Cerebral Edema

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Cerebral Edema? What are the typical findings for this disease?

Cerebral edema (CE) results from an increase in brain fluid content and may be life-threatening, requiring prompt recognition and management. Symptoms according to children’s age groups are summarized in Table I.

Table I.

Age Group	No increase in ICP	Mild to moderate increase in ICP	Severe increase in ICP
Neonates and infants	Irritability, crying or asymptomatic	Inconsolable crying, poor feeding, vomiting, lethargy, seizures or irritabilityBulging fontanelle, widened sutures, persistent downward eye deviation and increased head circumference	Reduced level of consciousness and posturingUnilateral or bilateral dilated pupils with poor reactivity, reduced level of consciousness and Cushing’s triad
Toddlers and school age children	Headache, irritability or asymptomatic	Headache, vomiting, diplopia, lethargy, seizures or irritabilityAbducens palsy, abnormal pupillary reactions and papilledema	Reduced level of consciousness and posturingUnilateral or bilateral dilated pupils with poor reactivity, reduced level of consciousness and Cushing’s triad

CE may or may not be associated with increased intracranial pressure (ICP). CE may occur either due to cellular injury and swelling (cytotoxic CE) or disruption of the blood-brain barrier (vasogenic CE). CE may arise in a variety of neurologic and non-neurologic illnesses.

The most common cause of CE is traumatic brain injury (including sport-related concussions, neurocysticercosis, malignant encephalitis) – other causes include infections (meningitis, cerebral malaria), stroke (ischemic, hemorrhagic and embolic), hydrocephalus, hypoxic-ischemic encephalopathy, intracranial sinus venous thrombosis, hypertension, altitude sickness, and brain tumors.

Common non-neurologic illnesses associated with CE include diabetic ketoacidosis, fulminant hepatic failure, ingestions and electrolyte abnormalities such as hyponatremia. Children with CE may be completely asymptomatic or exhibit varying degrees of symptoms specific to age. Children with CE require close monitoring and management, preferably in a pediatric intensive care unit.

If CE is associated with increased ICP, invasive ICP monitoring and neurosurgical support may be vital to improving outcomes. Management of CE consists of general principles of stabilization of airway, breathing and circulation, as well as specific measures to reduce CE and preserve cerebral perfusion with corticosteroids, hyperosmolar therapy, management of underlying disorders and in certain instances, neurosurgical interventions such as drainage of cerebrospinal fluid (CSF) and decompressive craniectomy.

Typical findings:

Under normal circumstances, the sum of the volumes of the brain, blood and CSF remains constant as defined by the Monroe-Kellie doctrine. The volume of the brain can be altered by blood, tumor, mass or CE, or a combination of these factors resulting in elevated ICP. CE may be asymptomatic or symptomatic depending upon the extent of changes. The severity of symptoms vary by age (due to the presence or absence of an open fontanelle) and increase in ICP.

What other disease/condition shares some of these symptoms?

Diseases/conditions that can mimic signs/symptoms of cerebral edema include:

Altered consciousness (including coma)
Headache (including migraine)
Seizure
Intoxication
Intestinal obstruction (volvulus, intussusception)
Esotropia due to syndromes (Mobius, Duane)
Optic neuritis
Hypertrophic pyloric stenosis
Macrocephaly

What caused this disease to develop at this time?

Cerebral edema occurs due to an increase in brain fluid content and can be divided into three forms: cytotoxic, vasogenic and interstitial, or a combination (Table II).

Table II.

Cytotoxic	Hypoxic ischemic brain injury (near drowning, cardiac arrest)
	Traumatic brain injury
	Metabolic disease (urea cycle disorders, organic acidemias)
	Hepatic encephalopathy associated with fulminant hepatic failure
	Reye’s syndrome
	Infections (encephalitis, meningitis)
	Diabetic ketoacidosis
	Toxic ingestions (aspirin, ethylene glycol, methanol, endosulfan, ecstasy)
	Water intoxication/ hyponatremia
Vasogenic	Brain tumors
	Brain abscess
	Stroke
	Hypercapnia
	Posterior reversible encephalopathy syndrome associated with hypertension
	Hepatic encephalopathy associated with fulminant hepatic failure
	Metabolic disease (urea cycle disorders, organic acidemias)
	Diabetic ketoacidosis
	Lead toxicity
	High altitude cerebral edema
Interstitial	Obstructive hydrocephalus

Cytotoxic edema is characterized by cellular swelling, that typically commences in the foot processes of astrocytes and subsequently, involves neurons, other glial cells and endothelial cells with an accompanying reduction in the extracellular space. It occurs without a disruption in the blood-brain barrier and is likely due to cellular energy depletion. This results in the failure of the adenosine triphosphate-dependent sodium potassium pump, with resultant accumulation of sodium and water within the cells. It occurs in both gray and white matter.

Vasogenic edema occurs due to alterations in the blood-brain barrier (BBB) with breakdown in the tight endothelial junctions resulting in the formation of a plasma-derived protein-rich exudate. It occurs in both gray and white matter, but it tends to predominate within the white matter.

Interstitial edema results from an increase in brain fluid caused by the blockage of CSF flow pathways. It occurs in the periventricular white matter in association with hydrocephalus. The BBB remains intact and the edema is in the extracellular space and of the same composition as CSF.

Various combinations of mechanisms can also contribute to cerebral edema, especially with prolonged ischemia. Table III gives a classification of cerebral edema according to various factors.

Table III.

Type	Blood-brain barrier	Site	Location	Mechanism
Cytotoxic	Intact	White and gray	Intracellular	Cellular failure
Vasogenic	Disrupted	White	Extracellular	Increased vascular permeability
Interstitial	Intact	White	Extracellular	Impaired CSF outflow

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

General laboratory studies such as blood glucose and urine ketones (diabetic ketoacidosis), electrolytes (diabetic ketoacidosis, hyponatremia), blood gas analysis (diabetic ketoacidosis, hypercapnia, metabolic disease), liver functions and ammonia (hepatic encephalopathy), lead and other drug levels (lead encephalopathy, toxic ingestions), microbial cultures from blood and CSF (infections), and markers of autoimmune disease (vasculitides) are helpful to diagnose disorders that are associated with CE.

A lumbar puncture is a useful test to measure CSF pressure and obtain pertinent CSF studies to help diagnose conditions associated with CE. CSF pressure is affected by the positioning of the child as well as the use of sedation. A lumbar puncture is absolutely contraindicated when an intracranial mass is suspected (altered mental status, focal neurological deficits, and papilledema). In such circumstances, imaging studies must be obtained and a neurosurgeon should be consulted for further measurement of CSF pressure.

Electroencephalography (EEG) is a useful modality to diagnose seizures and altered states of consciousness associated with CE.

Would imaging studies be helpful? If so, which ones?

Computerized tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US) are useful to diagnose CE as well as underlying causes of CE.

1. Computerized tomography (CT) of the brain (See Figure 1).

Findings can range from:

a. enlarged ventricular system

b. transependymal flow of CSF

c. obliteration of basal cisterns and sulci (See Figure 2).

d. evidence of herniation

e. specific lesions (tumors, hemorrhage, infections, abnormalities of skull bones) with midline shift and mass effect

f. generalized CE with loss of gray-white differentiation

Advantages – easy to obtain (quick study, can avoid sedation), less expensive

Disadvantages – insensitive to image the posterior fossa, higher risk of radiation exposure (can be minimized using dose specific pediatric protocols), especially if serial imaging is required. (One pediatric dose adjusted head CT = approx 300 chest radiographs)

2. Magnetic resonance imaging (MRI) of the brain

Findings can range from

a. changes seen on CT

b. findings of diffuse axonal injury (DAI)

c. detection of microhemorrhages

d. Increase in optic nerve sheath diameter

Advantages – greater detail, better prognostication of neurocognitive outcomes, no risk of radiation, superior to image posterior fossa lesions, diffusion weighted imaging may be able to distinguish between cytotoxic and vasogenic edema

Disadvantages – difficult to obtain in non-cooperative patients with greater risks (long study, risk of sedation in the setting of CE), more expensive

3. Ultrasonography – useful when the fontanelle is open (See Figure 3).

Findings can range from

a. effacement of sulci (See Figure 4).

b. enlarged ventricular system

c. hemorrhage

d. slit like ventricles

Other less commonly used modalities include transcranial doppler ultrasound, positron emission tomography (PET), near infra-red spectroscopy (NIRS) and visual evoked potentials (VEP).

Confirming the diagnosis

The Brain Trauma Foundation published guidelines developed by experts in pediatric traumatic brain injury in 2012 that are helpful to diagnose, monitor and manage CE with increased ICP in the setting of traumatic brain injury. These guidelines are freely available at the Brain Trauma Foundation website. These guidelines often reflect expert opinion due to the lack of pediatric studies.

If you are able to confirm that the patient has Cerebral Edema, what treatment should be initiated?

Children with suspected or confirmed CE should be promptly referred and transferred to a pediatric intensive care unit, preferably with pediatric neurocritical care and neurosurgical capabilities as this condition is often associated with elevated ICP and risk of herniation. The goals for treatment of CE in the setting of increased ICP include avoidance of hypoxia and maintenance of cerebral perfusion. Treatment of CE with increased ICP in the context of traumatic brain injury consists of both first-tier and second-tier therapies as outlined below. This outline can be adapted for management of CE with increased ICP in the setting of other etiologies.

First-tier therapies consist of careful attention to the ABCs (including securing the airway, maintaining normal ventilation and adequate perfusion with careful management of blood pressure), elevation of the head to 30 degrees, sedation and analgesia, drainage of CSF, neuromuscular blockade and hyperosmolar therapy (mannitol or hypertonic saline). The first priority consists of managing the ABCs to prevent hypoxia and hypotension to prevent further cerebral injury and worsening of CE. Elevation of the head of the bed has been shown to increase cerebral venous drainage and reduce ICP. The institution of appropriate sedation and analgesia helps to reduce cerebral metabolism and in turn, CE. Drainage of CSF via an external ventriculostomy catheter reduces ICP and maintains cerebral perfusion. Neuromuscular blockade after appropriate sedation is achieved can reduce ICP by reducing muscle tone. Hyperosmolar therapy with either mannitol or hypertonic saline reduces CE by facilitating movement of water from the intracellular compartment to the extracellular compartment.

Second-tier therapies should be considered when first-tier therapies are ineffective and include lumbar CSF drainage, decompressive craniectomy, controlled hyperventilation, high-dose barbiturate therapy and moderate hypothermia (32-34 C). Lumbar CSF drainage requires placement of a external ventriculostomy catheter by a neurosurgeon and subsequent close monitoring for controlled drainage of CSF. Decompressive craniectomy is useful in focal etiologies such as traumatic brain injury or stroke and involves displacement of the skull bone overlying the affected region by a neurosurgeon to reduce ICP. Controlled hyperventilation to produce cerebral vasoconstriction due to hypocapnia is useful to control refractory increases in ICP, and is used as a bridge to a more definitive therapy. High-dose barbiturate therapy and moderate hypothermia are therapies requiring considerable expertise and may help reduce cerebral metabolism and in turn, CE.

Additionally, treatment should be directed to the underlying etiology of CE. For example, surgery may be indicated for resection of tumors and vascular malformations, drainage of abscesses and blood collections, and shunting of hydrocephalus. Similarly, aggressive medical management may be necessary for diabetic ketoacidosis, hepatic encephalopathy, inborn errors of metabolism, stroke, intracranial sinus venous thrombosis, and malignant hypertension. In case of altitude sickness, descent to lower elevations is recommended.

Medications such as acetazolamide and other diuretics such as furosemide may be considered in the context of interstitial CE with chronically increased ICP to reduce CSF production. Corticosteroids may be useful to reduce CE in the setting of vasogenic edema associated with brain tumors and inflammatory processes such as tuberculous meningitis and vasculitides. Corticosteroids have no benefit in limiting cytotoxic edema, and osmotic agents such as mannitol and hypertonic saline have only limited benefit in reducing brain water from cytotoxic edema due to concurrent disruption in autoregulation with most of the processes that cause this form of swelling.

What are the adverse effects associated with each treatment option?

First-tier therapies and adverse effects:

1. Elevation of the head to 30 degrees: this may be associated with reduced cerebral perfusion in some instances. Additionally, with head elevation, every effort should be made to keep the head midline and avoid falls from the bed.

2. Sedation and analgesia: adverse effects may include oversedation and cardiorespiratory compromise. Depending on the agent(s) used, other effects may include immunocompromise and endocrine dysfunction.

3. Drainage of CSF: this may be associated with overdrainage, especially with changes in position, dislodgement of the catheter and infectious complications.

4. Neuromuscular blockade: this practice can result in critical illness myopathy and persistent weakness in survivors.

5. Hyperosmolar therapy: the use of mannitol may be associated with the development of hypovolemia from brisk diuresis with resulting hypotension and hypoperfusion of the brain parenchyma. Hypertonic saline solutions may result in thrombophlebitis especially when infused via peripheral venous catheters.

Second-tier therapies and adverse effects:

1. Lumbar CSF drainage: this may be associated with overdrainage, especially with changes in position, dislodgement of the catheter and infectious complications.

2. Decompressive craniectomy: this approach may result in uncontrolled bleeding, herniation, and infectious complications.

3. Hyperventilation: this therapy can result in reduced cerebral blood flow and reduced cerebral perfusion with worsening of cerebral injury.

4. High-dose barbiturate therapy: adverse effects may include oversedation and cardiorespiratory compromise. Other effects may include immunocompromise and endocrine dysfunction.

5. Moderate hypothermia: this practice needs to be performed in centers that are capable of induced hypothermia. Adverse effects include coagulopathy, arrhythmias, hyperglycemia, electrolyte abnormalities and increased risk of infections.

Medications such as acetazolamide and other diuretics may be associated with acidosis and resulting cardiac disturbances as well as hypovolemia. Steroids have numerous adverse effects including hypertension, hyperglycemia, impaired wound healing, immunodeficiency, and bone demineralization.

What are the possible outcomes of Cerebral Edema?

The outcome of CE depends on the underlying etiology and extent and duration of increase in ICP associated with CE. For example, acute increase in ICP related to shunt malfunctions may be easily reversed with minimal consequences. In contrast, increase in ICP associated with severe traumatic brain injury that is resistant to all therapies is usually associated with very poor outcomes. CE with chronically increased ICP may result in gradual loss of neurological function which may be partially reversible with control of increased ICP.

The first-tier therapeutic options to treat CE with increased ICP have a more favorable risk/benefit ratio compared with the second tier therapies. Second-tier therapies require institutions and personnel capable of undertaking these approaches.

What complications might you expect from the disease or treatment of the disease?

CE can result in a wide range of complications depending on the extent of increase in ICP and rapidity of increase in ICP. Complications include visual loss, cerebral atrophy with cognitive decline and loss of milestones, altered mental status and death. Treatment of CE with increased ICP is associated with risks and should be undertaken by experienced providers with adequate institutional capabilities.

How can Cerebral Edema be prevented?

CE can be prevented by early recognition and management of disease processes that are associated with the development of CE and increased ICP. Additionally, public health measures to minimize traumatic brain injury and popularize the recognition of common conditions associated with CE and increased ICP are highly important. For example, contact sports with high risk for pediatric head injury are being extensively reviewed and modified to make conditions of play safer with minimal risk for head injuries.

What is the evidence?

Most of the evidence and rationale for treatment options is derived from expert consensus as randomized controlled trials are lacking.

Guidelines for management of cerebral edema and raised ICP have been developed by the Brain Trauma Foundation and are freely available at www.braintrauma.org

“Guidelines for the acute medical management of severe traumatic brain injury in infants, children and adolescents”. Pediatr Crit Care Med. vol. 13. 2012. pp. S1-S82.

Frank, JI, Rosengart, AJ, Hall, JB, Schmidt, GA, Wood, LDH. “Chapter 65. Intracranial pressure: monitoring and management. In Principles of Critical Care, 3rd edition”. 2005.

Ongoing controversies regarding etiology, diagnosis, treatment

Controversies regarding etiology and pathophysiology of CE sub-types:

– What are the mechanisms of CE?

– Is CE reversible in certain circumstances?

Controversies regarding diagnosis of CE:

– What is the ideal imaging modality for diagnosis of CE?

– What is the best modality to monitor progression and/or resolution of CE?

Controversies regarding treatment of CE:

– Should asymptomatic CE always be treated as an emergency?

– What are the appropriate endpoints for hyperosmolar therapy?

– How should the different modalities for treatment of CE, especially with increased ICP be used?

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