Cerebral edema

Cerebral edema is a present with many common cerebral pathologies and risk factors for development of cerebral edema will depend on the cause.[1] The following were reliable predictors for development of early cerebral edema in ischemic strokes. [9][10]

• Younger age
• Higher severity of symptoms on the National Institutes of Health Stroke Scale
• Signs of current ischemia on clinical exam
• Decreased level of consciousness
• Hyper dense artery sign and larger affected area on CT imaging
• Higher blood glucose

In general, cytotoxic edema is linked to cell death in the brain through excessive cellular swelling.[1] During cerebral ischemia for example, the blood–brain barrier remains intact but decreased blood flow and glucose supply leads to a disruption in cellular metabolism and creation of energy sources, such as adenosine triphosphate (ATP).[1] Exhaustion of energy sources impairs functioning of the sodium and potassium pump in the cell membrane, leading to cellular retention of sodium ions.[1] Accumulation of sodium in the cell causes a rapid uptake of water through osmosis, with subsequent swelling of the cells.[19] The ultimate consequence of cytotoxic edema is the oncotic death of neurons.[1] The swelling of the individual cells of the brain is the main distinguishing characteristic of cytotoxic edema, as opposed to vasogenic edema, wherein the influx of fluid is typically seen in the interstitial space rather than within the cells themselves.[20] Researchers have proposed that "cellular edema" may be more preferable to the term "cytotoxic edema" given the distinct swelling and lack of consistent "toxic" substance involved.[18]

There are several clinical conditions in which cytotoxic edema is present:

• Commonly caused by traumatic brain injuries, intracerebral hemorrhage, and the early phase of ischemic stroke.[1]
• Also seen in acute liver failure where toxic waste, most notably ammonia, accumulates in the blood stream and crosses the blood-brain barrier.[5] Hyperammonemia in central nervous system (CNS) cells causes oxidative stress and mitochrondrial dysfunction, leading to astrocytic cell swelling.[1] Additionally, ammonia is converted to glutamine in CNS cells which acts as an osmolyte and draws further water into the cell through osmosis.[5] Cerebral edema occurs most commonly in conjunction with a rapid rise in ammonia levels.[5]
• Toxic exposures to methionine sulfoxime, cuprizone, isoniazid, triethyl tin, hexachlorophene, and hydrogen cyanide have been associated with cytotoxic edema and swelling of astrocytic cells.[21]
• Hypoxia, anoxia can lead to cytotoxic edema through several mechanisms[18]

Extracellular brain edema, or vasogenic edema, is caused by an increase in the permeability of the blood-brain barrier.[18] The blood-brain barrier consists of astrocytes and pericytes joined together with adhesion proteins producing tight junctions.[1] Return of blood flow to theses cells after an ischemic stroke can cause excitotoxicity and oxidative stress leading to dysfunction of the endothelial cells and disruption of the blood-brain barrier.[1] The breakdown of the tight endothelial junctions that make up the blood–brain barrier causes extravasation of fluid, ions, and plasma proteins, such as albumin, into the brain parenchyma.[18] Accumulation of extracellular fluid increases brain volume and then intracranial pressure causing the symptoms of cerebral edema.[1]

There are several clinical conditions in which vasogenic edema is present:

• CNS tumors, like glioblastoma and meningioma[1][21]
• Infections like meningitis, abscess, and encephalitis[1][21]
• Inflammatory central nervous system disease such as multiple sclerosis[1][22]
• Brain hemorrhage[21]
• Traumatic brain injuries can lead to increased intracranial pressure, local damage, reduced cerebral blood flow, and focal ischemia secondary to vasogenic edema.[4]
• Late stage of ischemic stroke after rapid recovery from cytotoxic edema[21]
• Hypertensive encephalopathy[21]
• Radiation injury[23]

In ionic edema, the solute concentration (osmolality) of the brain exceeds that of the plasma and the abnormal pressure gradient leads to accumulation of water intake into the brain parenchyma through the process of osmosis.[1] The blood-brain barrier is intact and maintains the osmotic gradient.[21]

The solute concentration of the blood plasma can be diluted by several mechanisms:

• Improper administration of intravenous fluids, isotonic or hypotonic.[21]
• Excessive water intake, syndrome of inappropriate antiduretic hormone (SIADH).[21]

• Rapid reduction of blood glucose in diabetic ketoacidosis or hyperosmolar hyperglycemic state.[18][21]
• Hemodialysis has been associated with ionic edema and cellular swelling.[18]

• Cerebral edema is a potentially life threatening complication of severely decreased sodium ion concentration in the blood (hyponatremia).[17]

Ionic brain edema can also occur around the sites of brain hemorrhages, infarcts, or contusions due to a local plasma osmolality pressure gradient when compared to the high osmolality in the affected tissue.[21]

Interstitial edema can be best characterized by in noncomunnicating hydrocephalus where there is an obstruction to the outflow of cerebrospinal fluid within the ventricular system.[1][21] The obstruction creates a rise the in intraventricular pressure and causes CSF to flow through the wall of the ventricles into the extracellular fluid within brain.[21] The fluid has roughly the same composition of CSF.[21]

Other causes of interstitial edema include but are not limited to communicating hydrocephalus, and normal pressure hydrocephalus.[18]

Hydrostatic extracellular brain edema is typically caused by severe arterial hypertension.[18] A difference in the hydrostatic pressure within the arterial system relative to the endothelial cells allows ultrafiltration of water, ions, and low molecular weight substances (such as glucose, small amino acids) into the brain parenchyma.[18] The blood-brain barrier is intact usually and the extent of the edema depends on the arterial pressure.[18] The regulatory processes of the brain circulation can function up to systolic arterial pressures of 150 mm Hg and will have impaired function at blood pressures higher.[18]

Cytotoxic, ionic, and vasogenic edema exist on a continuum.[24] The mechanism of the cause of cerebral edema can often overlap between these types.[24] In most instances, cytotoxic and vasogenic edema occur together.[25] When the two edema types evolve simultaneously, the damage of one type reaches a limit and will bring about the other type of injury.[25] For example, when cytotoxic edema occurs in the endothelial cells of the blood-brain barrier, oncotic cell death contributes to loss of integrity of the blood-brain barrier and promotes the progression to vasogenic edema.[24] When brain edema types are combined, there is typically a predominate form and the edema type and context of the cause must be determined in order to start appropriate medical or surgical therapy.[18] The use of specific MRI techniques has allowed for some differentiation between the mechanisms. [26]

If not properly acclimatized to high altitude, a person may be negatively affected by the lower oxygen concentration available.[27] These hypoxia-related illnesses include acute mountain sickness (AMS), high-altitude pulmonary edema, and high-altitude cerebral edema (HACE).[27] High altitude cerebral edema is a severe and sometimes fatal form of altitude sickness that results from capillary fluid leakage due to the effects of hypoxia on the mitochondria-rich endothelial cells of the blood–brain barrier.[28] The edema can be characterized by vasogenic cerebral edema with symptoms of impaired consciousness and truncal ataxia.[27]

Altitude-related illnesses can be prevented most effectively with slow ascent to high altitudes, an average ascent of 300 to 500 meters per day is recommended. Pharmacological prophylaxis with acetazoloamide or corticosteroids can be used in non pre-acclimatized individuals.[27] If symptoms of high-altitude cerebral edema do not resolve or worsen, immediate descent is necessary, and symptoms can be improved with administration of dexamethasone.[27]

Amyloid-related imaging abnormalities (ARIA) are abnormal differences seen in neuroimaging of Alzheimer's disease patients given targeted amyloid-modifying therapies.[29] Human monoclonal antibodies such as aducanumab, solanezumab, and bapineuzumab have been associated with these neuroimaging changes and additionally, cerebral edema.[16][29] These therapies are associated with dysfunction of the tight endothelial junctions of the blood-brain barrier, leading to vasogenic edema as described above. In addition to edema, these therapies are associated with microhemorrhages in the brain known as ARIA-H.[30] Familiarity with ARIA can aid radiologists and clinicians in determining optimal management for those affected.[16]

Posterior reversible encephalopathy syndrome is a rare clinical disease characterized by cerebral edema.[12] The exact pathophysiology, or cause, of the syndrome is still debated but is hypothesized to be related to the disruption of the blood-brain barrier.[12] The syndrome features acute neurological symptoms and reversible subcortical vasogenic edema predominantly involving the parieto-occipital areas on MR imaging.[31] PRES in general has a benign course, but PRES-related intracranial hemorrhage has been associated with a poor prognosis.[32]

Deep brain stimulation (DBS) is effective treatment for several neurological and psychiatric disorders, most notably Parkinson's disease.[33] DBS is not without risks and although rare, idiopathic delayed-onset edema (IDE) surrounding the DBS leads have been reported.[14] Symptoms can be mild and nonspecific, including reduction of the stimulation effect, and can be confused for other causes of edema.[14] Thus, imaging is recommended to rule out other causes.[14] The condition is generally self-limiting and the exact mechanism of the cause is unexplained.[14] Early identification can help persons affected avoid unnecessary surgical procedures or antibiotic treatments.[14]

Decompressive craniectomy is frequently performed in cases of resistant intracranial hypertension secondary to several neurological conditions and is commonly followed by cranioplasty.[15] Complications, such as infection and hematomas after cranioplasty occur in roughly about a third of cases.[15] Massive brain swelling after cranioplasty (MSBC) is a rare and potentially fatal complication of an uneventful cranioplasty that has recently been elucidated.[15] Preoperative sinking skin flap (SSF) and intracranial hypotension were factors associated with the development of MSBC after cranioplasty.[15][34] Data suggests that pathologic changes are triggered immediately following the procedure, especially an acute increase in intracranial pressure.[15]

With the rise of sophisticated treatment modalities such as gamma knife, cyber knife, and intensity modulated radiotherapy, a large number of individuals with brain tumors are treated with radiosurgery and radiotherapy.[13] Radiation-induced brain edema (RIBE) is a potentially life threatening complication of brain tissue radiation and is characterized radiation necrosis, endothelial cell dysfunction, increased capillary permeability, and breakdown of the blood brain barrier.[13] Symptoms include headache, seizure, psychomotor slowing, irritability, and focal neurological deficits.[13] Options for management of RIBE are limited and include corticosteroids, anti platelet drugs, anticoagulants, hyperbaric oxygen therapy, multivitamins, and bevacizumab.[13]

Brain tumor associated edema is a significant cause of morbidity and mortality in patients with brain tumors and characterized by a disruption of the blood brain barrier and vasogenic edema.[35] The exact mechanism is unclear but hypothesized that cancerous glial cells (glioma) of the brain can increase secretion of vascular endothelial growth factor (VEGF), which weakens the junctions of the blood–brain barrier.[36] Historically, corticosteroids such as dexamethasone were used to reduce brain tumor-associated vascular permeability through poorly understood mechanisms and was associated with systemic side effects.[36] Agents that target the VEGF signaling pathways, such as cediranib, have been promising in prolonging survival in rat models but associated with local and systemic side effects.[35]

Serial neuroimaging (CT scans and magnetic resonance imaging) can be useful in diagnosing or excluding intracranial hemorrhage, large masses, acute hydrocephalus, or brain herniation as well as providing information on the type of edema present and the extent of affected area.[1][3] CT scan is the imaging modality of choice as it is widely available, quick, and with minimal risks.[1] However, CT scan can be limited in determining the exact cause of cerebral edema in which cases, CT angiography (CTA), MRI, or digital subtraction angiography (DSA) may be necessary. MRI is particularly useful as it can differentiate between cytotoxic and vasogenic edema, guiding future treatment decisions.[1]

Intracranial pressure and its management is a fundamental concept in traumatic brain injury (TBI).[38] The Brain Trauma Foundation guidelines recommend ICP monitoring in individuals with TBI that have decreased Glasgow-Coma Scale (GCS) scores, abnormal CT scans, or additional risk factors such as older age and elevated blood pressure.[3] However, no such guidelines exist for ICP monitoring in other brain injuries such as ischemic stroke, intracerebral hemorrhage, cerebral neoplasm.[3]

Clinical researches have recommended ICP and cerebral perfusion pressure (CPP) monitoring in any persons with cerebral injury who are at risk of elevated intracranial pressure based on clinical and neuroimaging features.[38] Early monitoring can be used to guide medical and surgical decision making and to detect potentially life-threatening brain herniation.[38] There was however, conflicting evidence on the threshold values of ICP that indicated the need for intervention.[38] Researches also recommend that medical decisions should be tailored to the specific diagnosis (e.g. subarachnoid hemorrhage, TBI, encephalitis) and that ICP elevation should be used in conjunction with clinical and neuroimaging and not as an isolated prognostic marker.[38]