Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy.

BACKGROUND: In children with tuberous sclerosis, the PET tracer alpha[11C]methyl-L-tryptophan (AMT) has been shown to be selectively taken up by epileptogenic tubers, thus allowing differentiation from nonepileptogenic tubers in the interictal state. OBJECTIVE: To determine whether cortical areas showing increased AMT uptake in children without tuberous sclerosis complex with intractable neocortical epilepsy indicate the epileptogenic zone, and to assess the relative contributions of AMT and 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET abnormalities to the localization of epileptogenic cortical regions. METHODS: Areas of increased AMT and decreased FDG uptake were marked objectively as regions with abnormal asymmetry using an in-house written software in 27 children who underwent comprehensive evaluation for resective epilepsy surgery. The marked PET abnormalities were compared to the locations of scalp and subdural EEG epileptiform abnormalities, as well as histology and surgical outcome. RESULTS: Focal cortical increases of AMT uptake were found in 15 patients. The lobar sensitivity (39.0%) of AMT PET for seizure onset was lower, but its specificity (100%) was higher (p < 0.0001) than that of hypometabolism on FDG PET (sensitivity 73.2%, specificity 62.7%). AMT PET abnormalities were smaller than corresponding FDG PET hypometabolic regions (p = 0.002), and increased AMT uptake occurred in two patients with nonlocalizing FDG PET. Histologically verified cortical developmental malformations were associated with increased AMT uptake (p = 0.044). Subdural electrodes adjacent to the area of increased AMT uptake were most often involved in seizure onset. CONCLUSIONS: Focal increase of cortical AMT uptake in children is less sensitive but more specific for the lobe of seizure onset than corresponding FDG PET hypometabolism, and it is often associated with epileptogenic cortical developmental malformations. AMT PET can assist placement of subdural electrodes even when MRI and FDG PET fail to provide adequate localizing information. Cortical areas adjacent to increased AMT uptake should be carefully addressed by intracranial EEG because these regions often show a high degree of epileptogenicity.

Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction.

OBJECTIVE: To examine the relationship between autism and epilepsy in relation to structural and functional brain abnormalities in children with tuberous sclerosis complex (TSC). METHODS: Children with TSC and intractable epilepsy underwent MRI as well as PET scans with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and alpha-[(11)C]methyl-L-tryptophan (AMT). Based on the results of Autism Diagnostic Interview-Revised, Gilliam Autism Rating Scale, and overall adaptive behavioral composite (OABC) from Vineland Adaptive Behavior Scale, subjects were divided into three groups: autistic (OABC < 70; n = 9), mentally-retarded nonautistic (OABC < 70; n = 9), and relatively normal intelligence (OABC > or = 70; n = 8). RESULTS: PET studies showed that the autistic group had decreased glucose metabolism in the lateral temporal gyri bilaterally, increased glucose metabolism in the deep cerebellar nuclei bilaterally, and increased AMT uptake in the caudate nuclei bilaterally, compared to the mentally-retarded nonautistic group. In addition, a history of infantile spasms and glucose hypometabolism in the lateral temporal gyri were both significantly associated with communication disturbance. Glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nuclei were both related to stereotypical behaviors and impaired social interaction, as well as communication disturbance. CONCLUSIONS: These results suggest that generalized epilepsy in early life and functional deficits in the temporal neocortices may be associated with communication delays, and that functional imbalance in subcortical circuits may be associated with stereotypical behaviors and impaired social interaction in children with TSC.

Developmental changes of cortical and cerebellar motor control: a clinical positron emission tomography study with children and adults.

Functional neuroimaging data regarding the development of motor organization in normal children and adolescents are virtually unavailable because of ethical concerns. As an alternative approach, we studied child and adult lesion patients, focusing on movement of the hand ipsilateral to the lesion and on brain activations in the contralesional hemisphere. [15O]-water positron emission tomography was performed during rest and sequential finger-thumb tapping in 10 children (aged 6 to 14 years) and 15 adults (aged 18 to 74 years) with unilateral lesion. We expected more distinct activation/deactivation patterns during movement in adults than in children. While there were no group differences in activation of primary and secondary motor cortices, deactivations in nonmotor cortex were significantly more pronounced in adults than in children. This indirectly supports our hypothesis of developmental focalization of cerebral motor control. Activations in the cerebellum and vermis were significantly stronger in the adults than in the children, possibly reflecting normal developmental patterns.

Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography.

Several reports have indicated that cortical resection is effective in alleviating intractable epilepsy in children with tuberous sclerosis complex (TSC). Because of the multitude of cortical lesions, however, identifying the epileptogenic tuber(s) is difficult and often requires invasive intracranial electroencephalographic (EEG) monitoring. As increased concentrations of serotonin and serotonin-immunoreactive processes have been reported in resected human epileptic cortex, we used alpha-[11C]methyl-L-tryptophan ([11C]AMT) positron emission tomography (PET) to test the hypothesis that serotonin synthesis is increased interictally in epileptogenic tubers in patients with TSC. Nine children with TSC and epilepsy, aged 1 to 9 years (mean, 4 years 1 month), were studied. All children underwent scalp video-EEG monitoring, PET scans of glucose metabolism and serotonin synthesis, and EEG monitoring during both PET studies. [11C]AMT scans were coregistered with magnetic resonance imaging and with glucose metabolism scans. Whereas glucose metabolism PET showed multifocal cortical hypometabolism corresponding to the locations of tubers in all 9 children, [11C]AMT uptake was increased in one tuber (n=3), two tubers (n=3), three tubers (n=1), and four tubers (n=1) in 8 of the 9 children. All other tubers showed decreased [11C]AMT uptake. Ictal EEG data available in 8 children showed seizure onset corresponding to foci of increased [11C]AMT uptake in 4 children (including 2 with intracranial EEG recordings). In 2 children, ictal EEG was nonlocalizing, and in 1 child there was discordance between the region of increased [11C]AMT uptake and the region of ictal onset on EEG. The only child whose [11C]AMT scan showed no regions of increased uptake had a left frontal seizure focus on EEG; however, at the time of his [11C]AMT PET scan, his seizures had come under control. [11C]AMT PET may be a powerful tool in differentiating between epileptogenic and nonepileptogenic tubers in patients with TSC.

Imaging proliferation in vivo with [F-18]FLT and positron emission tomography.

Positron emission tomography (PET) is now regularly used in the diagnosis and staging of cancer. These uses and its ability to monitor treatment response would be aided by the development of imaging agents that can be used to measure tissue and tumor proliferation. We have developed and tested [F-18]FLT (3'-deoxy-3'-fluorothymidine); it is resistant to degradation, is retained in proliferating tissues by the action of thymidine kinase 1 (TK), and produces high-contrast images of normal marrow and tumors in canine and human subjects.

Task-related activations in heterotopic brain malformations: a PET study.

Positron emission tomography (PET) studies have shown normal or elevated levels of glucose metabolism in neuronal heterotopia, raising the issue of potential participation of heterotopic neurons in cognitive processing. We studied three patients with heterotopic malformations, using [(15)O]water PET and experimental conditions selected according to the location of the malformations. Task performance was associated with blood flow increases of > 17% within the heterotopia in each patient. In two, these occurred in left frontal heterotopia during sentence generation. In the third patient, activations for facial and visuospatial discrimination and picture naming were found in a right posterior heterotopion. Our findings may reflect participation of heterotopia in cognitive function and suggest that heterotopic neurons synapse with neurons in other brain regions.

Effects of cardiac sympathetic innervation on coronary blood flow.

BACKGROUND: The role of cardiac sympathetic nerves in regulating coronary blood flow is controversial. We sought to determine the degree to which cardiac efferent sympathetic signals modulate coronary blood flow. The heterogeneous sympathetic reinnervation in transplanted hearts provides a model for studying the vasomotor responses to adrenergic stimulation in reinnervated and denervated coronary territories of the same heart. METHODS: We studied 14 cardiac-transplant recipients who had normal coronary arteries and no evidence of rejection and 8 normal subjects. We used positron-emission tomography with [(11)C]hydroxyephedrine, an analogue of norepinephrine, to delineate sympathetic innervation. Using [(13)N]ammonia, we measured myocardial blood flow at rest, during adenosine-induced hyperemia, and in response to sympathetic stimulation induced by cold pressor testing. RESULTS: In the transplant recipients, the uptake of [(11)C]hydroxyephedrine was greater in the territory served by the left anterior descending artery (0.15+/-0.01) than in those served by the right coronary artery (0.07+/-0.01, P<0.001) or the circumflex artery (0.09+/-0.01, P<0.001). The basal flow was similar in all three regions, as was the percent increase in flow during hyperemia. However, the increase in flow in response to cold pressor testing was higher in the territory of the left anterior descending artery (46+/-10 percent) than in those of the right coronary artery (16+/-5 percent, P=0.01) or the circumflex artery (23+/-6 percent, P=0.06), although the changes in hemodynamics and levels of circulating catecholamines were similar. No such regional differences were observed in the normal subjects. CONCLUSIONS: Increases in coronary blood flow in response to sympathetic stimulation correlated with the regional norepinephrine content in the cardiac sympathetic-nerve terminals. These findings suggest that cardiac adrenergic signals play an important part in regulating myocardial blood flow.

[15O]-water PET and intraoperative brain mapping: a comparison in the localization of eloquent cortex.

[15O]-water PET was performed on 12 patients with structural lesions for localization of the motor (n = 5), language (receptive and expressive; n = 6), and visual cortex (n = 1). All these patients underwent interactive image-guided surgery using an infrared digitizer and intraoperative electrical stimulation mapping for motor, sensory, language, and visual cortex location. MRI-PET coregistration was performed using a surface matching approach that integrated functional information with interactive image guidance during the surgical procedure. An awake craniotomy with motor and sensory intraoperative stimulation was performed using a registered bipolar electrode that was tracked on real-time during the surgical procedure. Intraoperative functional findings were displayed and saved on the registered MRI images. The sites of functional PET activation during the performance of motor, visual and language tasks were then compared to the results of intraoperative cortical stimulation in 11 patients and visual evoked potentials in one. The results of the PET activation studies were concordant with the findings of intraoperative stimulation in all cases. During resection of the structural lesions, intraoperative stimulation was continued in the subcortical pathways, and five patients had positive responses on areas not identified by the functional PET. Furthermore, 3 patients showed transitory changes in function (speech arrest 1, naming difficulty 1, and motor weakness 1) that were reversible after changing the dissection technique or a brain retractor. [15O]-water PET was reliable in identifying the motor, visual, and language cortex. Language-related rCBF increases were highly distributive, although only part of these activations were subjected to intraoperative stimulation. We conclude that [15O]-water PET can be used for preoperative noninvasive identification of functional cortex and may be useful in neurosurgical preplanning. Intraoperative mapping still remains the main means to avoid neurological damage as it can be performed during the entire surgical procedure to avoid damage to cortex, pathways, and damage secondary to ischemia or edema (brain retraction).

Successful and unsuccessful approaches to imaging carcinoids: comparison of a radiolabelled tryptophan hydroxylase inhibitor with a tracer of biogenic amine uptake and storage, and a somatostatin analogue.

A mouse mastocytoma model was used to determine the biodistribution and tumour uptake of four radiopharmaceuticals developed to target the serotonin synthetic pathway in carcinoid tumours. Three of the compounds were competitive inhibitors of the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. Radiolabelled iodo-dL-phenylalanine (iodine-131 PIPA) was found to have the highest uptake and tumour-to-liver ratio. Four patients with known carcinoid tumours were then injected with 0.5 mCi 131I-PIPA and imaged at 1, 4, 24 and 48 h post-injection. The radiopharmaceutical, however, failed to localize in the known tumour sites. This result was in contrast to the authors experience of 131I- and 123I-MIBG imaging of carcinoid tumours. Seven patients with known metastatic carcinoid tumours, two patients with symptoms of recurrence following tumour resection, one patient with completely resected disease, and two patients with a flushing syndrome of uncertain aetiology were studied with 131I-MIBG. Three of the seven patients with known metastatic disease had positive 131I-MIBG scans. Both patients with clinical evidence of recurrent disease had negative scans, as did the patient who was considered to have had complete resection of her primary tumour. The two patients with idiopathic flushing syndrome also had negative scans. Among seven patients imaged with 123I-MIBG there were four true-negative scans and one false-negative, the latter in a patient with biochemical and CT evidence of recurrence. In a seventh patient with distant metastases there was variable uptake in some of the lesions. Four patients were studied with indium-111 pentetreotide . Two patients with metastatic carcinoid disease had positive scans, although hepatic metastases were not seen in one. Another two with idiopathic flushing syndrome had normal studies. The literature suggests that up 50% of carcinoid tumour cases are detected with 131I-MIBG, compared to a sensitivity of 87% reported with somatostatin receptor imaging using 111In-pentetreotide. The experience with 123I-MIBG is much less extensive. The mechanisms of carcinoid tumour localization for each of the three classes of radiotracers are discussed and contrasted to their varying sensitivities. The relative success of 131I-MIBG and 111In-pentetreotide relative to 131I-PIPA may be related to the fact that 131I-MIBG is actively taken up and stored by the enterochromaffin cells of the tumours and 111In-pentetreotide binds to cell surface receptors, whereas 131I-PIPA binds to tryptophan hydroxylase, which may be present in quantities too small to permit tumours to be imaged.

The kinetics of copper-62-PTSM in the normal human heart.

Copper-62-labeled pyruvaldehyde bis(N-4-methylthiosemicarbazone) copper(II) (PTSM) is a generator-produced myocardial perfusion tracer. Animal studies have shown high myocardial tissue extraction and prolonged retention. The aim of this study was to define myocardial kinetics of 62Cu-PTSM and to determine its suitability for evaluating myocardial perfusion at rest and during pharmacological vasodilation in human subjects. In six healthy volunteers, 62Cu-PTSM was administered at baseline and during a 6-min adenosine infusion (140 micrograms/kg/min). Dynamic PET imaging with high temporal resolution was performed over 20 min. Good image quality was observed at rest and following adenosine. Myocardial kinetics demonstrated prolonged tissue retention with a clearance half-life of 105 +/- 49 min at rest and 101 +/- 65 min following adenosine (p = ns). Copper-62-PTSM tissue retention was quantified and showed only a 1.97-fold increase from rest to adenosine studies. This suggests attenuation of tracer retention at high flow rates. Copper-62-PTSM represents a promising new radiopharmaceutical for the evaluation of myocardial perfusion in the human heart.

Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience.

Twenty-eight patients with histologically proven metastatic or invasive, unresectable pheochromocytomas, which were shown to concentrate and retain tracer doses of [131I]metaiodobenzylguanidine (131I-MIBG), were treated with therapeutic quantities of this radiopharmaceutical. Between one and six doses ranging from 97 to 301 mCi (cumulative dose 111-916 mCi) were administered. Partial response in tumor size was achieved in 8/28 patients and partial biochemical responses in 12/28 patients. No pharmacological toxicity was observed. Mild radiation sickness (nausea, vomiting, anorexia) occurred in 21/28. Minor degrees of leukopenia and thrombocytopenia were observed in 3/28. There were three cases of hypothyroidism but no significant hepatic, renal, adrenocortical or autonomic nervous dysfunction. We conclude that therapeutic 131I-MIBG can achieve significant therapeutic responses in some cases of malignant pheochromocytoma without pharmacological toxicity and only mild radiotoxicity.

Metabolism of iodine-131 metaiodobenzylguanidine in patients with metastatic pheochromocytoma.

Iodine-131 metaiodobenzylguanidine ([131I]MIBG) is used to image and treat human pheochromocytoma. As part of a pharmacodynamic study of this agent, we have evaluated its excretion and metabolism in nine pheochromocytoma patients undergoing MIGB therapy. Following diagnostic doses of [131I]MIBG given prior to therapy, 40 to 55% of the administered radioactivity generally appeared in the urine within 24 hr and 70 to 90% was recovered within 4 days. Reverse-phase high performance liquid chromatography was used to identify radioactive metabolites following therapeutic doses of [131I]MIBG. Unaltered [131I]MIBG was the major radioactive urinary component found, representing 75 to 90% of the total in all but one of the nine patients examined. The urine samples from the patient, whose rate of urinary excretion was the lowest of the group, contained [131I]-m-iodohippuric acid ([131I]MIHA) in amounts equal to that of [131I]MIBG, as well as small amounts of [131I]iodide and [131I]-m-iodobenzoic acid ([131I]MIBA). Iodine-131 MIHA and [131I]iodide were also minor components in the urine samples from the other eight patients. Trace quantities of [131I]MIBA and 131I-4-hydroxy-3-iodobenzylguanidine ([131I]HIBG) were also detected in a few of the patient urine samples examined. The 4- to 5-day metabolism profiles varied from patient to patient but were similar for the same patient following therapy doses given 4 mo apart. There was no obvious correlation between the presence of metabolites and the location of the tumors or the plasma or urinary catecholamine levels. Extraction of radioactivity from two pheochromocytomas removed from patients was determined to be primarily MIBG. These studies suggest that [131I]MIBG is a rapidly excreted, relatively stable radiopharmaceutical agent.

Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy.

The radiopharmaceutical iodine 131 metaiodobenzylguanidine (I-131 MIBG) has been shown to locate pheochromocytomas scintigraphically with a false-negative rate of approximately 13%. To improve image quality and reduce the false-negative rate, I-123 was examined as a radioactive label for MIBG, as it has many advantages over I-131, including superior dosimetry and better detection efficiency. Diagnostic doses of 0.5 mCi (18.5 MBq) I-131 MIBG and 10.0 mCi (370.0 MBq) I-123 MIBG with nearly equivalent radiation dosimetries were compared in 18 patients with known or suspected pheochromocytomas. Images of superior quality were obtained with I-123 MIBG in 18 of 18 patients, and in eight cases lesions not visualized on I-131 MIBG scintigraphy were portrayed. A further advantage of I-123 MIBG is that it permits single photon emission computed tomography (SPECT). This was performed in six cases and provided additional information in three cases. The adrenal medullae were definitely visualized using I-123 scintigraphy in eight of 14 patients still possessing adrenal glands, whereas I-131 MIBG images portrayed the adrenal medulla in only one of 14 cases. Five remaining patients had multiple abdominal tumor deposits that were difficult to differentiate from normal adrenal medullae.

Portrayal of pheochromocytoma and normal human adrenal medulla by m-[123I]iodobenzylguanidine: concise communication.

The radiopharmaceutical m-[131I]iodobenzylguanidine (I-131 MIBG), which is readily taken up by adrenergic vesicles, produces scintigraphic images of pheochromocytomas in man but rarely visualizes normal adrenal glands. Iodine-123 has many potential advantages over I-131 as a radiolabel for MIBG, including shorter half-life, freedom from beta emissions, and increased gamma-camera efficiency. In this study, diagnostic doses of MIBG labeled with I-131 and I-123, with nearly equivalent radiation dosimetry, were compared as imaging agents in eight patients with known or suspected pheochromocytoma. Images of superior quality were obtained with I-123 MIBG, and lesions not visualized using I-131 MIBG were portrayed. In addition, the normal adrenal medullae were visualized on the I-123 MIBG scintigrams in six out of eight patients.

Radiopharmaceutical treatment of malignant pheochromocytoma.

Apart from relieving effects of secreted catecholamines, treatments of malignant pheochromocytoma have achieved little success. When the radiopharmaceutical, meta-[131I] iodobenzylguanidine (I-131 MIBG ), was found to concentrate in some malignant pheochromocytomas, we calculated that this agent could impart therapeutic doses of radiation to these tumors. We therefore treated five patients with two to four doses of I-131 MIBG prepared in high specific activity, 8-11 Ci/mmol. Individual doses were given at 3- to 10-mo intervals and in 97- to 197-mCi amounts. Two patients exhibited subjective and objective benefits. Their tumors declined in size (to 28% and 30% of original volumes) and in hormone secretion (to 50% or less of baseline rates). The other three patients manifested few symptoms before treatment and showed few or no objective improvement afterward. The tumors of the patients who responded to I-131 MIBG (a) appeared to be more rapidly growing, (b) received more cumulative rads, and (c) were more predominantly in soft tissues (in contrast to bone) than those in the patients who obtained little benefit. No toxic effects were encountered during the treatments, and only minor and temporary untoward responses were seen later.

Adrenal medulla imaging agents: a structure-distribution relationship study of radiolabeled aralkylguanidines.

Fourteen 125I-labeled aralkylguanidines were synthesized and evaluated as potential imaging agents for the adrenal medullae and tumors of adrenomedullary origin. These guanidines are radiotracer analogues of guanethidine, an antihypertensive agent thought to mediate neuron blockade by uptake into adrenergic nerves. Dog adrenal medullae were used as a model to test radiotracer affinity for catecholamine storage tissue. Tissue distribution studies revealed that a number of radioiodinated guanidines showed pronounced localization in the adrenal medullae following intravenous injection, in certain cases exceeding that of either (-)-[3H]norepinephrine or [14C]guanethidine. (m-[125I]Iodobenzyl)guanidine (m-IBG, 2b) gave the best combination of high concentration and selectivity. The low adrenomedullary affinity observed with [14C]guanidine and m-[125I]iodobenzylamine demonstrates the uniqueness of the aralkylguanidine structure. Preliminary evidence suggests that 2b is a storage analogue of norepinephrine. [125I]2a is now being used clinically in imaging and radiotherapy of catecholamine tumors, such as pheochromocytoma.

Treatment of malignant pheochromocytoma with a new radiopharmaceutical.

A new radiopharmaceutical, [131I]metaiodobenzylguandine, concentrates in some malignant pheochromocytomas. Five patients were treated with two to four doses of [131I]MIBG (99-197 mCi/dose). Two patients had substantial subjective and objective responses. [131I]MIBG is the first chemically synthesized radiopharmaceutical of complex molecular structure to reduce cancer.

Spectrum of pheochromocytoma in multiple endocrine neoplasia. A scintigraphic portrayal using 131I-metaiodobenzylguanidine.

Six patients with multiple endocrine neoplasia (MEN) types 2a and 2b were investigated to determine the spectrum of pheochromocytoma by scintigraphy. Iodine-131-metaiodobenzylguanidine (131I-MIBG), a new imaging agent which concentrates in adrenergic neurotransmitter vesicles, was administered at 0.5 mCi/1.7m2 and scintiscans were taken at 24 and 48 hours. Two normotensive patients with normal plasma and urinary catecholamines had no adrenal tracer uptake. One patient with a modest and intermittent increase only in urinary catecholamine metabolites showed faint adrenal images. Two other patients with increased plasma and urinary catecholamines showed bilateral adrenal imaging patterns. The sixth patient who had increased norepinephrine and epinephrine secretion showed bilateral asymmetrical adrenal images, findings that were corroborated at operation. Functional as well as anatomic evidence of adrenal medullary abnormalities in patients with MEN-2 syndromes are demonstrated by 131I-MIBG scintigraphy. Therefore, the procedure can be used to define the extent of abnormalities of the adrenal medulla in these patients.