- Email: [email protected]
Single-Photon Emission Computed Tomography
76 Single-Photon Emission Computed Tomography Joseph C. Masdeu, MD, PhD
Keywords: brain disease, brain perfusion, functional neuroimaging, receptors,
single-photon emission computed tomography
I. Brief History and Method II. SPECT in Diseases of the Brain References
I. Brief History and Method Single-photon emission computed tomography (SPECT) was introduced in the early 1980s as an instrument for the evaluation of regional cerebral perfusion and receptor density studies [1]. For the performance of SPECT, a flow tracer or a receptor-binding substance is tagged with a radionuclide and injected intravenously (Fig. 1). The flow tracer is assumed to accumulate in different areas of the brain proportionally to the rate of delivery of nutrients to that volume of brain tissue [2]. SPECT images are generated using gamma cameras or ring-type imaging systems that record photons emitted by the tracer trapped in the brain (Fig. 2). SPECT results in better image quality than two-dimensional or planar imaging because focal sources of activity are not superimposed on one another. As a result, the contrast between the target and the background (the signalto-noise ratio) is greatly increased. Depending on the type of imaging system and tracer used, the resolution ranges
Neurobiology of Disease
from 14–17 mm full width at half maximum (FWHM) for single-head gamma cameras, now seldom used for brain imaging, to 8–10 mm FWHM for three- and fourhead camera systems and to 7–8 mm FWHM for specialpurpose ring-type imaging systems. In general, system cost is directly proportional to the number and complexity of camera heads or crystals. Scanning time in SPECT depends on the imaging system, the type of radiopharmaceutical, and the quality of image desired. High-resolution images of the whole brain can be obtained with current technology in about 20 to 30 minutes. The volume imaging capacity of most SPECT systems permits reconstruction at any angle—including the axial, coronal, and sagittal planes—or at the same angle of imaging obtained with computed tomography (CT) or magnetic resonance imaging (MRI) to facilitate image comparisons. 829
Copyright © 2007 by Elsevier (USA). All rights reserved.
830
Figure 1 Injection of a SPECT Perfusion Agent. These highly lipidsoluble agents tend to penetrate the blood-brain barrier and remain trapped in the perivascular space for several hours, enough to allow imaging. Brain areas with high perfusion, such as the cerebral cortex, have higher counts than those with lower perfusion, such as the white matter.
Figure 2 Distribution of a Radionuclide in the Brain Imaged by Quantification of the Photons That Interact with Sodium Iodine (NaI) Detectors. Careful collimation is essential for image quality. Mathematical algorithms similar to the ones used by other computed tomographic techniques, including Fourier transform, are used to reconstruct the distribution of the isotope in the brain.
A number of commercially available and experimental radiopharmaceuticals have been applied to SPECT studies of cerebral perfusion. The radiotracer is assumed to accumulate in different areas of the brain proportionally to the rate of delivery of nutrients to that volume of brain tissue and is described in units of ml/min/100 g. Studies in animals and humans have demonstrated that under properly controlled conditions SPECT data obtained with perfusion agents approximates perfusion closely enough to be meaningful in clinical and research studies [2]. Furthermore, most routine clinical applications of brain perfusion SPECT do not require quantitation of regional cerebral blood flow
Single-Photon Emission Computed Tomography (rCBF) and rely exclusively on the generation of images that reflect tracer uptake and retention only. Thus areas of abnormal activity are said to be hyper- or hypoperfused compared with a reference set, often the average cerebellar activity, when this structure is unlikely to be affected by the disease under study, or the average cortical activity in the same anatomical slice. The U.S. Food and Drug Administration (FDA) has approved three brain perfusion radiopharmaceuticals for clinical use. The oldest one, iodine-123 isopropyliodoamphetamine (IMP, Spectamine), distributes proportionally to rCBF over a range of flows but may be decreased with low plasma pH as in cerebral ischemia or acidosis. Brain activity remains relatively constant from 20 to at least 60 minutes after injection. Not commercially available in the United States, it is widely used in Japan. Technetium-99m hexamethylpropyleneamine oxime (HMPAO, Ceretec), a lipidsoluble macrocyclic amine, is available for routine clinical use [2]. Brain uptake is rapid and reaches its maximum within 10 minutes. Radiotracer distribution remains constant for many hours after injection. A third radiopharmaceutical, 99m Tc ethyl cysteinate dimer (ECD, Neurolite), has a rapid blood clearance, resulting in high brain-to-soft tissue activity ratios early and with less exposure to radiation [2]. The Tc-radiolabeled compounds are stable for about 6 hours, facilitating their use for the study of episodic phenomena, such as seizures. The inert gas xenon-133 has also been used to study rCBF. 133 Xe SPECT is performed after inhalation of the gas and is based on clearance techniques that relate the change in radiotracer activity over time to blood flow [2]. The principal advantage over other tracers that remain in the brain is that rCBF can be measured quantitatively and repeatedly without arterial sampling. 133 Xe does have major limitations, including poor spatial resolution and the need for specialized instrumentation. In addition to their use in determining perfusion, radiotracers can be used to determine biochemical interactions such as receptor binding. Postmortem studies have reported a severe depletion of cocaine recognition sites associated with the dopamine transporter (DAT) system in the striatum of patients with Parkinson’s disease (PD). Several analogues of cocaine have been investigated to develop DAT selective radioligands for SPECT imaging, of which 123 I 2-carbomethyl-3-(4-iodophenyl) tropane (-CIT) and 123 I-Ioflupane (123 I-fluoropropyl--CIT) are the most widely used. The main advantage of 123 I-Ioflupane is that images can be acquired from 3 to 6 hours after injection, compared with the 18 to 24 hours required for 123 I -CIT [3]. A D2 receptor marker (123 I-iodobenzamide) is also commercially available in Europe. Other 123 I-labeled ligands have been developed for imaging the cholinergic, noradrenergic, and GABAergic receptor systems. Brain perfusion SPECT is a safe procedure. The whole-body effective dose equivalent received from the
Single-Photon Emission Computed Tomography administration of 99m Tc HMPAO is 0.7 roentgen equivalent man (rem) per 20 millicurie dose. This effective dose equivalent value is similar to that received during a radionuclide bone scan, is 1.5 times that received from a CT of the abdomen and pelvis, and is 43% of the average annual background radiation in the United States. Most state-ofthe-art imaging systems are designed to reduce head motion and patient discomfort. Most clinical applications do not require arterial sampling. One of the major reasons for the interest in SPECT is that it represents a less expensive technique to do functional neuroimaging. The older and more accurate modality for functional neuroimaging is positron emission tomography (PET). Unlike PET, SPECT cannot measure regional cerebral metabolism, but it provides a qualitative estimate of rCBF, which in many neurological disorders is tightly coupled with brain metabolism. Thus SPECT provides functional information not available by conventional CT or MRI at a cost similar to that of CT.
II. SPECT in Diseases of the Brain The interest in SPECT has spawned a rich literature in the past few years. Unfortunately, many of the reports comprise only a few patients; large, well-controlled studies are rare. In addition, most studies have used as a standard the clinical diagnosis, lacking pathological confirmation. Another caveat has to do with the variable quality of the techniques used for clinical SPECT, which depends more on the operator than the CT or MRI. The reported results have usually been obtained at well-established nuclear medicine services and may not be generalizable to all institutions. Given the complexity of information derived from functional neuroimaging, the interpretation of results often requires a close collaboration between nuclear medicine physicians and clinicians. Therefore, the practical application of SPECT to clinical work varies widely among institutions, depending on the interests of nuclear medicine physicians and, more often, of neurologists or psychiatrists who refer patients for SPECT. Of the applications reviewed in this chapter, perhaps the most useful and widespread is ictal SPECT for epilepsy. But there are institutions, particularly in Europe, at which SPECT is used routinely in the management of patients with acute stroke, particularly when aggressive therapies, such as hemicraniectomy for massive hemispherical swelling, are carried out in select cases.
A. Stroke With the increasing availability of perfusion CT and diffusion and perfusion MRI, is SPECT still a useful tool to study perfusion, an obviously important variable in stroke
831 and stroke-prone patients? As interesting as this question may be, we only answer it partially in this review. Leaving aside for a moment the real-life availability of these techniques, there are no controlled studies comparing their usefulness and cost in the different settings relevant to clinical cerebrovascular disease, namely, (1) stroke prediction in the presymptomatic subject; (2) stroke prediction in the patient at risk; (3) diagnosis of an acute ischemic event; and (4) prognosis of the acute event [4]. Moreover, it is likely that such studies will never be carried out because the field of stroke imaging is evolving quickly and the real applicability of the different modalities used to study stroke depends on the availability of each modality at the clinical setting. Therefore, this discussion focuses on the potential of SPECT to answer clinically relevant questions, such as the following: (1) In the patient at risk of stroke, what is the mechanism and likelihood of suffering a stroke? (2) In the patient with a strokelike syndrome, what is the mechanism, how should it be treated, and what is the prognosis for recovery? 1. Risk of Stroke in Subjects at Risk a. Assessment of Cerebral Perfusion with Large-Vessel Stenosis Vasodilation caused by hypercapnia (inhalation of 5% CO2 or by acetazolamide injection (1 g intravenously 15 minutes before radionuclide injection) can be used to assess the vascular reserve of brain regions supplied by a stenotic or occluded artery. By using two isotopes, a Tc agent for a baseline blood flow measurement and an iodine agent for a postacetazolamide blood flow measurement, the separate distributions can be measured using two windows on some modern three-headed scanners [2]. Acetazolamide stress brain-perfusion SPECT has been found useful as a complementary method in determining selective carotid shunting during carotid endarterectomy. Shunts were necessary for 8 of 8 patients with a severely reduced vascular reserve compared with 4 of 67 who had a less severe reduction [4]. Patients who have had cerebral infarction are also at risk for additional ischemic lesions. In a group of patients with watershed hemispherical infarcts ipsilateral to a stenotic artery, those with white matter infarcts (Fig. 3) had worse reserve than those with cortical infarcts [4]. The second group may have compensated between the time of the infarction and the time of the SPECT or suffered infarction not on a hemodynamic but on an embolic basis. b. Subarachnoid Hemorrhage Ischemia from vasospasm is a major cause of morbidity and mortality following subarachnoid hemorrhage. Given the ability of SPECT to detect surface ischemia, this technique, when combined with transcranial Doppler, is a sensitive screening tool for the early detection of vasospasm and delayed ischemic deficits in an entire hemisphere or an isolated cortical branch. Acetazolamide SPECT has been used within the first 18 days
832
Single-Photon Emission Computed Tomography hemorrhage is its main contraindication, CT has become the standard imaging modality for acute stroke. MRI with echo-planar imaging is replacing CT at many institutions, because it adds information on tissue damage and potentially reversible perfusion defects. It also provides vessel visualization. Many see SPECT as an interesting technique but one whose potential benefits would be offset by the attendant delay in diagnosis and treatment. Although SPECT was first approved by the FDA for the study of cerebral ischemia, this technique is not used for acute stroke in the majority of U.S. hospitals. However, there are a number of active stroke centers around the world using perfusion SPECT for the evaluation of acute stroke [4]. SPECT may have a role in helping diagnose nonischemic neurological deficits and in predicting the need for thrombolysis, separating the patients who would not benefit from it either (1) because by the time the procedure is ready there is no perfusion deficit to be corrected by thrombolysis or (2) because the infarct is large and the ischemia is profound, with attendant capillary necrosis and a high risk for bleeding. In patients with large infarcts, SPECT may help determine which patients may benefit from holohemispheric decompression.
Figure 3 Use of Acetazolamide Challenge to Assess Vascular Reserve and Differentiate Ischemia from Diaschisis. A 51-year-old had transient left arm weakness. (A) A computed tomography scan showed hypodense areas in the watershed of the left hemispherical white matter. Duplex ultrasound revealed occlusion of the right internal carotid artery at the bifurcation. (B) hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) before acetazolamide showed hypoperfusion of the right middle cerebral artery (MCA) territory and the thalamus (usually supplied by the posterior circulation). (C and D) Two days later, SPECT was repeated after oral loading with acetazolamide. (C) The difference between the hemispheres became more obvious. Perfusion of the previously hypoperfused right thalamus became normal (diaschisis), but not in the cortical distribution of the right MCA. (D) Note the sharp difference between the ischemic territory of the MCA and the normal cortex supplied by the posterior cerebral artery, from the posterior circulation. Note: Actzd, acetazolamide.
after subarachnoid hemorrhage to predict which patients are likely to develop cerebral infarction [4]. Early and extensive reduction in cerebral vasodilatory capacity correlated with the development of cerebral infarction due to vasospasm following subarachnoid hemorrhage. As vasospasm can be treated with angioplasty, the application of techniques for early and accurate diagnosis of dangerous vasospasm is of obvious importance. 2. Acute Strokelike Syndrome For the diagnosis of stroke, time is of the essence. As evidence mounts that the therapeutic time window for acute stroke is narrow and that delaying effective therapy results in more tissue damage, the pressure is on to diagnose the cause of stroke as quickly as possible. Because thrombolysis is effective in acute stroke and intracerebral
a. Nonischemic Neurological Deficits Occasionally, the clinical situation arises of differentiating ischemia from epilepsy as the cause of a sudden neurological deficit, particularly in cases with a prolonged focal discharge, when the onset was not witnessed and the patient is unable to give a reliable account. Ischemia will cause an area of hypoperfusion on SPECT, whereas epileptic phenomena are often manifested by hyperperfusion, although postictally there is hypoperfusion (Fig. 4). Differentiating ischemia from focal epileptic phenomena is critical, as thrombolysis and other techniques to treat acute stroke are now available. Increased perfusion of the hemisphere contralateral to the affected limbs has also been reported with infantile alternating hemiplegia, transient aphasia, or neurosarcoidosis [4]. b. Prediction of Transient or Mild Ischemic Attack In patients with acute ischemic neurological symptoms studied with 99m Tc-ECD SPECT, those who had no perfusion deficit detectable by visual inspection of the SPECT scan despite clinical symptoms were symptom free after 7 days [4]. In the semiquantitative SPECT analysis, these patients had abnormal count densities in the affected region (activity less than 90% but more than 70% compared with the contralateral side). All patients with subsequent infarction n = 59 had values less than 70%. Performance of the procedure in the first few hours seems critical for the usefulness of the test from the patient management point of view and because the findings are less clear when the study is delayed. The apparently normal perfusion of a necrotic area has been called nonnutritional reperfusion [4]. This pattern on serial SPECT (hypoperfusion, normal perfusion, hypoperfusion) results
Single-Photon Emission Computed Tomography
Figure 4 Peri-ictal Hemiplegia. (A) Axial single-photon emission computed tomography (SPECT) showing increased perfusion of the left hemisphere obtained in a 58-year-old woman 26 hours after she was found in the street with a right-sided hemiplegia, global aphasia, and a gaze deviation to the left. Clinical findings persisted at the time of this SPECT. Computed tomography was negative. An electroencephalogram obtained 12 hours before the SPECT showed marked slowing over the left hemisphere but no epileptiform activity. Improvement ensued over a 1-week period, when the patient could give a history of having had a seizure disorder since her teens. (B) Follow-up SPECT after the patient had improved showed symmetrical perfusion of the hemispheres.
most likely from perfusion being restored after neuronal damage has already occurred. Inflammatory tissue at the site of infarction causes arteriolar dilation in the days and weeks following the infarct, with the resultant “normal” perfusion pattern. As the necrosed tissue is reabsorbed and inflammation abates, regional perfusion decreases and the area again becomes abnormal on SPECT. This mechanism would also explain why failure to show an area of necrosis may happen more readily with HMPAO, a better marker of perfusion, than with ECD, which is poorly retained by areas of necrosis [4]. Lesions in the cortex or deep gray nuclei are more likely to cause SPECT defects than purely white matter lesions, so a normal SPECT study may also predict a lacunar stroke [4]. c. Acute Ischemic Neurological Deficit After answering the critical question of whether the stroke is ischemic or hemorrhagic, by the use of CT or gradient echo MRI, the next step is to predict the likely usefulness of intravenous or, where permitted by protocol, intra-arterial thrombolysis. In some centers, decompression of a massively swollen hemisphere due to a large middle cerebral artery (MCA) infarct has been found to have a positive outcome if the procedure is performed before additional pressure damage occurs. It is therefore important to predict early who will develop severe hemispherical swelling. Using ECD SPECT in the first 6 hours after stroke, Barthel and co-workers were able to determine which patients would develop massive MCA-territory necrosis, with hemispherical herniation [5]. These patients have a high risk of hemorrhage following thrombolysis and could be helped
833 by early decompressive hemicraniectomy. Complete MCA infarctions were predicted with significantly higher accuracy with early SPECT (area under receiver operating characteristic curve [AUC] index 0.91) compared with early CT (AUC index 0.77) and clinical parameters (AUC index 0.73, p < 005). Furthermore, the predictive value increased when the findings on CT, clinical examination, and SPECT were considered [5]. Other studies have found SPECT to add predictive value to the clinical score on admission [4]. In summary, a patient with a normal ECD SPECT study performed within 3 hours of stroke onset will most likely recover spontaneously and does not require thrombolysis. A patient with a dense deficit in the entire MCA distribution has a high risk of hemorrhage with thrombolysis and, depending on age and other factors, should be considered for decompressive hemicraniectomy. The patients most likely to benefit from thrombolysis are the ones with less massive lesions [4]. A mismatch between the area acutely affected, as seen on diffusion-weighted imaging, and an MRI or SPECT perfusion study predicts shortly after the acute event which infarcts will become larger in the hours and days following the stroke. The infarct grows to match the area of severely decreased perfusion (between 12 and 20 ml per 100 g every minute) [4]. The area of mismatch is the ischemic penumbra, which often becomes necrotic as the process evolves. Using only 99m Tc-ECD SPECT, the dynamic study approximates a perfusion map of the region, whereas decreased uptake in the static study shows the nonviable area of the brain, albeit with somewhat poor spatial resolution [4]. This information is important because patients with a mismatch may benefit from neuroprotective therapies. Ideally, a study on acute neuroprotection should include only these patients. Because serial SPECT studies can be conducted about 30 minutes after one another using an initial smaller dose of the radioisotope and then a larger dose, after a few minutes using two different isotopes (99m Tc and 123 I), or after about 24 hours using the same isotope and dose, SPECT has been used to evaluate the effect of different therapeutic strategies on brain perfusion (Fig. 5) [2]. Among them are intra-arterial urokinase, intravenous recombinant tissue plasminogen activator, streptokinase, and rheopheresis [4]. Strategies that seek to open an occluded vessel can be particularly well evaluated by perfusion SPECT, a much less invasive procedure than arterial angiography or iodine-contrast CT and a less costly procedure than perfusion MRI. For intra-arterial thrombolysis, ischemic tissue with perfusion greater than 55% of cerebellar flow may be salvageable, even with treatment initiated 6 hours after onset of symptoms [4]. Ischemic tissue with perfusion greater than 35% of cerebellar flow still may be salvageable with early treatment (less than 5 hours). Ischemic tissue with perfusion less than 35% of cerebellar flow may be at risk for hemorrhage with thrombolysis [4].
834
Single-Photon Emission Computed Tomography
C. Infectious Diseases 1. Human Immunodeficiency Virus Encephalopathy
Figure 5 Repeated SPECT with Technetium-99m Ethyl Cysteinate Dimer in Two Patients. Patients (top and bottom rows) at baseline before intravenous (IV) recombinant tissue plasminogen activator (r-tPA) (left column), 6 to 8 hours after IV r-tPA (middle column), and 7 days after IV r-tPA (right column). The patient whose SPECT is displayed at the top row had a good outcome, unlike the one at the bottom. Reprinted, with permission, from Berrouschot, J., Barthel, H., Hesse, S., Knapp, W. H., Schneider, D., and von Kummer, R. (2000). Reperfusion and metabolic recovery of brain tissue and clinical outcome after ischemic stroke and thrombolytic therapy. Stroke 31, 1545–1551.
SPECT has also been used to evaluate the effect on cerebral perfusion of a number of vasodilators, including pentoxifylline, olprinone, and nimodipine, and of vasoconstrictors, including cocaine [4]. In this regard, xenon CT allows for the quantitative determination of rCBF, which can also be obtained with xenon SPECT, whereas SPECT with the more widely available radionuclides only provides a relative estimate [4].
B. Neoplasms Tracers labeled with thallium-201 have been used to attempt to quantify the malignancy grades of gliomas and to differentiate radiation necrosis from tumor recurrence. Higher malignancy tumors have a greater radionuclide uptake. As the uptake is higher with higher tumor perfusion, a mismatch is sought such that a high uptake on Tl SPECT more reliably points to tumor recurrence when perfusion SPECT shows a low tumor perfusion. Dual-isotope SPECT with 201 Tl to label the tumor and 99m Tc HMPAO to evaluate perfusion has given reliable results in small series [6]. More recently, 123 I--methyltyrosine has been used to differentiate radiation necrosis from the recurrence of malignant astrocytomas, brain metastases, primitive neuroendocrine tumors, clivus chordomas, ependymomas, pituitary tumors, and anaplastic meningiomas. False negatives are common with small tumors (<13 mm in diameter) because they test the limits of the resolution of clinical SPECT units [7].
In human immunodeficiency virus (HIV) encephalopathy SPECT shows decreased cortical uptake, often with focal defects that give the cortex a moth-eaten appearance [8]. The central gray nuclei generally have multifocal defects. Perfusion of the hemispherical white matter is also decreased. In some instances, decreased uptake in the periventricular regions mimics ventricular dilation, out of proportion to the dilation appreciated on CT or MRI. The pathogenesis of perfusion changes in HIV encephalopathy is still unclear. Microvascular changes, perhaps induced by cytokines secreted by infected macrophages, may result in decreased perfusion. An association exists between the severity of ocular microangiopathy, measured by conjunctival sludge and the number of retinal cotton-wool spots, and the severity of cerebral hypoperfusion [9]. By damaging the metabolic machinery of neurons, cytokines may also cause regional neuronal hypometabolism, leading to a decreased oxygen demand and therefore decreased regional perfusion. SPECT is particularly useful in instances of psychosis, mild attentional impairment, or depression in HIV-positive individuals with normal CT or MRI. The characteristic pattern described previously would favor HIV encephalopathy rather than reactive psychosis or depression. However, the SPECT findings in HIV encephalopathy are not pathognomonic. Similar perfusion changes can be observed in chronic cocaine users, patients with the chronic fatigue syndrome, or those with mild head trauma [9]. Because the perfusion pattern is not specific, it has to be evaluated in the context of the clinical presentation and with the information provided by MRI or CT. 2. Herpes Simplex Encephalitis Early treatment of herpes simplex encephalitis with acyclovir is particularly rewarding in patients who have a milder form of the disorder because they are likely to recover more fully. Unfortunately, the diagnosis in these patients may be delayed because they present with psychiatric syndromes or seizures and have negative MRI and CT. The cerebrospinal fluid may also be initially negative. SPECT changes may help in these cases [9]. An abnormally high accumulation of radiotracer in the affected temporal lobe may be present even at an early stage, when MRI is normal.
D. Head Trauma Early SPECT reveals perfusion abnormalities more extensive than anatomic changes seen on CT early after trauma, even in mild head injury [10]. The lesions on
Single-Photon Emission Computed Tomography SPECT of mild head trauma are of two types: (1) sharply circumscribed areas of hypoperfusion, with borders showing relative hyperperfusion; and (2) more diffuse areas of hypoperfusion, involving the occipitotemporal regions. The first type probably corresponds to contusions, with areas of cortical ischemia. The second type may be related to smaller, widespread contusions; to axonal injury of the long white matter tracts running anteroposteriorly, such as the visual radiations; or to both [10]. Few studies have looked at the neuropathological substrate of the changes observed on perfusion SPECT [10]. By studying small-vessel ultrastructure and mapping rCBF at different times within the first 3 weeks of head injury, a zone of ischemic brain was found in areas of hypoperfusion, which persisted for weeks or months. Ischemic areas had astrocytic swelling and microvascular compression, seen on electron microscopy. Focal zones of hyperemia were also present in 42% of patients within the first 2 weeks of injury. Early focal hyperemia appeared only within apparently normal tissue as judged by late MRI or CT. The extent of acute SPECT changes seems to correlate with the clinical severity of the posttraumatic syndrome [11]. As MRI may depict lesions not visible on CT, and vice versa, the combination of the two procedures is a more powerful predictor than either alone.
E. Seizure Disorders Seizures are associated with dramatic increases in cerebral blood flow, localized in partial seizures and global during generalized seizures, reflected on perfusion SPECT [12]. A SPECT study showing increased regional cerebral perfusion ictally in the same region that shows decreased regional cerebral perfusion interictally provides strong evidence for the epileptogenic nature of the lesion. In complex partial seizures, the seizure focus can be identified in 71% to 93% of ictal SPECT studies with a positive predictive value of 95%. In secondarily generalized epilepsy, SPECT may show increased cerebral blood flow locally despite a clinical picture suggesting a nonfocal onset. SPECT changes may also be useful in differentiating an epileptic disorder from a psychogenic one (pseudoseizure). As Tc-labeled compounds are bound on first pass through the brain, where they remain trapped for several hours, electroencephalogram (EEG)-guided ictal injections are used to obtain a snapshot of ictal perfusion [2]. The SPECT scan is performed hours later when the patient has recovered from the seizure and is cooperative. To be accurately recorded with SPECT, the seizure should be at least 5 seconds in duration, and the time from seizure onset to injection of the SPECT tracer should ideally be less than 45 seconds [12]. Longer delays may cause the tracer to be picked up by regions of seizure propagation, rather than the focus of origin. The ictal scan is analyzed for regions of increased
835 and decreased perfusion by subtracting the interictal perfusion scan to create a difference image. The computer-aided subtraction ictal SPECT is then co-registered to the patient’s MRI—the entire procedure is abbreviated as SISCOM—to facilitate interpretation and increase diagnostic and prognostic accuracy [12]. A SISCOM study requires hospitalization and long-term EEG monitoring, usually longer in the case of adults, with more infrequent seizures. As the imaging compound should be available at the time of seizure onset, only ECD or stable HMPAO can be used. Both compounds are stable for about 6 hours after reconstitution. If the patient has no seizures in this period, the compound has to be discarded. SPECT may define the site of seizure onset but lacks the specificity of MRI to determine the nature of the lesion causing epilepsy. Patient management depends on the nature of the lesion. For instance, the treatment of a medial temporal glioma differs from that of mesial temporal sclerosis. Therefore, MRI is the first-line noninvasive imaging modality in focal epilepsy or generalized epilepsy with a focal origin. Quantitative MRI has a sensitivity of 80%– 90% for the lateralization of temporal lobe epilepsy and is helpful in the detection of cortical abnormalities in children with intractable epilepsy. However, there are instances in which ictal SPECT has identified lesions not detected by MRI. Depth electrocorticography and intraoperative electrocorticography, though accurate in many forms of epilepsy, are both highly invasive. In cortical developmental disorders, these EEG techniques often fail to localize the epileptogenic area. PET is useful in focal epilepsy by showing hypometabolism of the affected areas. One study comparing interictal PET and ictal SPECT found similar performance of the two techniques [13]. Currently, SPECT in epilepsy is used mainly in the presurgical evaluation of patients and, rarely, in the evaluation of patients suspected of having pseudoseizures. When the ictal EEG bears such artifacts as to render it useless and the patient’s behavior is puzzling, a focal SPECT abnormality that correlates well with the ictal behavior would favor the diagnosis of true seizures. In the presurgical evaluation of patients with focal epilepsy, SISCOM is useful when the MRI is normal or when the localization of seizure origin by MRI and EEG are at odds [12]. It may also be helpful in patients with multilobar pathology. SISCOM may be used to identify a “target” for placement of intracranial EEG electrodes. Localization with SISCOM may obviate the need for intracranial EEG recordings in selected patients [12]. For example, patients with normal MRI and seizures of temporal lobe origin may not require chronic intracranial EEG monitoring if the extracranial ictal EEG pattern and peri-ictal SPECT studies are concordant. Other applications are at an investigational stage. SPECT has been used to map the area perfused with barbiturate during Wada’s test in the course of the evaluation for
836
Single-Photon Emission Computed Tomography
temporal lobe epilepsy surgery. The accuracy of SPECT localization of a seizure focus can be expected to improve further with the use of new radiopharmaceuticals directed at specific neurotransmitter- or antiepileptic medicationbinding sites.
F. Alzheimer’s Disease In Alzheimer’s disease (AD) SPECT shows decreased perfusion in the association cortex of the parietal lobe and the posterior temporal regions [14]. Frontal association cortex is predominantly affected in some cases, but usually it is not involved until late in the course of the disease. The occipital lobes are less involved, and the paracentral cortex is spared. Using a statistical factorial system to compare regional perfusion with SPECT in AD and controls, Johnson [15] could prove that regional perfusion was decreased in the AD group in the following regions: parietotemporal cortex, hippocampus, anterior and posterior cingulum, and dorsomedial and anterior nucleus of the thalamus. This pattern had a sensitivity of 86% and a specificity of 80%. Presymptomatically, those who developed AD showed a decreased perfusion in the hippocampus, anterior and posterior cingulate gyrus, and dorsomedial and anterior nucleus of the thalamus, all of them structures with an important role in memory and attention. This finding had a sensitivity of 78% and a specificity of 71% [15]. This and other clinical studies suffer from the lack of neuropathological confirmation of the diagnosis. In a group of 70 patients with dementia and 14 controls, all with autopsy, Jagust and colleagues [16] compared the diagnostic accuracy of the clinical criteria without and with the help of SPECT. The clinical diagnosis of probable AD was associated with a probability of 84% of a neuropathological diagnosis of AD. A positive SPECT increased the probability of a diagnosis of AD to 92%, whereas a negative SPECT lowered that figure to 70%. SPECT was most useful when the clinical diagnosis was of possible AD, with a probability of a diagnosis of AD of 67% without SPECT, of 84% with a positive SPECT, and of 52% with a negative SPECT [16]. The average score on the Mini-Mental test of the patients in this study was 13, indicating that they were suffering from serious dementia. However, it is interesting that the group in which SPECT supported most the diagnosis was that of possible AD, which logically includes those patients at an earlier stage. Whether SPECT can help identify at risk individuals was studied in a family with a presenilin-1 gene mutation [17]. Of this family, 23 people did not have the mutation, 18 had it but were cognitively intact, and 16 had already shown signs of cognitive impairment. Compared with those who did not have the mutation, those who did have it but did not have cognitive impairment had decreased perfusion in
the hippocampus, anterior and posterior cingulum, and parietal and frontal association cortex. This pattern on perfusion SPECT could separate correctly 86% of gene carriers and controls, indicating abnormalities in cerebral perfusion even in asymptomatic individuals with a presenilin-1 gene mutation. SPECT is also useful to help in the differential diagnosis of dementia, particularly in the early stages, when the cognitive findings can be ascribed to psychogenic disorders [14]. Patients with Pick’s disease or other frontotemporal dementias have prefrontal and anterior temporal uptake below the control range. Those with diffuse Lewy-body disease have lowered mesial occipital perfusion. Standard perfusion SPECT does not separate well vascular dementia from AD. Acetazolamide causes an increase of cerebral perfusion due to vasodilation in areas of the brain with an intact vascular reserve but not where the arterioles are already fully dilated, such as in ischemic areas or in areas with small-vessel arteriopathies. After the intravenous administration of 1 g of acetazolamide, perfusion increases in the originally hypoperfused parietotemporal areas of AD patients, whereas it remains the same or decreases in patients with cerebrovascular disease.
G. Basal Ganglia Disorders SPECT has been used to aid in the differential diagnosis of the parkinsonian syndromes, particularly by imaging the striatal DAT, and thereby providing an estimate of the involvement of the nigrostriatal pathway [3]. It has also been used to test potential neuroprotective therapies and the effect on neurodegeneration of medications used for PD, although the results obtained with SPECT and their interpretation are controversial [18]. Early in the disease it may be difficult to classify some patients with a parkinsonian syndrome. In typical PD there is a loss of presynaptic dopaminergic terminals in the striatum; therefore, there is a decrease of striatal uptake when the patient is studied with radioligands for DAT, such as 123 I -CIT or 123 I-Ioflupane. Patients who have normal studies are unlikely to have typical PD. In the ELLDOPA trial, 21 out of 135 cases (16%) felt clinically to have PD had normal 123 I- CIT SPECT [3]. These subjects have now been followed for up to 6 years, and both their clinical syndromes and their imaging findings are unchanged, not having progressed as in classical PD. Imaging of the cardiac sympathetic system reveals denervation in PD patients, even in early disease stages, and may differentiate between patients with multiple system atrophy and those with PD [19]. In Huntington’s chorea the caudate nuclei appear hypoperfused on SPECT, even in the early stages when there is no structural evidence of caudate atrophy on CT or MRI. Combined with genetic information, imaging studies of patients at risk may be
Single-Photon Emission Computed Tomography helpful in monitoring disease progression in early symptomatic or presymptomatic stages. Disease progression also must be monitored to test the effectiveness of new therapies aimed at halting neurodegeneration.
H. Diagnosis of Death on Neurological Criteria Cerebral-perfusion imaging with SPECT agents, particularly 99m Tc compounds, has been used for the diagnosis of brain death in difficult instances [20]. Absent cerebral perfusion is clearly shown on SPECT, but tomography is generally not needed; the anterior and two lateral planar views are sufficient. This technique has not been compared with conventional angiography, but it is more convenient than angiography when the diagnosis of death based on neurological criteria requires an arterial perfusion study.
Acknowledgments This review was supported by the UTE Fundación para la Investigación Médica Aplicada (Foundation for Applied Medical Research), Pamplona, Spain.
References 1. Catafau, A. M. (2001). Brain SPECT in clinical practice. Part I: perfusion. J. Nucl. Med. 42, 259–271. 2. Devous, M. D. (2005). Single-photon emission computed tomography in neurotherapeutics. NeuroRx 2, 237–249. 3. Catafau, A. M., and Tolosa, E. (2004). Impact of dopamine transporter SPECT using 123 I-Ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov. Disord. 19, 1175–1182. 4. Masdeu, J. C. (2003). Imaging of stroke with SPECT. In: “Imaging Cerebrovascular Disease” (V. Babikian, L. Wechsler, and R. T. Higashida, eds.), pp. 131–144. Butterworth-Heinemann, Boston. 5. Barthel, H., Hesse, S., Dannenberg, C., Rossler, A., Schneider, D., Knapp, W. H., Dietrich, J., and Berrouschot, J. (2001). Prospective value of perfusion and x-ray attenuation imaging with single-photon emission and transmission computed tomography in acute cerebral ischemia. Stroke 32, 1588–1597. 6. Vallejos, V., Balana, C., Fraile, M., Roussos, Y., Capellades, J., Cuadras, P., Ballester, R., Ley, A., Arellano, A., and Rosell, R. (2002). Use of 201 Tl SPECT imaging to assess the response to therapy in patients with high grade gliomas. J. Neurooncol. 59, 81–90.
837 7. Plotkin, M., Amthauer, H., Eisenacher, J., Wurm, R., Michel, R., Wust, P., Stockhammer, F., Rottgen, R., Gutberlet, M., Ruf, J., and Felix, R. (2005). Value of 123 I-IMT SPECT for diagnosis of recurrent non-astrocytic intracranial tumours. Neuroradiology 47, 18–26. 8. Tucker, K. A., Robertson, K. R., Lin, W., Smith, J. K., An, H., Chen, Y., Aylward, S. R., and Hall, C. D. (2004). Neuroimaging in human immunodeficiency virus infection. J. Neuroimmunol. 157, 153–162. 9. Masdeu, J. C., Van Heertum, R. L., and Abdel-Dayem, H. (1995). Viral infections of the brain. J. Neuroimaging 5(Suppl 1), S40–S44. 10. Masdeu, J. C., Abdel-Dayem, H., and Van Heertum, R. L. (1995). Head trauma: use of SPECT. J. Neuroimaging 5(Suppl 1), S53–S57. 11. Lee, B., and Newberg, A. (2005). Neuroimaging in traumatic brain imaging. NeuroRx 2, 372–383. 12. Cascino, G. D., So, E. L., Buchhalter, J. R., and Mullan, B. P. (2004). The current place of single-photon emission computed tomography in epilepsy evaluations. Neuroimaging Clin. N. Am. 14, 553–561, X. 13. Ho, S. S., Berkovic, S. F., Berlangieri, S. U., Newton, M. R., Egan, G. F., Tochon-Danguy, H. J., and McKay, W. J. (1995). Comparison of ictal SPECT and interictal PET in the presurgical evaluation of temporal lobe epilepsy. Ann. Neurol. 37, 738–745. 14. Masdeu, J. C., Zubieta, J. L., and Arbizu, J. (2005). Neuroimaging as a marker of the onset and progression of Alzheimer’s disease. J. Neurol. Sci. 236, 55–64. 15. Johnson, K. A., Jones, K., Holman, B. L., Becker, J. A., Spiers, P. A., Stalin, A., and Albert, M. S. (1998). Preclinical prediction of Alzheimer’s disease using SPECT. Neurology 50, 1563–1571. 16. Jagust, W., Thisted, R., Devous, M. D., Sr., Van Heertum, R., Mayberg, H., Jobst, K., Smith, A. D., and Borys, N. (2001). SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinicalpathologic study. Neurology 56, 950–956. 17. Johnson, K. A., Lopera, F., Jones, K., Becker, A., Sperling, R., Hilson, J., Londono, J., Siegert, I., Arcos, M., Moreno, S., Madrigal, L., Ossa, J., Pineda, N., Ardila, A., Roselli, M., Albert, M. S., Kosik, K. S., and Rios, A. (2001). Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology 56, 1545–1551. 18. Ravina, B., Eidelberg, D., Ahlskog, J. E., Albin, R. L., Brooks, D. J., Carbon, M., Dhawan, V., Feigin, A., Fahn, S., Guttman, M., GwinnHardy, K., McFarland, H., Innis, R., Katz, R. G., Kieburtz, K., Kish, S. J., Lange, N., Langston, J. W., Marek, K., Morin, L., Moy, C., Murphy, D., Oertel, W. H., Oliver, G., Palesch, Y., Powers, W., Seibyl, J., Sethi, K. D., Shults, C. W., Sheehy, P., Stoessl, A. J., and Holloway, R. (2005). The role of radiotracer imaging in Parkinson disease. Neurology 64, 208–215. 19. Eckert, T., and Eidelberg, D. (2005). Neuroimaging and therapeutics in movement disorders. NeuroRx 2, 361–371. 20. Facco, E., Zucchetta, P., Munari, M., Baratto, F., Behr, A. U., Gregianin, M., Gerunda, A., Bui, F., Saladini, M., and Giron, G. (1998). 99m Tc-HMPAO SPECT in the diagnosis of brain death. Intensive Care Med. 24, 911–917. 21. Berrouschot, J., Barthel, H., Hesse, S., Knapp, W. H., Schneider, D., von and Kummer, R. (2000). Reperfusion and metabolic recovery of brain tissue and clinical outcome after ischemic stroke and thrombolytic therapy. Stroke 31, 1545–1551.
Keywords: brain disease, brain perfusion, functional neuroimaging, receptors,
single-photon emission computed tomography
I. Brief History and Method II. SPECT in Diseases of the Brain References
I. Brief History and Method Single-photon emission computed tomography (SPECT) was introduced in the early 1980s as an instrument for the evaluation of regional cerebral perfusion and receptor density studies [1]. For the performance of SPECT, a flow tracer or a receptor-binding substance is tagged with a radionuclide and injected intravenously (Fig. 1). The flow tracer is assumed to accumulate in different areas of the brain proportionally to the rate of delivery of nutrients to that volume of brain tissue [2]. SPECT images are generated using gamma cameras or ring-type imaging systems that record photons emitted by the tracer trapped in the brain (Fig. 2). SPECT results in better image quality than two-dimensional or planar imaging because focal sources of activity are not superimposed on one another. As a result, the contrast between the target and the background (the signalto-noise ratio) is greatly increased. Depending on the type of imaging system and tracer used, the resolution ranges
Neurobiology of Disease
from 14–17 mm full width at half maximum (FWHM) for single-head gamma cameras, now seldom used for brain imaging, to 8–10 mm FWHM for three- and fourhead camera systems and to 7–8 mm FWHM for specialpurpose ring-type imaging systems. In general, system cost is directly proportional to the number and complexity of camera heads or crystals. Scanning time in SPECT depends on the imaging system, the type of radiopharmaceutical, and the quality of image desired. High-resolution images of the whole brain can be obtained with current technology in about 20 to 30 minutes. The volume imaging capacity of most SPECT systems permits reconstruction at any angle—including the axial, coronal, and sagittal planes—or at the same angle of imaging obtained with computed tomography (CT) or magnetic resonance imaging (MRI) to facilitate image comparisons. 829
Copyright © 2007 by Elsevier (USA). All rights reserved.
830
Figure 1 Injection of a SPECT Perfusion Agent. These highly lipidsoluble agents tend to penetrate the blood-brain barrier and remain trapped in the perivascular space for several hours, enough to allow imaging. Brain areas with high perfusion, such as the cerebral cortex, have higher counts than those with lower perfusion, such as the white matter.
Figure 2 Distribution of a Radionuclide in the Brain Imaged by Quantification of the Photons That Interact with Sodium Iodine (NaI) Detectors. Careful collimation is essential for image quality. Mathematical algorithms similar to the ones used by other computed tomographic techniques, including Fourier transform, are used to reconstruct the distribution of the isotope in the brain.
A number of commercially available and experimental radiopharmaceuticals have been applied to SPECT studies of cerebral perfusion. The radiotracer is assumed to accumulate in different areas of the brain proportionally to the rate of delivery of nutrients to that volume of brain tissue and is described in units of ml/min/100 g. Studies in animals and humans have demonstrated that under properly controlled conditions SPECT data obtained with perfusion agents approximates perfusion closely enough to be meaningful in clinical and research studies [2]. Furthermore, most routine clinical applications of brain perfusion SPECT do not require quantitation of regional cerebral blood flow
Single-Photon Emission Computed Tomography (rCBF) and rely exclusively on the generation of images that reflect tracer uptake and retention only. Thus areas of abnormal activity are said to be hyper- or hypoperfused compared with a reference set, often the average cerebellar activity, when this structure is unlikely to be affected by the disease under study, or the average cortical activity in the same anatomical slice. The U.S. Food and Drug Administration (FDA) has approved three brain perfusion radiopharmaceuticals for clinical use. The oldest one, iodine-123 isopropyliodoamphetamine (IMP, Spectamine), distributes proportionally to rCBF over a range of flows but may be decreased with low plasma pH as in cerebral ischemia or acidosis. Brain activity remains relatively constant from 20 to at least 60 minutes after injection. Not commercially available in the United States, it is widely used in Japan. Technetium-99m hexamethylpropyleneamine oxime (HMPAO, Ceretec), a lipidsoluble macrocyclic amine, is available for routine clinical use [2]. Brain uptake is rapid and reaches its maximum within 10 minutes. Radiotracer distribution remains constant for many hours after injection. A third radiopharmaceutical, 99m Tc ethyl cysteinate dimer (ECD, Neurolite), has a rapid blood clearance, resulting in high brain-to-soft tissue activity ratios early and with less exposure to radiation [2]. The Tc-radiolabeled compounds are stable for about 6 hours, facilitating their use for the study of episodic phenomena, such as seizures. The inert gas xenon-133 has also been used to study rCBF. 133 Xe SPECT is performed after inhalation of the gas and is based on clearance techniques that relate the change in radiotracer activity over time to blood flow [2]. The principal advantage over other tracers that remain in the brain is that rCBF can be measured quantitatively and repeatedly without arterial sampling. 133 Xe does have major limitations, including poor spatial resolution and the need for specialized instrumentation. In addition to their use in determining perfusion, radiotracers can be used to determine biochemical interactions such as receptor binding. Postmortem studies have reported a severe depletion of cocaine recognition sites associated with the dopamine transporter (DAT) system in the striatum of patients with Parkinson’s disease (PD). Several analogues of cocaine have been investigated to develop DAT selective radioligands for SPECT imaging, of which 123 I 2-carbomethyl-3-(4-iodophenyl) tropane (-CIT) and 123 I-Ioflupane (123 I-fluoropropyl--CIT) are the most widely used. The main advantage of 123 I-Ioflupane is that images can be acquired from 3 to 6 hours after injection, compared with the 18 to 24 hours required for 123 I -CIT [3]. A D2 receptor marker (123 I-iodobenzamide) is also commercially available in Europe. Other 123 I-labeled ligands have been developed for imaging the cholinergic, noradrenergic, and GABAergic receptor systems. Brain perfusion SPECT is a safe procedure. The whole-body effective dose equivalent received from the
Single-Photon Emission Computed Tomography administration of 99m Tc HMPAO is 0.7 roentgen equivalent man (rem) per 20 millicurie dose. This effective dose equivalent value is similar to that received during a radionuclide bone scan, is 1.5 times that received from a CT of the abdomen and pelvis, and is 43% of the average annual background radiation in the United States. Most state-ofthe-art imaging systems are designed to reduce head motion and patient discomfort. Most clinical applications do not require arterial sampling. One of the major reasons for the interest in SPECT is that it represents a less expensive technique to do functional neuroimaging. The older and more accurate modality for functional neuroimaging is positron emission tomography (PET). Unlike PET, SPECT cannot measure regional cerebral metabolism, but it provides a qualitative estimate of rCBF, which in many neurological disorders is tightly coupled with brain metabolism. Thus SPECT provides functional information not available by conventional CT or MRI at a cost similar to that of CT.
II. SPECT in Diseases of the Brain The interest in SPECT has spawned a rich literature in the past few years. Unfortunately, many of the reports comprise only a few patients; large, well-controlled studies are rare. In addition, most studies have used as a standard the clinical diagnosis, lacking pathological confirmation. Another caveat has to do with the variable quality of the techniques used for clinical SPECT, which depends more on the operator than the CT or MRI. The reported results have usually been obtained at well-established nuclear medicine services and may not be generalizable to all institutions. Given the complexity of information derived from functional neuroimaging, the interpretation of results often requires a close collaboration between nuclear medicine physicians and clinicians. Therefore, the practical application of SPECT to clinical work varies widely among institutions, depending on the interests of nuclear medicine physicians and, more often, of neurologists or psychiatrists who refer patients for SPECT. Of the applications reviewed in this chapter, perhaps the most useful and widespread is ictal SPECT for epilepsy. But there are institutions, particularly in Europe, at which SPECT is used routinely in the management of patients with acute stroke, particularly when aggressive therapies, such as hemicraniectomy for massive hemispherical swelling, are carried out in select cases.
A. Stroke With the increasing availability of perfusion CT and diffusion and perfusion MRI, is SPECT still a useful tool to study perfusion, an obviously important variable in stroke
831 and stroke-prone patients? As interesting as this question may be, we only answer it partially in this review. Leaving aside for a moment the real-life availability of these techniques, there are no controlled studies comparing their usefulness and cost in the different settings relevant to clinical cerebrovascular disease, namely, (1) stroke prediction in the presymptomatic subject; (2) stroke prediction in the patient at risk; (3) diagnosis of an acute ischemic event; and (4) prognosis of the acute event [4]. Moreover, it is likely that such studies will never be carried out because the field of stroke imaging is evolving quickly and the real applicability of the different modalities used to study stroke depends on the availability of each modality at the clinical setting. Therefore, this discussion focuses on the potential of SPECT to answer clinically relevant questions, such as the following: (1) In the patient at risk of stroke, what is the mechanism and likelihood of suffering a stroke? (2) In the patient with a strokelike syndrome, what is the mechanism, how should it be treated, and what is the prognosis for recovery? 1. Risk of Stroke in Subjects at Risk a. Assessment of Cerebral Perfusion with Large-Vessel Stenosis Vasodilation caused by hypercapnia (inhalation of 5% CO2 or by acetazolamide injection (1 g intravenously 15 minutes before radionuclide injection) can be used to assess the vascular reserve of brain regions supplied by a stenotic or occluded artery. By using two isotopes, a Tc agent for a baseline blood flow measurement and an iodine agent for a postacetazolamide blood flow measurement, the separate distributions can be measured using two windows on some modern three-headed scanners [2]. Acetazolamide stress brain-perfusion SPECT has been found useful as a complementary method in determining selective carotid shunting during carotid endarterectomy. Shunts were necessary for 8 of 8 patients with a severely reduced vascular reserve compared with 4 of 67 who had a less severe reduction [4]. Patients who have had cerebral infarction are also at risk for additional ischemic lesions. In a group of patients with watershed hemispherical infarcts ipsilateral to a stenotic artery, those with white matter infarcts (Fig. 3) had worse reserve than those with cortical infarcts [4]. The second group may have compensated between the time of the infarction and the time of the SPECT or suffered infarction not on a hemodynamic but on an embolic basis. b. Subarachnoid Hemorrhage Ischemia from vasospasm is a major cause of morbidity and mortality following subarachnoid hemorrhage. Given the ability of SPECT to detect surface ischemia, this technique, when combined with transcranial Doppler, is a sensitive screening tool for the early detection of vasospasm and delayed ischemic deficits in an entire hemisphere or an isolated cortical branch. Acetazolamide SPECT has been used within the first 18 days
832
Single-Photon Emission Computed Tomography hemorrhage is its main contraindication, CT has become the standard imaging modality for acute stroke. MRI with echo-planar imaging is replacing CT at many institutions, because it adds information on tissue damage and potentially reversible perfusion defects. It also provides vessel visualization. Many see SPECT as an interesting technique but one whose potential benefits would be offset by the attendant delay in diagnosis and treatment. Although SPECT was first approved by the FDA for the study of cerebral ischemia, this technique is not used for acute stroke in the majority of U.S. hospitals. However, there are a number of active stroke centers around the world using perfusion SPECT for the evaluation of acute stroke [4]. SPECT may have a role in helping diagnose nonischemic neurological deficits and in predicting the need for thrombolysis, separating the patients who would not benefit from it either (1) because by the time the procedure is ready there is no perfusion deficit to be corrected by thrombolysis or (2) because the infarct is large and the ischemia is profound, with attendant capillary necrosis and a high risk for bleeding. In patients with large infarcts, SPECT may help determine which patients may benefit from holohemispheric decompression.
Figure 3 Use of Acetazolamide Challenge to Assess Vascular Reserve and Differentiate Ischemia from Diaschisis. A 51-year-old had transient left arm weakness. (A) A computed tomography scan showed hypodense areas in the watershed of the left hemispherical white matter. Duplex ultrasound revealed occlusion of the right internal carotid artery at the bifurcation. (B) hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) before acetazolamide showed hypoperfusion of the right middle cerebral artery (MCA) territory and the thalamus (usually supplied by the posterior circulation). (C and D) Two days later, SPECT was repeated after oral loading with acetazolamide. (C) The difference between the hemispheres became more obvious. Perfusion of the previously hypoperfused right thalamus became normal (diaschisis), but not in the cortical distribution of the right MCA. (D) Note the sharp difference between the ischemic territory of the MCA and the normal cortex supplied by the posterior cerebral artery, from the posterior circulation. Note: Actzd, acetazolamide.
after subarachnoid hemorrhage to predict which patients are likely to develop cerebral infarction [4]. Early and extensive reduction in cerebral vasodilatory capacity correlated with the development of cerebral infarction due to vasospasm following subarachnoid hemorrhage. As vasospasm can be treated with angioplasty, the application of techniques for early and accurate diagnosis of dangerous vasospasm is of obvious importance. 2. Acute Strokelike Syndrome For the diagnosis of stroke, time is of the essence. As evidence mounts that the therapeutic time window for acute stroke is narrow and that delaying effective therapy results in more tissue damage, the pressure is on to diagnose the cause of stroke as quickly as possible. Because thrombolysis is effective in acute stroke and intracerebral
a. Nonischemic Neurological Deficits Occasionally, the clinical situation arises of differentiating ischemia from epilepsy as the cause of a sudden neurological deficit, particularly in cases with a prolonged focal discharge, when the onset was not witnessed and the patient is unable to give a reliable account. Ischemia will cause an area of hypoperfusion on SPECT, whereas epileptic phenomena are often manifested by hyperperfusion, although postictally there is hypoperfusion (Fig. 4). Differentiating ischemia from focal epileptic phenomena is critical, as thrombolysis and other techniques to treat acute stroke are now available. Increased perfusion of the hemisphere contralateral to the affected limbs has also been reported with infantile alternating hemiplegia, transient aphasia, or neurosarcoidosis [4]. b. Prediction of Transient or Mild Ischemic Attack In patients with acute ischemic neurological symptoms studied with 99m Tc-ECD SPECT, those who had no perfusion deficit detectable by visual inspection of the SPECT scan despite clinical symptoms were symptom free after 7 days [4]. In the semiquantitative SPECT analysis, these patients had abnormal count densities in the affected region (activity less than 90% but more than 70% compared with the contralateral side). All patients with subsequent infarction n = 59 had values less than 70%. Performance of the procedure in the first few hours seems critical for the usefulness of the test from the patient management point of view and because the findings are less clear when the study is delayed. The apparently normal perfusion of a necrotic area has been called nonnutritional reperfusion [4]. This pattern on serial SPECT (hypoperfusion, normal perfusion, hypoperfusion) results
Single-Photon Emission Computed Tomography
Figure 4 Peri-ictal Hemiplegia. (A) Axial single-photon emission computed tomography (SPECT) showing increased perfusion of the left hemisphere obtained in a 58-year-old woman 26 hours after she was found in the street with a right-sided hemiplegia, global aphasia, and a gaze deviation to the left. Clinical findings persisted at the time of this SPECT. Computed tomography was negative. An electroencephalogram obtained 12 hours before the SPECT showed marked slowing over the left hemisphere but no epileptiform activity. Improvement ensued over a 1-week period, when the patient could give a history of having had a seizure disorder since her teens. (B) Follow-up SPECT after the patient had improved showed symmetrical perfusion of the hemispheres.
most likely from perfusion being restored after neuronal damage has already occurred. Inflammatory tissue at the site of infarction causes arteriolar dilation in the days and weeks following the infarct, with the resultant “normal” perfusion pattern. As the necrosed tissue is reabsorbed and inflammation abates, regional perfusion decreases and the area again becomes abnormal on SPECT. This mechanism would also explain why failure to show an area of necrosis may happen more readily with HMPAO, a better marker of perfusion, than with ECD, which is poorly retained by areas of necrosis [4]. Lesions in the cortex or deep gray nuclei are more likely to cause SPECT defects than purely white matter lesions, so a normal SPECT study may also predict a lacunar stroke [4]. c. Acute Ischemic Neurological Deficit After answering the critical question of whether the stroke is ischemic or hemorrhagic, by the use of CT or gradient echo MRI, the next step is to predict the likely usefulness of intravenous or, where permitted by protocol, intra-arterial thrombolysis. In some centers, decompression of a massively swollen hemisphere due to a large middle cerebral artery (MCA) infarct has been found to have a positive outcome if the procedure is performed before additional pressure damage occurs. It is therefore important to predict early who will develop severe hemispherical swelling. Using ECD SPECT in the first 6 hours after stroke, Barthel and co-workers were able to determine which patients would develop massive MCA-territory necrosis, with hemispherical herniation [5]. These patients have a high risk of hemorrhage following thrombolysis and could be helped
833 by early decompressive hemicraniectomy. Complete MCA infarctions were predicted with significantly higher accuracy with early SPECT (area under receiver operating characteristic curve [AUC] index 0.91) compared with early CT (AUC index 0.77) and clinical parameters (AUC index 0.73, p < 005). Furthermore, the predictive value increased when the findings on CT, clinical examination, and SPECT were considered [5]. Other studies have found SPECT to add predictive value to the clinical score on admission [4]. In summary, a patient with a normal ECD SPECT study performed within 3 hours of stroke onset will most likely recover spontaneously and does not require thrombolysis. A patient with a dense deficit in the entire MCA distribution has a high risk of hemorrhage with thrombolysis and, depending on age and other factors, should be considered for decompressive hemicraniectomy. The patients most likely to benefit from thrombolysis are the ones with less massive lesions [4]. A mismatch between the area acutely affected, as seen on diffusion-weighted imaging, and an MRI or SPECT perfusion study predicts shortly after the acute event which infarcts will become larger in the hours and days following the stroke. The infarct grows to match the area of severely decreased perfusion (between 12 and 20 ml per 100 g every minute) [4]. The area of mismatch is the ischemic penumbra, which often becomes necrotic as the process evolves. Using only 99m Tc-ECD SPECT, the dynamic study approximates a perfusion map of the region, whereas decreased uptake in the static study shows the nonviable area of the brain, albeit with somewhat poor spatial resolution [4]. This information is important because patients with a mismatch may benefit from neuroprotective therapies. Ideally, a study on acute neuroprotection should include only these patients. Because serial SPECT studies can be conducted about 30 minutes after one another using an initial smaller dose of the radioisotope and then a larger dose, after a few minutes using two different isotopes (99m Tc and 123 I), or after about 24 hours using the same isotope and dose, SPECT has been used to evaluate the effect of different therapeutic strategies on brain perfusion (Fig. 5) [2]. Among them are intra-arterial urokinase, intravenous recombinant tissue plasminogen activator, streptokinase, and rheopheresis [4]. Strategies that seek to open an occluded vessel can be particularly well evaluated by perfusion SPECT, a much less invasive procedure than arterial angiography or iodine-contrast CT and a less costly procedure than perfusion MRI. For intra-arterial thrombolysis, ischemic tissue with perfusion greater than 55% of cerebellar flow may be salvageable, even with treatment initiated 6 hours after onset of symptoms [4]. Ischemic tissue with perfusion greater than 35% of cerebellar flow still may be salvageable with early treatment (less than 5 hours). Ischemic tissue with perfusion less than 35% of cerebellar flow may be at risk for hemorrhage with thrombolysis [4].
834
Single-Photon Emission Computed Tomography
C. Infectious Diseases 1. Human Immunodeficiency Virus Encephalopathy
Figure 5 Repeated SPECT with Technetium-99m Ethyl Cysteinate Dimer in Two Patients. Patients (top and bottom rows) at baseline before intravenous (IV) recombinant tissue plasminogen activator (r-tPA) (left column), 6 to 8 hours after IV r-tPA (middle column), and 7 days after IV r-tPA (right column). The patient whose SPECT is displayed at the top row had a good outcome, unlike the one at the bottom. Reprinted, with permission, from Berrouschot, J., Barthel, H., Hesse, S., Knapp, W. H., Schneider, D., and von Kummer, R. (2000). Reperfusion and metabolic recovery of brain tissue and clinical outcome after ischemic stroke and thrombolytic therapy. Stroke 31, 1545–1551.
SPECT has also been used to evaluate the effect on cerebral perfusion of a number of vasodilators, including pentoxifylline, olprinone, and nimodipine, and of vasoconstrictors, including cocaine [4]. In this regard, xenon CT allows for the quantitative determination of rCBF, which can also be obtained with xenon SPECT, whereas SPECT with the more widely available radionuclides only provides a relative estimate [4].
B. Neoplasms Tracers labeled with thallium-201 have been used to attempt to quantify the malignancy grades of gliomas and to differentiate radiation necrosis from tumor recurrence. Higher malignancy tumors have a greater radionuclide uptake. As the uptake is higher with higher tumor perfusion, a mismatch is sought such that a high uptake on Tl SPECT more reliably points to tumor recurrence when perfusion SPECT shows a low tumor perfusion. Dual-isotope SPECT with 201 Tl to label the tumor and 99m Tc HMPAO to evaluate perfusion has given reliable results in small series [6]. More recently, 123 I--methyltyrosine has been used to differentiate radiation necrosis from the recurrence of malignant astrocytomas, brain metastases, primitive neuroendocrine tumors, clivus chordomas, ependymomas, pituitary tumors, and anaplastic meningiomas. False negatives are common with small tumors (<13 mm in diameter) because they test the limits of the resolution of clinical SPECT units [7].
In human immunodeficiency virus (HIV) encephalopathy SPECT shows decreased cortical uptake, often with focal defects that give the cortex a moth-eaten appearance [8]. The central gray nuclei generally have multifocal defects. Perfusion of the hemispherical white matter is also decreased. In some instances, decreased uptake in the periventricular regions mimics ventricular dilation, out of proportion to the dilation appreciated on CT or MRI. The pathogenesis of perfusion changes in HIV encephalopathy is still unclear. Microvascular changes, perhaps induced by cytokines secreted by infected macrophages, may result in decreased perfusion. An association exists between the severity of ocular microangiopathy, measured by conjunctival sludge and the number of retinal cotton-wool spots, and the severity of cerebral hypoperfusion [9]. By damaging the metabolic machinery of neurons, cytokines may also cause regional neuronal hypometabolism, leading to a decreased oxygen demand and therefore decreased regional perfusion. SPECT is particularly useful in instances of psychosis, mild attentional impairment, or depression in HIV-positive individuals with normal CT or MRI. The characteristic pattern described previously would favor HIV encephalopathy rather than reactive psychosis or depression. However, the SPECT findings in HIV encephalopathy are not pathognomonic. Similar perfusion changes can be observed in chronic cocaine users, patients with the chronic fatigue syndrome, or those with mild head trauma [9]. Because the perfusion pattern is not specific, it has to be evaluated in the context of the clinical presentation and with the information provided by MRI or CT. 2. Herpes Simplex Encephalitis Early treatment of herpes simplex encephalitis with acyclovir is particularly rewarding in patients who have a milder form of the disorder because they are likely to recover more fully. Unfortunately, the diagnosis in these patients may be delayed because they present with psychiatric syndromes or seizures and have negative MRI and CT. The cerebrospinal fluid may also be initially negative. SPECT changes may help in these cases [9]. An abnormally high accumulation of radiotracer in the affected temporal lobe may be present even at an early stage, when MRI is normal.
D. Head Trauma Early SPECT reveals perfusion abnormalities more extensive than anatomic changes seen on CT early after trauma, even in mild head injury [10]. The lesions on
Single-Photon Emission Computed Tomography SPECT of mild head trauma are of two types: (1) sharply circumscribed areas of hypoperfusion, with borders showing relative hyperperfusion; and (2) more diffuse areas of hypoperfusion, involving the occipitotemporal regions. The first type probably corresponds to contusions, with areas of cortical ischemia. The second type may be related to smaller, widespread contusions; to axonal injury of the long white matter tracts running anteroposteriorly, such as the visual radiations; or to both [10]. Few studies have looked at the neuropathological substrate of the changes observed on perfusion SPECT [10]. By studying small-vessel ultrastructure and mapping rCBF at different times within the first 3 weeks of head injury, a zone of ischemic brain was found in areas of hypoperfusion, which persisted for weeks or months. Ischemic areas had astrocytic swelling and microvascular compression, seen on electron microscopy. Focal zones of hyperemia were also present in 42% of patients within the first 2 weeks of injury. Early focal hyperemia appeared only within apparently normal tissue as judged by late MRI or CT. The extent of acute SPECT changes seems to correlate with the clinical severity of the posttraumatic syndrome [11]. As MRI may depict lesions not visible on CT, and vice versa, the combination of the two procedures is a more powerful predictor than either alone.
E. Seizure Disorders Seizures are associated with dramatic increases in cerebral blood flow, localized in partial seizures and global during generalized seizures, reflected on perfusion SPECT [12]. A SPECT study showing increased regional cerebral perfusion ictally in the same region that shows decreased regional cerebral perfusion interictally provides strong evidence for the epileptogenic nature of the lesion. In complex partial seizures, the seizure focus can be identified in 71% to 93% of ictal SPECT studies with a positive predictive value of 95%. In secondarily generalized epilepsy, SPECT may show increased cerebral blood flow locally despite a clinical picture suggesting a nonfocal onset. SPECT changes may also be useful in differentiating an epileptic disorder from a psychogenic one (pseudoseizure). As Tc-labeled compounds are bound on first pass through the brain, where they remain trapped for several hours, electroencephalogram (EEG)-guided ictal injections are used to obtain a snapshot of ictal perfusion [2]. The SPECT scan is performed hours later when the patient has recovered from the seizure and is cooperative. To be accurately recorded with SPECT, the seizure should be at least 5 seconds in duration, and the time from seizure onset to injection of the SPECT tracer should ideally be less than 45 seconds [12]. Longer delays may cause the tracer to be picked up by regions of seizure propagation, rather than the focus of origin. The ictal scan is analyzed for regions of increased
835 and decreased perfusion by subtracting the interictal perfusion scan to create a difference image. The computer-aided subtraction ictal SPECT is then co-registered to the patient’s MRI—the entire procedure is abbreviated as SISCOM—to facilitate interpretation and increase diagnostic and prognostic accuracy [12]. A SISCOM study requires hospitalization and long-term EEG monitoring, usually longer in the case of adults, with more infrequent seizures. As the imaging compound should be available at the time of seizure onset, only ECD or stable HMPAO can be used. Both compounds are stable for about 6 hours after reconstitution. If the patient has no seizures in this period, the compound has to be discarded. SPECT may define the site of seizure onset but lacks the specificity of MRI to determine the nature of the lesion causing epilepsy. Patient management depends on the nature of the lesion. For instance, the treatment of a medial temporal glioma differs from that of mesial temporal sclerosis. Therefore, MRI is the first-line noninvasive imaging modality in focal epilepsy or generalized epilepsy with a focal origin. Quantitative MRI has a sensitivity of 80%– 90% for the lateralization of temporal lobe epilepsy and is helpful in the detection of cortical abnormalities in children with intractable epilepsy. However, there are instances in which ictal SPECT has identified lesions not detected by MRI. Depth electrocorticography and intraoperative electrocorticography, though accurate in many forms of epilepsy, are both highly invasive. In cortical developmental disorders, these EEG techniques often fail to localize the epileptogenic area. PET is useful in focal epilepsy by showing hypometabolism of the affected areas. One study comparing interictal PET and ictal SPECT found similar performance of the two techniques [13]. Currently, SPECT in epilepsy is used mainly in the presurgical evaluation of patients and, rarely, in the evaluation of patients suspected of having pseudoseizures. When the ictal EEG bears such artifacts as to render it useless and the patient’s behavior is puzzling, a focal SPECT abnormality that correlates well with the ictal behavior would favor the diagnosis of true seizures. In the presurgical evaluation of patients with focal epilepsy, SISCOM is useful when the MRI is normal or when the localization of seizure origin by MRI and EEG are at odds [12]. It may also be helpful in patients with multilobar pathology. SISCOM may be used to identify a “target” for placement of intracranial EEG electrodes. Localization with SISCOM may obviate the need for intracranial EEG recordings in selected patients [12]. For example, patients with normal MRI and seizures of temporal lobe origin may not require chronic intracranial EEG monitoring if the extracranial ictal EEG pattern and peri-ictal SPECT studies are concordant. Other applications are at an investigational stage. SPECT has been used to map the area perfused with barbiturate during Wada’s test in the course of the evaluation for
836
Single-Photon Emission Computed Tomography
temporal lobe epilepsy surgery. The accuracy of SPECT localization of a seizure focus can be expected to improve further with the use of new radiopharmaceuticals directed at specific neurotransmitter- or antiepileptic medicationbinding sites.
F. Alzheimer’s Disease In Alzheimer’s disease (AD) SPECT shows decreased perfusion in the association cortex of the parietal lobe and the posterior temporal regions [14]. Frontal association cortex is predominantly affected in some cases, but usually it is not involved until late in the course of the disease. The occipital lobes are less involved, and the paracentral cortex is spared. Using a statistical factorial system to compare regional perfusion with SPECT in AD and controls, Johnson [15] could prove that regional perfusion was decreased in the AD group in the following regions: parietotemporal cortex, hippocampus, anterior and posterior cingulum, and dorsomedial and anterior nucleus of the thalamus. This pattern had a sensitivity of 86% and a specificity of 80%. Presymptomatically, those who developed AD showed a decreased perfusion in the hippocampus, anterior and posterior cingulate gyrus, and dorsomedial and anterior nucleus of the thalamus, all of them structures with an important role in memory and attention. This finding had a sensitivity of 78% and a specificity of 71% [15]. This and other clinical studies suffer from the lack of neuropathological confirmation of the diagnosis. In a group of 70 patients with dementia and 14 controls, all with autopsy, Jagust and colleagues [16] compared the diagnostic accuracy of the clinical criteria without and with the help of SPECT. The clinical diagnosis of probable AD was associated with a probability of 84% of a neuropathological diagnosis of AD. A positive SPECT increased the probability of a diagnosis of AD to 92%, whereas a negative SPECT lowered that figure to 70%. SPECT was most useful when the clinical diagnosis was of possible AD, with a probability of a diagnosis of AD of 67% without SPECT, of 84% with a positive SPECT, and of 52% with a negative SPECT [16]. The average score on the Mini-Mental test of the patients in this study was 13, indicating that they were suffering from serious dementia. However, it is interesting that the group in which SPECT supported most the diagnosis was that of possible AD, which logically includes those patients at an earlier stage. Whether SPECT can help identify at risk individuals was studied in a family with a presenilin-1 gene mutation [17]. Of this family, 23 people did not have the mutation, 18 had it but were cognitively intact, and 16 had already shown signs of cognitive impairment. Compared with those who did not have the mutation, those who did have it but did not have cognitive impairment had decreased perfusion in
the hippocampus, anterior and posterior cingulum, and parietal and frontal association cortex. This pattern on perfusion SPECT could separate correctly 86% of gene carriers and controls, indicating abnormalities in cerebral perfusion even in asymptomatic individuals with a presenilin-1 gene mutation. SPECT is also useful to help in the differential diagnosis of dementia, particularly in the early stages, when the cognitive findings can be ascribed to psychogenic disorders [14]. Patients with Pick’s disease or other frontotemporal dementias have prefrontal and anterior temporal uptake below the control range. Those with diffuse Lewy-body disease have lowered mesial occipital perfusion. Standard perfusion SPECT does not separate well vascular dementia from AD. Acetazolamide causes an increase of cerebral perfusion due to vasodilation in areas of the brain with an intact vascular reserve but not where the arterioles are already fully dilated, such as in ischemic areas or in areas with small-vessel arteriopathies. After the intravenous administration of 1 g of acetazolamide, perfusion increases in the originally hypoperfused parietotemporal areas of AD patients, whereas it remains the same or decreases in patients with cerebrovascular disease.
G. Basal Ganglia Disorders SPECT has been used to aid in the differential diagnosis of the parkinsonian syndromes, particularly by imaging the striatal DAT, and thereby providing an estimate of the involvement of the nigrostriatal pathway [3]. It has also been used to test potential neuroprotective therapies and the effect on neurodegeneration of medications used for PD, although the results obtained with SPECT and their interpretation are controversial [18]. Early in the disease it may be difficult to classify some patients with a parkinsonian syndrome. In typical PD there is a loss of presynaptic dopaminergic terminals in the striatum; therefore, there is a decrease of striatal uptake when the patient is studied with radioligands for DAT, such as 123 I -CIT or 123 I-Ioflupane. Patients who have normal studies are unlikely to have typical PD. In the ELLDOPA trial, 21 out of 135 cases (16%) felt clinically to have PD had normal 123 I- CIT SPECT [3]. These subjects have now been followed for up to 6 years, and both their clinical syndromes and their imaging findings are unchanged, not having progressed as in classical PD. Imaging of the cardiac sympathetic system reveals denervation in PD patients, even in early disease stages, and may differentiate between patients with multiple system atrophy and those with PD [19]. In Huntington’s chorea the caudate nuclei appear hypoperfused on SPECT, even in the early stages when there is no structural evidence of caudate atrophy on CT or MRI. Combined with genetic information, imaging studies of patients at risk may be
Single-Photon Emission Computed Tomography helpful in monitoring disease progression in early symptomatic or presymptomatic stages. Disease progression also must be monitored to test the effectiveness of new therapies aimed at halting neurodegeneration.
H. Diagnosis of Death on Neurological Criteria Cerebral-perfusion imaging with SPECT agents, particularly 99m Tc compounds, has been used for the diagnosis of brain death in difficult instances [20]. Absent cerebral perfusion is clearly shown on SPECT, but tomography is generally not needed; the anterior and two lateral planar views are sufficient. This technique has not been compared with conventional angiography, but it is more convenient than angiography when the diagnosis of death based on neurological criteria requires an arterial perfusion study.
Acknowledgments This review was supported by the UTE Fundación para la Investigación Médica Aplicada (Foundation for Applied Medical Research), Pamplona, Spain.
References 1. Catafau, A. M. (2001). Brain SPECT in clinical practice. Part I: perfusion. J. Nucl. Med. 42, 259–271. 2. Devous, M. D. (2005). Single-photon emission computed tomography in neurotherapeutics. NeuroRx 2, 237–249. 3. Catafau, A. M., and Tolosa, E. (2004). Impact of dopamine transporter SPECT using 123 I-Ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov. Disord. 19, 1175–1182. 4. Masdeu, J. C. (2003). Imaging of stroke with SPECT. In: “Imaging Cerebrovascular Disease” (V. Babikian, L. Wechsler, and R. T. Higashida, eds.), pp. 131–144. Butterworth-Heinemann, Boston. 5. Barthel, H., Hesse, S., Dannenberg, C., Rossler, A., Schneider, D., Knapp, W. H., Dietrich, J., and Berrouschot, J. (2001). Prospective value of perfusion and x-ray attenuation imaging with single-photon emission and transmission computed tomography in acute cerebral ischemia. Stroke 32, 1588–1597. 6. Vallejos, V., Balana, C., Fraile, M., Roussos, Y., Capellades, J., Cuadras, P., Ballester, R., Ley, A., Arellano, A., and Rosell, R. (2002). Use of 201 Tl SPECT imaging to assess the response to therapy in patients with high grade gliomas. J. Neurooncol. 59, 81–90.
837 7. Plotkin, M., Amthauer, H., Eisenacher, J., Wurm, R., Michel, R., Wust, P., Stockhammer, F., Rottgen, R., Gutberlet, M., Ruf, J., and Felix, R. (2005). Value of 123 I-IMT SPECT for diagnosis of recurrent non-astrocytic intracranial tumours. Neuroradiology 47, 18–26. 8. Tucker, K. A., Robertson, K. R., Lin, W., Smith, J. K., An, H., Chen, Y., Aylward, S. R., and Hall, C. D. (2004). Neuroimaging in human immunodeficiency virus infection. J. Neuroimmunol. 157, 153–162. 9. Masdeu, J. C., Van Heertum, R. L., and Abdel-Dayem, H. (1995). Viral infections of the brain. J. Neuroimaging 5(Suppl 1), S40–S44. 10. Masdeu, J. C., Abdel-Dayem, H., and Van Heertum, R. L. (1995). Head trauma: use of SPECT. J. Neuroimaging 5(Suppl 1), S53–S57. 11. Lee, B., and Newberg, A. (2005). Neuroimaging in traumatic brain imaging. NeuroRx 2, 372–383. 12. Cascino, G. D., So, E. L., Buchhalter, J. R., and Mullan, B. P. (2004). The current place of single-photon emission computed tomography in epilepsy evaluations. Neuroimaging Clin. N. Am. 14, 553–561, X. 13. Ho, S. S., Berkovic, S. F., Berlangieri, S. U., Newton, M. R., Egan, G. F., Tochon-Danguy, H. J., and McKay, W. J. (1995). Comparison of ictal SPECT and interictal PET in the presurgical evaluation of temporal lobe epilepsy. Ann. Neurol. 37, 738–745. 14. Masdeu, J. C., Zubieta, J. L., and Arbizu, J. (2005). Neuroimaging as a marker of the onset and progression of Alzheimer’s disease. J. Neurol. Sci. 236, 55–64. 15. Johnson, K. A., Jones, K., Holman, B. L., Becker, J. A., Spiers, P. A., Stalin, A., and Albert, M. S. (1998). Preclinical prediction of Alzheimer’s disease using SPECT. Neurology 50, 1563–1571. 16. Jagust, W., Thisted, R., Devous, M. D., Sr., Van Heertum, R., Mayberg, H., Jobst, K., Smith, A. D., and Borys, N. (2001). SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinicalpathologic study. Neurology 56, 950–956. 17. Johnson, K. A., Lopera, F., Jones, K., Becker, A., Sperling, R., Hilson, J., Londono, J., Siegert, I., Arcos, M., Moreno, S., Madrigal, L., Ossa, J., Pineda, N., Ardila, A., Roselli, M., Albert, M. S., Kosik, K. S., and Rios, A. (2001). Presenilin-1-associated abnormalities in regional cerebral perfusion. Neurology 56, 1545–1551. 18. Ravina, B., Eidelberg, D., Ahlskog, J. E., Albin, R. L., Brooks, D. J., Carbon, M., Dhawan, V., Feigin, A., Fahn, S., Guttman, M., GwinnHardy, K., McFarland, H., Innis, R., Katz, R. G., Kieburtz, K., Kish, S. J., Lange, N., Langston, J. W., Marek, K., Morin, L., Moy, C., Murphy, D., Oertel, W. H., Oliver, G., Palesch, Y., Powers, W., Seibyl, J., Sethi, K. D., Shults, C. W., Sheehy, P., Stoessl, A. J., and Holloway, R. (2005). The role of radiotracer imaging in Parkinson disease. Neurology 64, 208–215. 19. Eckert, T., and Eidelberg, D. (2005). Neuroimaging and therapeutics in movement disorders. NeuroRx 2, 361–371. 20. Facco, E., Zucchetta, P., Munari, M., Baratto, F., Behr, A. U., Gregianin, M., Gerunda, A., Bui, F., Saladini, M., and Giron, G. (1998). 99m Tc-HMPAO SPECT in the diagnosis of brain death. Intensive Care Med. 24, 911–917. 21. Berrouschot, J., Barthel, H., Hesse, S., Knapp, W. H., Schneider, D., von and Kummer, R. (2000). Reperfusion and metabolic recovery of brain tissue and clinical outcome after ischemic stroke and thrombolytic therapy. Stroke 31, 1545–1551.