Cerebral infarction is caused by ischemia, restoring or improving the perfusion of ischemic tissues becomes the focus of treatment and should be carried out in the whole process to maintain a good cerebral perfusion pressure. The commonly used clinical measures can be summarized as follows.
1.Thrombolytic therapy
The presence of a semidark zone around the infarcted tissue is the basis of modern treatment for ischemic stroke. Even in the early stage of cerebral infarction, the central part of the lesion is already irreversibly damaged, but timely restoration of blood flow and improvement of tissue metabolism can salvage the semi-dark zone around the infarct with only functional changes and avoid the formation of necrosis. Most cerebral infarcts are intracranial arterial occlusions caused by thromboembolism; therefore, revascularization and restoration of flow is the most reasonable treatment.
It has been conclusively demonstrated that intravenous thrombolytic therapy with recombinant tissue-type fibrinogen activator (rt-PA) applied within 3 h of ischemic stroke onset not only significantly reduces the risk of death and severe disability, but also greatly improves the quality of life of survivors. Now, the U.S. FDA and European countries have approved its clinical application. The results of a randomized double-blind study conducted in China during the Ninth Five-Year Plan showed that intravenous thrombolytic therapy with urokinase is safe and effective for acute ischemic stroke patients with no significant hypointense changes in brain CT and clear consciousness within 6 h of onset. Three randomized controlled studies of intravenous thrombolysis with streptokinase have been performed, but all trials were terminated early due to increased mortality or poor outcomes; therefore, the available data do not support the clinical use of streptokinase thrombolysis for ischemic stroke.
Arterial thrombolysis has a higher rate of revascularization than intravenous thrombolytic therapy, but its benefits are offset by the delay. A randomized controlled study showed that intra-arterial thrombolysis with recombinant urokinase progenitor (r-proUK) within 6 h of onset was initially shown to be safe and effective in ischemic stroke patients with middle cerebral artery occlusion, but this conclusion needs further confirmation. Case studies suggest that thrombolysis may also be beneficial in patients with prolonged basilar artery occlusion, and that the time window and indications for thrombolysis may be appropriately relaxed because of the very high mortality rate of basilar artery thrombosis, for which thrombolysis may be the only salvage method. There is no information on the effectiveness and safety of transcarotid injection of thrombolytic drugs for ischemic stroke.
(1) Indications
① Age 18 to 75 years.
(2) Onset within 6 hours.
(3) Signs of cerebral impairment persist for more than 1 hour and are relatively severe (NIHSS score 7-22).
④ Intracranial hemorrhage has been excluded by brain CT, and there are no early cerebral infarction hypointense changes and other obvious early cerebral infarction changes.
⑤ The patient or family members signed the informed consent.
(2) Contraindications
① Previous intracranial hemorrhage, including suspected subarachnoid hemorrhage; history of cranial trauma in the last 3 months; gastrointestinal or urinary bleeding in the last 3 weeks; major surgical procedure in the last 2 weeks; arterial puncture in the last 1 week at a non-compressible site.
② History of cerebral infarction or myocardial infarction in the last 3 months. Except for those with old small cavities without residual neurological signs.
③ Those with severe cardiac, renal or hepatic insufficiency or severe diabetes mellitus.
④ Physical examination reveals evidence of active bleeding or trauma (e.g., fracture).
⑤ Have taken oral anticoagulants with INR > 1.5; have received heparin therapy within 48 hours (aPTT outside the normal range).
⑥ Platelet count <100,000/mm3 and blood glucose <2.7 mmol/L (50 mg).
(vii) Blood pressure: systolic blood pressure >180mmHg, or diastolic blood pressure >100mmHg.
⑧ Pregnancy.
⑨ Non-cooperation.
(3) Thrombolytic drug therapy
① Urokinase: 1,000,000 IU ~ 1,500,000 IU, dissolved in 100~200ml of saline and continued to be intravenous for 30min.
② rtPA: the dose is 0.9mg/kg (the maximum dose is 90mg), push 10% intravenously (1min) first, and the rest of the dose is given continuously by IV drip for 60min.
(4) Precautions for thrombolytic therapy
① Receive the patient to the ICU or stroke unit for monitoring.
(2) Perform neurological function assessment regularly, 1 time/15 min during intravenous drip of thrombolytic drug; then 1 time/30 min for the next 6 h; thereafter 1 time/60 min until 24 h.
③ Patients with severe headache, acute increase in blood pressure, nausea or vomiting should immediately discontinue thrombolytic drugs and undergo urgent cranial CT examination.
④ Monitoring of blood pressure: 1 time/15 min during the initial 2 h of thrombolysis, followed by 1 time/30 min during the next 6 h, and thereafter, 1 time/60 min until 24 h. If the systolic blood pressure is ≥185 mmHg or diastolic blood pressure is ≥105 mmHg, blood pressure should be checked more than once. Beta-blockers, such as labetalol and pentoxifylline, may be used as appropriate. If systolic blood pressure > 230 mmHg or diastolic blood pressure > 140 mmHg, sodium nitroprusside can be administered intravenously.
⑤ After intravenous thrombolysis, continue the comprehensive treatment and choose individualized plan according to the condition.
(6) Anticoagulation and antiplatelet agents are generally not used within 24 hours after thrombolytic therapy, and aspirin 300mg/d for 10 days is available for those without contraindications after 24 hours, and later changed to maintenance amount of 75-100mg/d.
(7) Do not place nasogastric tube, urinary catheter or intra-arterial pressure measuring catheter too early.
Recommendations.
1. Thrombolytic therapy
(1) Intravenous thrombolytic therapy should be actively used for strictly selected patients with acute ischemic stroke within 3h of onset. The first choice is rtPA. If rtPA is not available, urokinase can be used instead.
(2) Intravenous urokinase thrombolysis can be applied to patients with acute ischemic stroke of 3-6h onset, but the selection of patients should be more stringent.
(3) For acute ischemic stroke patients within 6 h of onset, intra-arterial thrombolysis studies can be considered in experienced and qualified units.
(4) The time window and indications for thrombolytic therapy for basilar artery thrombosis can be relaxed appropriately.
(5) Thrombolysis beyond the time window will mostly not increase the therapeutic effect and will increase reperfusion injury and bleeding complications, so it is not appropriate to thrombolysis, and thrombolysis should be disabled for patients in the recovery period.
2.Fiber-lowering therapy
A lot of evidence shows that fibrinogen and blood viscosity in plasma are increased in the acute phase of cerebral infarction. Snake venom preparations can significantly reduce plasma fibrinogen levels, and also increase fibrinolytic activity and inhibit thrombosis, which is more suitable for patients with combined hyperfibrinogenemia.
(1)Batroxolase
It has been used in China for many years and has accumulated some clinical experience. There was a multicenter, randomized, double-blind, placebo-parallel controlled study in China, in which patients with cerebral infarction in the internal carotid artery system within 72 hours of onset were enrolled. The results showed that bactrim was effective in the treatment of acute cerebral infarction, significantly reducing fibrinogen levels, improving symptoms quickly and significantly, and having mild adverse effects, but attention should also be paid to bleeding tendency.
(2) Fibrin-lowering enzyme
A recently completed multicenter, randomized, double-blind, placebo-controlled clinical trial in China confirmed that the application of domestic fibrinogen-lowering enzyme can effectively reduce fibrinogen levels in the blood of cerebral infarction patients, improve neurological function, and reduce the recurrence rate of stroke, with a better effect within 6 hours of onset. It is worth noting that fibrinogen decreased to below 130mg/dl increased the tendency of bleeding.
(3) Other fibrin-lowering agents
such as earthworm kinase and herbicase are also used clinically.
Recommendations.
(1) Early cerebral infarction (especially within 12 hours) can be used for fibrin-lowering treatment; patients with hyperfibrinogenemia should be more actively treated with fibrin-lowering treatment.
(2) The indications and contraindications should be strictly mastered.
3.Anticoagulation therapy
The purpose of anticoagulation therapy is to prevent early recurrence of ischemic stroke, prolongation of thrombus and prevent secondary thrombosis of small vessels in the distal part of the blockage, and to promote collateral circulation. However, although anticoagulation therapy in the acute phase has been widely used for many years, it has been controversial.
(1) Usual heparin (UFH)
Although UFH is commonly used abroad for the treatment of cerebral infarction, no clinical trials have been reported on full doses of UFH as a treatment option. A randomized controlled trial (IST) of low or moderate doses of UFH subcutaneously for acute cerebral infarction showed that although heparin reduced early recurrence of stroke, there was a concomitant increased risk of hemorrhage.
(2) Low-molecular heparin (LMWH)
The efficacy of low molecular heparin in the treatment of ischemic stroke has been evaluated differently in some foreign studies. In Hong Kong, clinical observation of two doses of LMWH, subcutaneous injection of low molecular heparin for 10 days for ischemic stroke within 48 hours of onset, showed a significant reduction in mortality at 6 months in the high-dose group (4100 U subcutaneous injection twice daily). However, three European clinical trials did not show the same results.
(3) Heparoid
The TOAST trial in the United States showed that heparinoids did not reduce the recurrence rate of stroke and did not alleviate the progression of the disease. However, heparinoids may be effective in large arteriosclerotic strokes when analyzed for stroke subtypes.
(4) Anticoagulation as adjunctive therapy
The use of heparin after intravenous thrombolysis increases the rate of revascularization, but also increases bleeding complications. More clinical trials are needed on the effect of preventing revascularization. Most foreign studies do not advocate the use of anticoagulation within 24 hours after thrombolysis. The use of anticoagulation therapy should be closely monitored and the amount of anticoagulant used should vary from person to person.
Recommendations.
(1) Routine and immediate use of anticoagulants is not recommended for patients with acute cerebral infarction in general.
(2) The use of anticoagulants within 24 hours is generally not recommended in patients treated with thrombolysis.
(3) In the absence of contraindications such as bleeding tendency, severe liver and kidney disease, and blood pressure >180/100mmHg, selective use of anticoagulants may be considered in the following cases.
(1) Patients with cardiogenic infarction (e.g. prosthetic valve, atrial fibrillation, myocardial infarction with appendage thrombosis, left atrial thrombosis, etc.), prone to recurrent stroke.
② Patients with ischemic stroke with protein C deficiency, protein S deficiency, active protein C resistance, and other vulnerable conditions; patients with symptomatic extracranial entrapment aneurysms; patients with intracranial and external arterial stenosis.
③ Patients with bedridden cerebral infarction can use low-dose heparin or corresponding doses of LMW to prevent deep vein thrombosis and pulmonary embolism.
4.Anti-platelet agents
Several studies have been performed to verify the effectiveness of aspirin or other antiplatelet agents in the treatment of ischemic stroke.
(1) Aspirin
The results of two large studies (IST, CAST) showed that early use of aspirin in ischemic stroke was effective in reducing mortality and disability, with no significant increase in symptomatic cerebral hemorrhage, but concomitant application with thrombolytic drugs increased the risk of bleeding.
(2) Other antiplatelet agents
There have been studies of the use of glycoprotein IIb/IIIa receptor inhibitors alone or in combination for the treatment of cerebral infarction. Small sample studies have shown that such agents are still safe.
Recommendations.
(1) Most patients without contraindications to non-thrombolysis should be started on aspirin as soon as possible (preferably within 48 hours) after stroke.
(2) Patients with thrombolysis should use aspirin 24 hours after thrombolysis, or a combination of aspirin and pentoxifylline extended release (see Chapter 2 for details).
(3) The recommended dose of aspirin is 150-300 mg/d, which is changed to prophylactic dose after 4 weeks.
5.Volume expansion
For patients with general ischemic cerebral infarction, there are no adequate randomized clinical control studies to support that volume expansion and pressure increase can improve the prognosis, but for acute cerebral infarction due to cerebral blood flow hypoperfusion such as watershed infarction, volume expansion therapy can be considered as appropriate, but attention should be paid to possible aggravation of cerebral edema, cardiac failure and other complications.
6.Chinese herbal medicine treatment
Animal experiments have shown that some single components of traditional Chinese medicine or multiple drug combinations such as Danshen, Chuanxiongzin, Panax notoginseng, Gekisin, and Ginkgo biloba preparations can reduce platelet aggregation, anticoagulation, improve cerebral blood flow, and reduce blood viscosity. Clinical experience has also shown beneficial effects on the prognosis of ischemic stroke. However, there are no large sample, randomized controlled studies showing clinical effectiveness and safety.
(iv) Neuroprotective agents
Many experimental and clinical studies have been conducted to investigate the effects of various neuroprotective agents. Many neuroprotective agents are effective when tested in animals, but there is a lack of convincing data from large samples of clinical observations. Currently, the commonly used ones are cytarabine, cerebrofacial, and calcium channel blockers.
Sub-hypothermia may be a promising treatment method, and studies are underway.
In conclusion, the use of neuroprotective agents may reduce cellular damage, enhance the effect of thrombolysis, or improve cerebral metabolism, but results from multicenter, randomized, double-blind, controlled clinical trials with large samples are lacking.