What treatment will produce the best functional results after brain ischemia or stroke.

After a stroke or brain ischemia symptoms may last from a few minutes to days or become permanent and irreversible if the lesion progresses to an infarct. Unfortunately the symptoms do not determine the cause of the stroke although it is critical to identify the cause of the symptoms. The cause may be

Case 1. A 73 year old man wakes up in the morning unable to move his right arm or leg. He tries to call for help but is only able to make unintelligible sounds. His wife discovers him and his son arranges to bring him to the hospital. He reaches the ER three hours later. He has diabetes and hypertension but has never complained of angina or palpitation. He did not have a headache before the onset of the symptoms. What has caused his stroke?

Case 2. A 34 year old woman who is under the care of a cardiologist for mitral stenosis has been having episodes of palpitation associated with fainting. At the end of one such episode she noticed weakness in her left leg and arm which lasted for several hours. As she had an appointment to see her cardiologist two days later she did not consult another doctor. What has caused her TIA?

  • Transient brain ischemia  or transient ischemic attack is now defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. This tissue-based definition of TIA relies on the absence of end-organ injury as assessed by imaging or other techniques. The proposed advantages of the tissue-based definition are that the defined end point is biological (tissue injury) rather than arbitrary (24 hours).
  • Intracerebral hemorrhage — Bleeding in intracerebral hemorrhage (ICH) is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma which spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The most common causes of ICH are hypertension, trauma, bleeding diathesis, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Vasculitis may be a cause.
  • A subarachnoid hemorrhage is a catastrophic event accompanied by a severe headache where the bleed is usually from a ruptured arterial aneurysm and the blood directly enters the CSF. SAH tends to occur at night and the symptoms develop rapidly. The bleed may last only seconds but tends to recur. The causes of intracerebral hemorrhage can also be responsible for an SAH. Brief loss of consciousness, seizure, nausea, vomiting, focal neurologic deficit, or stiff neck  occur first, if bleeding occurs into the brain as well neurological symptoms are likely to occur.
  • Brain ischemia can also be caused by thrombosis, embolism, systemic hypoperfusion. Ischemia versus hemorrhage — Noncontrast computed tomography (CT) is typically the first diagnostic study in patients with suspected stroke. The main advantages of CT are widespread access and speed of acquisition. CT is highly sensitive for the diagnosis of hemorrhage in the acute setting.
  • MRI is more sensitive than CT for the early diagnosis of brain infarction, although CT may identify subtle indicators of infarction within six hours of stroke onset in a significant number of patients.
  • Fluid-attenuated inversion recovery (FLAIR) MRI sequences and diffusion-weighted images (DWI-MRI) are especially useful in showing infarcts early after the onset of symptoms. In patients with ischemia who do not yet have brain infarction, both CT and MRI may be normal.
  • In a thrombotic stroke the use of alteplase is indicated if the diagnosis is made within 4.5 hours of onset. There is a 4-8% chance of an intracranial hemorrhage in older patients i.e. 80 years plus.

Embolic Stroke. This occurs when debris originating elsewhere lodges in an artery in the brain causing ischemia. The debris may be from a known cardiac source like a thrombus in the left atrium in mitral stenosis or in the left ventricle or a possible cardiac origin or the debris may originate in an artery like the aorta, or a source which cannot be proven to be in the heart or an artery.

Systemic hypoperfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain.

For an SAH an early triage with a CT scan or MRI is critical to preventing further brain damage.

Should we lower the blood pressure? and how soon?

The mean arterial blood pressure (MAP) is usually elevated in patients with an acute stroke. However, an acute elevation in blood pressure often represents an appropriate response to maintain brain perfusion. Hypertension may be chronic hypertension, an acute sympathetic response, or other stroke-mediated mechanisms. The decision to treat requires a balance between the potential danger of severe increases in blood pressure, and a possible decline in neurologic functioning when blood pressure is lowered. The hypertensive effect is transient, as blood pressure falls by as much as 20/10 mmHg within 10 days. So keep your eye on the blood pressure and if it declines spontaneously as the patient stabilises then do not interfere but if the patient has chronic hypertension and the pressure either rises or fails to fall then using the patient’s usual medication may be a good idea. When you start lowering the blood pressure is the critical decision and what will be your target? A blood pressure of or above 200 mmHg systolic needs to be lowered to a target of 20/10 mm Hg over six to eight hours not minutes. A lower blood pressure can be observed for 24 to 48 hours. Examine the patient for an increase in the neurological deficit as the BP falls. Do not use rapid acting hypotensive medications.

Embolic Stroke.

The NAVIGATE-ESUS trial randomly assigned patients with embolic stroke of undetermined source (ESUS) to treatment with rivaroxaban or aspirin. The trial was stopped early for futility after an interim analysis showed no benefit of rivaroxaban on the rate of stroke or systemic embolism but an increase in major bleeding in the rivaroxaban arm. Therefore, rivaroxaban should not be used as empiric treatment for patients with cryptogenic stroke, including ESUS. Presumptive anticoagulation for embolic stroke of undetermined source (ESUS) is generally not justified, but specific subgroups may derive benefit.

Oral anticoagulants have an established role in preventing cardioembolic stroke in patients with known nonvalvular atrial fibrillation. But even if the infarct pattern suggests an embolic mechanism, current guidelines recommend antiplatelet therapy over presumptive anticoagulation unless a specific embolic source is identified. Availability of newer oral anticoagulants has renewed interest in evaluating the suitability of presumptive anticoagulation.

Dabigatran vs. Aspirin for Embolic Stroke of Undetermined Source
Anthony S. Kim, MD reviewing Diener HC et al. N Engl J Med 2019 May 16

In the industry-sponsored RE-SPECT ESUS trial, 5390 ESUS patients were randomly assigned to dabigatran or aspirin. ESUS was defined as a nonlacunar stroke without significant extracranial or intracranial atherosclerosis with less than 6 minutes of atrial fibrillation demonstrated during at least 20 hours of monitoring.

Results of the primary efficacy analysis were neutral: Annualized rates of first recurrent stroke were 4.1% with dabigatran (177 events) and 4.8% with aspirin (207 events; P=0.10); nearly all events were ischemic stroke. The annualized rate of major bleeding was similar in the two groups: 1.7% with dabigatran (77 events) and 1.4% with aspirin (64 events); more clinically relevant nonmajor bleeding episodes occurred with dabigatran (70 versus 41).

This is the second neutral trial of newer anticoagulants for ESUS. The NAVIGATE ESUS trial evaluating rivaroxaban versus aspirin was terminated early for futility and for excess bleeding with rivaroxaban (NEJM JW Neurol Jul 2018 and N Engl J Med 2018; 378:2191) The authors of RE-SPECT ESUS do not report the same risk for major bleeding with dabigatran as was seen with rivaroxaban in NAVIGATE ESUS. Post hoc subgroup analyses suggest that closer evaluation of efficacy in the second year of follow-up and for preventing recurrent stroke may be fruitful. A modified concept of ESUS that focuses on thrombogenic atrial cardiopathy (as tested in the ongoing ARCADIA trial [NCT03192215]) looks especially promising.

What’s New?

Fluoxetine does not improve functional outcome after stroke (December 2018).

The recent FOCUS trial, which included over 3100 adult patients with acute stroke, found no benefit in functional outcome at six months for treatment with fluoxetine compared with placebo. Thus, the evidence does not support use of SSRIs for the purpose of promoting recovery after stroke.

Managing diabetes after an acute ischemic stroke.

No benefit of intensive glycemic control in acute stroke (August 2019)

Hyperglycemia is associated with poor outcomes after acute ischemic stroke, but small trials have suggested that tight glucose control with intravenous insulin is not beneficial and might be harmful. Adding to this evidence, a multicenter trial of over 1100 acute stroke patients found that insulin infusion therapy with a target glucose of 80 to 130 mg/dL did not improve 90-day functional outcomes compared with subcutaneous insulin on a sliding scale with a target glucose of 80 to 179 mg/dL [1]. Furthermore, treatment withdrawal for hypoglycemia or other adverse events was more common in the intensive treatment group. These findings confirm that intensive treatment of hyperglycemia with insulin infusion has no role in the setting of acute stroke. Nevertheless, in agreement with current guidelines, it is reasonable to treat severe hyperglycemia (glucose >180 mg/dL [>10 mmol/L]) with standard interventions such as subcutaneous insulin.

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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