The effect of diphenylhydantoin on thyroxine metabolism in man.

The effect of 5,5'-diphenylhydantoin on thyroxine metabolism was examined in five normal volunteers. Intravenous injection of radiothyroxine was followed by a 10-12 day control and subsequent 9-14 day treatment periods. During oral administration of diphenylhydantoin, plasma thyroxine concentration decreased to about 80% of its pretreatment level and the plasma radiothyroxine disappearance rate increased a maximum of 20% over control estimates. These changes were a result of increases in both urinary and fecal excretion of radioisotope.A minimum plasma thyroxine was apparent after 10-12 days of diphenylhydantoin administration. In two of the subjects, treatment was sufficiently prolonged to achieve this new steady state. In these subjects, the decrease in total body thyroxine was balanced by the increase in the fractional turnover rate. As a result, absolute thyroxine degradation during diphenylhydantoin administration was unchanged from the pretreatment values. Plasma ultrafiltration was used to estimate the free thyroxine fraction at regular intervals during the control and treatment periods. During diphenylhydantoin treatment, there was little or no change in this fraction and therefore, absolute free thyroxine decreased. Thyroxine-binding globulin and thyroxine-binding prealbumin capacities remained constant. These results indicate that thyroxine degradation can proceed at a normal rate in subjects receiving diphenylhydantoin despite decreases in plasma free thyroxine concentration. If free thyroxine is the only portion of the hormone available for cellular utilization, then free thyroxine clearance must be increased in these subjects. This increase in clearance could represent either a direct stimulation of peripheral thyroxine metabolism by diphenylhydantoin, or it could reflect the response of intrinsic regulatory systems to a diphenylhydantoin-mediated displacement of thyroxine from thyroxine-binding globulin. Whatever the mechanism for this effect, a decreased free thyroxine value in patients receiving diphenylhydantoin may not imply hypothyroidism.

Regional cardiac sympathetic denervation in patients with ventricular tachycardia in the absence of coronary artery disease.

OBJECTIVES: The aim of this study was to determine whether patients with ventricular arrhythmias in the absence of coronary artery disease also have abnormalities in sympathetic innervation. BACKGROUND: We have previously shown by cardiac sympathetic scintigraphy using iodine-123-metaiodobenzylguanidine (I-123-MIBG) that patients with ventricular tachycardia after myocardial infarction have regional cardiac sympathetic denervation. It is not known whether patients with ventricular tachycardia in the absence of coronary artery disease also have regional cardiac sympathetic denervation. METHODS: We performed cardiac I-123-MIBG and thallium-201 single-photon emission computed tomographic (SPECT) scans at rest in 18 patients (mean age 47 +/- 18 years) with cardiomyopathy (n = 6), left ventricular hypertrophy (n = 1), valvular disease (n = 2) or a structurally normal heart (n = 9) who presented with monomorphic (n = 15) or polymorphic (n = 3) ventricular tachycardia. These scans were compared with scans in 12 control patients without ventricular tachycardia (mean age 30 +/- 17 years) who had cardiomyopathy (n = 3) or a structurally normal heart (n = 9). Cardiac sympathetic denervation was defined as myocardial areas having thallium uptake with reduced or absent I-123-MIBG uptake. RESULTS: Twelve (67%) of 18 patients with ventricular tachycardia had regional cardiac sympathetic denervation compared with 1 (8%) of 12 patients who did not have ventricular tachycardia (p = 0.002). In the nine patients with a structurally normal heart and ventricular tachycardia, five (55%) patients had regional cardiac sympathetic denervation compared with zero of nine control patients with a structurally normal heart (p = 0.029). Five patients underwent right ventricular radiofrequency ablation for ventricular tachycardia, and sympathetic denervation was adjacent to the ablation site in one of these patients. CONCLUSIONS: Patients with ventricular tachycardia in the absence of coronary artery disease have abnormal cardiac sympathetic innervation detectable by cardiac sympathetic scintigraphy. The role of regional cardiac sympathetic denervation in arrhythmogenesis remains to be determined.

Regional sympathetic denervation after myocardial infarction in humans detected noninvasively using I-123-metaiodobenzylguanidine.

Transmural myocardial infarction in dogs produces denervation of sympathetic nerves in viable myocardium apical to the infarct that may be arrhythmogenic. It is unknown whether sympathetic denervation occurs in humans. The purpose of this study was to use iodine-123-metaiodobenzylguanidine (MIBG), a radiolabeled guanethidine analog that is actively taken up by sympathetic nerve terminals, to image noninvasively the cardiac sympathetic nerves in patients with and without ventricular arrhythmias after myocardial infarction. Results showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake indicating viable perfused myocardium, with no MIBG uptake. Such a finding is consistent with sympathetic denervation. One patient had frequent episodes of nonsustained ventricular tachycardia induced at exercise testing that was eliminated by beta-adrenoceptor blockade. Eleven of the 12 patients had ventricular tachycardia induced at electrophysiologic study and metoprolol never prevented induction. Sympathetic denervation was also detected in two of seven postinfarction patients without ventricular arrhythmias. Normal control subjects had no regions lacking MIBG uptake. This study provides evidence that regional sympathetic denervation occurs in humans after myocardial infarction and can be detected noninvasively by comparing MIBG and thallium-201 images. Although the presence of sympathetic denervation may be related to the onset of spontaneous ventricular tachyarrhythmias in some patients, it does not appear to be related to sustained ventricular tachycardia induced at electrophysiologic study.

HIPDM-SPECT in patients with medically intractable complex partial seizures. Ictal study.

Both interictal and ictal N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3,propanediamine -single photon emission computed tomography (HIPDM-SPECT) were performed in 16 patients with medically intractable complex partial seizures. Ictal HIPDM-SPECT localized epileptic foci in 13 of 14 patients with unilateral temporal focus and provided confirmative evidence of epileptic focus in 11 patients by demonstrating maximally increased regional cerebral perfusion (rCP) in epileptic foci that had shown decreased rCP in a previous interictal study. Ictal HIPDM-SPECT in two patients with bitemporal foci showed more complicated patterns consisting of slightly increased rCP in bilateral multifocal regions. Ictal HIPDM-SPECT was particularly useful for investigating epileptic foci, and correlation with simultaneously recorded ictal electroencephalograms provided further insight for localizing epileptic foci.

Stoichiometric Tc-99m RBC labeling using stable kit solutions of stannous chloride and EDTA: concise communication.

An in vitro Tc-99m labeling method is described, which utilizes stable stock solutions of stannous chloride and disodium edetate (EDTA). The kit procedure requires as little as 1 ml of patient blood, can be performed in only 15 min, and gives labeling yields in excess of 98%. By using EDTA, the binding capacity of RBCs for technetium is sufficient to produce Tc-99m RBC doses with specific concentration greater than 50 mCi/ml for first-pass cardiac studies. Scintigrams reveal a slight amount of bladder activity and splenic uptake, but at no time has the thyroid, stomach, or normal bowel been visualized. The predominant 20-hr blood-clearance half-time results in excellent image quality for over 24 hr--an essential property for following intermittent GI bleeding or for performing repeat cardiac function studies over a several-hour time interval.

Liver and kidney imaging with Ga-68-labeled dihydroxyanthraquinones.

This paper describes the preparation of alizarin (1,2-dihydroxyanthraquinone) and alizarin red S (sodium 1,2-dihydroxyanthraquinone-3-sulfonate) labeled with Ga-68, which is obtained from a new high-yield Ge-68 leads to Ga-68 generator. The uptake of Ga-68 alizarin by liver and spleen RES was studied in rats, dogs, and human, and amounted to 80-85% of the administered dose within 5 min after i.v. injection. Gallium-68 alizarin red S was preferentially accumulated in the renal parenchyma to an extent of 70% within 2 hr after i.v. administration. Both substances combine simple and fast preparation with the potential advantages of positron scintigraphy. Complete labeling of 1 mCi Ga-68 was achieved by 100 micrograms of each compound, amounts that are without any known measurable harm to humans (LD50 alizarin red S for i.v. injected mice = 70 mg/kg (8); LD50 alizarin for i.p. injected mice > 120 mg/kg (18)).

An automated method for the alignment of image pairs.

The computer comparison of two images of the same organ requires proper alignment of the images before further computer processing. This alignment can be achieved by (a) fixing patient position during the study, (b) alignment methods using analytical transformations, or (c) operator interaction. We propose an automated method based upon the cross-correlation between projections of the images. With fast Fourier transforms, the algorithm becomes computationally cheap.

In vivo kinetics of canine leukocytes labeled with technetium-99m HM-PAO and indium-111 tropolonate.

Two weeks after the introduction of osteomyelitis in three dogs, autologous leukocytes were dual-labeled with both [99mTc]HM-PAO and [111In]tropolonate, and reinjected. Blood sampling and imaging were then performed. Two weeks later, the same dogs received simultaneous injections of singly-labeled [99mTc]WBC and [111In]WBC for comparison. For both studies, blood samples were drawn over 6 hr to determine the respective blood clearance half-time (TB) and % recovery (%R0) of cell-bound radioactivity. There were no significant differences in the average TB results of the 99mTc and 111In groups, either within or between the dual- and singly-labeled studies. The %R0 of singly-labeled [99mTc]WBC was about half that of the other groups (p less than 0.01); however, this difference was attributed to the dissimilar radiochemical purity of the [99mTc]HM-PAO reagents. Region of interest analysis of the 6 and 24 hr images revealed no significant differences between either cell label in the relative or absolute in vivo uptake at known sites of osteomyelitis, noninfected surgery, and normal bone marrow.

Combined bone scintigraphy and indium-111 leukocyte scans in neuropathic foot disease.

It is difficult to diagnose osteomyelitis in the presence of neurotrophic osteoarthropathy. We performed combined [99mTc]MDP bone scans and indium-111 (111In) leukocyte studies on 35 patients who had radiographic evidence of neuropathic foot disease and clinically suspected osteomyelitis. The [111In]leukocyte study determined if there was an infection and the bone scan provided the anatomic landmarks so that the infection could be localized to the bone or the adjacent soft tissue. Seventeen patients had osteomyelitis and all showed increased [111In]leukocyte activity localized to the bone, giving a sensitivity of 100%. Among the 18 patients without osteomyelitis, eight had no accumulation of [111In]leukocytes, seven had the [111In]leukocyte activity correctly localized to the soft tissue, two had [111In]leukocyte activity mistakenly attributed to the bone, and one had [111In]leukocyte accumulation in a proven neuroma which was mistakenly attributed to bone. These three false-positive results for osteomyelitis reduced the specificity to 83%. Considering only the 27 patients with a positive [111In]leukocyte study, the combined bone scan and [111In]leukocyte study correctly localized the infection to the soft tissues or bone in 89%. Uninfected neurotrophic osteoarthropathy does not accumulate [111In]leukocytes. We found the combined bone scan and [111In] leukocyte study useful for the detection and localization of infection to soft tissue or bone in patients with neuropathic foot disease.

Evaluation of bone-marrow scanning with technetium-99m sulfur colloid in pediatric oncology.

Eighty-six technetium-99m sulfur colloid (Tc-SC) bone-marrow scans in 56 pediatric oncology patients were reviewed. The distribution of the sulfur colloid was similar to that in adult bone marrow in normal children older than 10 yr, and involved progressively more marrow of the extremities in normal children under 10 years of age. After irradiation or chemotherapy there was an extension of the Tc-SC to peripheral marrow sites. There was also diminished uptake of the tracer in sites corresponding to irradiated areas. In most patients there was recovery of these defects by 6 mo after completion of therapy. Tumor replacement of the marrow was reflected in the scans, and the extent of the scan defect paralleled the course of the disease. In four patients, despite normal bone scans and radiographs, marrow-scan abnormalities due to tumor replacement were present and confirmed by needle aspiration and/or biopsy. In two other patients, the marrow-scan abnormality preceded radiographic and histologic evidence of tumor metastasis. Two patients who responded clinically showed persistent defects; biopsy in one revealed fibrosis. Technetium-99m sulfur colloid bone-marrow scanning appears to be a sensitive monitor of marrow alteration caused by metastases, irradiation damage, or tissue fibrosis in children receiving treatment for cancer.

A quantitative evaluation of rheumatoid arthritic activity with Tc-99m HEDP.

In an attempt to develop a quantitative method of evaluating rheumatoid arthritic activity, Tc-99m HEDP joint uptake values and joint-to-bone ratios were studied in ten adult rheumatoid arthritic patients and 17 nonarthritic patients. A joint-to-bone activity ratio of 1.8 at the fourth hour after injection (RA Index) discriminated clinically active rheumatoid arthritic joints from control joints with 95% accuracy. Serial studies on five patients during drug trial demonstrated a positive correlation between RA Index and the clinical manifestations of rheumatoid arthritic activity. The RA Index may be a useful quantitative parameter for evaluation of rheumatoid arthritic activity following therapy.

Localization of technetium-99m pertechnetate in peripheral nerve tumors.

Technetium-99m pertechnetate scintigraphy in three patients with pathologically proven peripheral nerve tumors (six in total) demonstrated its ability to assess accurately the size, location, and the extent of all lesions. Pertechnetate localized only in areas of abnormal nerve involvement and all lesions were better seen in delayed images than the earlier ones. Pertechnetate imaging appears to be a promising method of noninvasive evaluation of clinically evident and occult tumors of peripheral nerve origin.

Direct comparison of fluorine-18-FDG SPECT, fluorine-18-FDG PET and rest thallium-201 SPECT for detection of myocardial viability.

UNLABELLED: Twenty consecutive patients were evaluated for presumptive myocardial viability using rest TI-SPECT, FDG-PET and FDG-SPECT. The FDG studies were performed after rest TI-SPECT to guide intervention or medical management. METHODS: Twenty patients with proven coronary artery disease, either known or suspected to have previous myocardial infarction and persistent perfusion defects shown by rest reinjection TI-SPECT, underwent FDG-PET and subsequent FDG-SPECT with a three-detector SPECT camera. FDG-PET and SPECT images were compared by five observers to determine if any fixed thallium segments were visualized by either FDG imaging method. RESULTS: Thirteen of 60 fixed segments were shown probably viable by FDG-SPECT (8 of 20 patients) and 14 of 60 by FDG PET (7 of 20 patients). Two patients had fixed thallium segments found probably viable with FDG by SPECT alone and one by PET alone. CONCLUSION: FDG is shown to provide additional information about myocardial viability. Both SPECT, using a three-detector camera, and PET with a specialized instrument are equally effective for imaging FDG in this application.

Comparison of purified indium-111 granulocytes and indium-111 mixed leukocytes for imaging of infections.

Several methods have been proposed for the separation and labeling of white blood cells for the diagnosis of suspected infection. We retrospectively compared 105 patients imaged with 111In purified granulocytes (GRAN) to 106 patients imaged with 111In mixed leukocytes (MIX). We found that in acute infection the sensitivity of GRAN and MIX were both high and not statistically different. In chronic infections the sensitivities were lower than for acute infections. Again, there was no significant difference between GRAN and MIX with the borderline significant exception of MIX being superior to GRAN in chronic soft tissue infections (p = 0.06). We then had independent observers blindly grade the degree of lesion visualization. We found that delayed images visualized the lesions better than early images (p = 0.0001) and acute infection was better visualized than chronic infection (p = 0.03). We concluded that, in routine clinical practice, MIX is probably the agent of choice for three reasons: (a) easier preparation, (b) comparable sensitivity in acute infection and, (c) borderline superior sensitivity in chronic infection.

Acetazolamide enhancement of HIPDM brain flow distribution imaging.

Six patients with symptomatic cerebral vascular disease were studied with 133Xe regional cerebral blood flow measurements and HIPDM cerebral imaging after the administration of acetazolamide. The results obtained from this small group suggest this technique may have high sensitivity for detection of cerebral vascular disease.

Clinical comparison of indium-111 acetylacetone and indium-111 tropolone granulocytes.

This clinical study compares the efficacy of two 111In white blood cells preparations. Seventy-six patients were imaged after an injection of granulocytes (GRAN) isolated on a Ficoll-Hypaque gradient and labeled with [111In]acetylacetone (ACAC) in saline; 105 patients were imaged after an injection of GRAN isolated on a metrizamide-plasma gradient and labeled with [111In]tropolone (TROP) in plasma. Early (2-4 hr), intermediate (4-6 hr), and delayed (24 hr) images were obtained. The specificity was quite high (94-100%) in both preparations and no statistical differences could be found. The sensitivity for ACAC-GRAN for the early, intermediate, and delayed images were 39%, 63%, and 64%, respectively; for TROP-GRAN it was 80%, 89%, and 92%, respectively. In all cases the TROP-GRAN images were significantly more sensitive than the ACAC-GRAN images obtained at the same time after injection (p less than 0.001 for early and delayed images, 0.01 less than p less than 0.025 for intermediate images). For ACAC-GRAN the intermediate and delayed images were significantly more sensitive than the early images, while no significant difference could be found for TROP-GRAN. In a blinded experiment, the ability of TROP-GRAN to demonstrate a lesion was compared to that of ACAC-GRAN. TROP-GRAN demonstrated the lesions better than ACAC-GRAN, both in the early and late images (p less than 0.001). TROP-GRAN visualization scores at 4-6 hr equaled those obtained 24 hr after injection. In conclusion, GRAN separated and labeled in plasma with TROP are superior to those separated and labeled in saline with ACAC in three ways: higher visualization scores, earlier visualization of the lesion, and greater sensitivity.

Evaluation of complicating osteomyelitis with Tc-99m MDP, In-111 granulocytes, and Ga-67 citrate.

Studies with gallium-67 and three-phase bone imaging (TPBS), though very sensitive, are not very specific in evaluating suspected osteomyelitis (OM) that is superimposed upon other diseases causing increased bone turnover. A total of 57 patients with suspected OM were studied; this included 48 with increased bone turnover. All of the patients were studied with granulocytes labeled with In-111 acetylacetone (In-111 GRAN), TPBS and 29 of these patients had Ga-67 studies as well. In-111 GRAN had a sensitivity of 100% in acute OM and 60% in chronic OM, with a specificity of 96%. Gallium-67 was excellent in ruling out OM when the study was normal, or in ruling in OM when the relative uptake of Ga-67 exceeded the uptake of Tc-99m MDP, or when the Ga-67 in bone had a different distribution from the TPBS. Unfortunately, these criteria were met in only 28% of our subjects. We conclude that when added to TPBS, the In-111 GRAN study plays an important role in detecting complicating OM.

Prospective study of magnetic resonance imaging and SPECT bone scans in renal allograft recipients: evidence for a self-limited subclinical abnormality of the hip.

We recently reported that typical abnormalities of avascular necrosis (AVN) in magnetic resonance images (MRI) of the hips of asymptomatic renal transplant recipients whose plain radiographs are normal may improve spontaneously and even disappear completely. We present the results of serial bone scans, most of which were performed with single-photon emission computed tomography obtained over periods as long as 24 mo after transplantation in 72 of these patients. Three paired imaging studies (i.e., MR and bone scan performed within 30 days of each other) were available for each of these patients. In three patients, both the MR images and the bone scans showed changes consistent with bilateral AVN within 4 mo after transplantation. All three patients developed hip pain which was bilateral in two and unilateral in one. Two patients (three hips) required surgical intervention at which time AVN was found on pathologic examination of all three hips. None of the remaining 69 patients developed hip pain during the study. However, in nine patients whose MR studies were consistently normal, at least one bone scan was abnormal (13 hips). The presence of AVN was pathologically confirmed in each of the hips subjected to surgery. Where the imaging findings were identical to those in the asymptomatic patients as well as those in whom the imaging abnormality regressed, we suggest that the subclinical imaging abnormalities represent mild AVN, which is reversible in some cases. Since the process was identified in 10 hips by MRI and in 13 hips by bone scan, both studies are needed to detect subclinical AVN. This may be important if treatment of subclinical disease is clearly shown to prevent progression to symptomatic AVN.

Pulmonary thromboembolism: current status report on the role of nuclear medicine.

The normal perfusion study continues indisputably to rule out the presence of pulmonary embolism (PE) with reasonable certainty. However, the abnormal perfusion study requires additional specificity. Many retrospective and one prospective correlation of contrast pulmonary angiography (CPA) have largely substantiated the efficacy of ventilation imaging and increasing specificity, especially with a high-probability (HP) interpretation to approximately a 90% predictive value. In most studies, the predictive value of a low-probability (LP) interpretation also approaches 90%. Intermediate-probability (IP) ventilation-perfusion (V-P) studies are the most frequent reason for performing pulmonary angiography, although LP studies with a stated prior clinical HP should also have CPA. Ventilation imaging technique is not as uniformly established as for perfusion studies, leading to some continued variability in interpretative criteria; yet criteria proposed by Biello and his colleagues have begun to be widely adopted. Aerosol inhalation imaging is developing, but has not been widely used, while problems continue with central airways deposition. The importance of contemporary correlative chest x-rays (CXR) especially when normal, have been emphasized, as well as new findings of the import of serial post-V-P CXRs, especially in HP studies without CPA or negative CPA. CPA continues to be the most specific diagnostic test for PE when properly performed, and is complimented and enhanced by use of prior V-P findings; although it is clear that too few CPAs are being performed. Consequently, there has been too much clinical dependence on V-P imaging. The value of prospective clinical probability estimates in patient management has been better substantiated. Reemphasis on thromboembolism as a systemic disease with use of some objective evaluation of the presence of peripheral thrombosis is becoming a part of clinical rationale, with the integrated long-leg radionuclide venograms (RNV) being one of the reasonable approaches. Multicenter studies have demonstrated, contrary to prior contentions, that V-P imaging leads to a significant net reduction and use of anticoagulants, as well as having overall significant efficacy in effecting patient management in suspected PE. Some of the controversies surrounding V-P imaging are expected to be resolved with the completion of the ongoing multiinstitute Prospective Investigation of Pulmonary Embolic Diagnosis (PIOPED) study.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of metallic osseous implants with nuclear medicine.

Nuclear medicine has proven to have a valuable role in the evaluation of osseous metallic implants, particularly with joint prostheses, but can assist with evaluation of other appliances as well. The nuclear arthrogram has become an invaluable adjunct to simultaneously performed radiographic contrast arthrography. This application has been best evaluated in what is one of the most common of orthopedic prosthesis problems, namely, loosening of total hip prostheses. Experience indicates that both sensitivity and specificity of loosening of the femoral component can be increased to over 90% through combined use of nuclear with radiographic contrast arthrography. Furthermore the combination of routine skeletal scintimaging with the nuclear arthrogram adds a significant dimension to precise localizing of the nuclear arthrographics agent In-111 chloride. Nuclear medicine also plays an important role in further evaluating the presence of infection associated with metallic implants with In-111 WBC preparations being superior to Ga-67 as the radiopharmaceutical tracer. Infection has been detected with a sensitivity of 73% and a specificity of 93% in our series using combined In-111 WBC and simultaneous skeletal imaging with conventional Tc-99m MDP. Acute infections are more readily identifiable than chronic in association with prostheses.