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PURPOSE The aim of this study was to describe and analyze dosing patterns for patients with ITB treatment over time and to identify possible subgroups demonstrating diversity in patterns. DESIGN A retrospective design. METHODS For 81 patients from six different hospitals, baclofen doses from the first 2 years of treatment were identified using medical records. Line graphs of each patient's doses were analyzed and grouped based on similarities in dosing pattern. FINDINGS The analyses of the dosing patterns resulted in four different subgroups classified as stable, slow increase, rapid increase, and fluctuating. CONCLUSION The results highlight the clinical challenge of predicting dose development over time. CLINICAL RELEVANCE TO REHABILITATION NURSING This study provides rehabilitation healthcare professionals with a better understanding of intrathecal baclofen dose development. Illustrations of the four subgroups can be used as an educational tool for patients, family, and caregivers.

Objectives To describe the pharmacological treatments (2005-2017) and the healthcare utilization (1997-2016) for patients with narcolepsy in Sweden in order to create a framework for future organizational and economic analyses. Material & Methods Patients of all ages with a diagnosis of narcolepsy registered in the National Patient Registry in specialist care in Sweden were included and information on treatments for narcolepsy was retrieved from The Swedish Prescribed Drug Register. Results We collected 2508 patients with narcolepsy, 43,3% men and 56,7% women and 47,9% were prescribed modafenil, 33,8% metylphenidate and 26,2% amphetamine. In total, 3817 treatments were initiated. Patients treated with amphetamine had a higher mean age. More women than men used modafinil, methylphenidate, amphetamine and antidepressants. The narcolepsy population had more outpatient than inpatient healthcare. Patients treated with sodium oxybate had more outpatient visits than other narcolepsy patients, before and during treatment (p = .00). Conclusions This study gives valuable information on pharmaceutical treatments and healthcare utilization for patients with narcolepsy and can be used to estimate the healthcare cost in the future. Patients with sodium oxybate treatment had more outpatient visits than other patients before and during treatment which may be due to the need to monitor potentially severe side-effects or may indicate that patients with sodium oxybate treatment have a severe disease. The number of included patients was less than expected; however, this may depend on patients escaping our collection of data, which does not contain information from primary care. Funding Agencies|UCBUCB Pharma SA

The COVID‐19 pandemic has brought challenges for healthcare management of patients with multiple sclerosis (MS). Concerns regarding vulnerability to infections and disease‐modifying therapies (DMTs) and their complications have been raised. Recent published guidelines on the use of DMTs in relation to COVID‐19 in MS patients have been diverse between countries with lack of evidence‐based facts. In Sweden, there exists a particular interest in anti‐CD20 therapy as a possible risk factor for severe COVID‐19 due to the large number of rituximab‐treated patients off‐label in the country. Rapid responses from the Swedish MS Association (SMSS) and the Swedish MS registry (SMSreg) have resulted in national guidelines on DMT use for MS patients and implementation of a COVID‐19 module in the SMSreg. Recently updated guidelines also included recommendations on COVID‐19 vaccination with regard to the different DMTs. Social distancing policies forced implementation of telemedicine consultation to replace in‐person consultations as part of regular MS health care. Patient‐reported outcome measures (PROMs) in SMSreg have been useful in this respect. This paper reports our experiences on the progress of national MS health care during the COVID‐19 pandemic, in addition to offering an overview of the present scientific context.

PAX6 gene mutations cause a variety of eye and central nervous system (CNS) abnormalities. Aniridia is often accompanied by CNS abnormalities such as pineal gland atrophy or hypoplasia, leading to disturbed circadian rhythm and sleep disorders. Less is known on the coincidence of narcolepsy in this patient group. We aimed to find out whether the circadian rhythm or sleep-wake structure was affected in patients with aniridia. Four members of a family segregating with congenital aniridia in two generations were included in the study. The patients were subjected to genetic testing for a PAX6 mutation, multiple sleep latency test, whole-brain magnetic resonance imaging (MRI), hypocretin-1 in cerebrospinal fluid, and Human Leukocyte Antigen DQ beta1*06:02. All four members were heterozygous for the pathogenic c.959-1G>A mutation in the PAX6 gene. Sleep disturbance was observed in all family members. The index patient was diagnosed with narcolepsy. MRI showed a hypoplastic pineal gland in all members. We describe the first case of a patient with PAX6 haploinsufficiency, aniridia and pineal gland hypoplasia diagnosed with narcolepsy type-1, suggesting a complex sleep disorder pathogenesis.

Ecstatic seizures constitute a rare form of epilepsy, and the semiology is diverse. Previously, brain areas including the temporal lobe and the insula have been identified to be involved in clinical expression. The aim of this report is to review changes in ecstatic seizures in a patient before and after operation of a hypothalamic hamartoma, and to scrutinize the relation to gelastic seizures. In this case, the ecstatic seizures disappeared after surgery of the hamartoma but reappeared eleven years later. Clinical information was retrospectively obtained from medical records, interviews, and a questionnaire covering seizure semiology that pertained to ecstatic and gelastic seizures. Our findings imply a possible connection between gelastic and ecstatic seizures, originating from a hypothalamic hamartoma. To our knowledge, this location has not previously been described in ecstatic seizures. Gelastic seizures may in this case were associated with ecstatic seizures. We speclate patients with ecstatic seizures may have an ictal activation of neuronal networks that involves the insula. Our case may add information to the growing knowledge concerning ecstatic seizures., Highlights • Semiology of a seizure may be explained by the dynamic interaction of different areas. • There may be a connection between gelastic and ecstatic seizures. • Gelastic seizures may be a possible trigger of ecstatic seizures.

Purpose Oligodendrogliomas are heterogeneous tumors in terms of imaging appearance, and a deeper understanding of the histopathological tumor characteristics in correlation to imaging parameters is needed. We used PET-to-MRI-to-histology co-registration with the aim of studying intra-tumoral 11C-methionine (MET) uptake in relation to tumor perfusion and the protein expression of histological cell markers in corresponding areas. Methods Consecutive histological sections of four tumors covering the entire en bloc-removed tumor were immunostained with antibodies against IDH1-mutated protein (tumor cells), Ki67 (proliferating cells), and CD34 (blood vessels). Software was developed for anatomical landmarks-based co-registration of subsequent histological images, which were overlaid on corresponding MET PET scans and MRI perfusion maps. Regions of interest (ROIs) on PET were selected throughout the entire tumor volume, covering hot spot areas, areas adjacent to hot spots, and tumor borders with infiltrating zone. Tumor-to-normal tissue (T/N) ratios of MET uptake and mean relative cerebral blood volume (rCBV) were measured in the ROIs and protein expression of histological cell markers was quantified in corresponding regions. Statistical correlations were calculated between MET uptake, rCBV, and quantified protein expression. Results A total of 84 ROIs were selected in four oligodendrogliomas. A significant correlation (p

Background: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. Methods: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Results: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Conclusions: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor for developing glioma-related seizures or glioma.

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Background: Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. Objectives: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. Method: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient. Results: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment. Conclusions: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.

OBJECTIVES Off-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis. MATERIAL AND METHODS Review of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6 years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital. RESULTS Presently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%. CONCLUSIONS The share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly.

To investigate patient satisfaction with intrathecal baclofen treatment, complications from the treatment, and the impact of general expectations on treatment outcome in relation to satisfaction.A multicentre study with cross-sectional design. Data were collected through questionnaires and patient records. Patients were recruited from six outpatient intrathecal baclofen clinics in Sweden. Eighty-three patients who had been treated with intrathecal baclofen for 1-4 years were included. For patients unable to communicate, data were collected through a proxy. The Patient Global Impression of Change was used to measure patients' general satisfaction with change from intrathecal baclofen treatment. The Life Orientation Test - revised, was used to measure general expectations/optimism.General satisfaction with intrathecal baclofen treatment was high; 51/77 patients reported "much improved" or "very much improved." There was no relationship between the two main outcomes (general satisfaction and general expectations/optimism) (rMost patients/proxies reported a high level of satisfaction with intrathecal baclofen treatment. The reported satisfaction with intrathecal baclofen treatment was not dependent on general expectations. Implications for Rehabilitation Patients with intrathecal baclofen treatment report low levels of health and quality of life at the same time as they are highly satisfied with their treatment. Intrathecal baclofen should be equally offered to both optimistic and less optimistic patients. Patients who are able to/not able to communicate, differs in characteristics and should be informed and followed up in different ways in daily clinical practice.

Background Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas). Patients and methods Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student’s t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves. Results There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003−0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011−0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657−0.815. Conclusions Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

Perfusion magnetic resonance imaging (MRI) can be used in the pre-operative assessment of brain tumours. The aim of this prospective study was to identify the perfusion parameters from dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) perfusion imaging that could best discriminate between grade II and III gliomas. MRI (3 T) including morphological ((T2 fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W)+Gd)) and perfusion (DCE and DSC) sequences was performed in 39 patients with newly diagnosed suspected low-grade glioma after written informed consent in this review board-approved study. Regions of interests (ROIs) in tumour area were delineated on FLAIR images co-registered to DCE and DSC, respectively, in 25 patients with histopathological grade II (n = 18) and III (n = 7) gliomas. Statistical analysis of differences between grade II and grade III gliomas in histogram perfusion parameters was performed, and the areas under the curves (AUC) from the ROC analyses were evaluated. In DCE, the skewness of transfer constant (k trans) was found superior for differentiating grade II from grade III in all gliomas (AUC 0.76). In DSC, the standard deviation of relative cerebral blood flow (rCBF) was found superior for differentiating grade II from grade III gliomas (AUC 0.80). Histogram parameters from k trans (DCE) and rCBF (DSC) could most efficiently discriminate between grade II and grade III gliomas.

PURPOSE: Standard radiological/topographical classifications of gliomas often do not reflect the real extension of the tumor within the lobar-cortical anatomy. Furthermore, these systems do not provide information on the relationship between tumor growth and the subcortical white matter architecture. We propose the use of an anatomically standardized grid system (the Brain-Grid) to merge serial morphological magnetic resonance imaging (MRI) scans with a representative tractographic atlas. Two illustrative cases are presented to show the potential advantages of this classification system. METHODS: MRI scans of 39 patients (WHO grade II and III gliomas) were analyzed with a standardized grid created by intersecting longitudinal lines on the axial, sagittal, and coronal planes. The anatomical landmarks were chosen from an average brain, spatially normalized to the Montreal Neurological Institute (MNI) space and the Talairach space. Major white matter pathways were reconstructed with a deterministic tracking algorithm on a reference atlas and analyzed using the Brain-Grid system. RESULTS: In all, 48 brain grid voxels (areas defined by 3 coordinates, axial (A), coronal (C), sagittal (S) and numbers from 1 to 4) were delineated in each MRI sequence and on the tractographic atlas. The number of grid voxels infiltrated was consistent, also in the MNI space. The sub-cortical insula/basal ganglia (A3-C2-S2) and the fronto-insular region (A3-C2-S1) were most frequently involved. The inferior fronto-occipital fasciculus, anterior thalamic radiation, uncinate fasciculus, and external capsule were the most frequently associated pathways in both hemispheres. CONCLUSIONS: The Brain-Grid based classification system provides an accurate observational tool in all patients with suspected gliomas, based on the comparison of grid voxels on a morphological MRI and segmented white matter atlas. Important biological information on tumor kinetics including extension, speed, and preferential direction of progression can be observed and even predicted with this system. This novel classification can easily be applied to both prospective and retrospective cohorts of patients and increase our comprehension of glioma behavior. De 2 sista författarna delar sistaförfattarskapet.

Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with 11C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBVmax) and the minimum mean diffusivity (MDmin) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors. The correlation between rCBVmax (r = 0.19, P = 0.38) and MDmin (r = −0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBVmax. Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBVmax suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.

OBJECTIVE Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed. METHODS Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices. RESULTS Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H–positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences. CONCLUSIONS The authors present a new method for the coregistration of histological and radiological characteristics of en bloc–removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.

Background and Purpose.Low-grade gliomas show infiltrative growth in white matter tracts. Diffusion tensor tractography can noninvasively assess white matter tracts. The aim was to preoperatively assess tumor growth in white matter tracts using quantitative MR tractography (3T). The hypothesis was that suspected infiltrated tracts would have altered diffusional properties in infiltrated tract segments compared to noninfiltrated tracts.Materials and Methods.Forty-eight patients with suspected low-grade glioma were included after written informed consent and underwent preoperative diffusion tensor imaging in this prospective review-board approved study. Major white matter tracts in both hemispheres were tracked, segmented, and visually assessed for tumor involvement in thirty-four patients with gliomas grade II or III (astrocytomas or oligodendrogliomas) on postoperative neuropathological evaluation. Relative fractional anisotropy (rFA) and mean diffusivity (rMD) in tract segments were calculated and compared with visual evaluation and neuropathological diagnosis.Results.Tract segment infiltration on visual evaluation was associated with a lower rFA and high rMD in a majority of evaluated tract segments (89% and 78%, resp.). Grade II and grade III gliomas had similar infiltrating behavior.Conclusion.Quantitative MR tractography corresponds to visual evaluation of suspected tract infiltration. It may be useful for an objective preoperative evaluation of tract segment involvement.

The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

Adult low-grade gliomas (LGG) are poorly circumscribed diffusely infiltrative brain tumours localised mainly in the cerebral hemispheres. They affect otherwise healthy individuals with an average age of ∼40 years at the time of diagnosis. Low-grade gliomas in adults are classified as grade II gliomas according to the World Health Organisation (WHO) classification of brain tumours and consist mainly of astrocytomas, oligodendrogliomas and oligoastrocytomas (Louis et al, 2007). The median survival for LGG is 5–10 years, but clinical outcome varies considerably (Lote et al, 1997). For some patients the disease has an indolent course for many years, whereas others experience rapid tumour progression from the time of diagnosis. Treatment is unsatisfactory and there is no cure for LGG (Soffietti et al, 2010). There is consensus but no evidence that maximal surgical resection prolongs survival in LGG (Keles et al, 2001; Duffau, 2009). A large randomised trial designed to define the optimal timing of radiotherapy showed a prolonged symptom-free survival for patients with LGG receiving adjuvant radiotherapy compared with those irradiated at progression, but no difference in overall survival (Karim et al, 2002; van den Bent et al, 2005). For optimal patient management, clinical parameters with an impact on survival have to be taken into account (Pignatti et al, 2002; Soffietti et al, 2010). Negative prognostic factors for survival are old age, astrocytoma histology, neurological deficit at presentation, large tumour diameter, contrast enhancement and tumours crossing midline (Pignatti et al, 2002). The presence of two or less unfavourable factors identifies low-risk groups, and for these low-risk patients it is probably a good strategy to defer radiotherapy until tumour progression (Pignatti et al, 2002). Many treatment decisions, however, remain unsolved. The clinical management of patients with LGG will benefit from prognostic and predictive biomarkers that can guide therapeutic decisions. One such example is the combined loss of chromosomal arms 1p/19q, the molecular hallmark of oligodendrogliomas and a strong prognostic and predictive marker in these tumours (Ohgaki and Kleihues, 2005). PROX1 is a transcription factor expressed in the heart, liver, lens, skeletal muscles, pancreas, kidney and in the CNS (Zinovieva et al, 1996). The Drosophila homologue of PROX1, prospero, resembles a tumour suppressor gene by preventing neuroblast self-renewal. In the absence of prospero, cells accumulate forming brain tumours (Betschinger et al, 2006). It has been suggested that PROX1 has a similar role in human malignancies. Decreased expression of PROX1 was found in hepatocellular carcinomas, sporadic breast cancer and carcinomas of the biliary system (Shimoda et al, 2006; Laerm et al, 2007; Versmold et al, 2007). In contrast, PROX1 was overexpressed in colorectal cancer and found to have a role in promoting cancer progression (Petrova et al, 2008). We have recently shown that PROX1 protein is overexpressed in human astrocytic tumours, with highest levels in grade III and IV astrocytomas (Elsir et al, 2010). These findings suggest that PROX1 may act as a prognostic factor in human gliomas. In the present study, we have studied the presence of PROX1 protein in correlation with patient survival in a cohort of patients with LGG.

Gliomas are common primary brain tumours that occur as low-grade (LGG) and high-grade gliomas (HGG). Typically occurring in younger adults, LGG has an indolent course with a median survival of 5-10 years, but carries an inherent potential for transforming into HGG. The thesis focused on LGG in adults, with the aim of identifying prognostic biomarkers for LGG.Paper I. Epileptic seizures are common symptoms in LGG. In a retrospective study, the correlation between 11C-methionine (MET) uptake, measured by Positron Emission Tomography (PET), and seizure activity was assessed in 101 patients with LGG. Although there was no correlation between MET uptake and seizure activity, survival was longer in patients who were seizure-free before surgery.Paper II. This finding prompted the search for common genetic pathways for both tumour and seizure development and a review of genetic polymorphisms in focal epilepsy and glioma risk. Cell cycle and immune response genes affecting both glioma and seizure risk were identified, and genes involved in synaptic transmission presented potential candidates for future studies.Paper III. The transcription factor PROX1 plays a pivotal role in normal development and carcinogenesis of various organs. The prognostic value of PROX1, together with established clinical and molecular prognostic factors for survival, was retrospectively assessed in 116 patients with LGG. High PROX1 expression in the tumour was associated with shorter survival.Paper IV. DNA repair enzymes, such as ERCC6, are crucial for maintaining genomic stability in glioma response to radiotherapy. An association between the polymorphism rs4253079, mapped to ERCC6, and longer survival in patients with LGG and HGG was identified.Paper V. As LGG typically presented as non-contrast enhancing tumours on morphological MRI (magnetic resonance imaging), the value of combined MET PET with physiological MRI for preoperative diagnosis was assessed in a prospective study of 32 patients with suspected LGG. Representative tumour areas were identified through a combination of perfusion-MRI with MET PET, which can be used as a baseline investigation for follow-up over time.Conclusions: The parameters seizure-freedom before surgery, the polymorphism rs4253079 in ERCC6 and low PROX1 expression in the tumor were identified as favorable prognostic biomarkers.

BACKGROUND. Patients with glioma exhibit a great variability in clinical symptoms apart from variations in response to therapy and survival. Many patients present with epileptic seizures at disease onset, especially in case of low-grade gliomas, but not all have seizures. A large proportion of patients develop refractory seizures. It is likely that the variability in epileptic symptoms cannot exclusively be explained by tumor-related factors, but rather reflects complex interaction between tumor-related, environmental and hereditary factors. MATERIAL AND METHODS. No data exist on susceptibility genes associated with epileptic symptoms in patients with glioma. However, an increasing number of candidate genes have been proposed for other focal epilepsies such as temporal lobe epilepsy. Some of the susceptibility candidate genes associated with focal epilepsy may contribute to epileptic symptoms also in patients with glioma. RESULTS. This review presents an update on studies on genetic polymorphisms and focal epilepsy and brings forward putative candidate genes for tumor-associated epilepsy, based on the assumption that common etiological pathways may exist for glioma development and glioma-associated seizures. CONCLUSION. Genes involved in the immune response, in synaptic transmission and in cell cycle control are discussed that may play a role in the pathogenesis of tumor growth as well as epileptic symptoms in patients with gliomas.

Sir, We read with interest the report ‘Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review’ and wish to emphasize that lymphopenia, which may be the most important risk factor for progressive multifocal leukoencephalopathy (PML), failed to be mentioned. In their thorough literature review, Henegar et al. 1 found that most systemic lupus erythematosus (SLE) patients (32 out of 35) were on immunosuppressant therapy (IST) at the time of PML diagnosis. Even though the IST type was discriminated, individual duration and effect of IST on the immune system could not be analysed. A recent case report from our units was associated with a fatal outcome. 2 The patient had severe CD4 þ T cell lymphopenia. Our review of the literature revealed that information about lymphocyte counts was scarce, but when available lymphopenia was invariably present in SLE patients with PML. PML was initially described in patients subjected to chemotherapy 3 and is a feared complication of idiopathic CD4 þ T cell lymphopenia. 4 Altogether, such compelling evidence leads us to believe that in order to prevent PML in SLE, lymphocyte counts should be frequently monitored and IST adjusted in order to avoid severe lymphopenia. Current recommendations support maintaining a total count above 1000 � 10 6 /L, 5 but in current practice we believe the management of lymphopenia in SLE remains an unmet need.

Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with ¹¹C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBV(max)) and the minimum mean diffusivity (MD(min)) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBV(max) corresponded with hotspot regions in all tumors, regions with MD(min) corresponded with hotspot regions in 20/23 tumors. The correlation between rCBV(max) (r = 0.19, P = 0.38) and MD(min) (r = -0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBV(max). Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBV(max) suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.

The PROX1 transcription factor, also known as Prospero in flies, plays a critical role in the development of various organs especially the lymphatic and central nervous systems. Mutations in Prospero induce brain tumor development in flies due to the lack of normal asymmetric neural stem cell division. Less is known about the expression and function of PROX1 in human brain tumors. First, we investigated expression of PROX1 using immunohistochemistry in 56 human astrocytic gliomas of different grades. PROX1 was found to be overexpressed in the majority of high grade tumors but not in grade I tumors or control tissue. Secondly, we addressed the prognostic value of PROX1 in a clinical cohort of patients with grade II gliomas (n=116). The number of PROX1 immunoreactive cells was used as a variable in survival analysis. Patients with tumors showing high PROX1 protein expression had poor outcome in the univariate analysis as well as in the multivariate analysis compared to those with low PROX1 expression. Thirdly, we found that PROX1 was expressed in glioma cell lines and we noted an apparent positive correlation between expression of PROX1 and the pluripotency factor SOX2. Depletion of SOX2 using siRNA inhibited glioma cell proliferation and reduced the levels of PROX1. Acute loss of PROX1 did not impair glioma cell proliferation in vitro. We conclude that PROX1 may constitute a useful tool for diagnosing and grading of astrocytic glioma distinguishing grade III and IV tumors from grade I and II tumors. PROX1 is also a novel predictor of survival for grade II gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5560. doi:1538-7445.AM2012-5560