Developing education in environmental health and medicine focusing on neurology: Initiatives in Sweden (the UPRISE model), France, and Turkey.

BACKGROUND: The role of environmental factors in neurological disorders constitutes a topic of increasing importance. Teaching in European universities should expand and update this field gaining future health professionals including adjacent disciplines. AIM: To describe recent efforts to create courses that cover crucial interdisciplinary content that we believe should be included in modern education, and to adapt modern pedagogic strategies. METHODS: In collaboration with RISE (Rencontres Internationales Santé Environnement), elective courses focused on Environmental Health and Medicine (EHM) were developed, in France, Sweden, and Turkey. The courses combined classic teaching methods and new pedagogic and digital solutions to create environment-related health awareness and facilitate future interprofessional collaboration in this field. RESULTS: UPRISE is an innovative elective course introduced in 2020 in Sweden's Uppsala University with the participation of lecturers from several countries and aim to recruit students from different universities. A total of 45, mainly female students (68%), participated in the course. In Strasbourg, France, a novel course on environmental medicine was held in 2019-2023 and examined 90 students, of which more than half were female. Nine graduate nurse students in Turkey attended ten seminar series focused on EHM. Overall, students expressed satisfaction with the courses. CONCLUSIONS: This European project for courses in higher education arising from RISE was met with appreciation and challenges from academic institutions. However, due to considerable efforts to introduce the EHM concept, a unique compulsory course for all medical students in the second year of training started in 2023 in all French medical faculties. In 2023, UPRISE was integrated into ENLIGHT, the European University Network to promote equitable quality of Life, sustainability, and Global engagement through Higher education Transformation.

Characterization of the Increase in Narcolepsy following the 2009 H1N1 Pandemic in Sweden.

(1) Background: In the context of the H1N1 pandemic and the Pandemrix vaccination campaign, an increased number of narcolepsy cases were noted in several countries. In Sweden, this phenomenon was attributed to the effect of the Pandemrix vaccination in the first place. Studies from China indicated that narcolepsy could occur as a consequence of the H1N1 infection itself. We performed an analysis of the increase, with a specific interest in age and sex distribution. We also aimed to validate the origin of the excess cases, post hoc. (2) Methods: Data for narcolepsy patients (ICD code G 47.4, both type 1 and type 2) distributed by sex and age at 5-year intervals, annually between 2005 and 2017, were retrieved from the National Patient Register. Information on the total population was collected from the Swedish Population Register. (3) Results: The number of narcolepsy cases increased markedly from 2009 to 2014 compared to the period before 2009. A particular increase in 2011 among children and teenagers was observed. The sex ratio did not change significantly during the study period. (4) Conclusions: Our results support an association between the increased prevalence of narcolepsy cases and Pandemrix vaccination, but the effect of the virus itself cannot be ruled out as a contributing factor.

Case report: a novel deep intronic splice-altering variant in DMD as a cause of Becker muscular dystrophy.

We present the case of a male patient who was ultimately diagnosed with Becker muscular dystrophy (BMD; MIM# 300376) after the onset of muscle weakness in his teens progressively led to significant walking difficulties in his twenties. A genetic diagnosis was pursued but initial investigation revealed no aberrations in the dystrophin gene (DMD), although immunohistochemistry and Western blot analysis suggested the diagnosis of dystrophinopathy. Eventually, after more than 10 years, an RNA analysis captured abnormal splicing where 154 nucleotides from intron 43 were inserted between exon 43 and 44 resulting in a frameshift and a premature stop codon. Normal splicing of the DMD gene was also observed. Additionally, a novel variant c.6291-13537A>G in DMD was confirmed in the genomic DNA of the patient. The predicted function of the variant aligns with the mRNA results. To conclude, we here demonstrate that mRNA analysis can guide the diagnosis of non-coding genetic variants in DMD.

A comprehensive diagnostic approach in suspected neurosarcoidosis.

Neurosarcoidosis presents a diagnostic challenge in clinical settings, as it has no pathognomonic symptoms or signs and a wide range of differential diagnoses. The aim of this report is to present the pathological features of our group of patients, obtained through a systematic diagnostic approach. This retrospective cohort study enrolled all adult patients primarily diagnosed with neurosarcoidosis at the neurology department of a tertiary center in Sweden over a period of 30 years, from 1990 to 2021. We identified 90 patients, 54 with possible neurosarcoidosis and 36 with probable neurosarcoidosis. CNS biopsy revealed an alternative diagnosis for 24 patients, who were then excluded. The collected data from medical records included demographic and clinical characteristics, systemic and/or neurological isolated involvement, various laboratory tests, including cerebrospinal fluid (CSF), serum analysis, imaging studies (MRI, FDG-PET/CT, and HRCT), nerve conduction studies, electromyography, and pathology reports of central nervous system (CNS), and extra-neural tissue biopsies. Sixty-six patients were included in our cohort. The median age at onset of symptoms was 49 years, with a similar sex distribution. Cranial neuropathies (38%), motor deficit (32%), headache (16%), and pituitary dysfunction (12%) were the most common presenting features. CSF studies were abnormal in 77% of the patients, who showed lymphocytosis (57%), elevated protein (44%), oligoclonal bands (40%), elevated ACE (28%), and raised T lymphocyte CD4+/CD8+ ratios (13%). Strikingly, MRI showed that 17% of the patients presented with isolated pituitary gland lesions. FDG-PET/CT was performed in 22 patients (33%) and confirmed systemic sarcoidosis in 11. Despite our extensive workup, the final classification for our patients only allowed for a definite diagnosis in 14 patients; the remainder were classified as probable (32) or possible (20) neurosarcoidosis. Since 2007, the employment of a structured laboratory and imaging approach and the increasing number of CNS biopsies have facilitated and improved the process of correct attribution in patients with presumptive neurosarcoidosis, especially in patients with isolated neurological lesions. We highlight a higher frequency of pituitary lesions due to neurosarcoidosis than has been classically described. A detailed laboratory diagnostic workup is included.

Aniridia with PAX6 mutations and narcolepsy.

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.

Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences.

Elucidating patients´ experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants' experiences through semi-structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants' personal life, employment, and daily activities. The participants' experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief.

Progressive Multifocal Leukoencephalopathy and Systemic Lupus Erythematosus: Focus on Etiology.

Progressive multifocal leukoencephalopathy (PML) caused by reactivation of the JC virus (JCV), a human polyomavirus, occurs in autoimmune disorders, most frequently in systemic lupus erythematosus (SLE). We describe a HIV-negative 34-year-old female with SLE who had been treated with immunosuppressant therapy (IST; steroids and azathioprine) since 2004. In 2011, she developed decreased sensation and weakness of the right hand, followed by vertigo and gait instability. The diagnosis of PML was made on the basis of brain MRI findings (posterior fossa lesions) and JCV isolation from the cerebrospinal fluid (700 copies/ml). IST was immediately discontinued. Cidofovir, mirtazapine, mefloquine and cycles of cytarabine were sequentially added, but there was progressive deterioration with a fatal outcome 1 year after disease onset. This report discusses current therapeutic choices for PML and the importance of early infection screening when SLE patients present with neurological symptoms. In the light of recent reports of PML in SLE patients treated with rituximab or belimumab, we highlight that other IST may just as well be implicated. We conclude that severe lymphopenia was most likely responsible for JCV reactivation in this patient and discuss how effective management of lymphopenia in SLE and PML therapy remains an unmet need.

Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data.

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.

Neurological Impairment Linked with Cortico-Subcortical Infiltration of Diffuse Low-Grade Gliomas at Initial Diagnosis Supports Early Brain Plasticity.

Diffuse low-grade gliomas (DLGG) are slow-growing brain tumors that in spite of an indolent behavior at onset show a continuous expansion over time and inevitably transform into malignant gliomas. Extensive tumor resections may be performed with preservation of neurological function due to neuroplasticity that is induced by the slow tumor growth. However, DLGG prefer to migrate along subcortical pathways, and white matter plasticity is considerably more limited than gray matter plasticity. Whether signs of functional decompensating white matter that may be found as early as at disease presentation has not been systematically studied. Here, we examined 52 patients who presented with a DLGG at the time of radiological diagnosis. We found a significant correlation between neurological impairment and eloquent cortico-subcortical tumor localization, but not between neurological function and tumor volume. These results suggest that even small tumors invading white matter pathways may lack compensatory mechanisms for functional reorganization already at disease presentation.

Does intrathecal baclofen have a place in the treatment of painful spasms in friedreich ataxia?

We present the case of a 50-year-old female patient with Friedreich ataxia (FA) who was treated successfully with an intrathecal baclofen (ITB)-delivering pump for painful spasms. To our knowledge, this is the second reported case of FA where ITB relieved painful and disabling spasms. We suggest that ITB should be considered in the treatment of disabling spasms in patients with FA.

Perfusion and diffusion MRI combined with ¹¹C-methionine PET in the preoperative evaluation of suspected adult low-grade gliomas.

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.

Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas.

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.

Tumor-associated epilepsy and glioma: are there common genetic pathways?

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.