Search

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5–9 (months)) was available in 3,773 and age at onset (median:67, IQR:61–73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10−6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Purpose: To present the clinical and histopathological characteristics of a rare case of ductal carcinoma in situ ex pleomorphic adenoma in the lacrimal gland. Observations: A 73-years-old Caucasian female presented with complaints of double vision and pain in the left eye region. Clinical examination revealed ptosis and exophthalmos of the left eye as well as diplopia on downward gaze. Magnetic resonance imaging of the left orbit demonstrated a 17 × 22 mm homogeneous tumor in the left lacrimal fossa. The tumor was excised in toto. Histopathological examination revealed a pleomorphic adenoma with ductal structures with benign looking epithelial cells, surrounded by myoepithelial cells. Tumor areas with cribriform architecture consisting of ductal structures with abnormal luminal epithelial cells and intact myoepithelial cell layer were also present. The surgical margins were clear. All luminal and myoepithelial cells were positive for cytokeratin 7, the luminal cells in the cribriform areas were positive for human epidermal growth factor 2 and androgen receptor. The myoepithelial cells were positive for cytokeratin 5, calponin and focally for glial fibrillar acid protein. The findings were diagnostic for ductal carcinoma in situ ex pleomorphic adenoma. Next generation sequencing Oncomine Comprehensive Assay mutation analysis found mutations in the BRCA2 (p.K3326*), BAP1 (p.S395*), and TP53 (p.E285K) genes in the ductal carcinoma in situ and BRCA2 (p.C9976A) in the pleomorphic adenoma part. Conclusion and importance: To our knowledge, this tumor is only the second described ductal carcinoma in situ ex pleomorphic adenoma of the lacrimal gland.

Cerebrospinal fluid-based real-time quaking-induced conversion (CSF RT-QuIC) is currently the most prominent method for early detection of sporadic Creutzfeldt–Jakob disease (sCJD), the most common prion disease. CSF RT-QuIC delivers high sensitivity (>90%) and specificity (100%), which has been demonstrated by large ring-trial studies testing probable and definitive sCJD cohorts. Following the inclusion of CSF RT-QuIC in the revised European CJD Surveillance Network diagnostic criteria for sCJD, it has become a standard diagnostic procedure in many prion disease reference or surveillance centers around the world. In this study, we present the implementation of the second-generation CSF RT-QuIC (commonly known as Improved QuIC or IQ) at the Danish Reference Center for Prion Diseases (DRCPD). The method’s sensitivity and specificity were evaluated and validated by analyzing 63 CSF samples. These 63 samples were also analyzed at the National CJD Research and Surveillance Unit (NCJDRSU), based at the University of Edinburgh, UK; analysis was carried out using the first generation or previous CSF RT-QuIC method (PQ). The sensitivity and specificity of PQ during tests at the NCJDRSU were 92% and 100%, respectively. Using these 63 CSF samples, the agreement between the two RT-QuIC generations at DRCPD and NCJDRSU prion laboratories was 100%.

Objective. Histopathological examinations will diminish as minimally invasive epilepsy surgery increasingly replaces open surgery. The objective of this study was to test if visual and computer-aided quantitative analyses of presurgical high-quality 3 Tesla MRIs complying with the International League Against Epilepsy (ILAE) Neuroimaging Task Force recommendations can inform on histopathological diagnosis. Methods. Ninety-two patients from Copenhagen and Oslo University Hospitals fulfilled patient-, imaging-, and histopathological inclusion criteria: 69 patients were diagnosed with hippocampal sclerosis (HS) ILAE type 1 or 2, and 23 patients had normal appearing hippocampi or other histopathology than HS (no-HS). MRIs from 52 healthy controls (HC) were included. Image processing was performed in FreeSurfer v.6.0 with the built-in cross-sectional hippocampal subfield segmentation tool and multimodal MRI input. Volume outputs were used to calculate volume asymmetry ratios (VARs) for whole hippocampus (WH) and subfields. Results. HS patients had significantly larger WH VARs compared to no-HS patients and HC, with a sensitivity=0.93 and specificity=1.0 for histopathological HS diagnosis. Visual MRI assessment yielded a sensitivity=0.90 and specificity=0.96 for histopathological HS diagnosis. CA1 and CA4 VARs and the number of seizure-free patients were not significantly different in HS ILAE type 1 compared to type 2 patients. Significance. FreeSurfer analyses of presurgical MRIs are excellent at separating patients histopathologically diagnosed with HS from patients with other pathology or normal appearing hippocampi. Using the FreeSurfer hippocampal subfield segmentation tool did not allow for separating HS ILAE subtypes.

Background: Neurological complications during and after SARS-CoV-2 infection have been frequently described. The detection of either SARS-CoV-2 RNA or specific antibodies against SARS-CoV-2 in cerebrospinal fluid in the context of concomitant neurological manifestations indicates neuroinfection. Methods and Results: This is a retrospective descriptive analysis of cerebrospinal fluids and serum samples from 2 hospitalized patients and autopsy findings from 2 patients who died at home. Samples were analysed by 3 independent enzyme-linked immunosorbent assays. Specific antibodies against SARS-CoV-2 were detected in cerebrospinal fluids and paired serum in all 4 cases. Levels of antibodies in cerebrospinal fluids were highest in samples from a deceased man with critical progression of COVID-19 and detectable SARS-CoV-2 viral RNA in cerebrospinal fluid, serum, 4 brain biopsies and 15 additional tissue samples, though immunohistochemical staining for SARS-CoV-2 in brain tissue did not detect the virus. Conclusion: Detection of SARS-CoV-2 antibodies in paired serum and cerebrospinal fluid may support the presence of SARS-CoV-2 neuroinflammatory disease in patients with COVID-19 and neurological manifestations.

Aims: Intraductal papillary mucinous neoplasms (IPMNs) may be precursor lesions of pancreatic cancer. The path towards malignancy is associated with mutations in tumour suppressor - and oncogenes that may serve as biomarkers during diagnostic investigation. A novel micro forceps has made it possible to obtain biopsies from the cyst wall for analysis by next generation sequencing (NGS), providing an opportunity for early detection and intervention. However, the impact of spatial tumour heterogeneity on the representability of the biopsies has not been determined. The primary aim is to characterise the impact of molecular heterogeneity of the luminal cyst wall on tissue sampling strategies with small biopsies. Methods: We performed NGS and immunohistochemical phenotyping on 18 resected IPMNs with varying degrees of dysplasia and for a subset, concomitant carcinoma, using a commercially available NGS-panel of 51 oncogenes. We simulated endoscopic biopsies by performing punch biopsies (PBs) of the cyst wall from resected specimens. Results: In total, 127 NGS analyses were performed. Concomitant KRAS and GNAS was a common feature of the IPMNs. Mutations in KRAS and GNAS were associated with low-grade dysplasia whereas alterations in TP53, SMAD4, CDKN2A and PIK3CA were associated with high-grade dysplasia and/or carcinoma. The mutational analysis of the PBs from the cyst wall was compared with the whole lesion. No difference was detected between PBs and whole lesions when the cumulated mutational profile in increasing order of randomly performed PBs was compared. Conclusions: Small IPMN biopsies from the cyst wall are adequate to yield a molecular diagnosis.

Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.

In the present manuscript, we report the clinical presentation and challenging diagnostic work-up of a sporadic Creutzfeldt–Jakob disease patient with confirmed VV1 subtype and heterozygous 1-octapeptide repeat deletion in the prion protein gene. The described patient was a 58-year-old woman. Interestingly, most of the reported patients with the VV1 subtype to date are men with an average age of 44 years at disease onset. The patient was observed clinically from symptoms onset until her death 22 months later. This report describes the patient’s insidious clinical evolution and the paraclinical examinations and pathology reports gathered at different time points of disease progression. Unfortunately, the absence of typical clinical and paraclinical features of classic sporadic Creutzfeldt–Jakob disease made the brain biopsy surgery necessary. This case report illustrates the diagnostic difficulties posed by the phenotypic heterogeneity of sporadic Creutzfeldt–Jakob disease and urges clinicians to consider this diagnosis even in patients who do not fulfil the typical clinical disease criteria. Furthermore, it highlights the need for real-time quaking-induced conversion method adaptation for detection of rare sporadic Creutzfeldt–Jakob disease subtypes with certain prion protein gene variants.

Objectives: To address the diagnostic accuracy of endoscopic ultrasound guided through-the-needle-biopsies (TTNBs) and simultaneously obtained cytology samples from pancreatic cysts compared to the final histopathological diagnosis of the surgical specimen, and to give an overview of ancillary tests performed on TTNBs. Methods: A literature search was conducted in MEDLINE, Embase and Scopus. Studies were included in the meta-analysis, if they had data for TTNB, cytology and a surgical specimen of pancreatic cysts as reference standard. The assessment of the risk of bias and quality of the included studies was conducted using the modified QUADAS-2 tool. Results: Ten studies with 99 patients were included in the meta-analysis. Data regarding study design and clinicopathological features were extracted systematically. For TTNB, pooled sensitivity was 0.86 (95 % CI 0.62−0.96), specificity 0.95 (95 % CI 0.79−0.99) and area under the curve (AUC) 0.86 for the diagnosis of a mucinous cyst and pooled sensitivity was 0.78 (95 % CI 0.61−0.89), specificity 0.99 (95 % CI 0.90−0.99) and AUC 0.92 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.69 (95 % CI 0.50−0.83), specificity 0.47 (95 % CI 0.28−0.68) and AUC 0.49. For cytology performed simultaneously, pooled sensitivity was 0.46 (95 % CI 0.35−0.57), specificity 0.90 (95 % CI 0.46−0.99) and AUC 0.64 for the diagnosis of mucinous cysts, and pooled sensitivity was 0.38 (95 % CI 0.23−0.55), specificity 0.99 (95 % CI 0.90−0.99) and AUC 0.84 for the diagnosis of a high-risk cyst. For a specific diagnosis, pooled sensitivity was 0.29 (95 % CI 0.21−0.39), specificity 0.45 (95 % CI 0.25−0.66) and AUC 0.30. Furthermore, immunohistochemical stains can be useful to establish the specific cyst subtype. Conclusions: TTNBs have a higher sensitivity and specificity than cytology for the diagnosis of mucinous cyst and high- risk cysts of the pancreas.

Invasive intraductal papillary mucinous neoplasms (inv-IPMNs) have a better prognosis than regular pancreatic ductal adenocarcinoma (PDAC), but no association with status of surgical margins and microscopic infiltration patterns has previously been described. The aim of this study is to review patterns of invasion and the predictive value of clinical guidelines in terms of rates of resection of high-grade dysplasia (HGD) and cancer among intraductal papillary mucinous neoplasms (IPMNs). Consecutively, resected IPMNs between 2011 and 2017 were analyzed. Data were obtained from a prospectively maintained database. A total of 132 patients were identified. Out of these, 38 patients with inv-IPMNs, initially identified as solid lesions suspicious of cancer, were compared with a control group of 101 patients with ordinary PDAC. Lower rates of vascular invasion, perineural invasion, lymph node metastasis, advanced T stage, and R1 status were characteristic of the inv-IPMNs in addition to better overall survival (OS) for a low tumor stage. Furthermore, as novel findings, the PDACs presented with resection margin involvement of 3 or more positive margins (31.3% vs. 9.5%, p = 0.044), associated with poor OS. Of the patients presenting as pT3, the inv-IPMN less often invaded more than one extrapancreatic anatomical structure (40.1% vs. 63.9%, p = 0.03). Regarding the predictive value of clinical guidelines, the frequency of resected HGD in IPMNs with high-risk stigmata (n = 54) and IPMNs with worrisome features was 30.7%, and the frequency of invasive carcinoma was 5.7%. In conclusion, we report a low resection rate of high-risk IPMNs and present novel findings describing inv-IPMNs as a less infiltrative phenotype compared with regular PDAC.

OBJECTIVE: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients.METHODS: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related.RESULTS: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated.CONCLUSION: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes sugges

Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow-up. In this paper we review the biomarkers that we currently use in the diagnostic work-up of brain tumors.

Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.

This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother's clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.

INTRODUCTION: Autoimmune hypophysitis is a rare disease of the pituitary, which may affect vision by inflammation and compression of the optic chiasm. However, intrachiasmatic abscess formation has not been previously reported.METHODS: In this study, we report a case of a 29-year-old female with bitemporal hemianopia due to a cystic intrasellar tumor. The patient underwent surgical decompression of the lesion, which was found to be an intrachiasmatic abscess.RESULTS: The histologic findings were consistent with IgG4 hypophysitis.CONCLUSION: This rare clinical presentation suggests that in case of a disproportionate degree of visual impairment in relation to the size of the lesion, suspicion should lead to an intrachiasmatic lesion.

Aims: To evaluate whether the use of intra-arterial methylene blue injection improves lymph node yield, and to determine whether a higher lymph node count results in upstaging in colorectal cancer. Method and results: We performed a retrospective study of colorectal cancer specimens (n=234) 1year after implementation of the method. All colorectal cancer specimens from the previous year served as our control group. Data concerning tumour characteristics, lymph node count, number of positive lymph nodes and success of methylene injection had been prospectively collected in accordance with the department's ongoing registration. The method was easy to implement and perform with a high rate of success (86%). The number of identified lymph nodes was highly significantly improved in the study group (P<0.0001). In resections with pT1/T2 tumours, we demonstrated a significant increase in the number of resection specimens containing positive lymph nodes, with an increase in pN1 resections from 9.4% in the control group to 26.7% in the study group (P=0.04). Conclusions: The methylene blue technique significantly improves lymph node identification in colorectal cancer specimens, and the improved lymph node identification leads to upstaging of International Union Against Cancer (UICC) pT1/pT2 cancers.