eEdE-35
WHAT RADIOLOGISTS SHOULD KNOW
ABOUT BRAIN DEATH: RADIOLOGIC
SIGNS OF A NONRADIOLOGIC
DIAGNOSIS
Joseph Gastala, MD; Aristides Capizzano, MD; Patricia Kirby, MD; Toshio
Moritani, MD, PhD
University of Iowa Hospitals and Clinics
DISCLOSURES
•
The authors have no financial or nonfinancial relationships to disclose
OUTLINE
• Introduction
• Definitions
• Diagnostic criteria and ancillary testing
• Pathophysiology and pathology
• Imaging Findings
• Summary
INTRODUCTION
•
Concept of brain death was first described by Mollaret and Goulon in 1959 when
they described “le coma depasse” of comatose patients supported by mechanical
ventilators with absent electroencephalographic recordings, absent intracranial flow,
or total brain necrosis at autopsy[1], basing death off neurologic criteria.
•
Early recognition of brain death is important to expedite organ transplantation,
provide closure for loved ones, and prevent unnecessary negative medical
interventions.
•
As will be discussed, brain death is a clinical diagnosis that is not always
straightforward. Ancillary tests (EEG, angiography, transcranial Doppler, and
scintigraphy) are included in the criteria as confirmed tests. However, radiologists
usually encounter brain death or nearly brain death cases on other imaging
modalities including CT, CT angiogram, CT perfusion, MRI, MR angiogram and
diffusion weighted imaging, which often demonstrate characteristic findings.
•
This educational exhibit will illustrate pathophysiology and pathology and
demonstrate the utility of multimodal imaging findings. Radiologists should
understand brain death and their role in recognizing, reaching, and expediting the
diagnosis.
DEFINITIONS
• The definition of “brain death” according to the Uniform Determination of
Death ACT[2]
• “Irreversible cessation of functions of the entire brain, including the brain
stem”
• As a purely biologic definition, “death” is the irreversible cessation of critical
functions in an organism as a whole[3].
• The equivalence of death with brain death is not universally accepted, but it
has been accepted throughout most of the Western world[4, 5, 6]
PREREQUISITES FOR THE DIAGNOSIS
•
The diagnosis of brain death requires consideration of the clinical setting and
that the cause of brain death be known; this is often elucidated by CT scan[7]. In
patients with coma of undetermined origin, the diagnosis of brain death can be
difficult and complex.
•
The irreversibility of the patient’s clinical state needs to be established[8, 9]
•
Mimics and reversible causes include[8]:
• Locked in syndrome
• Hypothermia
• Drug intoxication
• Severe electrolyte, acid-base, and endocrine disturbances
Prerequisites
Neurologic
Exam
Ancillary
Testing
DIAGNOSTIC CRITERIA
•
The diagnosis of brain death is made on clinical grounds and neurologic exam. In the United
States, clinical criteria have been set forth by the American Academy of Neurology [7, 8]
• Documentation of coma
• Absence of motor responses to painful stimulus
• Supraorbital nerve pressure, temporomandibular joint pressure, sternal rub, or
nail-bed pressure
• Absence of brain-stem reflexes
• Absence of pupillary responses, corneal reflexes, caloric responses, gag reflexes,
coughing in response to tracheal suctioning, sucking and rooting reflexes
• Apnea
• Absence of respiratory drive
Prerequisites
Neurologic
Exam
Ancillary
Testing
WHEN THE DIAGNOSIS IS UNCERTAIN
•
Sometimes the clinical criteria cannot be applied due to uncertainty about the
reliability of the neuroogic examination, or when the apea test cannot be performed.
These situations include[9,11]:
• Situations in which cranial nerves may not be adequately examined, e.g. severe
facial trauma, preexisting pupillary abnormalities
• Cases in which neuromuscular paralysis is present or when profound metabolic
and endocrine disturbances are not readily reversed
• Patients with severe pulmonary disease resulting in carbon dioxide retention
rendering the apnea test nondiagnostic
•
In these cases, ancillary testing should be considered
Prerequisites
Neurologic
Exam
Ancillary
Testing
ANCILLARY TESTS FOR BRAIN DEATH
•
There are two general categories of confirmatory tests for brain death[10]. There are
four ancillary tests that have been approved by the American Academy of Neurology:
• Confirmation of loss of electrical activity
• Electroencephalography (EEG)
• Demonstration of loss of cerebral blood flow
• Cerebral angiography
• Transcranial Doppler (TCD) ultrasonagraphy
• Cerebral scintigraphy
•
Other studies have not yet been approved by the American Academy of Neurology
•
However, findings on MRI/MRA and CTA have been shown to correlate with brain
death, and these findings must be recognized by the radiologist
Prerequisites
Neurologic
Exam
Ancillary
Testing
ELECTROENCEPHALOGRAPHY
•
Widely available and used in the determination of brain death in many countries
•
Electrical activity will be absent above 2 uV at a sensitivity of 2 uV/mm with a filter
setting at 0.1 or 0.3 s and 70 Hz
•
Artifacts can be common if high gain amplification is used
CEREBRAL ANGIOGRAPHY
•
Generally accepted as the gold standard among techniques that measure intracranial
flow[40]
•
No cerebral filling should be demonstrated above the level of carotid or vertebral artery
•
Invasive, requires specialized skill, not always readily available
TC-99M HMPAO SCINTIGRAPHY
•
Noninvasive, excellent correlation with cerebral angiogram
•
Multiple flow patterns have been described[12]
•
No intracranial flow provides straightforward confirmation of brain death; flow within cerebrum
and cerebellum rules out the diagnosis
•
Preservation of cerebellar flow with absence of cerebral flow is not diagnostic, but patients will
usually end up progressing to brain death
•
Lack of cerebellar flow with preservation of cerebral flow is an indeterminate finding[13]
•
Hot nose sign due to obstruction of internal carotid artery flow and subsequent increased external
carotid flow into collateral and extracranial circulation through center of the face [14]
•
Disadvantages are that it is not widely available on an urgent basis
Tc-99m HMPAO scintigraphy in a patient
with clinically diagnosed brain death
demonstrates no intracranial vascular flow.
TRANSCRANIAL DOPPLER
•
Noninvasive and inexpensive, with great portability
•
Cerebral circulatory arrest is indicated by flow patterns without forward flow progress,
progressing from 1) decrease in diastolic flow, 2) disappearance of diastolic flow, 3)
oscillating pattern with retrograde flow in diastole, 4) short systolic spikes, and finally 5)
absence of Doppler signal[15]
•
Has been shown to correlate with four vessel angiography in intracranial circulatory
arrest[15]. Cerebral circulatory arrest in the basilar and both middle cerebral arteries
correctly predicted fatal brain damage in all patients in one study[16]
•
Disadvantage of TCD is that it is highly operator dependent
TCD patterns of cerebral circulatory
arrest, taken from the right middle
cerebral artery. A) Low diastolic
velocity, B) systolic peaks with zero
diastolic velocity, C) oscillating pattern
with negative flow in diastole, D) short
systolic spikes. Reprinted with
permission from Hadani et al. [17]
ETIOLOGY
• Brain death is preceded by a massive, irreversible brain injury[18]
• Most common causes of brain death in adults are traumatic brain injury
and subarachnoid hemorrhage
• In the ICU, brain death is most commonly seen in large ischemic strokes
or hypoxic-ischemic encephalopathy
• This injury leads to edema and massive destruction of tissue despite
continued advanced life support
GROSS PATHOLOGY
• Brain herniation occurs due to elevated intracranial
pressure
• Tonsillar herniation
• Uncal herniation
• Transtentorial herniation
• Transtentorial herniation leads to compression of
the brainstem with stretching and laceration of
pontine perforating branches of the basilar artery
or thrombosis and venous infarction. These lead to
duret hemorrhages
• Brain will increasingly take on a dusky, congested,
and discolored appearance once intracranial blood
flow has arrested[40]
Gross pathology specimens of
tonsillar transtentorial herniation
Gross pathology demonstrating
uncal herniation
Duret hemorrhages
MICROPATHOLOGY
• Diffuse cytotoxic edema occurs throughout the gray and white matter, with intracellular edema
occurring within the astrocytes in gray matter and within the oligodendroglial cell bodies, astrocytes,
myelin sheaths, and axons in white matter[27]
• Interstitial edema occurs in periventricular tissues presumably from CSF reabsorption and increased
transependymal flow
• Autolysis is a phenomenon that occurs with anoxia related to release of intracellular compounds,
which can be a result of delayed fixation[40], and can occur along with changes from brain death
A
B
C
Micropathology slides show A) vacuolation of white matter and B) decreased myelin staining (LFB stain).
Compare this with C) normal controls (LFB stain).
PATHOPHYSIOLOGY OF BRAIN DEATH
Edema
Increased ICP
Cerebral
circulatory
arrest
Electrocerebral
silence
MECHANISM OF BRAIN EDEMA
Inciting process:
Trauma, hypoxia, hemorrhage, tumor,
toxicity
•
•
•
•
Disruption of bloodbrain barrier
Vasogenic edema
Biomolecular mediators
•
of injury
Cytotoxic edema
An inciting process generates cerebral edema or mass effect.
Cerebral blood flow is dictated by local autoregulatory mechanisms, related
to regional concentrations of CO2[19]; the inciting process disturbs these
mechanisms
Disturbances in blood flow, oxygen, or glucose supply causes loss in neural
and blood-brain barrier function[20]
Additionally, occlusion of vessels induces a change in blood gas values and
pH with associated acidosis and increase in lactate[20]
These changes lead to edema. Classically, two types of edema are
described
• Vasogenic edema
• Extracellular edema caused by influx of water when blood-brain
barrier is disrupted
• Decreased cerebral perfusion causes alteration in blood gases
with increased pCO2 and causing secondary arterial vasodilation,
contributing to extracellular water and edema [21]
•
Cytotoxic edema
• Intracellular edema of glial cells
• Metabolically mediated[20]
•
The combination of vasogenic and cytotoxic edema increases brain
volume[21], and have the potential to increase intracranial pressure.
Edema is greatest by 24 to 72 hours after the event [19]
Brain Edema
•
CYTOTOXIC EDEMA AND CELL DEATH
Inciting event
The molecular cascade leading to cytotoxic edema and subsequent changes
leading to cell death is complex, and the following is an oversimplification.
Decreased local or global
cerebral perfusion,
traumatic injury
•
Cytotoxic Edema
• Normally, Na/K ATPase pump creates an
intracellular/extracellular sodium and potassium gradient
• Decreased global or local perfusion causes decreased
clearance of lactate and increased acidosis.
• Failure of ATP production occurs due to ischemia, in
addition to membrane depolarization and acidosis. This
causes subsequent failure of the Na/K pump
• There is subsequent shift of K+ into extracellular space,
and Na+ ions and subsequently water into intracellular
space[22]
•
Glutamate
• Traumatic brain injury is associated with large quantities
of extracellular glutamate due to failure of presynaptic
ion pumps and calcium-mediated exocytosis[21]
• Ischemic neuronal injury also induces release of large
quantities of glutamate into extracellular space of the
brain due to failure of the glutamate transporter, which
normally maintains the normal glutamate gradient within
neurons [22, 24]
Glutamate
Na/K
ATPase
Na+
Water
Cytotoxic
edema
Failure of of electron transport
chain
Mitrochondria
CYTOTOXIC EDEMA AND CELL DEATH
Inciting event
The molecular cascade leading to cytotoxic edema and subsequent changes
leading to cell death is complex, and the following is an oversimplification.
Decreased local or global
cerebral perfusion,
traumatic injury
•
Ca2+
Glutamate
Calcium
• Glutamate opens channels for calcium entry with binding
to ionotropic receptors [25, 26]
• Intracellular calcium subsequently enters the mitochondria
through a calcium uniporter, and mitrochondrial calcium
increases
Receptor activation
Na/K
ATPase
Oxygen
radicals
Increased Ca2+
Na+
Water
Cytotoxic
Apoptotic
edema
cascade
Failure of of electron transport
chain
Mitrochondria
•
Mitochondria and cell death
• Increased intramitochondrial calcium causes generation of
reactive oxygen species[21] which further damages lipids,
proteins, and DNA of the cell
• High intramitochondrial concentration of Ca2+ causes
release of cytochrome C with further alteration of electron
transport and further decreases in energy [22, 25]
• Cytochrome C and other proteins activate the apoptotic
cascade leading to cell death
PATHOPHYSIOLOGY OF BRAIN DEATH
Edema
Increased ICP
Cerebral
circulatory
arrest
Electrocerebral
silence
INCREASED INTRACRANIAL PRESSURE
• Edema and mass effect, when extensive, cause
associated rises in intracranial pressure
• Cerebral perfusion pressure (CPP) is the driving
arterial pressure gradient across cerebral
vasculature, and is related to mean arterial pressure
(MAP) and ICP[21]
• CPP=MAP-ICP
• Increasing intracranial pressure decreases
CPP
Edema and mass effect
Decreased
CPP
Increased intracranial
pressure
Arteriole
vasodilation
Increased
CBV
Cerebral circulatory arrest
• Autoregulation is the process of maintaining cerebral
blood flow over varying cerebral perfusion pressures.
Arteriole vasodilation is the response to maintain
cerebral blood flow over decreased cerebral
perfusion pressures.
• This vasodilation leads to an increase in cerebral
blood volume
• A vicious cycle may ensue in which increases in CBV
cause further increases in ICP, and the cycle begins
again by decreasing CPP
INTRACRANIAL PRESSURE AND
INTRACRANIAL VOLUME REGULATION
• Total intracranial volume = Blood + CSF + Brain tissue + Water[20]
• The rigid cavity of the skull leaves very limited ability to compensate for swelling, edema, or mass
effect. [21]
• Compensatory mechanisms for increased brain volume include decreasing CSF (decreased
production, increased absorption, shunting to spinal subarachnoid space) or shunting venous blood
[21]
• The main compensatory process for restoring equilibrium is CSF reabsorption. When most of the CSF
has been reabsorbed, the brain will occupy the areas previously occupied by CSF, leading to
herniation[20]
• Herniation leads to loss of consciousness and eventually respiratory failure, which further exacerbates
ischemia and contributes to further increases in intracranial pressure.
• Even in processes of global ischemia and multifocal processes, there are differences in perfusion from
one region of the brain to another[19], and not all areas of the brain are affected equally and uniformly.
PATHOPHYSIOLOGY OF BRAIN DEATH
Edema
Increased ICP
Cerebral
circulatory
arrest
Electrocerebral
silence
CEREBRAL CIRCULATORY ARREST
• Eventually venous congestion results, causing further increases in ICP.
• As edema develops, a threshold is reached in which ICP rises
exponentially to small changes in edema [29]
• When intracranial pressure exceeds diastolic pressure, there is loss of
perfusion[29, 30]
ELECTROCEREBRAL SILENCE
• Cerebral circulatory arrest leads ultimately to electrocerebral silence
• Brain death is always accompanied by electrocerebral silence, although
not all cases of electrocerebral silence are brain death[31]
RADIOLOGIC IMAGING FINDINGS
• Most of the imaging findings are related to increased intracranial
pressure and associated cerebral circulatory arrest
• It is important for the radiologist to recognize signs of brain
death to suggest and expedite the diagnosis of brain death
• MRI/MRA, CTA and CT perfusion studies have been shown to
correlate well with brain death
CT/CTA/CT PERFUSION
•
Noninvasive, widely available, great rapidity, and does not require a high level of
expertise to perform
•
Accuracy first demonstrated by Dupas et al.[36], who first introduced a 2-phase protocol
(arterial and mixed arterial and venous phase), with a 7 point scale. This was
subsequently was accepted as one of the ancillary tests for confirmation of brain death
in France. Additionally Austria, Switzerland, and Canada have adopted its use in
confirmation of brain death.
•
Frampas et al introduced an abbreviated 4 point scale, concluding lack of opacification
of MCAs and internal cerebral veins in CTA is efficient and reliable in brain death
diagnosis [37]
•
Residual brain perfusion can occur with decompressive craniectomy and skull defects,
leading to false positive results, and Welschehold et al. have proposed using lack of
opacification of the ICV as criteria, showing high sensitivity and specificity[38]
•
Shankar et al. demonstrated lack of cerebral blood flow and cerebral blood volume in the
brain stem with CT perfusion is very sensitive for brain death[39]
•
Disadvantages of the use of CTA are risk of renal damage for patients in consideration
for organ transplant
43 YEAR OLD MALE WITH AORTIC DISSECTION, POSTOPERATIVE
COURSE COMPLICATED BY ISCHEMIC BOWEL
A, B) Axial slices of a CT angiogram demonstrate
lack of opacification of intracranial circulation,
including internal cerebral veins and midline arteries.
There is opacification of the superficial temporal
artery and branches (green arrows)
A
B
C, D) Normal Axial CT angiogram of a normal patient
for comparison demonstrating opacification of all
intracranial arteries and internal cerebral veins (blue
arrows)
C
D
57 YEAR OLD FEMALE, INITIALLY PRESENTING WITH HEADACHES,
BECAME UNRESPONSIVE
C
B
A
D
A) Axial noncontrast CT demonstrates subdural hematoma (blue arrow) and midline shift (blue
arrow). B, C) Coronal and D) 3D CTA reconstructions demonstrate lack of opacification of
intracranial circulation
42 YEAR OLD FEMALE WITH WITNESSED FALL WHILE RUNNING, FOUND
TO HAVE DIFFUSE SAH
A, B, C) Axial 3D CTA
reconstructions demonstrate minimal
delayed opacification of intracranial
circulation more likely “nearly” brain
dearth.
C
B
A
D) Cerebral Blood Volume and E) Cerebral
Blood Flow CT perfusion images
demonstrate matched decreased CBV and
CBF within the supratentorium and
posterior fossa
D
E
MRI/MRA
• A number of signs have been associated with the diagnosis of brain death on MRI and
MRA [32, 33, 34, 35]
• Massive brain edema leads to transtentorial and foramen magnum herniation
• The increase in intracranial pressure and cerebral circulatory arrest leads to absence
of intracranial vascular flow
• There is poor gray matter/white matter differentiation with the brain edema on
conventional MRI
• Diffuse diffusion restriction results from diffuse cytotoxic edema, there is decreased
ADC values more prominent in white matter compared to gray matter, related to
differences in water accumulation in different cytoarchitectures [27]
• Transcortical and transcerebral vein signs can be seen, which has also been
described with acute stroke[35]
• Prominent nasal and scalp enhancement
• MRA can demonstrate non-visualization of intracranial vasculatures likely compatible
with conventional angiogram.
• Disadvantages of MRI /MRA include difficulty to obtain on ventilated patients and length of
time for scanning
48 YO FEMALE WITH PERFORATED COLON SECONDARY TO BOWEL
IMPACTION S/P COLOSTOMY, ADMITTED WITH AMS AND FOUND TO BE SEPTIC
A
B
C
D
A) Sagittal T1W image shows foramen magnum and
transtentorial herniation (green arrows), with massive
brain edema. There is loss of gray white differentiation
(orange arrow). B) Axial T2w shows loss of internal
carotid artery intracranial flow voids (yellow arrow). C,
D) Axial DWI and ADC map show diffusion restriction
and low ADC values more prominent in the white
matter more than cortex. E, F) Axial GRE and SWI
show transcortical (thin blue) and transcerebral (fat
blue arrows) vein signs[35].
E
F
32 YEAR OLD MAN PRESENTING WITH HEADACHE, LUMBAR PUNCTURE
WITH CSF CONSISTENT WITH VIRAL INFECTION
A
A) Sagittal T1W image
shows tonsillar herniation
(blue arrow) and loss of
cortical sulci (orange arrow).
B) Intracranial MRA
demonstrates loss of
vascular flow within the
supraclinoid internal carotid
arteries.
B
C, D) Axial DWI and ADC map
demonstrate diffuse diffusion
restriction with decreased ADC
values.
C
D
Vacuolation and decreased myelin
staining in white matter
SUMMARY
• Early recognition of brain death is important to expedite organ
transplantation, provide closure for loved ones, and prevent unnecessary
negative medical interventions.
• Brain death is a clinical diagnosis which can be a difficult diagnosis in the
presence of confounding factors. Ancillary tests (EEG, Angiogram , TCD,
Scintigraphy) are used to aid in confirmation of the diagnosis
• We illustrated pathophysiology and pathology and demonstrated the
utility of multimodal imaging findings including CT, CT angiogram, CT
perfusion, MRI, MR angiogram and diffusion weighted imaging.
• Radiologist can play a significant role in recognizing, reaching, and
expediting the diagnosis.
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