Structural and functional neuroimaging findings in substance-related disorders.

Intoxication with alcohol results in depressed global glucose metabolism that continues into the stages of withdrawal and abstinence. The decrease in metabolism, however, is not equal across the brain, with certain regions more affected than others. Such a pattern of disturbance suggests that the effect of alcohol on the brain cannot simply be a nonspecific depressant effect secondary to decreased blood flow or glucose transport into the cells but may be related to the dysfunction of the various neurotransmitter systems. Different authors have suggested the dysfunction to be related to the GABAergic, cholinergic, and dopaminergic systems. Long-term alcoholism is associated with atrophy of several brain regions. The frontal lobes and limbic structures seem to be most vulnerable. The data are encouraging with regard to the normalization in brain metabolism and in size of vulnerable brain regions with continued abstinence. In addition to findings of improvement in cognitive functioning and many health parameters, these findings arm clinicians with further data on the benefits of abstinence in the struggle to aid patients in maintaining their sobriety. Several areas remain to be addressed. In particular, clinicians are in need of data, neuroimaging and otherwise, that serve as prognostic indicators, thus allowing patients at higher risk for relapse to be identified and provided with more intensive treatment. A similar need exists for indicators of diagnostic heterogeneity that would guide the development of more highly tailored treatment regimens for identified subgroups of patients. Currently, we have rudimentary knowledge of the gender differences of the effects of alcohol and cocaine on the brain.

Functional brain imaging in neuropsychiatric disorders of childhood.

This review article presents a summary of the current state-of-the-art of functional brain imaging, with a primary focus on childhood neuropsychiatric disorders. Coverage is emphasized for developments that appear to be of current or potential future importance for the child neurologist and related pediatric specialist, and also from the perspective of the developmental neuroscientist. Emphasis is placed on the modalities of single photon emission computed tomography (SPECT), positron emission tomography (PET), and both "conventional" and "functional" magnetic resonance imaging, (MRI) including reference to the major new radiopharmaceutical and magnetic resonance-based imaging agents and techniques. The fundamental physicochemical processes underlying such studies are outlined, with citation of sources of more detailed information for the interested reader. A variety of imaging studies are reviewed for selected groups of childhood neuropsychiatric disorders, designed to illustrate the achievements and future promise of these imaging modalities. Areas of concentration are suggested for future imaging research in the field of childhood behavioral disorders, where these methods seem critical to improved understanding of pathogenetic mechanisms, as well as development of more effective treatment strategies.

Childhood brain tumor: neuroimaging correlated with disease outcome.

The authors explored the hypothesis that functional behavior of childhood brain tumors can be estimated by serial analysis of imaging (thallium-201 [201Tl] single-photon emission computed tomography and magnetic resonance imaging [MRI]) examinations. Seventy-five patients diagnosed on clinical or histologic grounds were monitored for a period of 1 day to 3.9 years (mean +/- S.D. = 1.39 +/- 1.10 years). Abnormal 201Tl uptake appeared to denote a subgroup of lesions with distinctly greater mortality and morbidity. Of 201Tl-positive patients, 17% died within the course of this study; no deaths occurred among the 201Tl-negative group. Other parameters of disease outcome also clearly separated the 201Tl-positive and 201Tl-negative groups, with the former demonstrating a 50% shorter period of recurrence-free survival from the time of diagnosis (two-tailed t test, P < 0.01). Significant enhancement with paramagnetic contrast agents paralleled 201Tl positivity in correlating with greater mortality but failed to predict duration of recurrence-free survival. The authors conclude that 201Tl activity provides significant predictive information of the expected biologic behavior of childhood brain tumors, both for duration of recurrence-free survival and for estimated life expectancy. This information complements and extends data provided by MRI enhancement patterns.

SPECT imaging in cerebral vasospasm following subarachnoid hemorrhage.

UNLABELLED: Cerebral vasospasm is a frequent complication after subarachnoid hemorrhage and contributes to overall morbidity and mortality. Arteriography is the standard test for determining the presence of vasospasm. A retrospective review of 16 patients with cerebral aneurysm was undertaken to assess the sensitivity and specificity of SPECT for diagnosis of vasospasm. Fourteen patients were hospitalized after subarachnoid hemorrhage and 2 patients were hospitalized for elective aneurysmal clipping. The patients' condition on discharge was correlated to clinical and SPECT evidence of vasospasm. METHODS: Vasospasm was defined as the new onset of neurological signs and symptoms not explained by rebleed or hydrocephalus. A total of 20 SPECT studies were performed for 16 patients during their admission and 14 of 16 patients had a single angiographic study. RESULTS: Thirteen of 16 patients had 14 episodes of clinical evidence of vasospasm and 14 SPECT studies were performed in these 13 patients. The sensitivity and specificity of SPECT in this retrospective study were 89% (8/9) and 71% (5/7), respectively. Our small sample of arteriograms yielded in comparison a sensitivity of 67% (2/3) and specificity of 100% (9/9). The one false-negative SPECT study occurred in conjunction with the one false-negative arteriogram in the presence of clinical findings consistent with vasospasm. Three false-positive SPECT studies occurred in 2 patients who had perfusion abnormalities in areas of normal CT findings without clinical or arteriographic evidence of vasospasm. Five of 5 patients who died became unresponsive as a result of clinically presumed vasospasm and 4 of 5 of these patients had diffuse or hemispheric SPECT perfusion defects. Of the 11 patients who survived, none became unresponsive; 1 of 11 had positive diffuse or hemispheric perfusion defects. CONCLUSION: SPECT is a sensitive and fairly specific test for corroboration of clinical findings of vasospasm. A negative SPECT study may obviate the need for arteriography. Unresponsiveness is the best predictor of poor outcome; however, hemispheric SPECT perfusion deficits are also associated with poor outcome.

Ictal and interictal technetium-99m-bicisate brain SPECT in children with refractory epilepsy.

UNLABELLED: Identification of epileptogenic foci in patients with refractory epilepsy remains a significant diagnostic challenge. Magnetic resonance imaging studies frequently fail to reveal an anatomic origin for the seizures, and scalp electroencephalography is often limited to identification of the involved hemisphere. Functional imaging modalities such as PET and SPECT are more promising tools for this application because they reflect the functional pathology associated with the seizure. These changes are more pronounced ictally, but until recently, no radiopharmaceutical was available that could be used routinely for ictal SPECT. The present study was therefore undertaken to determine whether 99mTc-bicisate could be used in ictal SPECT in pediatric patients with refractory epilepsy, to compare the patterns of ictal and interictal blood flow in these patients and to compare the localization information provided by ictal SPECT with that available from other techniques. METHODS: Technetium-99m-bicisate/SPECT was compared prospectively with scalp EEG for its ability to identify a possible seizure focus in pediatric patients with refractory epilepsy. Ictal and interictal SPECT studies were performed in 10 patients (3-19 yr old, mean age 10.9 +/- 4.3 yr; 7 female, 3 male) in whom MRI scans revealed no lesions that might be responsible for the seizures. RESULTS: Ictal SPECT was performed in all patients, and all ictal studies revealed focal perfusion abnormalities. By comparison, four of the interictal SPECT studies showed regional hypoperfusion that corresponded to the regions of hyperperfusion in the ictal studies, and three showed regional hyperperfusion corresponding to the hyperperfused regions in the ictal studies. Three interictal studies revealed no abnormal perfusion. Scalp EEG provided localization information in five patients. CONCLUSION: These initial results suggest that ictal SPECT with 99mTc-bicisate is a more promising tool for the identification of epileptogenic foci than interictal SPECT or scalp EEG in patients without focal abnormalities on MRI.

Correlation of 99mTc-HMPAO SPECT with EEG monitoring: prognostic value for outcome of epilepsy surgery in children.

Sixteen children who had focal cortical resections for medically intractable epilepsy were preoperatively evaluated with 99mtechnetium-labelled hexamethylpropyleneamineoxime single photon emission computed tomography (99mTc-HMPAO SPECT). Video-EEG monitoring was performed in all patients. Outcome was assessed according to the criteria of Engel et al. [1], at a mean follow up length of 13.4 +/- 8.7 months, in all patients. Interictal SPECT showed appropriate localization in 11/15 cases, of whom nine had a class 1 outcome and two had class 2 and 4 outcomes. Interictal SPECT did not correlate with ictal EEG in 4/15 patients, of whom two had a class 1 outcome, and two had class 3 and 4 outcomes. Two postictal studies obtained in group I showed good correlation with the area of ictal EEG onset, and both patients had a class 1 outcome. Interictal HMPAO SPECT imaging, when positively correlated with the ictal EEG focus or with the site of surgery determined by other means, may have prognostic value for outcome of cortical resections for epilepsy in children. The use of ictal and post-ictal studies shows promise for further improving prognostic information in this population.

Technetium-99m HmPAO brain SPECT and outcome of hemispherectomy for intractable seizures.

With recent descriptions of the modified hemispherectomies and hemicorticectomy, there has been renewed interest in hemispherectomy for treatment of intractable seizures with hemiparesis. Because long-term outcome remains uncertain, patient selection remains difficult. 99mTc-HmPAO brain SPECT has been a helpful adjunct in the evaluation of epilepsy surgery candidates. We report SPECT scan findings in 7 patients who underwent hemispherectomy and compare these results with scalp EEG findings. Six patients had unilateral SPECT findings and all had a favorable outcome, regardless of surface EEG findings.

Regional cerebral perfusion abnormalities after cardiac operations. Single photon emission computed tomography (SPECT) findings in children with postoperative movement disorders.

Despite the clinical and pathologic indicators implicating injury to the basal ganglia in children with hyperkinetic movement disorders, we were previously unable to identify lesions in these structures by means of cranial computed tomography or magnetic resonance imaging. We evaluated regional cerebral perfusion measured by single photon emission computed tomography (SPECT) with technetium 99m hexamethyl propylene amine oxime as a technique to localize functional cerebral abnormalities in eleven children who had a movement disorder after hypothermic cardiac surgery. Perfusion defects of the deep gray matter were noted in six of these eleven patients and cortical perfusion defects in nine. For both cortical and subcortical defects a strong right-sided predilection was present. Our findings suggest functional brain injury not detectable by conventional cranial computed tomography and magnetic resonance imaging in these patients. We speculate that these perfusion defects might relate to the behavioral and developmental sequelae in survivors of this syndrome. SPECT may identify subclinical injury in patients at risk for future neurodevelopmental problems and contribute to our understanding of the mechanisms of cerebral injury in the patient operated on for cardiac disease.

Investigating the pediatric central nervous system.

Imaging investigation of the pediatric central nervous system may be considered in terms of structural imaging and functional imaging. Established structural imaging modalities include ultrasonography, radiography, computed tomography, magnetic resonance imaging (MRI), cerebrospinal fluid imaging (eg, myelography), and angiography. Functional imaging technologies include single photon emission computed tomography (SPECT), positron emission tomography, magnetic resonance spectroscopy, and magnetic resonance perfusion imaging. Furthermore, more recent advances in computer software now allow the superimposed display of separate imaging modalities using image fusion techniques. This technique allows the superimposition of structural imaging data with functional imaging data, eg, SPECT and MRI, or the fusion of structural imaging modalities, eg, computed tomography and MRI. In this respect, current practical and investigative applications of structural and functional imaging of the pediatric central nervous system are reviewed.

Tumor uptake of 99mTc-MIBI and 201Tl by a 9L gliosarcoma brain tumor model in rats.

There have been several recent case reports of the accumulation of 99mTc-MIBI [hexakismethoxyisobutylisonitriletechnetium(I), Cardiolite, Sestamibi] in tumors, but no reports of the uptake of this radiopharmaceutical in an animal model. To address this question, the biodistributions of 99mTc-MIBI and 201Tl were compared in Fisher rats bearing 9L gliosarcomas. The results showed that, although the absolute uptake of the tracers by the tumor is relatively low (< 1% ID/g), the tumor-to-normal brain ratios are greater than 6:1 because of low uptake by normal brain. The tumor-to-normal brain ratio of 99mTc-MIBI exceeds that of other currently available 99mTc radiopharmaceuticals suggesting that 99mTc-MIBI may be of particular value in the clinical evaluation of brain tumors and that further investigation of this class of compounds as tumor-avid radiopharmaceuticals is necessary.

Brain single-photon emission computed tomography for behavior disorders in children.

Single-photon emission computed tomography (SPECT) of the brain has been used to define functional abnormalities in two groups of childhood behavior disorders: (1) a "primary" category in which there is exclusive or predominant presentation with cognitive and/or behavioral dysfunction and (2) encephalopathies, often defined etiologically at the biochemical or molecular level, in which clinical expression includes, but is not confined to, neural dysfunction. Radiopharmaceuticals available for such studies are manifold, but those used to date have been predominantly perfusion agents, eg, Xenon-133 (133Xe) and technetium-99m (99mTc) hexamethylpropylene amine oxime, and studies with [99mTc]bicisate are eagerly awaited. Xenon-133 studies require that the patient be in the field of view of the detector while the tracer is administered. This renders it difficult for a subject to perform cognitive and other exercises while being imaged, because the environment is quite foreign. On the other hand, the 99mTc-labeled perfusion agents permit a scintigraphic "snapshot" of regional cerebral blood flow during a behavioral event without having to have the patient under the imaging instrument. Thus, one can separate the administration of the radiotracer, which can be done under more controlled and physiological conditions, from the actual imaging. In addition, greater spatial resolution is achieved with the technetium-based agents. Currently, multidetector or dedicated annular crystal-type cameras are the preferred brain SPECT devices, and they are essential to applications such as cortical "activation mapping" or tomographic detection of receptor systems. Close attention to technical detail and standardization of the child's behavioral environment during the investigation are critical to a successful study. The relative advantages and disadvantages of qualitative versus semiquantitative analysis of imaging date are reviewed. Among primary behavioral disorders, 133Xe SPECT studies in attention deficit disorder-hyperactivity (ADHD) have suggested a pattern of hypoperfusion of striatal and periventricular structures with sensorimotor cortical hyperperfusion. This pattern is consistent with some neurophysiological models of the disorder. In cerebral palsy, perfusional abnormalities have paralleled clinical deficits and may offer information to help predict outcome. The important field of childhood affective disorders (schizophrenia, juvenile autism, depression, etc) remains largely unstudied with SPECT. Finally, representative examples of the use of SPECT to study perfusion in encephalopathies with behavioral expression (phenylketonuria, MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome, Wilson's disease, etc) are given.

Thallium-201 versus technetium-99m-MIBI SPECT in evaluation of childhood brain tumors: a within-subject comparison.

We previously found that 201TI SPECT is a highly specific agent for detection of metabolic activity of childhood brain tumors. To compare the relative diagnostic accuracy of 201TI and a technetium-based tumor-avid agent, we have obtained SPECT in 19 children using 201TI (37-111 MBq) followed immediately by 99mTc-methoxyisobutylisonitrile (MIBI) (370-740 MBq) intravenously. Moderate to intense focal uptake of both tracers characterized true positive cases (n = 6). Lesion boundaries were better defined by MIBI. Uptake of MIBI by choroid plexus occurred despite pretreatment with potassium perchlorate (6 mg/kg) and complicated interpretation of deep/paraventricular lesions. Preliminary assessment indicated sensitivity approximately 67% (TI and MIBI); specificity approximately 91% (TI); approximately 100% (MIBI). Two tumors (medulloblastoma, dysgerminoma) were TI/MIBI nonavid. Semi-quantitative assessment of tracer uptake was made using a ratio of radioactivity in tumor-containing areas compared to uninvolved brain. Ratio values were (mean +/- s.d.) 7.88 +/- 7.70 (TI) and 27.1 +/- 36.41 (MIBI). The spectrum of tumor avidity is similar for TI and MIBI. Clearer identification of boundaries by MIBI may be an advantage in applications, e.g., radiotherapy port planning.

Nuclear medicine in the pediatric chest.

Nuclear medicine enables functional evaluation of organ systems not possible with standard anatomic imaging modalities. The pathophysiology necessitating scintigraphic examination of the pediatric patient is often different from that in the adult and therefore calls for new or modified applications of nuclear medicine. This article briefly reviews such application, with the scope limited to the evaluation of the pediatric chest and organ systems.

Quantitative evaluation of 99mTc-hexamethylpropylenamineoxime brain SPECT in childhood-onset epilepsy.

In 10 patients with childhood-onset epilepsy, quantitative evaluation (QE) of interictal regional cerebral blood flow (rCBF) using technetium-99m-hexamethylpropylenamine oxime (99mTc HMPAO) single-photon emission computed tomography (SPECT) was correlated with seizure foci localized by electroencephalography (EEG). Eighty regions of interest (5 x 5 pixels) were placed at five different neocortical areas in both cerebral hemispheres, in coronal and transaxial planes. Mean counts/pixel were calculated for each region and multiple right-left comparisons were done. Quantitative evaluation of 99mTc-HMPAO increased detection of rCBF abnormalities by 26%. Abnormal EEG patterns correlated with abnormal rCBF in 75% of cases (Phi = 0.788, p < 0.001), and with visually detected abnormalities in 50% (Phi = 0.493, p < 0.001). Discordance between EEG and SPECT was most frequent in patients with non-localizing EEG (n = 3). In childhood-onset epilepsy, quantitative evaluation of brain perfusion scans provides: (a) objective estimates of interictal rCBF; (b) more precise detection of epileptogenic foci, when used to complement EEG.

Regional cerebral perfusion in Landau-Kleffner syndrome and related childhood aphasias.

Assessment of cerebral perfusion may elucidate pathogenesis of Landau-Kleffner syndrome (LKS). We obtained 99mTc-HMPAO SPECT studies in five children with LKS and in three children with syndromes of verbal-auditory agnosia. In LKS, perfusion showed temporoparietal asymmetry (9.56% +/- 3.44%) (n = 4) or bilateral parietal abnormality (n = 1). SPECT in non-LKS patients was normal (n = 1), showed (n = 1) totihemispheral hypoperfusion accompanying structural abnormality or (n = 1) a pattern resembling but distinct from LKS. Seizures in LKS patients had never occurred (n = 1), were controlled satisfactorily (n = 2), or poorly (n = 2). Maximum EEG abnormality was left centrotemoral-occipital (n = 1), left frontocentral (n = 1), bitemporal/left central (n = 1), and left central/parasagittal (n = 1). Asymmetric temporoparietal perfusion appears characteristic of LKS, differing from findings in other childhood linguistic disturbances. This abnormality occurs across a spectrum of seizure expression, diverging from the distribution of EEG abnormalities. The SPECT abnormalities parallel PET-defined LKS metabolic abnormalities, and may indicate central pathogenetic features of the disorder.

201Tl/99mTc-HMPAO SPECT imaging of treated childhood brain tumors.

To assess whether thallium-201 thallous chloride (Tl) can detect childhood tumors and whether diagnostic effectiveness improves with combined blood flow imaging, 28 children (1.0-18.6 years) were studied using single photon emission computed tomography (SPECT): Tl (1.3-1.8 mCi intravenously), followed in 13 of the patients by technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO; 8-18 mCi intravenously). Tl-uptake was markedly increased with histologically confirmed recurrent brain tumors (N = 12). Tl-avid tumors comprised several histologic types, including 6 astrocytomas/gliomas as well as nonastrocytic neoplasms, such as medulloblastoma and ependymoma. A questionable false-positive study was observed with a treated medulloblastoma. Tl failed to detect 5 tumors (i.e., 2 medulloblastomas, 1 ependymoma, 1 malignant schwannoma, and initially 1 low-grade astrocytoma). The sensitivity and specificity of 201Tl-SPECT for detection of childhood brain tumors was 76.9% and 93.3%, respectively. The mean tumor-to-normal brain ratio for Tl was 2.5 +/- 0.5 (N = 7). In some of the patients, 201Tl-SPECT allowed a more precise assessment of the functional state of the tumor than was possible with computed tomography and magnetic resonance imaging. HMPAO distribution was variously normal, increased or decreased at the site of tissue abnormality, and abnormal blood flow was demonstrated in the remaining neuraxis, in 3 of the 7 patients. Changes in tissue perfusion did not correlate with Tl findings, but were evaluated in only one false-negative study.

L-methionine uptake by human cerebral cortex: maturation from infancy to old age.

Age-associated changes in amino acid transport from blood to normal frontal cortex were studied using positron emission tomography (PET). Seventeen patients, 1.8-71 yr, were injected intravenously with tracer doses of [11C] L-methionine and a baseline PET scan was obtained. To assess competitive inhibition of [11C]L-methionine uptake, patients received either oral L-phenylalanine or an i.v. infusion of amino acids 1 hr before a second PET study. Uptake of [11C]L-methionine by frontal cortex decreased seven-fold between 1.8 and 71 yr (r = -0.71; p less than 0.05). Blood-to-brain transfer of [11C]L-methionine, at 4.5 yr, exceeded mean adult values by more than five-fold. Competitive inhibition reduced L-methionine uptake in all patients older than 4.6 yr. These developmental changes parallel findings in animals. The neutral amino acid transport system may modulate human brain amino acid levels to meet changing developmental metabolic needs.