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The Department of Diagnostic and Interventional Imaging

VARIOUS PATTERNS OF TC-99m-BICISATE CEREBRAL PERFUSION
SCINTIGRAPHY IN DIAGNOSIS OF BRAIN DEATH: ADVANTAGES
AND PITFALLS OF USING THIS AGENT

Bruce J. Barron, M.D., Simi Ronit Anidjar, M.D. and Lamk M. Lamki, M.D.

The University of Texas Medical School-Houston Department of Radiology and

Memorial Hermann Hospital, Houston, Texas

Corresponding Author: Bruce J. Barron, M.D.
Address: 6431 Fannin, Suite 2.132
Houston, Texas 77030
Telephone: 713.704.1789
Fax: 713.704.1596
Email: Bruce.J.Barron@uth.tmc.edu
ABSTRACT
INTRODUCTION
DISCUSSION
CASES
METHODS
CONCLUSIONS
BIBLIOGRAPHY
 
ABSTRACT:
Rapid, reliable determination of brain death is becoming increasingly more important, especially at major trauma and transplant centers. Ever since brain death criteria have been proposed, physicians have tries to determine an optimal method of evaluation. Numerous studies have demonstrated "blood flow", when in fact the patient was not alive. Tc-DTPA or Tc-Pertechnetate flow studies and angiography, have either too many false positives to make these ideal methods of brain death determination or too awkward to carryout. We discuss here our experiences with over 300 hundred studies using Tc-99m-ECD. The various patterns we have identified will be categorized and examples will be given.
 
INTRODUCTION:
HISTORICAL PERSPECTIVE
With the vast improvement in medical technology, patients can be maintained on life support for a long time. The issue of brain death has many legal implications. With the current state of transplant surgery, a timely determination must be made. Before the advent of life support technology, this type of dilemma did not occur as frequently. Historical events, including the discovery of brain waves, renal and cardiac transplant surgery, have provided an extreme interest in brain death. One of the first mentions of brain death was by French neuropsychologists Mollaret and Goulon, in 1959 (1). They described a state in which the brain was irreversibly damaged, and in which cardiac and pulmonary functions can be maintained. This condition was called coma de passe (a state beyond coma) (1,2).
 
In 1968, the Ad-Hoc Committee of the Harvard Medical School produced the first set of criteria for the determination of brain death, introducing "irreversible coma " and the use of electroencephalography (EEG). In 1981, the President's Commission Report resulted in the now famous "Uniform Determination of Death act' (3). The Uniform Determination of Death Act introduced the currently accepted criteria of death, i.e. the irreversible cessation of circulatory and respiratory function, or the "irreversible cessation of cerebral and brain stem functions" (2,4). The general concepts of the Uniform Determination Act were accepted by 48 states shortly thereafter. It is important that we, as physicians, understand the legal definition of brain and the implications of cerebral blood flow imaging in determining this state.
 
Confirmatory tests evaluating absent physiologic function have included the apnea test, atropine test, electroencephalography, cerebral function monitoring, and auditory brain stem response. Absence of pupillary, light, corneal, oculocephalic, oculovestibular, oropharyngeal, and respiratory reflexes reflect brain stem death. Absent cerebral function is manifested by deep coma, unreceptivity, and unresponsitivity Cessation of intracranial perfusion is easier to establish than function. Hence, the cerebral blood flow study. Edema, necrosis and autolysis of the brain lead to increased intracranial pressure, which overcomes cerebral perfusion pressure and impedes cerebral blood flow. Lack of cerebral perfusion is the diagnostic criteria for brain death. Complicating conditions and reversible causes include drug and metabolic intoxication, hypothermia, shock and children (2).
DISCUSSION:
The diagnosis of brain death is a clinical determination. The accurate and timely determination of brain death in patients in coma, on mechanical life support, has proven critical with respect to organ donation and efficacious use of costly life support systems (2, 4). Confirmatory tests have evolved to increase certainty of such a diagnosis. These are electroencephalography (EEG), four vessel cerebral angiography, and radionuclide cerebral blood flow angiography (1) CT scanning with contrast, sonographic echoencephalography, Doppler shift ultrasound, digital subtraction angiography, and MRI scanning (2,4,5,6).
 
Although four-vessel angiography represents the gold standard of diagnostic imaging, it is invasive and impractical, requiring the transportation of the patient to the radiology department (2,4). More importantly, false positive angiograms are not uncommon. The absence of EEG activity is an important factor in the determination of brain death, but it always be used. For example, many patients with traumatic head injury or vascular insult, such as intracranial hemorrhage, are placed in a barbiturate coma to help reduce cerebral edema. By doing so, the criteria of absent EEG activity can no longer be employed. It has been shown that anesthetics can cause a reduction in CBF but they do not eliminate it completely (7). Radionuclide cerebral angiography is the modality least affected by the patient's condition or medications. As CBF imaging with Tc-ECD does not require withdrawal of medical therapies, and allows earlier brain death determination, this method is superior to neurophysiological methods (8). Scintigraphic cerebral perfusion has proven to be much more advantageous in terms of noninvasiveness, simplicity, bedside application and easy interpretation than the other two tests discussed (1).
 
Numerous radiopharmaceuticals have been employed for scintigraphic cerebral perfusion, including technetium-99m-pertechnetate, Tc-99m-glucoheptonate, Tc-99m-DTPA, Tc-99m-HMPAO (Ceretecâ), and most recently, Tc-99m-Bicisate (ECD, Neuroliteâ). A complicating factor of technetium-99m-pertechnetate-glucoheptonate and DTPA is false negativity due to the presence of activity within the sagittal sinus or misleading soft tissue hyperemia, a factor, which has caused delay in the determination of brain death and eliminated recruitment of organs, which were otherwise suitable for transplantation. Additionally, with Tc-99m-DTPA and Tc-99m-Pertechnetate, the diagnosis of brain death must be made from the arterial perfusion study alone, as these agents cannot cross the blood-brain barrier to allow evaluation of cerebral uptake of the agents. Accurate diagnosis is dependent upon correct injection technique, and hence more technique dependent. (8, 9).
 
The advent of both Tc-99m-HMPAO and the Tc-99m-ECD and their ability to cross the blood-brain barrier has enabled imaging of cerebral metabolism (3,6). Tc-99m-ECD uptake is reported to be significantly more linear with respect to regional cerebral blood flow and demonstrates better internal (gray to white ratio) and external (brain to body) contrast (8) than Tc-99m-HMPAO. Absence of brain activity, even in the presence of questionable perfusion, confirms a clinical diagnosis of brain death. Tc-99m-HMPAO and Tc-99m-ECD metabolic phase images are confirmatory, but patterns of uptake related to skull fractures, scalp hematomas, intracranial hemorrhage, carotid injury, or surgical instrumentation may act as complicating factors and pitfalls that can hinder a scan determination of brain death. Additionally, technical factors such as a poor bolus, delayed imaging following bolus administration or retained radioactivity from a previous study may impede a correct diagnosis. We have presented, here in this pictorial essay examples of these various patterns and pitfalls, which may be confusing to the novice, as well as helpful advice for proper interpretation of the images, and avoidance of these pitfalls.
 
Click here for VIDEO
 
CASES:
 
Abnormal Cerebral Blood Flow Studies:
 
FIGURE 1. 
Evolution from normal to positive study.		 FIGURE 2. 
Poor arterial perfusion study due to suboptimal technique.		 FIGURE 3.
Missed arterial flow secondary to delayed imaging.
34-year-old female s/p MVA Poor bolus.  
   
 

FIGURE 4.
Advantage of Tc-99m ECD and Tc-99m HMPAO versus Tc-99m DTPA . 17-month-old female s/p closed
 head injury.

FIGURE 5.
Absent perfusion and function of one cerebral hemisphere.
53-year-old male status post subarachnoid hemorrhage secondary to ruptured aneurysm on the left. 		FIGURE 6.
17 y.o. male with gunshot wound to the right head and neck with resultant dissection and occlusion of the right ICA. 
   
FIGURE 7.
Presence of sagittal sinus activity with absent brain metabolism.
57 y/o female with left basal ganglial bleed 		FIGURE 8.
Scalp hematoma mimicking intracranial activity in the presence of brain death.
39 y/o male s/p MVA with extensive skull, face, and neck injuries.
FIGURE 9.
 57 y/o female s/p massive ICH, right greater than left.
 

 
 
FIGURE 10.
Photopenic defects with persistent cerebral perfusion and metabolism.
41 y/o male with history of longstanding hypertension and resultant intracranial hemorrhage on the right.		 FIGURE 11.
65 year old male status post subarachnoid hemorrhage secondary to ruptured aneurysm on the left.
FIGURE 12.
53 y/o male with history of previous right frontal lobectomy s/p cardiac arrest.
FIGURE 13.
Extracranial versus intracranial leakage of activity via skull defect in the presence of brain death.
24-year-old male status post GSW to the head.
FIGURE 14.
51 y/o male s/p to the head with entrance through the right parietal bone and exit through left parietal bone.
FIGURE 15.
Retained intracranial activity from a previous study in the presence of brain death.
19 y/o male s/p MVA with closed head injury, cerebral edema and downward herniation.


   
FIGURE 16.
Dichotomy between perfusion and metabolism.
35 y/o female s/p fall with closed head injury.
 		FIGURE 17.
Various atypical patterns.
60-year-old male status post MVA, in which the patient was ejected from the cab of an 18-wheeler truck and suffered multiple head and face injuries.
 FIGURE 18.
15 y/o male w/p GSW to the head.
 

FIGURE 19
The role of SPECT Imaging in determining brain death.
17 y/o female s/p MVA with resultant closed head injury. 		FIGURE 20.
34 y/o who had an intracerebral bleed to subsequently sustained a fall and head injury. Patient underwent surgery and received a surgical flap.		 FIGURE 21.
30 year old male s/p MVA and CHI
 
FIGURE 22
30 year old female who fell backward out of a car and asphyxiated after the fall.
FIGURE 23
4 year old with PNET supratentorial brain tumor diagnosed 2 1/2 years earlier.
FIGURE 24
47 year old with aneurismal bleed
     
   
METHODS
We reviewed over 300 cerebral blood flow studies performed since July of 1995, and uncovered the following normal and abnormal patterns discussed below, including potential false positives and false negatives. The cerebral blood flow studies were performed at bedside.
 
Initially 15-20 mCi Tc-99m-DTPA was used. However, when Tc-99m-ECD became available all subsequent studies were performed with this agent. Approximately 20 mCi is injected, preferably into a central line. Sequential anterior flow images are obtained using a portable gamma camera. Immediate and 20 minute delayed static images are obtained in the anterior and anterior oblique projections. In some cases involving small infants, a rubber band tourniquet was used to reduce scalp blood flow.
Click here to view Video.
 
TABLE I :
SCINTIGRAPHIC INTERPRETATION:
Normal Cerebral Blood Flow Findings
1. Presence of flow in both common carotid arteries
2. Presence of flow in anterior and middle cerebral arteries ("three-pronged fork") and the regions supplied by them (10)
3. Presence of activity in the sagittal sinus
 
TABLE II:
ABNORMAL CEREBRAL BLOOD FLOW FINDINGS:
1. Visualization of common carotids is needed to ensure technically satisfactory study.
2. Absence of arterial flow in the region supplied by the anterior and middle cerebral arteries ("hollow skull" sign is noted     during the first pass study (10).
3. Abrupt cut-off of arterial flow is usually seen at the skull base.
4. Sagittal or venous sinus activity is occasionally identified on the perfusion study due to collateral vessels and does not preclude the diagnosis of brain death (seen in 10 to 20% of patients).
5. "Hot nose" sign is often seen due to the shunting of blood through the external carotid arteries (10)
6. Absence of brain uptake is noted on the delayed static images.
7. Increased flow is seen in the region of a skull fracture or skin flap secondary to craniotomy. Static images generally show no uptake, but occasional activity tracking along the fracture may be seen.
8. Small focal areas of activity may be seen in the site of active cerebral bleeding.
 
PATTERNS OF TC-99M RADIONUCLIDE UPTAKE: (Brain Metabolic Activity):
Distinguishing between the maintenance of cerebral blood flow and brain death on a cerebral perfusion scintigraphy study is usually a straightforward determination. Unfortunately, not all of the cerebral blood flow studies can be easily classified into normal or brain dead categories. As mentioned previously, the presence of skull fractures, cephalohematomas, intracranial hemorrhage, or post-surgical changes can be misleading and delay diagnosis. Technical factors may also act as pitfalls in evaluating a brain scan. The following patterns of uptake were encountered in our review of the cases:
 
TABLE III:
PATTERNS OF UPTAKE:
 1. Normal cerebral perfusion and metabolic activity (non-brain dead).
 2. Decreased, but persistent cerebral perfusion and metabolism (non-brain dead).
 3. Absent cerebral perfusion and metabolism (positive study; brain dead).
 4. Poor cerebral perfusion study secondary to suboptimal technique (non-brain dead).
 5. Absent perfusion and metabolism involving one hemisphere (non-brain dead).
 6. Presence of sagittal sinus activity without cerebral perfusion and metabolism (brain-dead).
 7. Photopenic defects in the presence of cerebral perfusion and metabolism (non-brain dead).
 8. Scalp hematomas mimicking intracranial activity with absent cerebral perfusion and metabolism (brain dead).
 9. Extracranial versus intracranial leakage via skull defect with absent cerebral perfusion and metabolism (brain dead). 10. Intracranial activity due to incomplete clearance from previous study in the absence of cerebral perfusion and metabolism (brain dead).
11. Dichotomy between cerebral perfusion and metabolism (non-brain dead).
12. No cerebral perfusion or metabolism with "cold nose" (brain dead).
13. No cerebral perfusion or metabolism with increased scalp activity (brain dead).
14. Activity seen in posterior fossa, but not supratentorally. (brain dead)
15. Activity seen only along a fracture line or skin flap. (brain dead).
 
TABLE IV:
ARTIFACTS:
1. Skull defects or pressure screws may cause focal "cold" areas.
2. Skin flaps may demonstrate increased flow and scalp activity. Anterior and lateral views should sort this out.
3. Skull fracture may cause a focal area of increased flow, mimicking the middle cerebral artery distribution.
4. Active intracerebral bleeding can cause focal increasing activity.
5. Activity remaining from a prior cerebral flow study.
CONCLUSIONS:
The cases presented cover most possibilities one may encounter when performing cerebral blood flow studies. Hopefully the information will serve as a useful guide in the interpretation of these studies. The following conclusions can be drawn:

1. Radionuclide cerebral perfusion scintigraphic studies are sensitive measures of brain flow and function and can be performed and interpreted with relative ease. There is no known contraindication for using CBF studies in patients in barbiturate coma, in a hypothermic state, or with hypotension.

2. Diminished, but persistent intracranial flow and/or metabolism cannot confirm brain death. If the patient is clinically deteriorating or demonstrates questionable scintigraphic findings, a repeat study in 12 hours is indicated.

3. Tc-99m-Bicisate (ECD), Neuroliteâ) and Tc-99m-HMPAO (Ceretecâ)) offer the advantage of evaluating brain metabolism as opposed to their predecessors such as Tc-99m-DTPA which cannot cross the blood-brain barrier.

4. The absence of brain metabolism is necessary for the diagnosis of brain death when utilizing Tc-99m-Bicisate and Tc-99m-HMPAO.

5. Tc-99m-Bicisate offers improved gray to white matter differentiation and increased brain to body contrast as compared with Tc-99m-HMPAO (8).

6. SPECT imaging may assist in assessing the presence of intracranial activity when static planar imaging is inconclusive. However, this is generally not necessary.
 

ACKNOWLEDGMENT:

I would like to extend my appreciation to my secretary, Catherine Yarborough, and her summer assistant, Kristen Bailey, for their assistance in the preparation of this manuscript.
 

BIBLIOGRAPHY:

1. Mollaret, P., Goulan, M.: Le coma depasse. Rev Neurol (Par) 1959; 101:5-15.

2. Morayati, S.J., et al.: The determination of death and the changing role of medical imaging. Radiographics, Sept., 1988; 8(5): 967-969.

3. Guidelines for the determination of death. JAMA 1981; 246(19): 2184-2186.

4. Wieler, H., et al. Tc-99m-HMPAO cerebral scintigraphy. A reliable, noninvasive determination of brain death. Clin. Nuc. Med., Feb., 1993; 18(2) 104-109.

5. Valle, G, et al: Lug, G, et al: Considerations of brain death on a SPECT cerebral perfusion study, Clin. Nuc. Med., Nov., 1993; 18(11): 953-954.

6. Lu, G, et al: Findings on Tc-99m-HMPAO brain imaging in death. Clin. Nuc. Med., Nov., 1996; 1(11):891-893.

7. Costa DC, Lui D and Ell PJ. Tc-99m HMPAO uptake in rat brain: sensitivity to physiological and pharmacological intervention "in vivo". J Nucl Med, 1987,26:146-147

8. Patterson, J.C., et al: SPECT image analysis using statistical parametric mapping: comparison of technetium-99m-HMPAO and technetium-99m-ECD. J. Nucl. Med., Nov., 1997; 38(11): 1721-1725.

9. Masanori, L. et al: Regional differences in technetium-99m-ECD clearance on brain SPECT in healthy images. J Nucl. Med.,   Aug., 1997; 38(8): 1253-1260.

10. Mrhac L, Zakko, S., Parikh, Y.: Brain death: the evaluation of semi-quantitative parameters and other signs in HMPAO scintigraphy. Nucl. Med. Commun., Dec., 1995; 16(12); 1016-1020.
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