Clinical manifestations

Presentation and course

• Symptoms vary based on the cause, location, and extent of edema.

In early stages, cerebral edema may be asymptomatic. Symptoms of cerebral edema generally include headaches, nausea, vomiting, seizures, drowsiness, visual disturbances, dizziness, and in severe cases, coma and death. Patients with a large hemispheric infarction who are at risk for cerebral edema and herniation have severe neurologic deficits on presentation with forced gaze deviation, visual field deficits, hemiplegia, and aphasia, depending on the hemisphere involved.

Prognosis and complications

Cerebral edema is a complication of several neurologic disorders and brain injury. Cerebral edema is the cause of death in 5% of all patients with cerebral infarction and mortality after large ischemic strokes with cerebral edema ranges from 20% to 30% despite medical and surgical interventions. Fewer than 10% of ischemic strokes are classified as malignant or massive because of the presence of space-occupying cerebral edema that is severe enough to produce brain tissue shifts and herniation (30). Cerebral edema usually develops between 2 to 5 days after onset of symptoms. Large territory ischemic strokes can lead to the rapid development of malignant brain edema and increased intracranial pressure. Cerebral edema in the context of a malignant middle cerebral artery infarct has a mortality of 50% to 80% if treated conservatively. Individuals with cerebral edema had a worse 3-month functional outcome than those without edema. These effects were more pronounced with increasing extent of cerebral edema and were independent of the size of the infarct.

Cerebral edema may contribute to secondary injury in traumatic brain injury and thus, may be a useful prognostic indicator. Cerebral edema is the strongest predictor of outcome in patients with severe traumatic brain injury, accounting for up to 50% of mortality (14). In a retrospective study of patients with mild traumatic brain injury, those with cerebral edema documented by measurements of gray and white matter CT density had a mortality rate over 10 times that of the entire study population (47). The association of brain edema with increased in-hospital risk of death was observed in traumatic brain injury across all levels of severity. Edema in the acute and chronic phases of traumatic brain injury is associated with a worse neurologic and clinical outcome.

Biological basis

	• Signs and symptoms of cerebral edema are due to rise of intracranial pressure due to extracellular as well as intracellular fluid accumulation.
	• Risk factors predispose to the formation and aggravation of cerebral edema.
	• Pathogenesis varies according to the cause of edema, eg, traumatic brain injury, stroke, infections, neuroinflammation, etc.

Etiology and pathogenesis

Intracranial pressure and cerebral edema are subject to autoregulation and intracranial compliance according to the Monro-Kellie doctrine, which states that during health, the volume occupied by the contents of the cranium must remain in dynamic equilibrium—the implication being that the fluid influx rate must equal the efflux rate.

Vasogenic cerebral edema. This results from disruption of blood-brain barrier due to disease, eg, peritumoral edema that allows proteins to flow more freely into the extravascular space followed by osmotic draw of fluid into the brain interstitium. Acute CNS injury can trigger chronic dysregulation of glymphatic clearance of interstitial solutes and thus aggravate cerebral edema.

Osmotic cerebral edema. This is often described as a subtype, which occurs if 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. The blood-brain barrier is intact and maintains the osmotic gradient.

Cytotoxic edema. This appears soon after injury to the brain and is also referred to as cellular edema as it mainly involves the astrocyte swelling. Several ion transporters, which contribute to cytotoxic edema formation by mediating osmolytic uptake, include the following:

• Sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel • Sodium-potassium-chloride transporter subtype 1 transporter • Sodium-hydrogen exchanger • Excitatory amino acid transporters

By depleting extracellular sodium ions (Na+), cytotoxic edema generates a new Na+ gradient across the blood-brain barrier that favors the influx of vascular Na+. Various Na+ transporters expressed by brain endothelial cells then enable Na+ osmolytes to follow this new electrochemical gradient inward across the blood-brain barrier. Water follows, resulting in the formation of a subtype of cerebral edema called ionic edema, which can cause brain swelling.

Aquaporin channels are recognized as important mediators of water fluxes in cerebral edema. Of the several known aquaporin channels, only aquaporin-1, aquaporin-4, aquaporin-9, and aquaporin-11 are expressed in the CNS. Aquaporin-4 is the major aquaporin expressed by astrocytes and is the dominant contributor to cerebral edema formation and clearance. As passive channels, aquaporins are completely dependent upon the activity of ion transporters for water flux (44).

Important causes of cerebral edema are listed in Table 1 and pathomechanisms for some of the causes are described in the following text.

Table 1. Causes of Cerebral Edema

	• Primary malignant brain tumors • Cerebral metastases
Cerebral hypoxia
	• Carbon monoxide poisoning • Cardiac or respiratory arrest • Hemorrhagic shock • High-altitude cerebral edema
Cerebrovascular disorders
	• Acute cerebral hemispheric infarction • Cerebral venous thrombosis • Intracerebral hemorrhage • Reversible cerebral vasoconstriction syndromes • Subarachnoid hemorrhage
CNS infections
	• Bacterial: meningitis, brain abscess • Protozoal infections: cerebral malaria, cerebral toxoplasmosis • Viral: encephalitis
Drug-induced brain edema from use of therapeutic drugs
Heat stroke
Hypertensive encephalopathy
Metabolic disorders
	• Diabetic ketoacidosis • Hepatic encephalopathy • Hyponatremia
Neurotoxicity
	• Heavy metal poisoning, eg, lead • Heroin intoxication
Obstructive hydrocephalus causing interstitial edema
Postoperative following neurosurgical procedures
	• Aneurysm surgery following subarachnoid hemorrhage • Deep brain stimulation • Obliteration of large arteriovenous malformations • Procedures involving manipulation of brain tissue
Posterior reversible encephalopathy syndrome
Radiation-induced cerebral edema
Reye syndrome
Traumatic brain injury
	• Edema associated with cerebral lacerations/hemorrhage in closed head injury • Shaken impact syndrome in child abuse

Cerebral edema in stroke. Cerebral edema is most often seen with large cerebral hemispheric infarctions. Cerebral ischemia leads to free radical production. Lipid hydroperoxide has a stimulatory effect on the activities of Na+, K+-ATPase and the arachidonate cascade of brain microvasculature. Ischemic brain edema would therefore lead to an elevation in the level of hydroperoxides that will, in turn, enhance the activities of Na+, K+-ATPase as well as the arachidonate cascade of brain microvasculature, leading to a vicious circle that further aggravates cerebral edema. The increase in activity of microvascular-Na+, K+-ATPase results in increased sodium influx across the blood-brain barrier and it is this influx (not of proteins) that probably is the principal cause of ischemic brain edema. Coincident with the development of brain edema, there is an increase in eicosanoid synthetic capacity of the brain microvasculature. Thrombolytic therapy in stroke reperfuses tissues and improves outcome but when treatment is delayed it can aggravate cerebral edema.

An experimental study using MRI, radiolabeled tracers, and multiphoton imaging in rodent stroke models showed that CSF surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels (32). This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. These findings could provide a basis for development of strategies for treatment. One of these strategies was tested in mice by blocking a water channel on astrocytes, cells in the brain that help direct water through the glymphatic system. Mice that lacked the channel were slower to develop edema after stroke, suggesting that a similar treatment could show promise in human patients. In addition to blocking water flow, future treatments could potentially prevent edema by slowing the spread of stroke-induced electrical activity in the brain. These electrical storms continue to barrage the brain for days after stroke, inciting edema each time they happen.

Role of glymphatic system in the CNS against brain edema after stroke. The glymphatic system, through the perivascular space and aquaporin 4 (AQP4) on astrocytes, clears brain metabolic waste and maintains the stability of the internal environment within the brain. Changes in the glymphatic system after stroke may be an important contributor to brain edema. Understanding and targeting the molecular mechanisms and the role of the glymphatic system in the formation and regression of brain edema after stroke could promote the exclusion of fluids in the brain tissue and promote the recovery of neurologic function in stroke patients (50).

Cerebral edema following traumatic brain injury. Cerebral edema and associated increased intracranial pressure are major immediate consequences of traumatic brain injury that contribute to most early deaths. Cerebral edema in traumatic brain injury is due to the combined mass effects of extravasated blood, cytotoxic edema, vasogenic edema, and osmolyte-driven brain swelling. Vasogenic edema after traumatic brain injury results from blood-brain barrier compromise resulting in net water and proteinaceous fluid influx into the interstitium. There are multiple contributors to this process including cellular retraction via actin and myosin light chain kinase contraction of the cytoskeleton, cytotoxic edema in endothelial cells resulting in membrane disruption and eventual oncotic death, decreased water efflux, degradation of tight junction proteins, and activation of inflammatory cells (24).

Continuous prophylactic hyperosmolar therapy is not recommended as resuscitation fluids in neurointensive care because data on its effects on long-term clinical outcomes are scarce. The Continuous Hyperosmolar Therapy for Traumatic Brain-Injured Patients trial showed that in patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurologic status at 6 months (38).

Peritumoral edema. This is associated with primary brain tumors as well as brain metastases. Corticosteroids are used for the treatment of peritumoral cerebral edema with dexamethasone as the drug of choice. Agents such as bevacizumab should be considered in patients who are unable to completely wean off steroids as well as those who have symptomatic edema and are on immunotherapy (13). An increased understanding of the complex pathophysiology of peritumoral vasogenic edema is needed to discover new agents that are safer and more effective.

Posterior reversible encephalopathy syndrome. This is a serious neurologic disorder consisting of headache, visual disturbances, seizures, impaired consciousness, and radiological evidence of vasogenic edema of the posterior cerebral white matter. It is occasionally complicated by cerebral hemorrhage or ischemia. The main risk factors are hypertension, preeclampsia, eclampsia, acute kidney injury, and several drugs.

Cerebral edema in hyponatremia. Decrease in serum sodium concentration of less than 136 mmol/L, which is caused by an excess of water relative to solute, is a common electrolyte abnormality in neurologic patients termed “hyponatremia”. Several drugs are known to induce hyponatremia. Signs and symptoms include nausea, headache, irritability, muscle spasms as well as cramps, seizures, and impairment of consciousness. Uncorrected acute severe hyponatremia creates an osmotic gradient between the brain and the plasma, which promotes the movement of water from the plasma into brain cells, causing cerebral edema, elevated intracranial pressure, and potentially, death due to cerebral herniation. Most of the cases of hyponatremia due to neurosurgical pathology are caused by the syndrome of inappropriate antidiuresis but acute glucocorticoid insufficiency is an important contributing factor (17).

Drug-induced cerebral edema. This is a less known cause of cerebral edema and is described in detail elsewhere (22). Some examples are listed in Table 2.

Table 2. Drug-Induced Cerebral Edema

Manifestation	Drugs/mechanisms/references
Acute liver failure with cerebral edema	Hepatotoxic drugs, eg, antimicrobials (16)
Cerebral edema due to neurotoxicity	A patient with relapsed pre-B cell acute lymphoblastic leukemia died from fulminant cerebral edema following chimeric antigen receptor T-cell infusion, which caused astrocyte and blood-brain barrier dysfunction (46).
Cerebral edema with augmented AQP1 protein levels and focal lesions in the cerebral parenchyma	Inhaled gold nanoparticles used for targeted drug delivery to the brain can induce cerebral edema involving the Caveolin 1-dependent accumulation on endothelial AQP1 (08).
Hyperammonemic encephalopathy with cerebral edema	Valproic acid-induced hyperammonemia with high levels in the brain is a major factor responsible for cytotoxic cerebral edema.
Hyponatremic encephalopathy	Drug-induced hyponatremia, eg, cerebral edema in a patient on duloxetine and hydrochlorothiazide, caused by syndrome of inappropriate antidiuresis hormone secretion (42)
Posterior reversible encephalopathy syndrome (with cerebral edema)	• Antineoplastics (particularly VEGF inhibitors), eg, sorafenib (29) • Immunosuppressants • Drugs that increase blood pressure • Drugs causing fluid and sodium retention
Modified from (22)

Risk factors for the development of cerebral edema. These can be identified according to the cause of cerebral edema. Some examples are:

Diabetic ketoacidosis. The most common risk factors for developing cerebral edema are newly diagnosed diabetes mellitus, young age, first episode and severity of diabetic ketoacidosis, and administration of bicarbonate. It is associated with an increase in serum osmolality. Rapid correction of blood glucose and serum osmolality can lead to cerebral edema, particularly in children and adolescents.

Hyponatremia. This is a risk factor/cause of cerebral edema. Hyponatremic encephalopathy accounts for almost all brain damage in patients with hyponatremia.

Risk of developing cerebral edema in ischemic stroke patients. In a retrospective study on ischemic stroke patients with initial CT scans that did not show cerebral edema, the following 6 variables obtained during the first 24 hours of hospitalization were predictive of subsequent development of cerebral edema with the probability as a percentage figure (33):

(1) Total anterior circulation syndrome, 100% (2) Hyperdense middle cerebral artery, 100% (3) Glasgow Coma Scale, closed eyes, 68.0% (4) Vomiting, 53.1% (5) Lacunar circulation syndrome, 21.2% (6) White matter lesions, 10.8%

The E-score was obtained by algebraic sum of a positive point for the variables 1, 2, 3, and 4 and a negative point for the variables 5 and 6. The score of 1 was sufficient to predict a probability of edema development exceeding 50%. The probability further increased as the score increased.

Quantitative posterior circulation net water uptake in early posterior circulation stroke is an important biomarker for malignant cerebellar edema. Besides Acute Stroke Prognosis Early CT Score as a predictor of malignant cerebellar edema, lesion water uptake measurements may further support identifying patients at risk for malignant cerebellar edema at an early stage, indicating stricter monitoring and consideration for further therapeutic measures (06).

Epidemiology

• Incidence and prevalence of cerebral edema varies according to the cause.

Epidemiology of cerebral edema is not easy to assess because of its association with many common neurologic disorders. The incidence of this disorder should be considered in terms of its potential causes.

Cerebral edema is present in approximately 31% of persons with ischemic strokes within 30 days after onset (49). Malignant cerebral edema accompanying ischemic infarction and intracerebral hemorrhage, when severe, may increase mortality to approximately 80% (Kochanek et al 2009). In 1 study, cerebral edema was found in 28% of patients with thrombolysis-treated ischemic strokes and it was severe in 10% of the cases (45).

Cerebral edema occurs in 20% to 30% of patients with acute liver failure and increases mortality to approximately 55% (05).

In traumatic brain injuries, cerebral edema occurred in greater than 60% of those with mass lesions and in 15% of those with initial normal CT scans (24).

Prevention

Prevention of cerebral edema is based on:

• Adequate management of the primary cause. • Management of risk factors for development of cerebral edema. • Recognition of the early symptoms and signs to prevent evolution into severe form of cerebral edema, which is difficult to treat.

An example of prevention of cerebral edema based on management of risk factors is slow correction and close monitoring of serum glucose and osmolality in diabetic ketoacidosis. In a youngster with new-onset diabetes mellitus, standard management with regular insulin and intravenous fluids resulted in a rapid drop in serum osmolality with development of fatal cerebral edema (26).

Drugs in development aim to modulate the degree and timing of activating/inhibiting molecular targets such as Sur1-Trpm4 channel (targeted by glibenclamide) that contribute to edema formation in early stages as described in the section on pathophysiology.

Differential diagnosis

Confusing conditions

In a patient who presents with signs and symptoms of raised intracranial pressure, eg, after head injury, stroke, or brain tumor, it is difficult to determine clinically if the raised pressure is due to the primary lesion or the associated edema or both. Brain imaging is helpful in sorting this out in most of the cases. Differential diagnosis in most of the cases is between the various conditions associated with cerebral edema.

Associated or underlying disorders

These are the causal agents described in the Biological basis section.

Diagnostic workup

	• Monitoring of level of consciousness
	• Brain imaging
	• Intracranial pressure monitoring
	• Biomarkers

Most of the patients are initially admitted to the intensive care and the level of consciousness is monitored along with any fluctuations in neurologic signs.

Brain imaging. CT scans and MRI can help in diagnosing or excluding intracranial hemorrhage, large intracranial masses, acute hydrocephalus, or brain shifts across the midline as well as providing information on the type of edema present and the extent of affected area. MRI can differentiate between cytotoxic and vasogenic edema for guiding future treatment decisions.

Intracranial pressure monitoring. This is used commonly in traumatic brain injury and should be considered in any person with cerebral injury who is at risk of elevated intracranial pressure based on clinical and neuroimaging features. For making decisions about treatment, intracranial pressure elevation should be used in conjunction with clinical and neuroimaging findings and not as an isolated prognostic biomarker.

Biomarkers of cerebral edema. Biomarkers of cerebral edema include the following:

	• Displacement of CSF from baseline to 24-hour CT is a promising early biomarker for the development of midline shift and worsening of neurologic outcome (11).
	• There is a consistent/reproducible association between elevated microdialysate glutamate concentration and intracranial hypertension, most pronounced in contusions and patients with secondary ischemia (07).
	• In large-hemispheric stroke studies, serum matrix metalloprotein-9 (MMP-9) levels consistently correlate with malignant cerebral edema and are responsive to Sur1/Trpm4 inhibition with glibenclamide (40). MMP-9 is a promising potential biomarker of cerebral edema and blood-brain barrier breakdown in traumatic brain injury that warrants further exploration in human studies.
	• Spatially clustered ABCC8 (encoding Sur1) polymorphisms contained within a region of DNA encoding the Sur1-receptor site and Trpm4-pore interface have been reported to predict measures of cerebral edema and outcome after traumatic brain injury (25).

Management

	• Methods of treatment of cerebral edema include general as well as specific medical measures, nonpharmacological approaches, and surgery.
	• A personalized approach may be used to select the best method(s) suitable for an individual patient.

Principles of management of cerebral edema are shown in Table 3.

Table 3. Principles of Management of Cerebral Edema

	• Control hyperglycemia • Fluid management and cerebral perfusion • Maintain blood pressure for optimal blood flow to the brain situation • Seizure prophylaxis • Sedation and analgesics if needed • Withdrawal of the causative drug in drug-induced cerebral edema
Specific medical measures
	• Barbiturates • Glucocorticoids • Osmotic therapy
Specific pharmacotherapy
	• Antiedema agents in clinical trials, eg, glibenclamide
Nonpharmacological measures
	• Elevating the head of the bed • Hyperventilation • Hypothermia • Hyperbaric oxygen therapy • Lower body temperature if there is fever • Nutritional support
Surgical procedures
	• CSF diversion procedures for reducing intracranial pressure • Decompressive craniotomy

Aims of the treatment are reduction of intracranial pressure, neuroprotection, and addressing the cause if possible. General supportive measures are like those for any seriously ill neurologic patients. Most of the current methods such as osmotic therapy and decompressive craniotomy are nontargeted, as they address secondary mechanisms rather than primary molecular pathways and outcome is not always favorable. New antiedema agents in clinical trials have the potential for prophylactic treatment to prevent the formation of edema and thereby reduce its adverse mass effect and increased intracranial pressure (43). Examples of other methods of treatment are as follows:

Barbiturate coma. This is a widely accepted procedure for managing diffuse cerebral edema. A study has demonstrated that barbiturates in conjunction with standard medical therapy can be used to safely reduce postoperative refractory intracranial pressure and intraoperative brain swelling in children with focal brain lesions (31).

Osmotic therapy. Regardless of the cause of cerebral edema, osmotherapy (eg, mannitol or hypertonic saline) is the mainstay of medical therapy currently and should be administered as soon as possible. However, as a nontargeted therapy, it has limitations such as rebound effect. A study has evaluated the variability and mean plasma concentrations of the water and electrolyte balance parameters in critically ill patients with raised intracranial pressure treated with osmotic therapy and their influence on mortality (48). The mortality is high with electrolyte disequilibrium as the independent predictor of mortality regardless of the treatment method used. Variations of plasma sodium, chloride, and osmolality are the most deleterious factors regardless of the absolute values of these parameters.

Antiedema agents in clinical trials. As of September 2021, 80 studies are listed on all aspects of cerebral edema at the U.S. government web site: ClinicalTrials.gov.These include all methods of treatment and only 40 refer to pharmaceuticals.

New pharmacotherapies. Those targeting molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma (37). One of the promising drugs in clinical trials is glibenclamide.

Intravenous glibenclamide (BIIB093). This is an investigational compound for the prevention and treatment of severe cerebral edema. Glibenclamide, a sulfonylurea drug and potent inhibitor of SUR1-TRPM4 ion channel, was reformulated for intravenous injection, known as BIIB093. Emerging clinical data show that BIIB093 has the potential to transform our management of patients with large hemisphere infarction, contusion-traumatic brain injury, and other conditions in which swelling leads to neurologic deterioration and death (35). Osmotherapy with intravenous glibenclamide for malignant cerebral edema was tested in a phase 2 prospective, double-blind, randomized, placebo-controlled study on patients with malignant edema due to large hemispheric infarction (19). In this trial, osmolar therapies were often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after large hemisphere infarction have yet to be defined.

Hypothermia. This is therapeutic cooling of the human body to reduce the metabolism and is used for neuroprotection in stroke, traumatic brain injury, and miscellaneous hypoxic/ischemic encephalopathies accompanied by cerebral edema. Mild hypothermia (320 to 330 C) for a few hours can have neuroprotective effects. Approaches to induce hypothermia include cooling the entire body all at once or inserting cooling devices into the arteries that supply the brain with blood. Clinically and experimentally, the key phases of hypoxic/asphyxic injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 hours post insult. Neuroprotection by therapeutic hypothermia against brain damage associated with cerebral edema is variable in animal models as shown in neuropathological as well as neuroimaging end points and differences in individual brain-derived neurotrophic factor levels may explain some of these findings (12). There is now compelling evidence from randomized controlled trials that mild to moderate induced hypothermia significantly improves survival and neurodevelopmental outcomes of hypoxic-ischemic encephalopathy in infancy and midchildhood (15).

Hyperbaric oxygen. Cerebral edema in a patient with traumatic brain injury can be treated with hyperbaric oxygen, which counteracts hypoxia/ischemia, improves cerebral oxidative metabolism, and reduces cerebral edema (21). Hyperbaric oxygen can alleviate cerebral edema in heat stroke by counteracting tissue ischemia as well as hypoxia and has antiinflammatory effects (34). Steroid-resistant malignant cerebral edema following volume-staged stereotactic radiosurgery treatment of a cerebrovascular malformation has been successfully treated with hyperbaric oxygen (27).

Decompressive craniotomy. This is done in cases of malignant cerebral edema following a large hemispheric stroke or traumatic brain injury. A randomized study in adults with severe diffuse traumatic brain injury and refractory intracranial hypertension showed that early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the intensive care unit but was associated with unfavorable outcomes (10). An international, multicenter, parallel-group, superiority, randomized trial compared last-tier secondary decompressive craniectomy with continued medical management for refractory intracranial hypertension after traumatic brain injury (20). At 6 months, decompressive craniectomy for severe and refractory intracranial hypertension after traumatic brain injury resulted in mortality that was 22 percentage points lower than that with medical management. The rates of moderate disability and good recovery with surgery were like those with medical management. Surgery, however, was associated with higher rates of vegetative state and more severe disability than medical management, which argues for further investigation into the selection of patients for decompressive craniectomy after traumatic brain injury and for the development of more refined clinical decision-making tools. Quality of life is an individual determination, and one should engage patients’ surrogates in discussions that focus on the patients’ previously stated wishes and personal values (41). Results of a systematic review and metaanalysis of randomized clinical trials suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients but the benefit of surgery after day 2 and in elderly patients remains uncertain (36). In a study where patients were categorized in 2 groups ‒ “small flaps” and “large flap” based on head size ‒ better intracranial pressure control was achieved in patients who underwent a large decompressive craniectomy (ratio > 65%) when compared with smaller craniectomy sizes (39).

Guidelines for management of acute cerebral edema. These have been described according to conditions in which it occurs (09):

Subarachnoid hemorrhage. Use of symptom-based bolus dosing of hypertonic sodium solutions rather than sodium target-based dosing is recommended for managing intracranial pressure or cerebral edema in subarachnoid hemorrhage patients.

Traumatic brain injury. Use of hypertonic sodium solutions rather than mannitol is recommended for initial management of elevated intracranial pressure or cerebral edema in traumatic brain injury patients. Mannitol is an effective alternative in traumatic brain injury patients in whom hypertonic sodium solutions are contraindicated. Use of hypertonic sodium solutions or mannitol in the prehospital setting to specifically improve neurologic outcomes for traumatic brain injury patients is not recommended.

Acute ischemic stroke. Use of either hypertonic sodium solutions or mannitol is recommended for initial management of intracranial pressure or cerebral edema in acute ischemic stroke patients. Clinicians should consider administering hypertonic sodium solutions for managing intracranial pressure or cerebral edema in acute ischemic stroke patients who do not respond to mannitol. Use of prophylactic scheduled mannitol in acute ischemic stroke patients is not recommended.

Intracerebral hemorrhage. Use of hypertonic sodium solutions rather than mannitol is recommended for managing intracranial pressure or cerebral edema in intracerebral hemorrhage patients. Use of either symptom-based bolus dosing or targeted sodium concentration is an appropriate hypertonic sodium solution strategy for managing intracranial pressure or cerebral edema in intracerebral hemorrhage patients. It is not recommended to use corticosteroids to improve neurologic outcome in intracerebral hemorrhage patients due to potential for increased mortality and infectious complications.

Bacterial meningitis. Use of intravenous dexamethasone 10 mg every 6 hours for 4 days is recommended for reducing neurologic sequelae in patients with community-acquired bacterial meningitis. Use of intravenous dexamethasone 0.15 mg/kg every 6 hours for 4 days is recommended as an alternative dose for bacterial meningitis patients with low weight or those who cannot take corticosteroids. It is recommended to administer dexamethasone before or with the first dose of antibiotic in bacterial meningitis patients. Use of corticosteroids for 2 weeks or more is recommended in patients with tuberculosis meningitis.

Hepatic encephalopathy. Either hypertonic sodium solutions or mannitol is recommended for managing intracranial pressure or cerebral edema in hepatic encephalopathy patients. Osmolar gap rather than osmolarity thresholds should be used during treatment with mannitol for monitoring risk of acute kidney injury. Severe hypernatremia and hyperchloremia during treatment with hypertonic sodium solutions should be avoided due to the association with acute kidney injury.

Personalized approach to management of cerebral edema. There are multiple methods of treatment for several types of cerebral edema that require personalization of the combination of treatments that are suitable for an individual patient. Because cerebral edema in traumatic brain injury is a diffuse, multifaceted, heterogeneous, and dynamic process, it may be prudent to complement these measures with other forms of multimodal monitoring, imaging studies, and phenotypic and genetic biomarkers to provide a personalized approach (23). The underlying mechanisms contributing to cerebral edema and clinical intracranial pressure targets may differ between patients based on a variety of characteristics including age, gender, injury characteristics, and genetics. A personalized approach should address these factors. Bedside neuromonitoring will enable rapid stratification of severe traumatic brain injury patients based on individual pathophysiology for optimizing edema targeting strategies.

Even a surgical procedure such as decompressive craniotomy for malignant cerebral edema in large hemispheric stroke may require a personalized approach to the complex decision-making process. It is difficult to decide who will require early or preemptive surgery and who might benefit from postponing surgery until clear evidence of deterioration emerges. Neurologists also have to ascertain by discussion with the patient’s relatives and preoperative predictions whether quality of life or disability is acceptable (03).

Outcomes

This is discussed along with various treatments.

Special considerations

Pregnancy

Cerebral venous sinus thrombosis occurs more frequently during pregnancy and puerperium.

Pediatric age groups. See MedLink Neurology article Pediatric cerebral edema.

Geriatric age groups. The elderly patients are more susceptible to cerebral edema, particularly that associated with severe traumatic brain injury and large hemisphere stroke, and outcome is poorer than younger adult patients.

Anesthesia

The anesthetist plays an important role in management of cerebral edema during neurosurgical procedures and postoperative care of the patient who may develop cerebral edema following neurosurgical procedures. Some anesthetic agents may have a beneficial effect. For example, sevoflurane sedation attenuates early cerebral edema formation through stabilization of the adherens junction protein beta catenin in an animal model of subarachnoid hemorrhage (02).