FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes.

To determine the usefulness of [18F]fluorodeoxyglucose (FDG) whole body FDG-PET in the diagnosis of tumours in patients with paraneoplastic neurological syndromes (PNS), we prospectively studied 20 patients with paraneoplastic antibodies in whom conventional imaging gave negative or inconclusive results for the presence of tumour. All 20 patients had neurological manifestations compatible with PNS and well-characterized paraneoplastic antibodies (12 anti-Hu, one anti-Hu and anti-CV2, one anti-CV2, four anti-Yo, one anti-Ri and one anti-amphiphysin). The mean delay between the onset of neurological symptoms and FDG-PET was 10 months (range 1-54). In these 20 patients, abnormal uptake was demonstrated in 18 patients, with some patients having abnormal signal in several areas. We observed abnormal uptake in the mediastinum (13 cases), lung (two cases), breast (two cases), parotid gland (one case), or the cervical, supraclavicular or axillary lymph nodes (seven cases). Following FDG-PET, the histological diagnosis of the tumour was made in 14 patients (small cell lung carcinoma in eight cases, breast adenocarcinoma in two, lung adenocarcinoma in two, axillary metastasis of ovary carcinoma in one, and malignant thymoma in one). Two other patients with abnormal FDG uptake showed radiological evidence of lung cancer, but a histological diagnosis could not be obtained. In two other patients, initial FDG-PET showed abnormal FDG uptake that was not confirmed a few months later by repeat FDG-PET. In the two patients with negative FDG-PET, peritoneal carcinomatosis was diagnosed in one and no tumour was found in the other. In our series, the sensitivity of FDG-PET for tumour detection was >83% demonstrating a clear role of this technique in the management of patients with PNS. However, in our series, the specificity of FDG uptake was only 25% due to unexplained abnormal FDG uptake in three patients and in abnormal FDG uptake due to a benign tumour in one patient. Over the study period, we saw 73 other patients with PNS and paraneoplastic antibodies. A tumour was demonstrated in 71 out of 73 by conventional techniques. Since false-positive and false-negative results are possible with FDG-PET and in most patients with PNS, the tumour is demonstrated by conventional techniques, we believe that FDG-PET should be reserved, at the moment, for patients with well-defined PNS antibodies when conventional imaging fails to identify a tumour or when lesions are difficult to biopsy.

Electrical stimulation of precentral cortical area in the treatment of central pain: electrophysiological and PET study.

The clinical, electrophysiological and haemodynamic effects of precentral gyrus stimulation (PGS) as a treatment of refractory post-stroke pain were studied in 2 patients. The first patient had a right hemibody pain secondary to a left parietal infarct sparing the thalamus, while the second patient had left lower limb pain developed after a right mesencephalic infarct. In both cases, spontaneous pain was associated with hyperpathia, allodynia and hypoaesthesia in the painful territory involving both lemniscal and extra-lemniscal sensory modalities in patient 1, extra-lemniscal sensory modality only in patient 2. Both patients were treated with electrical PGS by means of a 4-pole electrode, the central sulcus being per-operatively located using the phase-reversal of the N20 wave of somatosensory evoked potentials. No sensory side effect, abnormal movement or epileptic seizure were observed during PGS. The analgesic effects were somatotopically distributed according to the localization of electrode on motor cortex. A satisfactory long-lasting pain control (60-70% on visual analog scale) as well as attenuation of nociceptive reflexes were obtained during PGS in the first patient. Pain relief was less marked and only transient (2 months) in patient 2, in spite of a similar operative procedure. In this patient, in whom PGS eventually evoked painful dysethesiae, no attenuation of nociceptive RIII reflex could be evidenced during PGS. Cerebral blood flow (CBF) was studied using emission tomography (PET) with O-labeled water. The sites of CBF increase during PGS were the same in both patients, namely the thalamus ipsilateral to PGS, cingulate gyrus, orbito-frontal cortex and brainstem. CBF increase in brainstem structures was greater and lasted longer in patient 1 while patient 2 showed a greater CBF increase in orbito-frontal and cingular regions. Our results suggest that PGS-induced analgesia is somatotopically mediated and does not require the integrity of somatosensory cortex and lemniscal system. PGS analgesic efficacy may be mainly related to increased synaptic activity in the thalamus and brainstem while changes in cingulate gyrus and orbito-frontal cortex may be rather related to attentional and/or emotional processes. The inhibitory control on pain would involve thalamic and/or brainstem relays on descending pathways down to the spinal cord segments, leading to a depression of nociceptive reflexes. Painful dysesthesiae during stimulation have to be distinguished from other innocuous sensory side effects, since they may compromise PGS efficacy.

Diagnostic value of image processing in myocardial scintigraphy.

The diagnostic value of stress myocardial analog scintigrams, and of five image-processing methods, was assessed by a decisional analysis in 96 patients undergoing coronary arteriography. The methods involved digitalization, nine-point binomial smoothing, background subtraction by linear interpolation, stationary filtering, and a combination of them. The difference between after-test probabilities of having the disease with a positive or a negative examination provided a discriminant index for different prevalences of the disease. Though the processing methods failed to improve the detection of a circumflex stenosis, the stationary filter significantly increased the diagnostic value for the detection of stenosis in a left anterior descending artery for a large range of prevalence, and in a right coronary artery at high prevalence. Thus, the filter seemed to provide a useful tool for enhancing the diagnostic value of myocardial scintigraphy.

Exercise increases the lung clearance of inhaled technetium-99m DTPA.

The regional lung clearance of a deposited aerosol of [99mTc] diethylenetriaminepentaacetic acid was successively computed at rest and at exercise in seven nonsmoking volunteers in upright posture. The subjects were seated on a bicycle with their backs against a gamma camera. At rest there was a gradient of clearance from the apex to the base of the lung, the apical clearance being significantly higher. At exercise this regional gradient was enhanced by a large and significant increase of the apical clearances (3.40 +/- 0.63% min-1 s.d. compared with 1.82 +/- 0.75% min-1 s.d. at rest, n = 7, p less than 0.01). By contrast the changes of the basal clearances were slight and unsignificant (1.46 +/- 0.71% min-1 s.d. compared with 1.40 +/- 0.82% min-1 s.d.). This increase of the apical lung clearance could be attributed primarily to the increase of apical blood flow induced by exercise and to the subsequent increase of the permeability surface area product.

Parameter and index images of benzodiazepine receptor concentration in the brain.

UNLABELLED: In vivo studies of ligand-receptor interactions with PET data are based on different approaches that provide either quantitative results (receptor density and affinity) or indices that are assumed to be correlated with the receptor concentration. The aims of this study are to obtain parametric images of benzodiazepine receptor concentration and of flumazenil affinity and to study the validity of two receptor concentration indexes. METHODS: A three-compartment ligand-receptor model, [11C]flumazenil, and experimental data obtained using a three-injection protocol in human volunteers were used to acquire parametric images. The delayed activity method and the apparent distribution volume (estimated using a two-compartment model) were also tested and their results compared with those of the multi-injection approach. RESULTS: Parametric images of receptor density, affinity and all kinetic parameters were obtained with acceptable variation coefficients. A correlation between receptor density and apparent affinity was found (r = 0.83; p < 0.0005). The correlation between receptor concentration and apparent distribution volume (estimated with three- and two-compartment models, respectively) was accessed using both a linear (the usual hypothesis) and a nonlinear correlation derived from the relationship between the receptor density and the affinity. CONCLUSION: In spite of the complexity of this protocol (three injections, a 2-hr experiment, blood sampling and a metabolite study), we showed that the multi-injection approach is suitable for parametric brain imaging. By using this approach as a reference, we deduced that the distribution volume and delayed activity images are valid methods in the usual range of the benzodiazepine receptor concentrations found in the human brain.

Computation of ventilation-perfusion ratio with Kr-81m in pulmonary embolism.

Diagnostic difficulties occur in pulmonary embolism (PE) during visual analysis of ventilation-perfusion images in matched defects or in chronic obstructive lung disease (COPD). In 44 patients with angiographically confirmed PE and in 40 patients with COPD, the regional ventilation-perfusion ratios (V/Q) were therefore computed using krypton-81m for each perfusion defect, and were displayed in a functional image. In patients with PE and mismatched defects, a high V/Q (1.96) was observed. A V/Q greater than 1.25 was also found in nine of 11 patients having PE and indeterminate studies (studies with perfusion abnormalities matched by radiographic abnormalities). COPD was characterized by matched defects and low V/Q. The percentage of patients correctly classified as having PE or COPD increased from 56% when considering the match or mismatched character to 88% when based on a V/Q of 1.25 in the region of the perfusion defect. This quantitative analysis, therefore, seems useful in classifying patients with scintigraphic suspicion of PE.

Regional distribution of ventilation-perfusion ratios in acute pulmonary embolism.

Regional ventilation perfusion ratios have been computed in 44 patients with acute pulmonary embolism with a gamma-camera using Krypton 81m, a short-life radionuclide delivered by inhalation and infusion. This noninvasive technique is performed during tidal breathing and can be easily repeated. High V/Q's are detected in the embolic regions and low V/Q's in the nonembolic regions with a shift of the perfusion distribution towards these low values. This pattern disappears with recovery. This technique can be used in clinical practice for diagnostic purposes.

Interpretation of the krypton-81m dynamic series: the distribution of a tidal breath.

Lung scans during cyclic breathing of krypton-81m, an isotope with a 13-s half-life, were acquired in "list mode," where both temporal and spatial information are preserved. Subjects in the left lateral decubitus position breathed with two tidal volumes at each of two frequencies. Profiles of total activity over the acquisition period were examined. They showed little effect of frequency or tidal volume on the distribution of air between dependent and non-dependent regions. Dynamic series for ensemble-averaged breaths were constructed. The regional flow per unit volume was shown to correspond to the time derivative of the regional activity of the dynamic series divided by the corresponding activity. Both the relative timing of the gas flow to different lung regions and the flow per unit volume as a function of time were obtained from the dynamic series. The dependent lung was seen to be better ventilated throughout the respiratory cycle except for brief periods at the start of inspiration and the end of expiration. Most of the dead-space gas can be construed to enter and leave the dependent lung.

Hemodynamic, gas exchange, and hormonal consequences of LBPP during PEEP ventilation.

Hemodynamic, gas exchange, and hormonal response induced by application of a 25- to 40-mmHg lower body positive pressure (LBPP), during positive end-expiratory pressure (PEEP; 14 +/- 2.5 cmH2O) were studied in nine patients with acute respiratory failure. Compared with PEEP alone, LBPP increased cardiac index (CI) from 3.57 to 4.76 l X min-1 X m-2 (P less than 0.001) in relation to changes in right atrial pressure (RAP) (11 to 16 mmHg; P less than 0.01). Cardiopulmonary blood volume (CPBV) measured in five patients increased during LBPP from 546 +/- 126 to 664 +/- 150 ml (P less than 0.01), with a positive linear relationship between changes in RAP and CPBV (r = 0.88; P less than 0.001). Venous admixture (Qva/QT) decreased with PEEP from 24 to 16% (P less than 0.001) but did not change with LBPP despite the large increase in CI, leading to a marked O2 availability increase (P less than 0.001). Although PEEP induced a significant rise in plasma norepinephrine level (NE) (from 838 +/- 97 to 1008 +/- 139 pg/ml; P less than 0.05), NE was significantly decreased by LBPP to control level (from 1,008 +/- 139 to 794 +/- 124 pg/ml; P less than 0.003). Plasma epinephrine levels were not influenced by PEEP or LBPP. Changes of plasma renin activity (PRA) paralleled those of NE. No change in plasma arginine vasopressin (AVP) was recorded. We concluded that LBPP increases venous return and CPBV and counteracts hemodynamic effects of PEEP ventilation, without significant change in Qva/QT. Mechanical ventilation with PEEP stimulates sympathetic activity and PRA apparently by a reflex neuronal mechanism, at least partially inhibited by the loading of cardiopulmonary low-pressure reflex and high-pressure baroreflex. Finally, AVP does not appear to be involved in the acute cardiovascular adaptation to PEEP.

Paradoxical metabolic response of the human brain to a single electroconvulsive shock.

Regional brain protein synthesis was evaluated with positron emission tomography (PET) and L-(S-[11C]methyl)methionine ([11C]MET) in depressive patients, before and 3 h after an electroconvulsive shock (ECS), when energy supply is restored, and in healthy volunteers. Depressive patients presented apparent lower protein synthesis than normals, in agreement with known reduction of cerebral activity. In contrast, ECS resulted in a significant increase (56%, P < 0.05) in global cortical protein synthesis. This paradoxical hyperactivation of cellular protein metabolism in response to seizures and the fact that synaptic activity is further reduced after electroconvulsive therapy (ECT), may provide new insights for understanding the mechanism of action of ECT.

Slowly progressive anarthria with late anterior opercular syndrome: a variant form of frontal cortical atrophy syndromes.

We describe eight patients with slowly progressive speech production deficit combining speech apraxia, dysarthria, dysprosody and orofacial apraxia, and initially no other deficit in other language and non-language neuropsychological domains. Long-term follow-up (6-10 years) in 4 cases showed an evolution to muteness, bilateral suprabulbar paresis with automatic-voluntary dissociation and frontal lobe cognitive slowing without generalised intellectual deterioration. Most disabled patients presented with an anterior opercular syndrome (Foix-Chavany-Marie syndrome), and pyramidal or extrapyramidal signs. CT and MRI findings disclosed asymmetric (left > right) progressive cortical atrophy of the frontal lobes predominating in the posterior inferior frontal region, notably the operculum. SPECT and PET revealed a decreased cerebral blood flow and metabolism, prominent in the left posterior-inferior frontal gyrus and premotor cortex, extending bilaterally in the most advanced cases. Pathological study of two cases showed non-specific neuronal loss, gliosis, and spongiosis of superficial cortical layers, mainly confined to the frontal lobes, with no significant abnormalities in the basal ganglia, thalamus, cerebellum, brain stem (except severe neuronal loss in the substantia nigra in one case), and spinal cord. We propose to call this peculiar syndrome Slowly Progressive Anarthria (SPA), based on its specific clinical presentation, and its metabolic and pathological correlates. SPA represents another clinical expression of focal cortical degeneration syndromes, that may overlap with other similar syndromes, specially primary progressive aphasia and the various frontal lobe dementias.

Assessment of cerebrovascular reactivity by dynamic susceptibility contrast-enhanced MR imaging.

In patients with cerebrovascular disease the acetazolamide (ACZ) test is performed to evaluate the decrease in cerebral perfusion pressure (CPP) through the investigation of the vasomotor reactivity (VMR). This latter is currently assessed with ACZ with several methods. Recently, magnetic resonance imaging (MRI) techniques have been developed that are sensitive to stimulus-induced changes in blood flow. Dynamic susceptibility contrast material-enhanced gradient-echo MRI techniques (DSC-MRI) might be an attractive tool to assess VMR. We aimed to test the ability of DSC-MRI in the assessment of VMR. Relative hemodynamic parameters rCBV, MTT, and rCBF were evaluated at baseline after the first injection of gadopentetate dimeglumine and 10 min after the intravenous administration of ACZ (1 g) with a second bolus of contrast agent. Assessment of hemodynamic parameters was performed over the whole hemisphere and also within regions of interest. The significances of the mean differences, before and after ACZ, were assessed with repeated-measures ANOVA with two within factors: laterality (right-left) and ACZ. DSC-MRI with ACZ test was performed in ten healthy controls (aged 51.4+/-16.2 years). The cerebral hemispheric ratio for the three parameters (cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF)) ranged between 1.01 and 1.03. The mean gray matter-to-white matter ratio for CBV, CBF and MTT were 2.44, 2.41 and 1.05, respectively. As the laterality effect was not significant, left and right hemispheric values were averaged. A significant increase of all hemodynamic parameters was observed after ACZ (P<0.01-0.001). The same changes for CBV, CBF and MTT were observed after ACZ according to the regions of interest (P<0.006-0.015). DSC-MRI is a non-invasive method which enables the assessment of VMR. This technique may be added to any conventional MRI in order to detect a hemodynamic impact of an ICA stenosis. Therefore, it might be useful in determining the appropriate management when the indication for surgical versus medical therapy is in question.

Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part I: Brain glucose metabolism is increased after GABAA receptors activation.

Though gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human central nervous system, the metabolic response to GABA system activation remains imperfectly known. We studied in vivo with positron emission tomography (PET) the variations of glucose metabolism in the human brain after stimulation of the GABAA receptors by systemic administration of the specific GABAA agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). These investigations were performed in three normal volunteers and as part of presurgical evaluation for temporal lobe epilepsy in six patients. While clinical and electroencephalographic (EEG) monitoring showed a sedative effect and sleepiness after THIP administration, glucose metabolism was paradoxically increased in grey matter structures, which are known to have a high density of GABAA receptors. These findings suggest that the pharmacological activation of GABA pathways, although inhibitory and producing a decrease of vigilance, increases the energetic demand at least during a phase of GABA agonist action, probably at the synaptic or at the glial cell level.

Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part II: The focal hypometabolism is reactive to GABAA agonist administration in TLE.

Positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) was used to study the metabolic response of focal hypometabolism to the administration of a specific GABAA agonist (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), THIP, in six temporal lobe epilepsy (TLE) patients. After THIP injection, the increase of glucose metabolism in the hypometabolic focus was larger than the mean increase reported in the whole brain (Part I; Epilepsy Res., 19 (1994) 45-54). Within the hypometabolic focus, this increase was significantly higher in regions with the lowest basal metabolic level. This metabolic response in the hypometabolic focus, observed in the absence of any epileptic discharge during FDG accumulation and PET data acquisition, suggests that GABAA receptors are up-regulated or, at least, preserved in TLE.

Processing of Xe-127 regional pulmonary ventilation by factor analysis and compartmental modeling.

A regional lung ventilation was modeled in five cases using Xe-127 during the first 3 min of wash-out. A factor analysis of the dynamic structures algorithm allowed estimation of the elementary kinetics and their respective proportions contained in time series images. Each factor was interpreted as the sampling of a compartment. It was associated to a factor image representing its spatial distribution and to a percentage of the total collected information. In the study, three factors were estimated: a fast clearance in the lower lung regions (28.9%), a slower clearance in the upper regions (33.4%), and a slow kinetics in blood and tissues containing dissolved xenon (37%). Estimates of the kinematics components obtained from a factor analysis of dynamic structures (FADSs) were used for compartmental analysis. The authors applied this method to the study of the regional ventilation distribution to establish the model and some possible variations. (FADSs) and region of interest results were used for modeling and compared.

Error analysis on parameter estimates in the ligand-receptor model: application to parameter imaging using PET data.

Positron emission tomography and compartmental models allow the in vivo analysis of radioligand binding to receptor sites in the human brain. Benzodiazepine receptor binding was studied using a three-compartmental model and [11C]flumazenil. Four and five parameters were estimated from a single kinetic curve obtained with a multi-injection protocol, and parametric maps of receptor density and of the individual kinetic parameters were created with four-pixel sampling of the experimental images. The coefficient of variation on each estimated model parameter was calculated using the diagonal elements of the covariance matrix. However, these estimates are valid only under some statistical hypotheses which are not always verified with PET data. Thus, in order to verify the validity of the coefficient of variation of each parameter calculated with the covariance matrix, these results have been compared with the more rigorous statistical results provided by a Monte Carlo simulation. The study showed a negligible difference between the results obtained by the two methods for a low noise level in time-concentration curves encountered using large ROIs. However, this bias becomes less negligible when the noise level is high and some estimations of the coefficients of variation were unacceptable (> 100%) with the five-parameter model. Such difficulties did not occur with the four-parameter model which led to parametric images with good quality and acceptable estimates of coefficients of variation (less than 20% in about 75% of the ROIs).

Auditory cortex activity changes in long-term sensorineural deprivation during crude cochlear electrical stimulation: evaluation by positron emission tomography.

We studied three right-handed human volunteers who have been prelingually deaf for 16 to 26 years. We measured cerebral regional activity (rA) using 15O labelled water and positron emission tomography (PET) during rest and during electrical cochlear stimulation of the right ear. The stimulus consisted of crude constant current squared pulses, it is currently employed in cochlear implant screening. Two subjects described a subjective auditory sensation under cochlear stimulation, the third did not. An increment of the rA (which is linked to the regional cerebral blood flow) in the auditory cortex was observed in all subjects, activation was ipsilateral to stimulation in one subject and contralateral in two subjects. These findings suggest 1) that auditory pathways to the cortex can remain functional a long time after prelinguistic auditory deprivation, 2) that the auditory cortex can be activated by a crude electrical stimulation of the cochlea in the absence of perception of the auditory stimulus, 3) that PET does not seem to offer any advantage for screening patients who have been prelingually deaf for a long time.

A controlled positron emission tomography study of obsessive and neutral auditory stimulation in obsessive-compulsive disorder with checking rituals.

Ten nondepressed patients with obsessive-compulsive disorder (OCD) who were characterized by predominant checking rituals were compared with 10 age- and sex-matched control subjects. Hemispheric and regional cerebral blood flow levels (rCBF) were measured with positron emission tomography (H2 15O) across four conditions: rest, auditory stimulation with idiosyncratic normal or abnormal obsession, auditory stimulation with neutral verbal stimuli, and rest. Order of neutral and obsessive stimulation was randomized. Higher subjective responses to obsessive than to neutral stimulation were found in both groups; subjective response was higher in OCD patients when obsessive stimulation was presented first. A four-way analysis of variance (group x stimulation order x hemisphere x condition [neutral or obsessive stimulation]) was performed on stimulation minus rest normalized rCBF values. Control subjects had significantly higher rCBF in the thalamus and putamen. A trend toward higher rCBF in OCD patients was found in the superior temporal regions. When neutral stimulation was presented first, rCBF was significantly higher in the caudate region of control subjects. Obsessive stimulation was associated with higher rCBF than neutral stimulation in orbitofrontal regions in both groups of subjects. Under obsessive stimulation, superior temporal and orbitofrontal activities were correlated in OCD patients but not in control subjects. Our study suggests specific abnormalities of information processing in the basal ganglia and temporal structures of compulsive checkers.

Measurement of lung volume with 81Krm in a dynamic scintigram.

The meaning of 81Krm counts obtained in a dynamic series of gated lung ventilation scans was evaluated in terms of flow rate, lung volume, or the flow/volume ratio. Flow and volume signals were recorded together with scintigraphic events in 29 subjects breathing 81Krm and after its decay, 127Xe as a tracer of lung volume. Gated ventilation scans and respiratory signals were reconstructed. Statistical analyses were carried out for linear regressions between total normalized counts detected by the gamma camera and (1) flow rate, (2) lung volume and (3) flow/volume ratio. Inspiration and expiration were analysed separately. For both isotopes, the best correlation was obtained between counts and lung volume (r greater than 0.93). No correlation was obtained between counts and flow rate or flow/volume ratio. Thus, we conclude that 81Krm count variations in gated scans correlate well with tidal volume.

Amines for brain tomoscintigraphy.

Amines like N-isopropyl-p-123I-iodoamphetamine (IMP) and hydroxy 123I-iodobenzyl propyl diamine (HIPDM) associated with brain tomoscintigraphy have proved their worth for detecting ischaemic abnormalities. Even though the chemistry of their metabolism and their biodistribution are not fully understood, their application in the study of parenchymal impairment in stroke and reversible ischaemia yields additional information compared to the other methods of imaging like CT or MRI. The concept of a steady state in brain with a wash in/wash out model has been considered especially with IMP, to explain the evolution of the activity pattern with time when comparing early and delayed images. (This review leads to foresee the prognosis of of ischaemic diseases when redistribution is taken into account.)