Hybrid MR-PET of brain tumours using amino acid PET and chemical exchange saturation transfer MRI.

PURPOSE: PET using radiolabelled amino acids has become a promising tool in the diagnostics of gliomas and brain metastasis. Current research is focused on the evaluation of amide proton transfer (APT) chemical exchange saturation transfer (CEST) MR imaging for brain tumour imaging. In this hybrid MR-PET study, brain tumours were compared using 3D data derived from APT-CEST MRI and amino acid PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). METHODS: Eight patients with gliomas were investigated simultaneously with 18F-FET PET and APT-CEST MRI using a 3-T MR-BrainPET scanner. CEST imaging was based on a steady-state approach using a B1 average power of 1µT. B0 field inhomogeneities were corrected a Prametric images of magnetisation transfer ratio asymmetry (MTRasym) and differences to the extrapolated semi-solid magnetisation transfer reference method, APT# and nuclear Overhauser effect (NOE#), were calculated. Statistical analysis of the tumour-to-brain ratio of the CEST data was performed against PET data using the non-parametric Wilcoxon test. RESULTS: A tumour-to-brain ratio derived from APT# and 18F-FET presented no significant differences, and no correlation was found between APT# and 18F-FET PET data. The distance between local hot spot APT# and 18F-FET were different (average 20 ± 13 mm, range 4-45 mm). CONCLUSION: For the first time, CEST images were compared with 18F-FET in a simultaneous MR-PET measurement. Imaging findings derived from18F-FET PET and APT CEST MRI seem to provide different biological information. The validation of these imaging findings by histological confirmation is necessary, ideally using stereotactic biopsy.

Integrated boost IMRT with FET-PET-adapted local dose escalation in glioblastomas. Results of a prospective phase II study.

PURPOSE: Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [(18)F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue. METHODS AND MATERIALS: In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET((72 Gy)) and PTV-MR((60 Gy)). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores. RESULTS: Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR((60 Gy)). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires. CONCLUSION: Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies.

[Use of amino acid PET in the Diagnostic and Treatment Management of cerebral gliomas]. / Anwendung der Aminosäure-PET in der Diagnostik und Therapie von zerebralen Gliomen.

Structural as well as functional imaging methods are of special importance in neurooncology. Improvements of radionuclide and magnetic resonance-based imaging modalities over the past decade have enabled clinicians to non-invasively assess the dynamics of disease-specific processes at the molecular level in patients with malignant gliomas. To date, a range of complementary imaging parameters have been established in the diagnostic work-up of patients with brain tumours. Magnetic resonance imaging (MRI) provides morphological information as well as functional information such as vascular permeability, cell density, tumour perfusion, and metabolic information by using magnetic resonance spectroscopy. The use of radiolabelled amino acids for positron emission tomography (PET) allows a better delineation of tumour margins and improves targeting of biopsy and radiotherapy, and planning surgery. In addition, amino acid imaging appears useful in distinguishing tumour recurrence from non-specific post-therapeutic scar tissue, in predicting prognosis in low-grade gliomas, and in monitoring metabolic response during treatment. Taken together, MRI and PET provide complementary information about tumour biology and activity, thereby resulting in an improved understanding of the kinetics of tumour growth and therefore allow new insights into the pathophysiology of malignant brain tumours. However, multimodal imaging studies comparing the value of amino acid PET and functional methods of MRI (e. g., perfusion and diffusion weighted imaging) are needed. From these studies, surrogate MRI and PET imaging techniques need to be derived to gain complementary structural and functional information of brain tumours that can be placed into common clinical practice which will optimise the clinical management of patients with malignant gliomas.

[Diagnostic work-up in Whipple's disease with cerebral involvement]. / Zerebraler Morbus Whipple: Welche Diagnostik ist Sinnvoll?

The diagnostic work-up in the case of a suspected cerebral involvement of Whipple's disease involves neuroimaging and analysis of cerebrospinal fluid (CSF) including polymerase chain reaction (PCR) assays for Tropheryma whipplei. As neurological findings may be complex and unspecific, extracerebral symptoms often lead to the suspicion of Whipple's disease. We report the cases of two patients in whom the suspected diagnosis of Whipple's disease could not be proved either by endoscopy or by the analysis of CSF. Only by means of a cerebral biopsy was the diagnosis assumed and specific therapy was initiated.

[Variety of symptoms after drug use of gamma-hydroxybutyric acid (GHB)]. / Symptomvielfalt nach Konsum der Droge Gamma-Hydroxybuttersäure (GHB).

Gamma-hydroxybutyric acid (GHB, "liquid ecstasy") and its legal prodrugs gamma-butyrolactone and 1,4-butanediol are gaining importance as recreational drugs in Germany. Because of the wide availability of GHB and its prodrugs physicians are increasingly being confronted with cases of intoxication. The effect of GHB intoxication is comparable with those of alcohol and/or benzodiazepines. Likewise, symptoms of withdrawal may occur. In this review, we summarise current data regarding the history, pharmacodynamics and pharmacokinetics of the drug as well as the relevant symptoms of intoxication or withdrawal as they pertain to neurology and psychiatry.

[Brain metastases-Interdisciplinary approach towards a personalized treatment]. / Hirnmetastasen ­ interdisziplinär zu einer personalisierten Behandlung.

The incidence, treatment and prognosis of patients with brain metastases have substantially changed during the last decades. While the survival time after diagnosis of cerebral metastases was on average a maximum of 3-6 months only 10 years ago, the survival time could be significantly improved due to novel surgical, radiotherapeutic and systemic treatment modalities. Only a few years ago, the occurrence of brain metastases led to a withdrawal from systemic oncological treatment and the exclusion of drug therapy studies and to a purely palliatively oriented treatment in the sense of whole brain radiation therapy (WBRT) with or without surgery. The increasing availability of targeted and immunomodulatory drugs as well as adapted radio-oncological procedures enable increasingly more personalized treatment approaches. The aim of this review article is to demonstrate the progress and complexity of the treatment of brain metastases in the context of modern comprehensive interdisciplinary concepts.

Systemic thrombolysis with rt-PA in patients under 40 years of age: a subgroup analysis of the Cologne Stroke Experience.

BACKGROUND: While the application of intravenous systemic thrombolysis (IVT) with rt-PA (recombinant tissue plasminogen activator) in older patients is currently moving into the focus of epidemiological studies, only few data are available regarding the application in young patients ≤40 years. Single-center data of a thrombolysis register were analyzed with respect to safety and efficacy of the treatment of young patients. METHODS: In a retrospective subgroup analysis of 450 patients treated by IVT within a 3-hour time window, patients ≤40 years were identified (n = 20). Clinical data [age, pretherapeutic stroke severity (National Institute of Health Stroke Scale, NIHSS), OTT (onset to-treatment time), rt-PA-dose, DNT (door[-]to[-]needle time), rate of symptomatic intracranial hemorrhages] and medical history were determined. The clinical outcome was assessed by the mRS (modified Rankin Scale). The results were compared to those of patients >40 years (n = 430). RESULTS: Twenty patients ≤40 years (mean age 32 years) out of 450 patients (4%) were treated by IVT. The percentage of predisposing diseases and vascular risk factors was significantly lower when compared to patients >40 years (p < 0.05). In contrast, the percentage of smokers was significantly higher (55 vs. 24%; p < 0.05). In comparison to patients >40 years, OTT, DNT and NIHSS at admission were not significantly different. After 3 months, 11 of 20 young patients (55%) showed a favorable outcome (mRS 0-1) and 80% were functionally independent (mRS 0-2). In the group of patients >40 years (n = 430), the respective percentages were significantly lower [p < 0.05; 34% (mRS 0-1) and 52% (mRS 0-2), respectively]. Symptomatic intracranial hemorrhages were not observed (in patients >40 years: 4%, p < 0.05). CONCLUSIONS: In comparison to the cohort of patients >40 years, IVT in young patients is safe and leads to a significantly better outcome after 3 months. Our data therefore encourage the use of IVT in young patients.

A giant bilateral calcified chronic subdural hematoma.

BACKGROUND: A calcified chronic subdural hematoma is a rare disease and its neuroradiological presentation is variable. The degree of calcification extends from thin calcified inner membranes to dense calcification and even ossification of the hematoma. Previous reports described a maximum of two hematoma cavities with calcified inner hematoma membranes. METHODS: Neuroimaging report with illustrative computerized tomography images. RESULTS: A patient with a bilateral symptomatic calcified chronic subdural hematoma, or so-called "armoured brain", was admitted to our intensive care unit with clinical signs of increased intracranial pressure. Computerized cranial tomography demonstrated multiple bilaterally located hematoma cavities with thin calcified inner membranes. After neurosurgical intervention by bilateral burr hole trepanation, clinical symptoms improved. CONCLUSIONS: Our case of a calcified chronic subdural hematoma presents with an uncommon imaging pattern with more than four hematoma cavities bounded by predominantly convex- and concave-configured thin calcified inner membranes.

Imaging biological activity of a glioblastoma treated with an individual patient-tailored, experimental therapy regimen.

PURPOSE: To monitor the metabolic effects of an individual patient-tailored, experimental glioma therapy regimen that included repetitive multiple neurosurgical resections, radiosurgical interventions, and an adjuvant maintenance therapy based on the tyrosine kinase inhibitor imatinib in combination with the chemotherapeutic agent hydroxyurea (HU). PROCEDURES: Therapeutic effects were monitored in a 26-year-old male patient with a glioblastoma multiforme by multimodal imaging using sequential L: -[methyl-(11)C]-methionine positron emission tomography (MET-PET) and MRI. The normalized MET uptake and volume of the metabolically active tumor were assessed sequentially. RESULTS: The individual patient-tailored, experimental glioma therapy caused a continuous decline of metabolically active tumor volume, associated with clinical remission over a period of more than two years. CONCLUSIONS: MET-PET seems to be useful for monitoring patient-tailored, experimental glioma therapy regimens, especially when patients are treated with a multi-step therapeutic regimen. Monitoring and guidance of those experimental therapy regimens by MET-PET in a larger patient group are needed to confirm its clinical value.

Selective immune adsorption treatment of severe Guillain Barré syndrome in the intensive care unit.

BACKGROUND: The effectiveness of plasma exchange and intravenous application of immunoglobulins (IVIG) for the treatment of the Guillain Barré syndrome (GBS) has been demonstrated in large collectives. In contrast, there are only a few investigations in GBS patients with severe symptoms admitted to the intensive care unit (ICU) and treated with selective immune adsorption (SIA). We compared the efficacy and safety of SIA only versus SIA followed by IVIG in patients with severe GBS. METHODS: Patients with severe GBS admitted to the ICU were treated with SIA only or in combination with IVIG. Severity of symptoms was assessed using Hughes grades and severe GBS was defined as ≥ 3. Data were acquired retrospectively for the last 10 years (1998-2008). RESULTS: Data from 30 GBS patients (age 53 ± 16 years) with severe symptoms (Hughes grade 5: 30% [n = 9], grade 4: 57% [n = 17], grade 3: 13% [n = 4]) were analyzed. The mean Hughes grade at admission was 4.2 ± 0.7. Ten patients were treated by SIA only, 20 patients were treated sequentially with SIA followed by IVIG (30 g/d) over 3 days. The number of SIA sessions was 3.2 ± 0.8. Improvement of Hughes grade 4.2 ± 0.7 to 3.4 ± 0.9 (P < 0.001) occurred within 14.6 ± 15.5 days. Treatment with SIA only was as effective as the sequential therapy with IVIG. The Hughes grade decreased significantly in the group of patients where SIA was performed only (P = 0.008) and in the sequential treatment group (P < 0.001), respectively. In one patient SIA had to be terminated after one session due to ICU complications. Other severe side effects were not observed. CONCLUSIONS: In severely affected GBS patients admitted to ICU treatment with SIA seems to be safe and effective. In comparison to treatment with SIA only, sequential therapy with IVIG was not more effective.

Applications of PET imaging of neurological tumors with radiolabeled amino acids.

Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced magnetic resonance imaging (MRI). However, the capacity of structural MRI to differentiate neoplastic tissue from non-specific treatment changes may be limited especially after therapeutic interventions such as neurosurgical resection, radio- and chemotherapy. Metabolic imaging using PET may provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. In contrast to the widely used ¹8F-2-fluoro-2-deoxy-D-glucose, which exhibits a poor tumor-to-background contrast within the brain, amino acid tracers provide high sensitivity to detect primary tumors, recurrent or residual gliomas, including most low-grade gliomas. The method improves targeting of biopsy and provides additional information of tumor extent, which is helpful for planning neurosurgery and radiotherapy. In the further course of the disease, amino acid positron-emission tomography (PET) allows a sensitive monitoring of treatment response, the early detection of tumor recurrence, and an improved differentiation of tumor recurrence from treatment-related changes. In the past, the method had only limited availability due to the use of radiopharmaceuticals with a short half-life. In recent years, however, novel amino acid tracers labeled with positron emitters with a longer half-life have been developed and clinically validated which allow a more efficient and cost-effective application. These developments and the well-documented diagnostic performance of PET using radiolabeled amino acids suggest that its application continues to spread and that the method may be available as a routine diagnostic technique for certain indications in the near future.

Novel neuroimaging findings in a patient with cerebral Whipple's disease: a magnetic resonance imaging and positron emission tomography study.

The authors report a 43-year-old patient with histopathologically proven cerebral Whipple's disease. Magnetic resonance imaging (MRI) revealed a multilayered left frontal lesion without mass effect, no perifocal brain edema, no contrast enhancement, and a thin shell of fluid signal that presented as an incomplete, open ring. An [11C]methionine positron emission tomography (PET) study showed low uptake below the threshold that is characteristic for brain tumors. In precise co-registration to the MR images, the PET data showed that increased uptake was mainly located in the direct adjacent part of the MRI lesion. The fluid signal on MRI corresponded to the extensive outflow of fluid from the lesion, which was observed during neurosurgical resection, and also to the neuropathological findings. The authors conclude that this cerebral manifestation of Whipple's disease made a unique and hitherto undescribed appearance on MRI; uptake pattern of PET amino acid tracer may help in the preoperative distinction of inflammatory from neoplastic lesions.

Long-term outcome in patients with Guillain-Barré syndrome requiring mechanical ventilation.

We aimed to determine long-term disability and quality of life in patients with Guillain-Barré syndrome (GBS) who required mechanical ventilation (MV) in the acute phase. Our retrospective cohort study included 110 GBS patients admitted to an intensive care unit and requiring MV (01/1999-08/2010) in nine German tertiary academic medical centers. Outcome was determined 1 year or longer after hospital admission using the GBS disability scale, Barthel index (BI), EuroQuol-5D (EQ-5D) and Fatigue Severity Scale. Linear/multivariate regression analysis was used to analyze predicting factors for outcome. Mean time to follow up was 52.6 months. Hospital mortality was 5.5 % and long-term mortality 13.6 %. Overall 53.8 % had a favorable outcome (GBS disability score 0-1) and 73.7 % of survivors had no or mild disability (BI 90-100). In the five dimensions of the EQ-5D "mobility", "self-care", "usual activities", "pain" and "anxiety/depression" no impairments were stated by 50.6, 58.4, 36.4, 36.4 and 50.6 % of patients, respectively. A severe fatigue syndrome was present in 30.4 % of patients. Outcome was statistically significantly correlated with age, type of therapy and number of immunoglobulin courses. In GBS-patients requiring MV in the acute phase in-hospital, and long-term mortality are lower than that in previous studies, while long-term quality of life is compromised in a large fraction of patients, foremost by immobility and chronic pain. Efforts towards improved treatment approaches should address autonomic dysfunction to further reduce hospital mortality while improved rehabilitation concepts might ameliorate long-term disability.

Deep brain stimulation of the subthalamic nucleus reversibly deteriorates stuttering in advanced Parkinson's disease.

The etiology of developmental stuttering is still unknown. In some patients, stuttering re-emerges or is aggravated with the onset of Parkinson's disease (PD). We here report on a patient with PD treated by deep brain stimulation of the subthalamic nucleus and severe deterioration of stuttering under effective stimulation. Positron emission tomography (PET) of regional cerebral blood flow (rCBF) in stimulation on- and off-conditions showed overactivation of cerebral and cerebellar motor systems during speech activation and was in line with recent PET studies investigating brain activation during stuttering. The abnormal rCBF pattern increased in the stimulation on-condition and was associated with a marked worsening of stuttering. Clinical and imaging findings in this patient support the hypothesis that the basal ganglia circuitry plays an important role in the pathophysiology of stuttering.

[Complications and diagnostic limitations of chronic meningitis]. / Komplikationen und diagnostische Grenzen bei chronischer Meningitis. Eine Kasuistik.

HISTORY AND ADMISSION FINDINGS: A 37-year-old woman was admitted with total loss of vision of the left eye within 24 hours. Additionally, she complained about fatigue, headache, chills, fever, muscle pain and neck stiffness since 4 days. At admission, the body temperature was 38.7 degrees C. Neurological examination revealed papilledema and meningism. INVESTIGATIONS: Ophthalmologic findings were consistent with a papillitis. The vision was lost, the pattern-shift checkerboard visual evoked potentials were not measurable. MRI of the brain and the optical nerve was without pathological findings, meningeal or cerebral Gadolinium enhancement was not present. The CSF analysis yielded a lymphocytic meningitis with 249 cells/mm (3), the glucose ratio of cerebrospinal fluid and serum was normal. DIAGNOSIS, TREATMENT AND COURSE: The papillitis was treated unsuccessfully with high-dose methylprednisolone, the left eye remained blind. Persistence of the pleocytosis under initial treatment with aciclovir and ceftriaxone, reduction of the glucose ratio of cerebrospinal fluid and serum and intrathecal immunoglobuline A -- synthesis required a change of the diagnostic and therapeutic regimen. Various common and rare differential diagnoses were considered and ruled out, a chronic meningitis of unclear aetiology with the complication of amaurosis was diagnosed. In consideration of the most probable diagnosis, a tuberculostatic therapy was initiated. A prolonged reduction of the pleocytosis and normalization of cerebrospinal fluid parameters could be observed. CONCLUSIONS: A large number of aetiologies can cause chronic meningitis; this case report reviews the most important differential diagnoses and highlights the limitations of the diagnostic work-up although various methods are available. Clinical course and symptoms of chronic meningitis are mild to moderate and may even be absent, but it can cause severe complications.

PET-based molecular imaging in neuroscience.

Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1-2 mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and "phenotyping" of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.