Key words : Ancillary, Blood flow, Confounding, Perfusion, Prognosis

Introduction
Brain death (BD) is defined as the complete and irreversible cessation of the entire brain function, including the brainstem. Brain death occurs after the destruction of enough neuronal cells in the brain, with both an irreversible loss of the capacity for consciousness (coma) and the absence of brainstem reflexes. The 2 main formulations in the understanding of BD are “brainstem death” and “whole brain death.” The brainstem contains essential cardiac and respiratory centers and partially contains the centers responsible for consciousness. Whole BD is the most widely accepted criteria in most countries.

The traditional definition of death is based on loss of circulatory and ventilatory functions. Medical advances in external life support made it possible to maintain and prolong life in deeply comatose patients and in patients with complete loss of all brain functions. The capability to maintain vital body functions after irreversible cessation of brain function has necessitated the reexamination of death criteria. The first standards of death by neurologic criteria, that is BD, were outlined in 1968 by a multidisciplinary committee at Harvard Medical School.¹ After the refinement of criteria during the next decade, both death by neurologic criteria and death by cardiovascular criteria were regarded as “death” of an individual.

Brain death accounts for approximately 1% to 2% of all deaths.2 Rates as high as 21% have been reported in the pediatric population.³ The inciting event leading to BD is an irreversible injury to the brain from either an intracranial or an extracranial cause. Regardless of the etiology, eventually BD occurs due to intense brain edema leading to an increase in intracranial pressure that is sufficient to compress the intracranial vasculature. The most common processes leading to BD are cardiopulmonary arrest, traumatic brain injury, subarachnoid hemorrhage, and intracerebral hemorrhage. The diagnosis of BD is based on an accurate and complete clinical neurological examination. The clinical criteria for diagnosing BD in the setting of severe neurologic injury include irreversible coma, absence of brainstem reflexes, and inability to breath spontaneously. In the presence of confounding medical factors or factors that interfere with clinical assessment, ancillary testing may be needed for the confirmation of BD diagnosis.

Substantial differences exist in the practice of BD determination worldwide. Some centers never perform ancillary testing when the clinical evaluation is complete. An ancillary test may decrease the risk of incorrect diagnosis, reduce observation time, expedite organ transplant when possible, and help family members to better comprehend and accept BD diagnosis. Characteristics of an ideal confirmatory evaluation are accuracy, availability, bedside evaluation, unaffected by drugs or metabolic disturbances, and ability to stand on its own as the sole means for confirming the diagnosis of BD. Despite intensive medical support, patients with BD will inevitably die within a relatively short period of time (days or weeks). However, some long-term survivors with external life support have been reported in the pediatric age group.⁴ In the absence of organ transplantation, one choice would be the discontinuation of support. However, ventilatory support generally continues until circulatory arrest. Although BD diagnosis is essential for organ transplantation, this diagnosis should be made regardless of the need for organ transplantation.

Basis of Ancillary Imaging Evaluation
The brain has a high metabolic activity and energy requirement, albeit a limited storage capacity. Tight coupling occurs between neuronal activity, cerebral blood flow (CBF), cerebral perfusion, and metabolism. Cerebral blood flow refers to the blood supply to the brain in a given period of time; cerebral perfusion, on the other hand, represents the delivery of blood to brain tissue. Cerebral perfusion is more susceptible to changes in intracranial pressure than CBF, and continued absence of blood flow is not compatible with neuronal function. Because of this, absence of blood flow has been considered as a reliable marker of BD. Ancillary imaging methods do not directly evaluate neuronal function, and parameters assessed stand as a surrogate for neuronal function. Imaging in BD is based on the demonstration of absence of brain blood flow and perfusion.

Cerebral blood flow of less than 20% of normal has been suggested to be incompatible with cerebral viability and may represent a threshold of irreversibility.^5-7 In a previous study, a correlation was found between CBF estimated by radionuclide cerebral angiography and flow measured by the microsphere technique.8 However, radionuclide angiography was not able to recognize or predict critically low CBF.

Ancillary Imaging Procedures: Evaluation of Blood Flow and Perfusion
Blood flow imaging can be performed with digital subtraction angiography (DSA), transcranial Doppler sonography (TCD), computed tomography angiography, magnetic resonance angiography, and radionuclide angiography. On the other hand, perfusion imaging is either by radionuclide parenchymal imaging or computed tomography perfusion imaging.

Also known as the 4-vessel angiography, cerebral DSA is generally considered as the gold standard for the demonstration of intracranial blood flow. However, it is technically demanding, invasive, and limited by the availability of expertise.⁹ Several recent meta-analyses have emphasized the lack of specificity data with DSA.^10,11

With its advantage of bedside evaluation and high availability, TCD is now commonly used for the determination of BD. Operator dependence and limitations due to available acoustic window are the main disadvantages.^9,12

Radionuclide Imaging
There are 2 main concepts in radionuclide BD evaluation: which radiopharmaceutical (nonlipophilic or lipophilic or both) and which imaging technique (planar or single-photon emission computed tomography [SPECT] or both).

Nonlipophilic radiopharmaceuticals
Nonlipophilic radiopharmaceuticals do not cross the blood brain barrier. Any Tc-99m-labeled agent can be used. The renal imaging agent DTPA is preferred because of its rapid blood clearance.

Lipophilic radiopharmaceuticals
Lipophilic radiopharmaceuticals cross the blood brain barrier and accumulate in brain parenchyma in close proportion to regional CBF. The most commonly used radiopharmaceutical for this purpose is Tc-99m hexamethyl-propyleneamine oxime (HM-PAO). Tc-99m ethyl cysteinate dimer and Tc-99m bicisate have also been used.^4,13

Radionuclide Imaging Methodology in Brain Death
Several radionuclide BD imaging methods are summarized in Table 1.

Radionuclide angiography
Blood flow studies can be performed using nonlipophilic or lipophilic agents. Immediately after the bolus injection of the radiopharmaceutical, 1- to 2-second frames are acquired in the anterior projection. The presence of activity in the anterior and middle cerebral arteries is evaluated. If a radionuclide angiography is performed using a nonlipophilic agent, blood flow evaluation with a lipophilic agent may not be necessary. However, if the angiographic study with the nonlipophilic agent is somehow compromised, it can still be performed using the lipophilic agent. A good quality bolus injection is mandatory for accurate flow evaluation. Absence of blood flow in intracerebral arteries confirms the diagnosis of BD. However, with radionuclide angiography, circulation of the posterior fossa cannot be evaluated. Image quality is restricted by low count statistics of 1- to 2-second frames, which may be responsible for equivocal results. An advantage of flow phase over parenchymal imaging is its independence from radiopharmaceutical quality control issues.

Static imaging with nonlipophilic agents
When using a nonlipophilic agent, static anteroposterior and lateral images of the skull are acquired after the completion of flow images to evaluate the presence of activity in intracranial venous sinuses. The absence of activity in transverse and sagittal sinuses further confirms the diagnosis of BD. In a previous study, 49% of patients with no flow on radionuclide angiography demonstrated sagittal sinus activity.¹⁴ No differences in the clinical outcome were shown between patients with and without sinus activity. Vascular supply by scalp vein collaterals may be responsible for sinus visualization in brain dead patients. In patients with a clinical diagnosis of BD, sinus activity generally disappears on a repeat study.¹⁵ This might also indicate the order of disappearance of activity in cerebral structures in the process of BD.

Static images may also reveal focal activity in the center of the face in the anterior projection, which was originally referred to as the “hot nose” sign. The activity ascribed to the nose was later shown to be in a more posterior location.¹⁶ In the study of Lee and colleagues, 77% of patients with no flow on radionuclide angiography demonstrated this finding.¹⁴ Although the presence of the “hot nose” sign by itself is nonspecific and can be observed in situations where diminished flow in internal carotid arteries results in increased external carotid flow, its existence in the presence of no flow may represent a secondary scintigraphic sign to further support the diagnosis of BD.

When the patient is a potential donor, after the completion of flow phase with DTPA, abdominopelvic images that include kidneys and bladder in the field of view may also provide information about renal function and the integrity of excretory system.¹⁷

Parenchymal imaging using lipophilic agents
In the absence of BD, immediately after the flow phase, the activity will start to accumulate in the brain parenchyma. Evaluation of parenchymal uptake can be performed by either planar or tomographic imaging. When tomographic imaging is not obtained, planar imaging from several different projections is recommended.¹⁸ For the evaluation of posterior fossa, lateral images are essential.¹⁹ When using lipophilic agents, in addition to parenchymal imaging, a radionuclide angiography is generally performed to further confirm the diagnosis. However, when the flow study is compromised for some reason, the absence of uptake in the parenchymal phase would be enough for the confirmation of BD diagnosis.

According to the most current guidelines, both lipophilic and nonlipophilic radiopharmaceuticals are acceptable in BD diagnosis. However, in general, the preference is toward the use of lipophilic compounds.²⁰

Positron emission tomography
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging is an excellent method for the evaluation of brain metabolic activity and for assessing the viability of parenchymal brain tissue. Several case series have reported use of FDG-PET in BD diagnosis.^21,22 Because of logistic problems and timely availability of FDG, the use of this technique is not common in the confirmatory diagnosis of BD.

Comparison of radionuclide imaging with clinical findings
In the presence of clinical BD diagnosis, depending on the methodology used, sensitivity rates for radionuclide imaging have been reported to range from 78% to 100%.^23-27 Guidelines for the determination of BD by clinical examination alone require an absence of confounding factors. If these factors cannot be eliminated, ancillary testing is required. Radionuclide studies may not be affected by the patient’s metabolic status or by therapy.^27,28 Scintigraphic evaluations have been performed for the confirmation of BD in patients with confounding factors. Similar to studies in patients without confounding factors, most of these patients were diagnosed as BD in either the first or the repeat radionuclide study.^13,27-29 In this patient group, the reported values for BD confirmation on the initial study ranged from 71% to 84%.

Ancillary testing is generally performed in the presence of a clinical BD diagnosis. Studies performed in patients with deep coma have revealed activity on radionuclide imaging in 82% to 100% of patients.^27,29-31 In a study from Bonetti and colleagues on 40 patients with coma with HM-PAO SPECT, 18% had no radionuclide uptake and 82% had radionuclide uptake.³⁰ Patients with no uptake had circulatory arrest within 7 days. Absence of radionuclide uptake in a comatose patient may predict impending death. In a study from Laurin and colleagues, all 10 patients with coma who were not yet clinically BD had varying degrees of uptake on HM-PAO study.²⁷ In a study from Schlake and colleagues, all patients with deep coma and apallic syndrome had uptake with HM-PAO.³¹ These results suggest that some degree of radionuclide uptake is likely in preterminal patients, and an ancillary testing would be more diagnostic when it is performed after clinical BD diagnosis.

Comparison of Ancillary Imaging Methods
Radionuclide angiography versus parenchymal imaging
In a retrospective analysis of 26 cerebral perfusion images using lipophilic (Tc-99m HM-PAO) and nonlipophilic agents (Tc-99m DTPA), delayed-phase with Tc-99m HM-PAO provided the same results for BD (14 positive and 12 negative) as the flow images from either agent.³² With HM-PAO, a high degree of agreement has been shown between radionuclide angiography and parenchymal imaging.²⁷ In the study of Mrhac and colleagues, in which radionuclide angiography and parenchymal imaging with lipophilic agent were used, parenchymal HM-PAO findings provided the most reliable results.³³ The general presentation of discordant cases was absent blood flow in the presence of uptake in the posterior fossa. Flow studies may reveal equivocal results.^5,28,34 However, the final outcome of patients with equivocal flow was generally similar to that of patients with no flow. When available, parenchymal imaging with a lipophilic agent is diagnostic in patients with no flow or equivocal flow.

Planar versus SPECT imaging using lipophilic agent
Scalp uptake may sometimes be misinterpreted as cerebral perfusion on planar imaging. Accurate differentiation of intracerebral activity from that of superficial activity is the major advantage of SPECT compared with planar imaging. In a previous study, SPECT imaging did not offer any additional advantage over planar imaging unless the patient had a scalp wound.²⁴

Radionuclide imaging versus other ancillary imaging methods
Several studies compared DSA and radionuclide imaging in the confirmation of BD and demonstrated congruent findings.^23,25 In a previous study of patients with a clinical BD diagnosis who were evaluated using TCD, TCD confirmed BD diagnosis in 90.5% of the patients.¹² Radionuclide evaluation with SPECT in the remaining ²⁵ patients revealed the absence of cerebral perfusion consistent with BD in 21 cases (87.5%). Brain SPECT confirmed BD diagnosis in a significant proportion of patients when TCD failed to do so. When TCD is performed, technical details are critically important; TCD is also not applicable in 10% to 20% of patients with poor acoustic window or in patients with significant structural damage to the cranium.^12,35

In a recent meta-analysis, the diagnostic utility of commonly used imaging investigations was evaluated.10 Significant heterogeneity existed in sensitivity and specificity estimates across studies. Heterogeneity in accuracy was greater within each ancillary test type than between ancillary test types, likely reflecting high variability in the methodological quality of included studies. It was found that HM-PAO perfusion (both with and without SPECT), electroencephalogram, and TCD had reasonable diagnostic accuracy. In clinically diagnosed BD cases, where ancillary tests were used in a confirmatory role, tests revealed similar sensitivities overall. The authors of this meta-analysis stated that, despite it being historically considered as the gold standard ancillary test for BD diagnosis, specificity estimation was not available for 4-vessel angiography among patients with coma. In another recent meta-analysis that evaluated ancillary tests in infants and children, radionuclide imaging using lipophilic agents had the highest sensitivity and specificity,11 with authors commenting that other ancillary tests, like TCD, need further studies to validate their accuracy.

False-Negative Ancillary Imaging Evaluation
Confirmatory testing is generally performed after the clinical BD diagnosis. Because of this, the validity of the sensitivity data is more reliable than the specificity data for ancillary imaging evaluations. However, in most studies with radionuclide imaging, false-negative cases have existed and generally the sensitivity was not 100% on the first evaluation. In addition to methodological problems, technical errors, and misinterpretation of images, the point of physiologic or anatomic focus may be responsible for discrepant results.

Flow-function discrepancy
Minimum blood flow levels needed for absence of neuronal function on clinical evaluation and absence of blood flow on imaging evaluation may be slightly different. The etiologic factor leading to BD and the presence of confounding factors may be responsible for the earliest loss of either flow or function. Determining which one is more common may be difficult to establish since patients are generally tested after clinical BD diagnosis. Presence of uptake in patients with clinical BD may be due to several factors. First, there may be an inadequate time interval between clinical diagnosis of BD and performance of ancillary imaging investigation. It is best to delay blood flow studies for at least 6 to 12 hours following the clinical diagnosis.³⁶ Second, cerebral decompression may reduce intracranial pressure. When the skull is no longer a closed space as a result of decompression due to the presence of open fontanelles, cerebrospinal fluid shunts, ventricular drains, open fractures, or skull defects, the time needed between the loss of neuronal function and the absence of blood flow on imaging investigation is longer and may be more than 48 hours in some cases.³⁶ Alterations in flow dynamics due to decompression can affect diagnostic performance of all ancillary imaging procedures that evaluate CBF, including DSA.

The point of anatomic focus
Clinical examination of BD and apnea testing are mainly an evaluation of brainstem function. On the other hand, ancillary imaging is not specifically focused on the brainstem. The reliability of SPECT imaging to evaluate the existence of brainstem uptake has not been conclusively established.³⁷ Cerebral uptake in the presence of a clinical BD diagnosis may be due to the presence of isolated brainstem death.

In recent years, isolated brainstem death has been identified as a new etiology of BD. Clinically, no differences exist between brainstem death and whole BD. Isolated disruption of the posterior cerebral circulation or isolated lesions to the brainstem causes irreversible loss of function of the brainstem. In a previous study, among all brain deaths, the incidence of posterior fossa lesions was 1.9%.³⁸ Computed tomography perfusion imaging was proposed as the imaging of choice for the determination of isolated brainstem death.^39,40 In previous studies that used radionuclide imaging, several patients were suspected to have isolated brainstem death.^31,33 In a case series of patients with primary posterior fossa lesions, 2 patients had no uptake on SPECT and 1 patient had only supratentorial uptake that disappeared on a repeat study.³⁸

Most patients with equivocal imaging findings or loss of viability in a significant portion of brain tissue either progressed to circulatory arrest in a short time or had a repeat study that showed absence of flow/uptake, thus confirming the diagnosis of BD.^{13,24,25,27,29,30,33,38,41} This finding suggests that minimal residual blood flow/uptake in the face of clinical BD is usually transient. This may also mean that the loss of viability in major parts of either cerebral hemispheres, cerebellum, or brainstem or viability only in a small, isolated part is not compatible with life. In other words, a clinical BD diagnosis may coexist with the presence of flow/uptake on the imaging evaluation, to only indicate that the process of dying is not complete yet. Diagnosis of BD is a critical decision for both physicians and patients’ families. In some institutions, this issue is the main reason of performing an ancillary imaging evaluation, even in the absence of confounding factors. An objective demonstration of the absence of radionuclide uptake within the brain may be the only means to help family members to comprehend and accept the diagnosis of BD. Diagnosis of BD carries ethical, social, and legal issues; the general clinical approach in the presence of such discrepant findings is to wait and repeat the study, even when, in some instances, this may mean losing the chance of a successful transplant.

Conclusions
The demonstration of absence of cerebral circulation is a reliable indicator of BD. There are currently no agreed-on universal criteria for determining BD by ancillary imaging investigation. However, several guidelines and meta-analyses have referred to radionuclide imaging as the most reliable, accurate, and validated ancillary procedure in the confirmation of BD. Whenever available, lipophilic agents should be preferred using tomographic imaging in all or as needed. False results may occur because of slight temporal delays in the flow-function relationship. The results of radionuclide studies may also suggest that the loss of viability in a significant proportion of brain tissue is not compatible with life. A few cases have also suggested that SPECT imaging has the potential to detect isolated brainstem death.

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