Frontoparietal 18F-FDG-PET hypo-metabolism in Lennox-Gastaut syndrome: Further evidence highlighting the key network.

INTRODUCTION: Lennox Gastaut syndrome (LGS) can be conceptualised as a "secondary network epilepsy", in which the shared electroclinical manifestations reflect epileptic recruitment of a common brain network, despite a range of underlying aetiologies. We aimed to identify the key networks recruited by the epileptic process of LGS using interictal 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (18F-FDG-PET). METHODS: Group analysis of cerebral 18F-FDG-PET, comparing 21 patients with LGS (mean age = 15 years) and 18 pseudo-controls (mean age = 19 years), studied at Austin Health Melbourne, between 2004 and 2015. To minimise the influence of individual patient lesions in the LGS group, we only studied brain hemispheres without structural MRI abnormalities. The pseudo-control group consisted of age- and sex-matched patients with unilateral temporal lobe epilepsy, using only the hemispheres contralateral to the side of epilepsy. Voxel-wise permutation testing compared 18F-FDG-PET uptake between groups. Associations were explored between areas of altered metabolism and clinical variables (age of seizure onset, proportion of life with epilepsy, and verbal/nonverbal ability). Penetrance maps were calculated to explore spatial consistency of altered metabolic patterns across individual patients with LGS. RESULTS: Although not always readily apparent on visual inspection of individual patient scans, group analysis revealed hypometabolism in a network of regions including prefrontal and premotor cortex, anterior and posterior cingulate, inferior parietal lobule, and precuneus (p < 0.05, corrected for family-wise error). These brain regions tended to show a greater reduction in metabolism in non-verbal compared to verbal LGS patients, although this difference was not statistically significant. No areas of hypermetabolism were detected on group analysis, although ∼25 % of individual patients showed increased metabolism (relative to pseudo-controls) in the brainstem, putamen, thalamus, cerebellum, and pericentral cortex. DISCUSSION: Interictal hypometabolism in frontoparietal cortex in LGS is compatible with our previous EEG-fMRI and SPECT studies showing that interictal bursts of generalised paroxysmal fast activity and tonic seizures recruit similar cortical regions. This study provides further evidence that these regions are central to the electroclinical expression of LGS.

Impact of 18F-FDG PET/CT on treatment of patients with differentiated thyroid carcinoma, negative 131I whole body scan and elevated serum thyroglobulin.

OBJECTIVES: 18F-FDG PET/CT is increasingly performed in patients with differen-tiated thyroid cancer. The aim of this study was to assess the clinical impact of 18F-FDG PET/CT on the management of patients with differentiated thyroid carcinoma who had elevated serum thyroglobulin (Tg) and negative 131I whole body scan (WBS). METHODS: 67 patients with differentiated thyroid carcinoma were included in this study. The findings of 18F-FDG PET/CT imaging were compared with histo-pathology, follow up imaging, or clinical follow-up results. The diagnostic accuracy of 18F-FDG PET/CT was evaluated for the entire patient group and for those patients with stimulated serum thyroglobulin levels of less than 5, 5-10, and more than 10 pmol/L as well as for local recurrences and metastases sites. The impact of 18F-FDG PET/CT on therapeutic management was also evaluated. RESULTS: 30/67 patients had positive findings on 18F-FDG PET/CT; 28 were true-positive and 2 were false-positive. 18F-FDG PET/CT results were true-negative in 36 patients and false-negative in 1 patient. The overall sensitivity, specificity, accuracy, PPV and NPV of 18F-FDG PET/CT were, 96.5%, 94.5%, 95.5%, 93.3%, and 97.2% respectively. Positive 18F-FDG PET/CT findings were directly correlated with stimulated serum thyroglobulin levels, 7.1% had Tg between 5-10, and 92.9% had Tg greater than 10 pmol/L. 18F-FDG PET/CT had a high or moderate impact on treatment management in 28 (41.8%) of patients. CONCLUSION: 18F-FDG PET/CT is able to improve diagnostic accuracy and have management impact in a therapeutically relevant way in patients with differentiated thyroid carcinoma who present with rising thyroglobulin level, negative 131I WBS, and clinical suspicion of recurrent disease.

Metabolic patterns and seizure outcomes following anterior temporal lobectomy.

OBJECTIVE: We investigated the relationship between the interictal metabolic patterns, the extent of resection of 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) hypometabolism, and seizure outcomes in patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection. METHODS: Eighty-two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant 18 FDG-PET hypometabolism, and at least 2 years of postoperative follow-up were included in this 2-center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre- and postoperative MRI scans coregistered with interictal 18 FDG-PET. RESULTS: Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). INTERPRETATION: The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1-10 ANN NEUROL 2019;85:241-250.

Generalized Lymph Node Activation after Influenza Vaccination on 18F FDG-PET/CT Imaging, an Important Pitfall in PET Interpretation.

We report on a 59-year-old female patient with an infected vascular graft investigated with 18F FDG-PET/CT. The first of two studies showed FDG activity in the left deltoid and ipsilateral axillary lymph nodes explained by influenza vaccination the day prior. The second 18F FDG-PET/CT showed multiple FDG-avid lymph nodes on both sides of the diaphragm without tracer accumulation at the vaccination site. Three months later the CT was negative for lymphadenopathy within the chest or abdominal region. Although influenza vaccination is a potential source of false positive results in FDG PET studies, generalised lymph node activation post vaccination is a rare finding with only one prior published report in individuals infected with HIV-1. This case emphasizes the necessity of taking a history of vaccination prior to a FDG PET study, and consideration of a vaccine-related immune response even without evidence of tracer activity at the vaccination site when generalised FDG-avid lymphadenopathy is encountered.

In vivo imaging of cellular proliferation in renal cell carcinoma using 18F-fluorothymidine PET.

OBJECTIVES: The ability to measure cellular proliferation non-invasively in renal cell carcinoma may allow prediction of tumour aggressiveness and response to therapy. The aim of this study was to evaluate the uptake of 18F-fluorothymidine (FLT) PET in renal cell carcinoma (RCC), and to compare this to 18F-fluorodeoxyglucose (FDG), and to an immunohistochemical measure of cellular proliferation (Ki-67). METHODS: Twenty seven patients (16 male, 11 females; age 42-77) with newly diagnosed renal cell carcinoma suitable for resection were prospectively enrolled. All patients had preoperative FLT and FDG PET scans. Visual identification of tumour using FLT PET compared to normal kidney was facilitated by the use of a pre-operative contrast enhanced CT scan. After surgery tumour was taken for histologic analysis and immunohistochemical staining by Ki-67. RESULTS: The SUVmax (maximum standardized uptake value) mean±SD for FLT in tumour was 2.59±1.27, compared to normal kidney (2.47±0.34). The mean SUVmax for FDG in tumour was similar to FLT (2.60±1.08). There was a significant correlation between FLT uptake and the immunohistochemical marker Ki-67 (r=0.72, P<0.0001) in RCC. Ki-67 proliferative index was mean ± SD of 13.3%±9.2 (range 2.2% - 36.3%). CONCLUSION: There is detectable uptake of FLT in primary renal cell carcinoma, which correlates with cellular proliferation as assessed by Ki-67 labelling index. This finding has relevance to the use of FLT PET in molecular imaging studies of renal cell carcinoma biology.

Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism.

BACKGROUND: Amyloid-beta (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD. METHODS: 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. (18)F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD. FINDINGS: (18)F-BAY94-9172 binding matched the reported post-mortem distribution of Abeta plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90-120 min after injection, higher neocortical SUVR was observed in AD patients (2.0 [SD 0.3]) than in healthy controls (1.3 [SD 0.2]; p<0.0001) or FTLD patients (1.2 [SD 0.2]; p=0.009). Visual interpretation was 100% sensitive and 90% specific for detection of AD. INTERPRETATION: (18)F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Abeta imaging into clinical practice.

Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies.

UNLABELLED: PET offers a noninvasive means to assess neoplasms, in view of its sensitivity and accuracy in staging tumors and potentially in monitoring treatment response. The aim of this study was to evaluate newly diagnosed primary brain tumors for the presence of hypoxia, as indicated by the uptake of 18F-fluoromisonidazole (18F-FMISO) and to examine the relationship of hypoxia to the uptake of 18F-FDG and molecular markers of hypoxia. METHODS: Seventeen patients with suspected primary glioma were enrolled prospectively in this study. Sixteen patients had histology, with 2 having metastatic disease. All patients had PET studies with 18F-FMISO and 18F-FDG and MRI studies. Immunohistochemistry was undertaken with tumor markers of angiogenesis and hypoxia. Patients were monitored for disease progression and statistical analysis of data was performed. RESULTS: Of the 14 patients with histology, 8 died with a median time of 16 mo (range, 2-30 mo) until death. Of those who died, 7 had positive and 1 had negative 18F-FMISO uptake. 18F-FMISO uptake was observed in all high-grade gliomas but not in low-grade gliomas. A significant relationship was found between 18F-FDG or 18F-FMISO uptake and expression of VEGF-R1 and Ki67 expression. Other immunohistochemical markers demonstrated a trend toward increased uptake but none was significant. CONCLUSION: 18F-FMISO PET provides a noninvasive assessment of hypoxia in glioma and was prognostic for treatment outcomes in the majority of patients. 18F-FMISO PET may have a role not only in directing patients toward targeted hypoxic therapies but also in monitoring response to such therapies.

Assessment of the role of FDG PET in the diagnosis and management of children with refractory epilepsy.

PURPOSE: We performed a retrospective analysis of the results of FDG PET scans in children with refractory epilepsy referred to our centre over an 8-year period, with a view to ascertaining the impact of FDG PET on subsequent patient management. METHODS: A questionnaire was used to assess the impact of FDG PET scan on diagnosis, management and clinical decision-making processes for epilepsy surgery from the managing clinician's perspective. FDG PET scan results were also compared with MRI, EEG and SPECT results and coded according to whether the FDG PET scan provided independent information and localisation of epileptogenic regions. RESULTS: A total of 118 eligible patients under the age of 14 years were identified, with questionnaires being completed on 113 evaluable patients (96%). The pre-PET management plan consisted of consideration for surgery in 92 patients (81%) and medical therapy for the remaining 21 patients (19%). Managing physicians rated FDG PET as providing information additional to that obtained with other investigations regarding epileptogenic sites in 88 patients (77%). FDG PET had either a minor or a major impact on clinical management in 58 patients (51%), principally with regard to surgical candidacy. CONCLUSION: FDG PET has a definite role in the assessment of paediatric patients with refractory epilepsy who are being considered for surgery. In the future, analysis of FDG PET data in specific subpopulations of children with refractory epilepsy may lead to novel insights regarding aetiology.

Impact of 2-deoxy-2[F-18]fluoro-D-glucose Positron Emission Tomography on the management of patients with advanced melanoma.

OBJECTIVES: Accurate staging of patients with melanoma is vital to guide appropriate treatment. 2-Deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has been reported to be a sensitive and specific technique for the staging of advanced melanoma, however, few studies provide information regarding its impact on patient management. METHODS: We retrospectively reviewed the FDG-PET scan results of 92 patients with melanoma who had 126 scans performed over a six-year period. These patients were seen at the specialist melanoma clinic at our Institution, and 84 patients (92%) had stage III or IV disease. FDG-PET scan results were correlated with computed tomography (CT) scans and other imaging when available, and with clinical follow-up of a minimum of three to six months. The impact of FDG-PET scans on patient management was also assessed. RESULTS: On a lesion-by-lesion analysis, FDG-PET had a sensitivity of 92%, a specificity of 88%, and an accuracy of 91%. FDG-PET correctly affected the clinical decision-making process in 40 of 126 patient studies (32%), particularly assisting in the selection of patients for surgery. CONCLUSION: FDG-PET has an important role in guiding the management of patients with advanced melanoma, particularly when surgery is contemplated.

Positron emission tomography with selected mediastinoscopy compared to routine mediastinoscopy offers cost and clinical outcome benefits for pre-operative staging of non-small cell lung cancer.

PURPOSE: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is an important staging procedure in patients with non-small cell lung cancer (NSCLC). We aimed to demonstrate, through a decision tree model and the incorporation of real costs of each component, that routine FDG-PET imaging as a prelude to curative surgery will reduce requirements for routine mediastinoscopy and overall hospital costs. METHODS: A decision tree model comparing routine whole-body FDG-PET imaging to routine staging mediastinoscopy was used, with baseline variables of sensitivity, specificity and prevalence of non-operable and metastatic disease obtained from institutional data and a literature review. Costings for hospital admissions for mediastinoscopy and thoracotomy of actual patients with NSCLC were determined. The overall and average cost of managing patients was then calculated over a range of FDG-PET costs to derive projected cost savings to the community. RESULTS: The prevalence of histologically proven mediastinal involvement in patients with NSCLC presenting for surgical assessment at our institution is 20%, and the prevalence of distant metastatic disease is 6%. Based on literature review, the pooled sensitivity and specificity of FDG-PET for detection of mediastinal spread are 84% and 89% respectively, and for mediastinoscopy, 81% and 100%. The average cost of mediastinoscopy for NSCLC in our institution is 4,160 AUD, while that of thoracotomy is 15,642 AUD. The cost of an FDG-PET scan is estimated to be 1,500 AUD. Using these figures and the decision tree model, the average cost saving is 2,128 AUDper patient. CONCLUSION: Routine FDG-PET scanning with selective mediastinoscopy will save 2,128 AUD per patient and will potentially reduce inappropriate surgery. These cost savings remain robust over a wide range of disease prevalence and FDG-PET costs.

Detection of occult bone metastases of lung cancer with fluorine-18 fluorodeoxyglucose positron emission tomography.

Accurate staging of cancer has a critical role in optimal patient management. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) is superior to CT in the detection of local and distant metastases in patients with non-small cell lung cancer. Although Tc-99 m methylene diphosphonate (MDP) bone scanning is well established in the evaluation of bone metastases, there are conflicting reports on the use of FDG PET in the evaluation of skeletal metastases. We report on a patient with locally advanced lung carcinoma in whom FDG PET accurately identified previously unsuspected widespread asymptomatic bone metastases (bone scan and X-rays negative, confirmed on MRI). Assessment of glucose metabolism with FDG PET might represent a more powerful tool to detect bone metastases in lung cancer compared with conventional bone scans.

Verbal memory in left temporal lobe epilepsy: evidence for task-related localization.

We explored the hypothesis that components of verbal memory are subserved by separate temporal lobe structures in patients with temporal lobe structures in patients with temporal lobe epilepsy [correction]. Uptake of 18F-fluorodeoxyglucose (FDG) measured by positron emission tomography, hippocampal volume, and memory for arbitrarily and semantically related verbal paired associates were examined in 27 patients with left temporary lobe epilepsy. Scores from memory tests performed outside the scanner were regressed against normalized resting FDG uptake at each voxel. Significant regression was seen in the left perirhinal cortex (Talaraich coordinates x, y, z: -29, 10, -34; p < 0.05) for arbitrarily related word pairs. For semantically related paired associates, significant regression was present in the left inferior temporal gyrus (x, y, z: -48, -18, -24; p < 0.05). In subsequent analyses, mean FDG uptake within a spherical region of interest centered on the perirhinal peak predicted performance on both tasks. Mean FDG uptake in a region of interest centered on the inferior temporal peak made an additional, independent contribution to memory for semantically related pairs. Hippocampal volumes did not explain any additional variance in memory scores. Our findings indicate that heterogeneity in the left temporal lobe structures mediating verbal memory function, and support the view that the perirhinal cortex is an important mnemonic substrate.

Positron emission tomography and epilepsy.

PURPOSE: This review examines the current role of positron emission tomography (PET) in the investigation and management of patients with epilepsy. PROCEDURES: A literature review utilizing MEDLINE(R) and other sources was undertaken. For the comparison of the accuracy of PET with magnetic resonance imaging (MRI) for seizure focus localization, only publications since 1994 were examined. Individual patient data was tabulated to provide figures for seizure focus localization rates for different types of focal epilepsy and the prognostic value of PET findings for epilepsy surgery outcome. RESULTS: The majority of PET studies used 2-deoxy-2-[18F]fluoro-D-glucose (FDG). The epileptogenic sites typically show reduced FDG uptake (hypometabolism). In patients with intractable temporal lobe epilepsy (TLE), unilateral temporal lobe hypometabolism (UTH) corresponding to the seizure focus was seen in 86% of patients. In the same population, MRI demonstrated relevant abnormalities in 76%. UTH contralateral to the seizure focus was rarely seen (3%). Following temporal lobectomy, 86% of patients with ipsilateral UTH had a good outcome. When MRI was normal, UTH predicted a good outcome in 82%. Fifty percent with bitemporal hypometabolism had independent bilateral foci, and in those who proceeded to surgery only 50% had a good result. In extratemporal epilepsy, hypometabolism relevant to the focus was seen in 67% but, as in TLE, it was often more extensive than pathological abnormality. Recently evidence of a role for 11C-Flumazenil has emerged with reduced binding in the primary epileptogenic site. 11C-Flumazenil abnormalities appear more restricted to abnormal cortex and may be a better guide to the extent of resection required for surgical success. CONCLUSIONS: FDG-PET has a key role in the evaluation of patients with intractable partial epilepsy, particularly when surgery is a treatment option. Development and application of more specific biochemical probes may further improve the clinical value of PET for the understanding and treatment of epilepsy.