Appendix

The Ischemic Cascade
The brain is the most complex organ in the human body. It contains hundreds of billions of cells that interconnect to form a complex network of communication. The brain has several different types of cells, the most important of which are neurons. The organization of neurons in the brain and the communication that occurs among them lead to thought, memory, cognition, and awareness. Other types of brain cells are generally called glia (from the Greek word meaning "glue"). These supportive cells of the nervous system provide scaffolding and support for the vital neurons, protecting them from infection, toxins, and trauma. Glia make up the blood-brain barrier between blood vessels and the substance of the brain.

Stroke is the sudden onset of paralysis caused by injury to brain cells from disruption in blood flow. The injury caused by a blocked blood vessel can occur within several minutes and progress for hours as the result of a chain of chemical reactions that is set off after the start of stroke symptoms. Physicians and researchers often call this chain of chemical reactions that lead to the permanent brain injury of stroke the ischemic cascade.

Primary Cell Death
In the first stage of the ischemic cascade, blood flow is cut off from a part of the brain (ischemia). This leads to a lack of oxygen (anoxia) and lack of nutrients in the cells of this core area. When the lack of oxygen becomes extreme, the mitochondria, the energy-producing structures within the cell, can no longer produce enough energy to keep the cell functioning. The mitochondria break down, releasing toxic chemicals called oxygen-free radicals into the cytoplasm of the cell. These toxins poison the cell from the inside-out, causing destruction of other cell structures, including the nucleus.

The lack of energy in the cell causes the gated channels of the cell membrane that normally maintain homeostasis to open and allow toxic amounts of calcium, sodium, and potassium ions to flow into the cell. At the same time, the injured ischemic cell releases excitatory amino acids, such as glutamate, into the space between neurons, leading to overexcitation and injury to nearby cells. With the loss of homeostasis, water rushes into the cell making it swell (called cytotoxic edema) until the cell membrane bursts under the internal pressure. At this point the nerve cell is essentially permanently injured and for all purposes dead (necrosis and infarction). After a stroke starts, the first cells that are going to die may die within 4 to 5 minutes. The response to the treatment that restores blood flow as late as 2 hours after stroke onset would suggest that, in most cases, the process is not over for at least 2 to 3 hours. After that, with rare exceptions, most of the injury that has occurred is essentially permanent.

Secondary Cell Death
Due to exposure to excessive amounts of glutamate, nitric oxide, free radicals, and excitatory amino acids released into the intercellular space by necrotic cells, nearby cells have a more difficult time surviving. They are receiving just enough oxygen from cerebral blood flow (CBF) to stay alive. A compromised cell can survive for several hours in a low-energy state. If blood flow is restored within this narrow window of opportunity, at present thought to be about 2 hours, then some of these cells can be salvaged and become functional again. Researchers funded by the NINDS have learned that restoring blood flow to these cells can be achieved by administrating the clot-dissolving thrombolytic agent t-PA within 3 hours of the start of the stroke.

Inflammation and the Immune Response
While anoxic and necrotic brain cells are doing damage to still viable brain tissue the immune system of the body is injuring the brain through an inflammatory reaction mediated by the vascular system. Damage to the blood vessel at the site of a blood clot or hemorrhage attracts inflammatory blood elements to that site. Among the first blood elements to arrive are leukocytes, white blood cells that are covered with immune system proteins that attach to the blood vessel wall at the site of the injury. After they attach, the leukocytes penetrate the endothelial wall, move through the blood-brain barrier, and invade the substance of the brain causing further injury and brain cell death. Leukocytes called monocytes and macrophages release inflammatory chemicals (cytokines, interleukins, and tissue necrosis factors) at the site of the injury. These chemicals make it harder for the body to naturally dissolve a clot that has caused a stroke by inactivating anti-clotting factors and inhibiting the release of natural tissue plasminogen activator. NINDS researchers are currently working to create interventional therapies that will inhibit the effects of cytokines and other chemicals in the inflammatory process during stroke.

These brain cells that survive the loss of blood flow (ischemia) but are not able to function make up the ischemic penumbra. These areas of still-viable brain cells exist in a patchwork pattern within and around the area of dead brain tissue (also called an infarct).

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