Intracranial Thrombolysis for Treatment of Acute stroke syndromes

Introduction

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            Intracranial thrombolysis (ICT) is a form of thrombolytic therapy in which fibrinolytic agents are utilized to dissolve clots formed in the cerebral arteries.  It is one of the most effective therapies in people suffering from acute ischemic stroke.  In ICT therapy, intravenous recombinant tissue plasminogen activator (rtPA) is utilized.  More than 4 randomized clinical trials have been conducted by different organizations to determine the effect of ICT on stroke patients.  However, only one of these trials, the one conducted by the NINDS seems to provide significant results that can be utilized clinically.  The NINDS trial found certain criteria to include or exclude the patient from performing ICT.  In the exclusion criteria patients who are likely not to benefit from the treatment or those who are likely to develop side-effects are not provided such treatment.

However, considering the list of exclusions, only a few numbers of patients are likely to benefit from ICT and hence can be provided with the treatment.  The NINDS however, has tried to differentiate between the exclusion criteria and the absolute contraindications of the procedure.  The exclusion criteria are those in whom the procedure cannot be performed due to safety considerations and also as the procedure would be life-threatening and not be safe.  The absolute contraindications list includes those patients in which the procedure would not be safe and no mention is given to the effectiveness of the procedure (Zivin, 2007 & Dirks, 2004).

Indications:

            Dirks et al developed an ‘inclusion criteria’ for ICT in acute stroke patients.  He basically wanted to include patients suffering from acute ischemic strokes where the onset has been clearly defined and in cases in which the deficit has been measurable.  CT scans of the brain should clearly show no signs of intracranial hemorrhage.  The treatment should be started within 3 hours following the development of acute ischemic stroke symptoms for it to be more effective and safe.  However, some studies demonstrate that ICT can also be beneficial to some patients with acute stroke which had started 3 to 6 hours before.  According to the MEDLINE search strategy; there were certain circumstances under which ICT can be performed.  These include:-

Cerebrovascular accidents
Infarction of the posterior cerebral artery
Infarction of the brainstem
Middle cerebral artery infarction
Anterior cerebral artery infarction
Combination of the above pathologies (Zivin, 2007 & Dirks, 2004)

Contraindications for ICT include:

Symptoms of intracranial hemorrhage exists on initial evaluation
Subarachnoid hemorrhage
Recent intracranial surgery
Serious trauma to the head
Previous stroke episodes
Previous history of intracranial hemorrhage
Hypertension existing during the procedure of above 185 mm Hg
Uncontrolled systolic or diastolic pressure of above 110 mg Hg that cannot be controlled using antihypertensive agents
Seizures coexisting with stroke during onset
Presence of an active internal hemorrhage site in the body at the time of evaluation
Presence of an intracranial tumor
A delay of more the 6 hours as the outcome would be poor and the patient is at a risk
Presence of an intracranial aneurysm
Presence of a known bleeding disorder
Administration of oral anticoagulants leading to a prothrombin time of more than 15 seconds
Platelet count of greater than 100000 per cubic mm
Elevated activated-pTP time (Zivin, 2007 & Dirks, 2004)

Need to determine the timing of acute stroke

            In a patient affected with acute stroke, treatment should be started with ICT as soon as possible, preferably within 3 hours of onset of the stroke.  This is because several meta-analysis studies conducted clearly demonstrate that the safety and the efficacy of the treatment are best when conducted within 3 hours of onset of the symptoms.  The thrombus with time becomes increasing un-dissolvable.  Besides, in the areas of thrombus formation, infarction of the brain tissue occurs, and slowly the area of infarction increases in size leading to focal neurological deficits.  Patients suffering from various forms of strokes including the mild forms and the rapidly progressing forms would benefit from ICT.  ICT can be utilized in both forms of strokes including the atherosclerotic form and the embolic form.  Several drugs are administered intravenously including streptokinase, tissue plasminogen activator and recombinant (genetically-engineered) prourokinase (Zivin, 2007, Kim, 2006 & Dirks, 2004).

Importance of CT scans

            CT Scans play a very important role in patients with stroke before they actually receive ICT therapy.  It can help to determine the cause of focal neurological deficit and differentiate the cause of Ischemic disease from other causes.  One of the most vital findings that is required through CT scans is whether the ischemia stroke is accompanied with intracranial bleeding, brain tumors and subarachnoid hemorrhage.  Intracerebral hemorrhage can usually be detected through CT imaging without any contrast media.  Within 3 to 24 hours following the stroke several findings are observed including:-

·         Hypodensity tissue areas corresponding to focal neurological deficit

·         Loss of demarcation between the white and gray mater

·         More precise hypodensity areas following 24 hours of the stroke

·         Differentiation between ischemic lesions and neoplastic lesions (especially when contrast media is utilized)

            CT scans are not specific of the size of the infarction and in certain cases hypodensity areas may not be detectable even 3 to 24 hours following the stroke.  The strong advantage CT scans have is that they are able to detect the presence of hemorrhage in the infarction areas.  Minute hemorrhages may be detectable during the initial stages but are not of much clinical significance (Zivin, 2007, Kim, 2006 & Dirks, 2004).

            MRI scans may have certain advantages over CT scans but are not preferred in patients with acute strokes.  MRI can detect early ischemia more easily compared to CT scans.  Following the onset of ischemia, defects in the blood flow can be identified.  MRI scans are not able to detect if the tissue damage is reversible or irreversible.  They are also not able to detect hemorrhage from ischemia.  Hence it may be difficult to make a judgment whether ICT could be performed in the patient.  CT scans are also able to detect the Hounsfield unit (HU) measurement of the thrombus formed in the patient with acute stroke.  It is important to note that thrombus with a lower HU count are more resistant to action with fibrinolytic agents and hence cannot be dissolved.  Platelet-rich thrombi have a lower HU count, whereas erythrocyte-rich thrombi show a higher HU count.  In this way, the CT findings are very useful in determining the efficacy of ICT and whether thrombolysis would occur or not.  Another factor which plays an important role in the destructibility of the thrombi is the age and size of the thrombus.  A large thrombus may be difficult to dissolve compared to a small thrombus, and in such cases recanalization would be difficult (Zivin, 2007, & Kim, 2006).

Different techniques that can be used in ICT

            Different fibrinolytic substances can be administered to help treat the thrombus including tissue plasminogen activator, streptokinase and recombinant prourokinase.  The drugs can be administered either intravenously or intra-arterially.  Usually t-PA is being administered intravenously whereas prurokinase is being administered intra-arterially (mainly depends on the time period at which ICT is performed).  Prurokinase is particularly useful when the patient is being treated following 3 to 6 hours following the stroke, as they can benefit to a limited extent.  tPA is usually given in a dose of 0.9 mg per kg body weight.  It is given as a 10 % bolus solution for a period of one minute initially.  The remaining solution is given over a period of one hour.  Patients who do not show response to tPA intravenously may be given tPA intra-arterially.  If the patient develops a heart attack along with acute stroke, angioplasty can be performed and tPA can also be administered.  Heparin may not be beneficial in patients with acute stroke.  However, neurological deficits occur leading to pulmonary embolism and deep vein thrombosis and hence in such patients, heparin therapy may also be required.  During the treatment of the patient, thorough monitoring of all vital signs is required.  The blood pressure should be maintained between 185 mm Hg to 110 mm Hg.  If the Blood pressure cannot be controlled, antihypertensive should be administered and then only ICT treatment should be used (Zivin, 2007, Kent, 2008, & Kim, 2006).

Outcome of the procedure

            The outcome of acute stroke when ICT is conducted within 3 hours of the occurrence of stroke is good.  People with mild strokes where the thrombus is small in size and who are attended to immediately, benefit the most.  If the stroke is severe and the infarct is large (determined through CT scan) may not have a good outcome.  Usually, treatment with ICT may not be recommended if the time period elapsed following occurrence of the stroke is great (three to six hours).  However, one study demonstrated that patients administered intra-arterial prourokinase 3 to 6 hours after the acute stroke, were able to benefit from treatment to a limited extent.  The outcome for people suffering from acute stroke and who receive ICT treatment has several positive effects including:-

·         Less chances of meeting with fatal outcomes due to acute stroke

·         More likely to lead a normal lifestyle following focal neurological deficit

·         More likely to gain independence a few months following therapy

·         Greater benefit of thrombolysis therapy occurs in women compared to men (Zivin, 2007, Kent, 2008, & Kim, 2006).

Conclusion

            At the moment, the effect and safety of intracranial therapy on acute stroke seems to be not understood clearly.  However, the few studies that have been conducted show very positive and promising effects of therapy.  The recommendations of the therapy would be changing depending on the outcomes of clinical trials.  The medical fraternity should also use the evidenced-based findings in treating patients with stroke.  Every effort should be made to evaluate the patient thoroughly and treat immediately so as to gain the positive effects of ICT.

References:

1.      Zivin JA. Ischemic Cerebrovascular Disease. In. Goldman L, ed. Goldman: Cecil Medicine. Philadelphia: Elsevier.

2.      Dirks M. Indications and contra-indications for intravenous thrombolysis in acute

ischemic stroke. Practise. 2004. http://www.practise-trial.org/docs%5CDelphiStudy.pdf

3.      Kim EY. Prediction of thrombolytic efficacy in acute ischemic stroke using thin-section noncontrast CT. Neurology. 2006; 67:1846–1848.

4.      Kent DV. The gender effect in stroke thrombolysis Of CASES, controls, and treatment-effect modification. Neurology. 2008; 71: 1080-1083.