Stroke Case File

Stroke Case File

Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH

Case 32

A 52-year-old man presents to the ED with a complaint of mild left-sided weakness  that began approximately 2 hours ago while he was performing yard work. The patient has a history of COPD and still smokes 1 pack of cigarettes per day. While  in the emergency department, he complains of a severe  headache associated with emesis. His BP is 190/100 mm Hg;  pulse is 76 beats/minute and regular.  Neurologic  examination shows no papilledema, dysarthria, or facial drooping. The patient then receives intravenous recombinant tissue plasminogen activator (rTPA) therapy  and shortly thereafter develops acute weakness of the left arm and leg along with slurred speech. An emergent repeat CT scan is performed (Figure 32-1).

Figure 32-1. CT imaging of the brain.

⯈What is the most likely diagnosis?

⯈What is the next step in the treatment of this patient?

ANSWER TO CASE 32:

Stroke

Summary: This 5 2-year-old man with COPD is seen in the ED for left-sided weakness. He receives rTPA therapy, and then develops marked left-sided weakness. A CT scan is performed. 

• Most likely diagnosis: Initially TIA versus stroke, then hemorrhagic complication of rTPA. 
• Next step: All anticoagulation therapy should be stopped, hypertension should be controlled, and any coagulopathy should be corrected.

ANALYSIS

Objectives

1. To understand the causes of cerebral vascular atherosclerosis and disease.
2. To understand the treatment of ongoing stroke.
3. To understand the common complications of stroke therapies.
4. To understand the medications for the prophylaxis of stroke.

Considerations

The patient has suffered the most feared complication of rTPA treatment, which is an intracranial bleed. The internal capsule is the most common area for strokes in hypertensive patients. Once intracranial bleeding is identified, all anticoagulation therapies are discontinued. Controlling the BP and reversing any clotting abnormalities is essential. The initial workup should include CT or MRI scans of the brain for determination of ischemic versus hemorrhagic stroke, while maintaining control of the BP. I think an extra space needs to be here? Initially, the patient has an acute nonhemorrhagic CVA. CVA is the second most common cause of death of adults in the United States. After rTPA therapy for his stroke, despite meeting all the criteria for administration of a clot dissolving drug rTPA, the patient succumbed to a well-identified side effect of this class of drugs and developed a hemorrhagic bleed in the area of the right internal capsule.

Approach To:

Stroke

Stroke and CVA rank second after ischemic heart disease (CAD) as a cause of life years lost to disability and death worldwide. The incidence of stroke varies among countries and increases exponentially with age. In Western societies, 80% of strokes are caused by focal cerebral ischemia due to arterial occlusion, and 20% are caused by hemorrhage. Ischemic brain injury culminates in anoxic cell death. Initially after arterial occlusion, an area of edema with structural integrity surrounds a central core of tissue death. This is the area that can recover from the first minutes to hours of the insult. No clinical deficits and findings necessarily reflect irreversible damage. Depending on the duration and severity of the ischemia, the edematous area may be incorporated into the infarct or normal tissue.

Thirty-day mortality rates are in the range of 10% to 17%. Older patients do worse after stroke; poor prognosis is also noted with the coexistence of ischemic heart disease and diabetes mellitus (DM). Mortality is related to the size of the infarct; the risk of death is as low as 2.5 % with lacunar infarcts and as high as 78% with space-occupying hemispheric infarcts.

TREATMENT

The dictum is "time is brain tissue." Hence, as soon as a patient is diagnosed with possible stroke, acute imaging should be performed to rule out a hemorrhagic process and the patient screened for possible thrombolytic therapy. The treatment with intravenous rTPA (alteplase) or IV thrombolytics when started within 3 hours after the onset of symptoms are effective in limiting the severity of stroke. The recommended rTPA dose is 0.9 mg/kg with a maximum of 90 mg, with the first 10% being given IV over a period of 1 minute, and the remaining 90% given within 1 hour. Treatment leads to a 31% to 50% favorable neurologic or functional outcome at 3 months. Symptomatic intracranial hemorrhage occurred in 6.4% of the rTPA group versus 0.6% in controls. Trials of IV rTPA therapy failed to find a benefit when thrombolytics were given within 6 hours after the onset of symptoms. The benefit of rTPA is greater the sooner the treatment is started.

Intracranial hemorrhage after thrombolysis is higher in patients with more severe, larger strokes and with older patients. Concerns of hemorrhage, the efficacy and safety of rTPA in patients with early ischemic changes on CT still exist. In the first 3 hours after the onset of symptoms, the appearance of ischemic changes on CT was not associated with increased risk of symptomatic intracranial hemorrhage or other bleeding outcomes after rTPA treatment. IV thrombolysis with rTPA can be used in the community setting with efficacy and safety.

Anticoagulation

Ischemic stroke occurs because of a thrombus or narrowing of the arteries. ASA dosing (160 or 300 mg/d) initiated within 48 hours after the onset of stroke and continued for 2 weeks leads to better survival and function by reducing risk of recurrent ischemic stroke. Routine use of ASA is recommended for secondary prevention of stroke after the first few weeks. ASA is inexpensive, has a good safety profile, and is effective in patients with ischemic stroke; however, it should be withheld for 24 hours in patients treated with the use of IV thrombolytics to decrease the risk of bleeding. Dipyridamole or clopidogrel therapy in the acute phase of ischemic stroke has not been tested in randomized trials. The incidence of ischemic stroke has declined in the middle and elderly age groups but has increased in younger patients, likely due to obesity and hypertension being the contributing factors. Providers should be aware of the rising risk of stroke in younger people. The incidence of acute ischemic stroke has dramatically increased in people under age 35 in both sexes, but i s still greater in males. Better detection of ischemic stroke with MRI may expose obesity and hypertension as the underlying cause. The use of unfractionated heparin, low-molecular-weight heparins, heparinoids, thrombin inhibitors, or oral anticoagulants in the acute phase of stroke improves functional outcomes.

Management of Cardiovascular Risk Factors

Aspirin (ASA) should be started after 24 hours (300 mg daily for the first 2 weeks) and extended release dipyridamole for secondary prevention. Aggressive management of cardiovascular risk factors including smoking cessation, treatment of hypertension, and initiating statin therapy is also recommended. Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke. Warfarin (Coumadin) therapy (and now oral apixaban in nonvalvular AF) to keep the international normalized ratio (INR) between 2 and 3 is the accepted therapy. Apixaban, a direct antithrombin inhibitor, does not require monitoring of the INR. These agents have been more effective than ASA for the prevention of stroke in patients with AE A narrow therapeutic window and the need for lifelong coagulation monitoring limits the use of warfarin (Coumadin). When warfarin (Coumadin) is used, maintenance of the INR in the therapeutic range is challenging and is achieved less than 60% of the time; suboptimal anticoagulation can lead to recurrent stoke. At least a third of patients with AF who are at risk for stroke are either not started on oral anticoagulant therapy or are not compliant with therapy. ASA reduces the risk of stroke in patients with AF by about 20% and is used to treat patients with atrial fibrillation for whom vitamin K antagonist therapy is contraindicated. Addition of clopidogrel to an ASA regimen in patients for whom vitamin K antagonist therapy is contraindicated further reduces the risk of stroke by 28%, but the combination increases the risk of major hemorrhage. A number of small molecular weight inhibitors of Factor Xa are currently available and can be delivered orally. Among these are rivaroxaban, apixaban, betrixaban, YM150, and DU-176b. Apixaban is a direct and competitive inhibitor of Factor Xa.

Prevention and Management of Complications

Patients with an acute stroke are at an increased risk for deep venous thrombosis (DVT) and pulmonary embolism (PE). This risk for DVT and PE increases with increasing age and stroke severity scores. Anticoagulant therapy does not improve the overall functional outcome, but subcutaneously administered low-dose unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) are recommended for patients at high risk for DVT and PE, and for those with immobility. Large supratentorial infarcts and space-occupying edema of the brain may lead to transtentorial or uncal herniation, usually between the second and fifth day after the onset of stroke. Intensive care units with these cases have reported early fatality rates of up to 78%. Medical therapy has proved ineffective in these cases of large space occupying lesions. Compared to medical therapy, surgery (hemicraniectomy, duraplasty, a dural patch to enlarge the intradural space) in the first 48 hours of the onset of stroke reduced the case fatality rate (22% vs 71%). Surgery appeared to be less beneficial for patients with aphasia, patients older than 50 years of age, and patients in whom surgery was performed on the second day versus the first day after stroke onset. Patients who received care in a stroke unit were more likely to survive, regain independence, and return home than those who do not receive such specialized care.

Hypercoagulable States

Hypercoagulable conditions can lead to strokes. The most common conditions in this group include oral contraceptive use, pregnancy, Factor V Leiden deficiency, protein C and S deficiencies, antithrombin III deficiency, and lupus anticoagulant. Patients with these conditions usually present with some form of deep venous thrombosis. Procoagulant states should be suspected especially when recurrent episodes of deep venous thrombosis are diagnosed. Arterial thrombosis should definitely increase awareness of the presence of one of these conditions. Clots can travel from the venous circulation through the heart via an atrial or ventricular septal defect to the left side of the heart and to the arterial circulation leading to the brain (paradoxical emboli) . Lupus anticoagulant is a specific immunoglobulin against phospholipids that prolongs the clotting time; it does not produce bleeding but instead a paradoxical procoagulant condition. It is seen in 25% of people with SLE, but is also seen in otherwise normal healthy subjects. In some people it is associated with an increased risk of blood clots and may be the cause of recurrent spontaneous abortions. Risk factors are SLE and a recent use of phenothiazine medication. Specialized clotting studies and levels of the factors involved are required to make an accurate diagnosis.

Prevention of Stroke

Secondary prevention of stroke and other cardiovascular complications is important. Prevention consists primarily of low-dose ASA and dipyridamole in patients with ischemic stroke, oral anticoagulation in patients with cardiac embolism, treatment of hypertension, statin therapy, and glucose control in patients with diabetes. Cessation of smoking and carotid endarterectomy in patients with ipsilateral carotid stenosis has been shown to be effective.

Even in the United States, only a minority of patients with acute ischemic stroke receive intravenous rTPA. The use of intravenous rTPA is currendy restricted to a 3-hour time window after the onset of symptoms with a potential benefit when used up to 6 hours after the onset of a stroke. Later use was improved by quantification of the ischemic penumbra with perfusion MRI/CT The intent of thrombolysis is to recanalize occluded arteries. Complete recanalization of an occluded middle cerebral artery 2 hours after the start of thrombolysis was achieved in one-third of patients. In some cases, continuous 2-MHz transcranial Doppler ultrasonography applied for 2 hours simultaneous with rTPA augmented the rate of arterial recanalization. The addition of intravenous galactose-based micro bubbles may also increase rates of recanalization along with Doppler therapy. Compared with intravenous thrombolysis, intra-arterial thrombolysis may increase the likelihood of recanalization. The administration of both intra-arterial recombinant pro-urokinase and intravenous heparin, compared with intravenous heparin alone, within 6 hours after the onset of stroke resulted in a higher rate of recanalization of the middle cerebral artery (66% vs 18%) and a higher rate of a favorable functional outcome at 3 months (40% vs 25%, P = 0.04).

Procedures required to deliver intra-arterial thrombolytic agents to the site of vascular occlusion involve more time than intravenous therapy. Thrombolytic therapy in which intravenous thrombolysis is followed by intra-arterial thrombolysis, may permit more rapid treatment and improved rates of recanalization. Mechanical thrombectomy in patients with acute intracranial occlusion of the intracranial carotid artery has resulted in a higher rate of recanalization.

Elevated blood pressure, hyperglycemia, and fever in the first hours to days after ischemic stroke have all been associated with poor long-term outcomes. Antihypertensive therapy during the acute phase of stroke is held unless the diastolic blood pressure exceeds 120 mm Hg or the systolic blood pressure exceeds 220 mm Hg in patients who do not receive rTPA. Monitoring blood pressure is recommended before, during, and after rTPA therapy. Intravenous antihypertensive therapy to maintain the systolic blood pressure <185 mm Hg and the diastolic blood pressure below 110 mm Hg is recommended. Hypothermia has also improved functional outcomes in trials involving patients with global cerebral ischemia after cardiac arrest and traumatic spinal cord injury, but the improvement was not consistent among those with traumatic brain injury.

Conclusions

Patients with signs and symptoms of CVA strongly suggestive of stroke should undergo prompt brain imaging (CT or MRI). MRI is more sensitive for early ischemic changes, but either method can fully rule out hemorrhage. In the absence of bleeding or other contraindications to thrombolysis such as spontaneous, complete clearing of the deficits, increase in BP to or > 185/110 mm Hg, or presentation >3 hours (possibly 6 hours) after the onset of symptoms, the patient should receive therapy with intravenous rTPA. Cardiovascular risk factors should be addressed, and anticoagulation should be initiated when atrial fibrillation is present.

RECENT IMPORTANT DISCOVERIES

Compared to ASA, apixaban had superior efficacy in reducing the risk for embolic events in patients with AF. It has a 50% level of bioavailability, and is partially excreted by the kidneys. Apixaban, at a dose of 2.5 mg twice daily is effective and safe for the prevention of DVT after elective orthopedic surgery. The direct thrombin inhibitor dabigatran gained a Class I recommendation as a useful alternative to warfarin (Coumadin) for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF. Risk factors for stroke or systemic embolization are increased in patients with prosthetic heart valves, hemodynamically significant valvular disease, renal failure (creatinine clearance <15 mL/min), and advanced liver disease (impaired baseline clotting function).

Routinely switching patients to dabigatran who are already successfully taking warfarin is not recommended and remains an individual decision. Dabigatran requires a twice daily dosing and greater risk of nonhemorrhagic side effects; thus, patients already taking warfarin with excellent INR control have little to gain by changing to dabigatran. The patient's compliance with a twice-daily dosing is a real issue. Management to sustain monitoring of INR is needed with warfarin also adds to cost and compliance. Most studies demonstrate a benefit to routine blood-pressure lowering treatment in the acute phase of stroke.

Selective serotonin reuptake inhibitors (SSRI) are effective after ischemic stroke. Some SSRIs improved motor recovery after stroke but this has not been universally confirmed. Fewer fluoxetine recipients than placebo recipients had depression and treatment with thrombolytic agents did not alter the findings. The SSRIs are therapeutic treatment of stroke and should be considered as an adjunct to physiotherapy in the rehabilitation of motor deficits in moderate-to-severe stroke. Reports of a decreased effect of clopidrogel in patients taking proton pump inhibitors (PPI) did not conclude that there was an increase in the risk for a recurrence of stroke in clopidogrel/PPI users. Vitamin supplementation did not prevent major CV events in patients with previous myocardial infarction, unstable angina, or stroke.

CLINICAL CASE CORRELATION

• See also Case 3 (Scoring Systems and Patient Prognosis), Case 27 (Traumatic Brain Injury), Case 30 (Altered Mental Status), and Case 31 (Status Epilepticus).

COMPREHENSION QUESTIONS

32.1  A 38-year-old man who presented to the ED with right leg weakness and right hand numbness is admitted to the ICU. He states that his symptoms started shortly after the completion of a workout. The patient is a recent college graduate with no past medical history, an occasional cigarette smoker, and a social drinker. Upon examination the patient has a weakness in the right lower extremity and equal bilateral handgrip. The patient's vital signs illustrate tachycardia and blood pressure 140/90 mm Hg. He is alert, awake, with no visible signs of facial drooping or slurred speech. An ECG on arrival to the ICU shows normal sinus rhythm compared to an irregular rhythm without discernable P waves with multiple PVCs on arrival to the ED. The brain CT scan was negative. What is the most likely diagnosis responsible for this patient's neurological symptoms?

A. Ischemic stroke with atrial fibrillation

B. Hemorrhagic stroke

C. Exercise- induced hypertension

D. New-onset atrial flutter

E. Endocarditis

32.2  A 35-year-old woman presents to the emergency room with the complaint of having fallen down several steps at a movie theater. The patient is tachycardic and normotensive with muscle strength 2 over 5 of the left upper extremity compared to the right extremity. Doppler ultrasound of the left lower extremity detected a deep venous thrombosis. The CT of the brain revealed a small hypodense lesion in the area of the right internal capsule. Clotting studies are pending. What is the likely cause of this patient's neurological symptoms ?

A. Intracranial bleed

B. Ischemic stroke secondary to a paradoxical emboli

C. Multiple sclerosis

D. Amyotrophic lateral sclerosis

E. Amniotic fluid embolism syndrome

ANSWERS TO QUESTIONS

32.1  A. This 35 -year-old male patient has experienced exercise-induced AF, and likely passed blood clots from the heart to the brain. The change in heart rhythm from AF back to normal sinus rhythm (NSR) produced and released a clot, provoking the neurological symptoms. This clot could have been generated either in the left atrium or the right atrium (atrial septal defect, ASD) reaching the arterial circulation. This patient experienced paroxysmal AF, when he developed a blood clot, likely in the atrial appendage, which was pumped out of the heart and reached his cerebral circulation. Should the patient's neurological symptoms resolve, this patient is classified as a transient ischemic attack (TIA) in which blood flow to a certain area of the brain was intermittently decreased. If neurological deficits persist, a stroke is diagnosed, and a repeat CT of the brain at 48 hours should reveal a hypodense area in the part of the brain involved. The patient will need a 24-hour Holter monitor to document the atrial fibrillation. Paroxysmal AF is the most dangerous arrhythmia because of the constant transition from arrhythmia to NSR, which increases the risk of stroke by placing blood clots into the circulatory system. This patient will initially need 3 to 6 months of anticoagulation therapy along with medication to control his heart rhythm. Evaluation for AF in a young patient should be undertaken (hyperthyroidism, drugs). Examining the need for long-term anticoagulation therapy in the context of benefits versus risk of paroxysmal atrial AF associated with the formation of blood clots is indicated. Maintaining NSR and preventing spontaneous, infrequent AF is foremost in this patient.

32.2  B. The patient has developed multiple thrombi and blood clots secondary to a hypercoagulable condition. Some potential causes include Factor V Leiden disorder, pregnancy, and lupus anticoagulant. Many undiagnosed blood disorders are discovered during pregnancy. One clue that this patient has a hypercoagulable condition is that she has had 2 previous miscarriages. The higher than normal estrogen state of pregnancy triggers hypercoagulability risk factors in patients with clotting disorders like Factor V Leiden, protein C and S, and antithrombin III. This patient developed a DVT while sitting for a prolonged period of time at the movie theater. The patient's neurological symptoms are caused by her hypercoagulable state which contributes to the development of thrombi and emboli that have entered into the microcirculation of the cerebral vasculature. Admission to the ICU and complete hematological panel to determine the diagnosis of her blood clotting disorder is indicated. A hematology and obstetrical consultation is also warranted. The immediate therapy is anticoagulation with heparin or enoxaparin (Lovenox, an injectable Xa inhibitor). The use of warfarin (Coumadin) is contraindicated in pregnancy, as it is teratogenic. Long-term anticoagulation is needed. Lupus anticoagulant usually presents as prolonged prothrombin time (PTT) without evidence of bleeding, in which case, the PTT gets further prolonged when mixed with half-normal plasma confirms the presence of a factor antibody (antiphospholipid). A factor deficiency causing the PTT prolongation would correct when mixed with normal plasma.

References

Foster C, Mistry N, Peddi PF, Sharma S. The Wa shington Manual of Medical Therapeutics. 33th ed. Philadephia: Lippincott Williams & Wilkins, 2010. 

Vander Worp HB, Acute ischemic stroke. N Engl] Med. 2007;357:2203-2204. 

Vander Worp HB, Raaijmakers TW, Kappelle LJ. Early complications of ischemic stroke. Curr Tr eat Options Neural. 2008;10:440-449.

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