Penumbra (medicine)

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In pathology and anatomy the penumbra is the area surrounding an ischemic event such as thrombotic or embolic stroke. Immediately following the event, blood flow and therefore oxygen transport is reduced locally, leading to hypoxia of the cells near the location of the original insult. This can lead to hypoxic cell death (infarction) and amplify the original damage from the ischemia; however, the penumbra area may remain viable for several hours after an ischemic event due to the collateral arteries that supply the penumbral zone.

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As time elapses after the onset of stroke, the extent of the penumbra tends to decrease; [1] therefore, in the emergency department a major concern is to protect the penumbra by increasing oxygen transport and delivery to cells in the danger zone, thereby limiting cell death. The existence of a penumbra implies that salvage of the cells is possible. There is a high correlation between the extent of spontaneous neurological recovery and the volume of penumbra that escapes infarction; therefore, saving the penumbra should improve the clinical outcome. [1]

Definition

One widely accepted definition for penumbra describes the area as "ischemic tissue potentially destined for infarction but it isn't irreversibly injured and [is therefore] the target of any acute therapies." [2] The original definition of the penumbra referred to areas of the brain that were damaged but not yet dead, and offered promise to rescue the brain tissue with the appropriate therapies. [3]

Blood flow

The penumbra region typically occurs when blood flow drops below 20 mL/100 g/min. [4] At this point electrical communication between neurons fails to exist. Cells in this region are alive but metabolic pumps are inhibited, oxidative metabolism is reduced but neurons may begin to depolarize again. [4] Areas of the brain generally do not become infarcted until blood flow to the region drops below 10 to 12 mL/100 g/min. [4] At this point, glutamate release becomes unregulated, ion pumps are inhibited and adenosine triphosphate (ATP) synthesis also stops which ultimately leads to the disruption of intracellular processes and neuronal death. [4]

Identification by imaging

Positron emission tomography (PET) can quantify the size of the penumbra, but is neither widely available nor rapidly accessible. Magnetic resonance imaging can estimate the size of the penumbra with a combination of two MRI sequences: [5]

Both of these sequences somewhat overestimates their volumes of interest, but the size of the penumbra can roughly be estimated by subtracting abnormal volume by DWI from abnormal volume by PWI. [5]

The penumbral area can also be detected based upon an integration of three factors. These factors include: the site of vessel occlusion, the extent of oligaemia (hypoperfused area surrounding the penumbra, but not at risk of infarction [1] ) at that moment, and the mismatch between this perfusion defect and the area of the brain already infarcted. [6]

Clinical relevance

A higher volume of penumbra around a cerebral infarction means a greater volume of potentially salvageable brain matter by thrombolysis and thrombectomy. Such therapies have a greater effect on regaining functions such as movement after a cerebral infarction. [7] After the initial ischemic event the penumbra transitions from a tissue remodeling characterized by damage to a remodeling characterized by repair. [3]

In the penumbra, microglia are thought to exert neuroprotective effects via specialized contacts with neuronal somata, termed somatic junctions. [8] Understanding and supporting these microglial actions could broaden the therapeutic window and lead to higher amount of preserved nervous tissue.[ citation needed ]

History

The first decade of research focused on physiologic profile of the penumbra tissue after stroke, mapping the cerebral blood flow, and quantifying oxygen and glucose consumption to define these areas. The second decade revealed the mechanism of the neuronal cell death. As the Biochemical pathways were dissected penumbral science became a rapidly evolving area of molecular biology. The third decade of penumbral research found a transitional leap as using positron emission tomography (PET) scanning can identify brain tissue with decreased blood flow and magnetic resonance imaging (MRI) has the ability to detect portions of the ischemic tissue that has not yet died. These images have allowed vision into the brain to see the areas of tissue that may be salvaged, the penumbra. [3]

Related Research Articles

<span class="mw-page-title-main">Cerebrovascular disease</span> Condition that affects the arteries that supply the brain

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

<span class="mw-page-title-main">Cerebral edema</span> Excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain

Cerebral edema is excess accumulation of fluid (edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compression of brain tissue and blood vessels. Symptoms vary based on the location and extent of edema and generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, coma and death.

<span class="mw-page-title-main">Infarction</span> Tissue death due to inadequate blood supply

Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the Latin infarctus, "stuffed into").

<span class="mw-page-title-main">Stroke</span> Death of a region of brain cells due to poor blood flow

A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioning properly.

<span class="mw-page-title-main">Cerebral hypoxia</span> Oxygen shortage of the brain

Cerebral hypoxia is a form of hypoxia, specifically involving the brain; when the brain is completely deprived of oxygen, it is called cerebral anoxia. There are four categories of cerebral hypoxia; they are, in order of increasing severity: diffuse cerebral hypoxia (DCH), focal cerebral ischemia, cerebral infarction, and global cerebral ischemia. Prolonged hypoxia induces neuronal cell death via apoptosis, resulting in a hypoxic brain injury.

<span class="mw-page-title-main">Desmoteplase</span>

Desmoteplase is a novel, highly fibrin-specific "clot-busting" (thrombolytic) drug in development that reached phase III clinical trials. The Danish pharmaceutical company, Lundbeck, owns the worldwide rights to Desmoteplase. In 2009, two large trials were started to test it as a safe and effective treatment for patients with acute ischaemic stroke. After disappointing results in DIAS-3, DIAS-4 was terminated, and in December 2014 Lundbeck announced that they would stop the development of desmoteplase.

<span class="mw-page-title-main">Intraparenchymal hemorrhage</span> Medical condition

Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma. The other form is intraventricular hemorrhage (IVH).

<span class="mw-page-title-main">Cerebral infarction</span> Medical condition

Cerebral infarction is the pathologic process that results in an area of necrotic tissue in the brain. It is caused by disrupted blood supply (ischemia) and restricted oxygen supply (hypoxia), most commonly due to thromboembolism, and manifests clinically as ischemic stroke. In response to ischemia, the brain degenerates by the process of liquefactive necrosis.

<span class="mw-page-title-main">Watershed stroke</span> Medical condition

A watershed stroke is defined as a brain ischemia that is localized to the vulnerable border zones between the tissues supplied by the anterior, posterior and middle cerebral arteries. The actual blood stream blockage/restriction site can be located far away from the infarcts. Watershed locations are those border-zone regions in the brain supplied by the major cerebral arteries where blood supply is decreased. Watershed strokes are a concern because they comprise approximately 10% of all ischemic stroke cases. The watershed zones themselves are particularly susceptible to infarction from global ischemia as the distal nature of the vasculature predisposes these areas to be most sensitive to profound hypoperfusion.

<span class="mw-page-title-main">Brain ischemia</span> Medical condition

Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply or cerebral hypoxia and thus leads to the death of brain tissue or cerebral infarction/ischemic stroke. It is a sub-type of stroke along with subarachnoid hemorrhage and intracerebral hemorrhage.

Animal models of ischemic stroke are procedures inducing cerebral ischemia. The aim is the study of basic processes or potential therapeutic interventions in this disease, and the extension of the pathophysiological knowledge on and/or the improvement of medical treatment of human ischemic stroke. Ischemic stroke has a complex pathophysiology involving the interplay of many different cells and tissues such as neurons, glia, endothelium, and the immune system. These events cannot be mimicked satisfactorily in vitro yet. Thus a large portion of stroke research is conducted on animals.

<span class="mw-page-title-main">Leptomeningeal collateral circulation</span>

The leptomeningeal collateral circulation is a network of small blood vessels in the brain that connects branches of the middle, anterior and posterior cerebral arteries, with variation in its precise anatomy between individuals. During a stroke, leptomeningeal collateral vessels allow limited blood flow when other, larger blood vessels provide inadequate blood supply to a part of the brain.

A silent stroke is a stroke that does not have any outward symptoms associated with stroke, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms, a silent stroke still causes damage to the brain and places the patient at increased risk for both transient ischemic attack and major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being amongst the predisposing factors.

<span class="mw-page-title-main">Perfusion MRI</span>

Perfusion MRI or perfusion-weighted imaging (PWI) is perfusion scanning by the use of a particular MRI sequence. The acquired data are then post-processed to obtain perfusion maps with different parameters, such as BV, BF, MTT and TTP.

<span class="mw-page-title-main">MRI sequence</span>

An MRI sequence in magnetic resonance imaging (MRI) is a particular setting of pulse sequences and pulsed field gradients, resulting in a particular image appearance.

Cerebral blood volume is the blood volume in a given amount of brain tissue.

Very low cerebral blood volume (VLCBV) is a measurement of hemorrhagic transformation degree in the tissue surrounding the lesion in strokes. It is counted as one of the penumbral imaging procedures along with less commonly used methods such as diffusion-weighted imaging (DWI). These are used to predict if there is going to be a hemorrhage after the treatment by tPA. In advanced centers, this measurement helps with using tPA beyond the standard time limit without risk of hemorrhage.

<span class="mw-page-title-main">Arterial occlusion</span>

Arterial occlusion is a condition involving partial or complete blockage of blood flow through an artery. Arteries are blood vessels that carry oxygenated blood to body tissues. An occlusion of arteries disrupts oxygen and blood supply to tissues, leading to ischemia. Depending on the extent of ischemia, symptoms of arterial occlusion range from simple soreness and pain that can be relieved with rest, to a lack of sensation or paralysis that could require amputation.

A cerebroprotectant is a drug that is intended to protect the brain after the onset of acute ischemic stroke. As stroke is the second largest cause of death worldwide and a leading cause of adult disability, over 150 drugs tested in clinical trials to provide cerebroprotection.

<span class="mw-page-title-main">Jean-Claude Baron</span> French stroke researcher

Jean-Claude Baron is an Emeritus Professor of Stroke Medicine at the University of Cambridge. He is also a Fellow of the Academy of Medical Sciences. He has authored around 450 peer-reviewed articles.

References

  1. 1 2 3 Guadagno J.; Calautti C.; Baron J. (2003). "Progress in imaging stroke: emerging clinical applications". British Medical Bulletin. 65 (1): 145–157. doi: 10.1093/bmb/65.1.145 . PMID   12697622.
  2. ↑ Fisher M, Ginsberg M (2004). "Current Concepts of the Ischemic Penumbra". Stroke. 32 (11_suppl_1): 2657–2658. doi: 10.1161/01.STR.0000143217.53892.18 .
  3. 1 2 3 Eng H Lo. (2008). "A New Penumbra: Transitioning from injury into repair after stroke". Nature Medicine . 14 (5): 497–500. doi:10.1038/nm1735. PMID   18463660. S2CID   205385488.
  4. 1 2 3 4 Hakim (September 1998). "The penumbra: The therapeutic window". Neurology. 51 (3): 44–6. doi:10.1212/wnl.51.3_suppl_3.s44. PMID   9744833. S2CID   44452236.
  5. 1 2 Chen, Feng (2012). "Magnetic resonance diffusion-perfusion mismatch in acute ischemic stroke: An update". World Journal of Radiology. 4 (3): 63–74. doi:10.4329/wjr.v4.i3.63. ISSN   1949-8470. PMC   3314930 . PMID   22468186.
  6. ↑ Rowley H (2001). "The four p's of acute stroke imaging: parenchyma, pipes, perfusion, and penumbra". American Journal of Neuroradiology. 22 (4): 599–601. PMC   7976007 . PMID   11290464.
  7. ↑ Herholz, K. (2000). "Functional Imaging Correlates of Recovery After Stroke in Humans". Journal of Cerebral Blood Flow & Metabolism. 20 (12): 619–631. doi: 10.1097/00004647-200012000-00001 . PMID   11129778.
  8. ↑ Cserép, Csaba; Pósfai, Balázs; Lénárt, Nikolett; Fekete, Rebeka; László, Zsófia I.; Lele, Zsolt; Orsolits, Barbara; Molnár, Gábor; Heindl, Steffanie; Schwarcz, Anett D.; Ujvári, Katinka; Környei, Zsuzsanna; Tóth, Krisztina; Szabadits, Eszter; Sperlágh, Beáta; Baranyi, Mária; Csiba, László; Hortobágyi, Tibor; Maglóczky, Zsófia; Martinecz, Bernadett; Szabó, Gábor; Erdélyi, Ferenc; Szipőcs, Róbert; Tamkun, Michael M.; Gesierich, Benno; Duering, Marco; Katona, István; Liesz, Arthur; Tamás, Gábor; Dénes, Ádám (31 January 2020). "Microglia monitor and protect neuronal function through specialized somatic purinergic junctions". Science. 367 (6477): 528–537. doi:10.1126/science.aax6752. PMID   31831638. S2CID   209343260.
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