Adult-onset encephalitis over two decades in easternmost Finland.

INTRODUCTION: The epidemiology of encephalitis varies by region and time. Available Finnish data are outdated and there are no data from eastern parts of the country nor concerning the occurrence autoimmune encephalitides. MATERIAL AND METHODS: Patients with encephalitis were identified from mandatory administrative registries in North Karelia Central Hospital. The diagnoses were verified, and data extracted by reviewing the patient records. Study period was 2010-2021. Only patients >16 years of age were included. RESULTS: 51 patients with a clinical encephalitis were identified (55 % men) identified with a median age of 65 years [interquartile range (IQR) 45, 73; total age range 16-88 years] indicating a crude incidence of 3.1/100,000 person-years for the entire study period. A specific aetiology could be identified in 31 cases (61 %) with Tick-borne encephalitis (TBE) being the most common one (20 % of all 51 cases), followed by Herpes simplex virus type 1 (HSV-1, 16 %) and Varicella Zoster virus (VZV, 14 %). Autoimmune aetiology was confirmed in 10 %. TBE was most often found in the youngest age group (16-52 years of age) and the herpes viruses in the oldest group (71 years or older). A specific cause was most often identified in the oldest patients (78 %). TBE patients were younger than patients with VZV (p=0.0009) or HSV-1 (p=0.0057) but there was no difference when they were compared to patients with autoimmune (p=0.27) or unknown (p=0.074) aetiology. At presentation, there were differences in the occurrence of some clinical signs and symptoms between aetiologies but nothing specific. Eight patients (16 %) were immunosuppressed. Inpatient seizures occurred in 10 patients (20 %). In these cases, the etiology was HSV-1 in 50 % and TBE or VZV in none. A full recovery was observed in 51 % of all patients while three patients (6 %) had died of the encephalitis while in hospital or shortly after discharge. CONCLUSIONS: Adult-onset encephalitis was more common and the patients older in easternmost Finland than previously reported in other parts of the country. TBE, HSV-1 and VZV are the most commonly identified specific aetiologies whereas a fifth of the cases are probably caused by autoimmunity. Prognosis depended on aetiology but was very good in the majority of cases.

Case-Fatality Rate in Parkinson's Disease: A Nationwide Registry Study.

BACKGROUND: Patients with Parkinson's disease (PD) may have an increased risk of mortality, but robust estimates are lacking. OBJECTIVE: To compare mortality rates nationally between patients with PD and controls. METHODS: The case-fatality rates of Finnish PD patients diagnosed in 2004-2018 (n = 23,688; 57% male, mean age at diagnosis = 71 years) and randomly selected sex- and age-matched control subjects (n = 94,752) were compared using data from national registries. The median follow-up duration was 5.8 years (max 17 years). RESULTS: The case-fatality rate in patients with PD was higher than that in matched controls (HR 2.29; 95% CI 2.24-2.33; P < 0.0001). Excess fatality among PD patients was already present at 1 year from diagnosis and then plateaued at 29% at 12 years after diagnosis. The long-term relative hazard of death in PD patients vs. matched controls did not differ based on sex. Patients with early-onset PD (age at diagnosis <50 years old) had the highest relative hazard of death (HR 3.36) compared to matched control subjects, and the relative hazard decreased with higher age at diagnosis. The seven-year excess risk of death decreased during the study period, especially in men. In patients with PD, male sex, increasing age, and increasing comorbidity burden were associated with an increased risk of death. CONCLUSIONS: An increased risk of death among PD patients was evident from early on. The increase in risk was greatest among young-onset patients. The excess risk in early PD declined during the study period, particularly in men. The reasons for this are unknown.

Exposure to systemic antibiotics in outpatient care and the risk of multiple sclerosis.

BACKGROUND: Infections, early life exposures and the microbiome have been associated with the aetiology of multiple sclerosis (MS). Data on any possible roles of antibiotics is scarce and conflicting. OBJECTIVE: The objective of this study was to investigate associations between outpatient systemic antibiotic exposure and the risk of MS in a nationwide case-control setting. METHODS: Patients with MS were identified from the nation MS registry and their exposure to antibiotics was compared with that of persons without MS, provided by the national census authority. Antibiotic exposure was investigated using the national prescription database and analyzed by Anatomical Therapeutic Chemical (ATC) category. RESULTS: Among the 1830 patients with MS and 12765 control persons, there were no associations between exposure to antibiotics in childhood (5-9 years) or adolescence (10-19 years) and the subsequent risk of MS. There was also no association between antibiotic exposure 1-6 years before disease onset and the risk of MS, save for exposure to fluoroquinolones in women (odds ratio: 1.28; 95% confidence interval: 1.03, 1.60; p = 0.028) which is probably associated with the increased infection burden in the MS prodrome. CONCLUSION: Use of systemic prescription antibiotics was not associated with subsequent MS risk.

Amyotrophic Lateral Sclerosis in Southwestern and Eastern Finland.

INTRODUCTION: The incidence of amyotrophic lateral sclerosis (ALS) worldwide is approximately 1-2.6/1,000,000 and prevalence is 5-6/100,000. ALS has been suggested to be relatively common in Finland, but epidemiological information on the subject is scarce and outdated. MATERIAL AND METHODS: Patients with ALS diagnostic codes were identified from mandatory administrative registries in the provinces of Southwestern Finland (population circa 430,000) and North Karelia (population circa 170,000), together comprising 11.7% of the total population of Finland. The diagnoses were verified, and data were extracted by reviewing the patient records. Incidence period was 2010-2018, and the prevalence date was December 31, 2018. Age-standardization was performed using the European Standard Population 2013 (ESP2013). RESULTS: Overall crude incidence of ALS was 4.2/100,000 person-years in Southwestern Finland (ESP2013: 4.0/100,000) and 5.6/100,000 person-years in North Karelia (ESP2013: 4.8/100,000), while crude prevalences were 11.9/100,000 (ESP2013: 10.5/100,000) and 10.9/100,000 (ESP2013: 9.3/100,000), respectively. Mean age at diagnosis was 65.5-71.6 years in women (higher in Southwestern Finland compared to North Karelia, p = 0.003) and 64.7-67.3 years in men (no difference between provinces, p = 0.39). The diagnosis had been made in 50% before the age of 70 years in Southwestern Finland and before the age of 65 years in 51% in North Karelia. Genetic testing had been conducted in 28% of all patients with the most common findings being SOD1 and C9orf72. After the diagnosis, mean survival was 2.0-2.7 and median survival 1.3-1.4 years. Onset phenotype (p < 0.001), age at diagnosis (p < 0.001), and genotype (p = 0.001) predicted survival. Riluzole had been used by 25% of patients and tracheostomy and invasive ventilation (TIV) had been performed in <1%. CONCLUSIONS: Both incidence and prevalence of ALS in Finland are among the highest in the world but with some notable differences between the eastern and southwestern parts of the country. Low median life expectancy may be related to the advanced age of patients and the high prevalence of C9orf72 repeat expansion in Finland as well infrequent use of TIV and riluzole.

Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do.

Finland is a relatively small genetic isolate with a genetically non-homogenous population. Available Finnish data on neuroepidemiology of adult-onset disorders are limited, and this paper describes the conclusions that can be drawn and their implications. Apparently, Finnish people have a (relatively) high risk of developing Unverricht-Lundborg disease (EPM1), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Spinal muscular atrophy, Jokela type (SMAJ) and adult-onset dystonia. On the other hand, some disorders, such as Friedreich's ataxia (FRDA) and Wilson's disease (WD), are almost absent or completely absent in the population. Valid and timely data concerning even many common disorders, such as stroke, migraine, neuropathy, Alzheimer's disease and Parkinson's disease, are unavailable, and there are virtually no data on many less-common neurological disorders, such as neurosarcoidosis or autoimmune encephalitides. There also appear to be marked regional differences in the incidence and prevalence of many diseases, suggesting that non-granular nationwide data may be misleading in many cases. Concentrated efforts to advance neuroepidemiological research in the country would be of clinical, administrative and scientific benefit, but currently, all progress is blocked by administrative and financial obstacles.

A severe neurodegenerative disease with Lewy bodies and a mutation in the glucocerebrosidase gene.

Several heterozygous variants of the glucocerebrosidase gene (GBA1) have been reported to increase the risk of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD has been reported to be more severe than idiopathic PD, and more deleterious variants are associated with more severe clinical phenotypes. We report a family with a heterozygous p.Pro454Leu variant in GBA1. The variant was associated with a severe and rapidly progressive neurodegenerative disease with Lewy bodies that were clinically and pathologically diverse. Pathogenicity prediction algorithms and evolutionary analyses suggested that p.Pro454Leu is deleterious.

Clinical spectrum and genotype-phenotype associations in Finnish patients with Wilson's disease.

Genotype-phenotype correlation data covering all ages of Wilson's disease onset in Caucasian patients are limited. We therefore analyzed genotype-phenotype correlations in a retrospective cohort of Finnish patients. Six homozygous (HoZ) and 11 compound heterozygous (CoHZ) patients were included. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis (p > 0.30 for all) between HoZ and CoHZ patients, but HoZ patients had an earlier age of diagnosis (median 6.7 versus 34.5; p = 0.003). Severe liver affliction was almost exclusively associated with the p.H1069Q variant. Patients with p.H1069Q had a later mean age of diagnosis (30.2 ± 11.6 vs. 8.7 ± 4.9 years; p < 0.001) compared to those without. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis between p.H1069Q-positive and p.H1069Q-negative patients (p > 0.54 for all). These results suggest that population-specific factors may partly explain the high clinical variability of Wilson's disease.

Association of biallelic RFC1 expansion with early-onset Parkinson's disease.

BACKGROUND AND PURPOSE: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. METHODS: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. RESULTS: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%-3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40-48 years and their disease course had been unremarkable apart from the early onset. CONCLUSIONS: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.

Treatment Courses of Patients Newly Diagnosed with Multiple Sclerosis in 2012-2018.

Treatment options for multiple sclerosis (MS) are now numerous, but it is unclear which Disease-Modifying Treatment (DMT) is the optimal choice for a given patient. Treatment switches are common, both because of side effects and because of lack of efficacy. There are few data available on the treatment courses of patients newly diagnosed with MS in the current DMT era. All patients newly diagnosed with MS in 2012-2018 at North Karelia Central Hospital were identified (N = 55), and those with complete follow-up data available (N = 43) were included. The minimum follow-up from diagnosis was 44 months with a maximum of 9 years. Seven patients (16%) had no DMT at any time during the follow-up. Treatment was most often initiated with interferon or glatiramer acetate (69%), but 72% of these treatments were discontinued. After cladribine, teriflunomide and fingolimod showed the best treatment persistence. Patients who experienced their first MS symptoms at ≥40 years of age all continued with their initial treatment category until the end of the follow-up. In a third of the patients who had received a DMT, at the end of the follow-up, the treatment had been escalated to fingolimod, cladribine or natalizumab. Only 13 patients (28%) continued with their initial DMT until the end of the follow-up.

Exploring Alkyl-O-Alkyl Ether Structures in Softwood Milled Wood Lignins.

Recent studies have suggested that there are significant amounts of various alkyl ether (Alk-O-Alk; Alk = alkyl) moieties in a spruce native lignin preparation, milled wood lignin (SMWL). However, the comprehensive NMR assignment to these moieties has not been addressed yet. This study focused on investigating different types of Alk-O-Alk structures at the α- and γ-positions of the lignin side chain in an heteronuclear single-quantum coherence (HSQC) spectrum of SMWL using experimental NMR data of lignin and synthesized model compounds. Ambiguous structural features were predicted by computer simulation of 1H and 13C NMR spectra to complement the experimental NMR data. As a result, specific regions in the HSQC spectrum were attributed to different Alk-O-Alk moieties of Alk-O-Alk/ß-O-4 and Alk-O-Alk/ß-ß' structures. However, the differences between the specific regions were rather subtle; they were not well separated from each other and some major lignin moieties. Furthermore, SMWL contained a large variety of Alk-O-Alk moieties but in minute individual amounts, resulting in rather broad, superimposing resonances. Thus, evaluation did not allow assigning individual types of Alk-O-Alk moieties from the HSQC spectra; instead, they were quantified as total (α- and γ-linked) Alk-O-Alk based on the balance of structural units in the 13C NMR spectra. At last, potential formation mechanisms of various Alk-O-Alk ether structures in lignin biosynthesis, lignin aging, and during ball milling of wood were hypothesized and discussed.

Controlled register-based study of road traffic accidents in 12,651 Finnish cancer patients during 2013-2019.

BACKGROUND: Little controlled evidence exists on road traffic accident (RTA) risk among patients diagnosed with cancer, while clinicians are often requested to comment their ability to drive. The aim of this study was to evaluate RTA risk in a population-based cohort of cancer patients living in Southwest Finland. PATIENTS: All adult patients diagnosed with cancer in 2013-2019 were included. Acute appendectomy/cholecystectomy and actinic keratosis patients without cancer were selected from the same region as the control cohort. Participants were cross-referenced to a national driving licence database, yielding 12,651 cancer and 6334 control patients with a valid licence. Due to marked differences in their clinical presentation, the cancer cohort was divided into nine cancers of interest (breast, prostate, colorectal, lung, melanoma, head & neck, primary brain tumours, gynaecological and haematological malignancies). The nationwide law-regulated motor liability insurance registry was searched for all RTAs leading to injury with claims paid to not- or at-fault participants. At-fault drivers were verified based on sex and birth year. RESULTS: During a median follow-up of 34 months, 167 persons were at-fault drivers in RTAs leading to injury. Among the nine cancers of interest, RTA risk did not differ from the control cohort. Among cancer patients, multivariable regression suggested male sex and opioid use, but not advanced cancer stage or given systemic therapy, as the most influential risk factors for RTA. CONCLUSIONS: Cancer diagnosis itself was not associated with increased RTA risk, but other associated symptoms, medications, comorbidities or specific cancer subgroups may.

Motor dysfunction as a primary symptom predicts poor outcome: multicenter study of glioma symptoms.

Background and objectives: The objectives of this study were to investigate the prognostic value of primary symptoms and leading symptoms in adult patients with diffuse infiltrating glioma and to provide a clinical perspective for evaluating survival. Methods: This study included a retrospective cohort from two tertiary university hospitals (n = 604, 2006-2013, Tampere University Hospital and Turku University Hospital) and a prospective cohort (n = 156, 2014-2018, Tampere University Hospital). Preoperative symptoms were divided into primary and leading symptoms. Results were validated with the newer WHO 2021 classification criteria. Results: The most common primary symptoms were epileptic seizure (30.8% retrospective, 28.2% prospective), cognitive disorder (13.2% retrospective, 16.0% prospective), headache (8.6% retrospective, 12.8% prospective), and motor paresis (7.0% retrospective, 7.1% prospective). Symptoms that predicted better survival were epileptic seizure and visual or other sense-affecting symptom in the retrospective cohort and epileptic seizure and headache in the prospective cohort. Predictors of poor survival were cognitive disorder, motor dysfunction, sensory symptom, tumor hemorrhage, speech disorder and dizziness in the retrospective cohort and cognitive disorder, motor dysfunction, sensory symptom, and dizziness in the prospective cohort. Motor dysfunction served as an independent predictor of survival in a multivariate model (OR = 1.636). Conclusion: Primary and leading symptoms in diffuse gliomas are associated with prognoses in retrospective and prospective settings. Motor paresis was an independent prognostic factor for poor survival in multivariate analysis for grade 2-4 diffuse gliomas, especially in glioblastomas.

Association of CHA2DS2-VASc Score with Long-Term Incidence of New-Onset Atrial Fibrillation and Ischemic Stroke after Myocardial Infarction.

The CHA2DS2-VASc score is a reliable tool used to estimate the risk of ischemic stroke (IS) in patients with atrial fibrillation (AF). Few tools exist for the prediction of new-onset AF (NOAF) after myocardial infarction (MI) and its relation to IS. We studied the usefulness of CHA2DS2-VASc in predicting NOAF and IS in a long-term follow-up after MI. Consecutive MI patients without baseline AF (n = 70,922; mean age: 68.2 years), discharged from 20 hospitals in Finland during 2005−2018, were retrospectively studied using national registries. The outcomes of interest after discharge were NOAF- and IS-assessed with competing risk analyses at one and ten years. The median follow-up was 4.2 years. The median baseline CHA2DS2-VASc score was 3 (IQR 2−5). The likelihood of both NOAF and NOAF-related IS increased stepwise with this score at one and ten years (all p < 0.0001). The one-year-adjusted subdistribution hazard ratio (sHR) was 4.03 (CI 3.68−4.42) for NOAF in patients with CHA2DS2-VASc scores ≥6 points. The cumulative incidence of IS was 15.2% in patients with NOAF vs. 6.2% in patients without AF at 10 years after MI (adj. sHR 2.12; CI 1.98−2.28; p < 0.0001). Coronary artery bypass surgery was associated with a higher NOAF incidence compared to percutaneous coronary intervention (adj. sHR 1.87; CI 1.65−2.13; p < 0.0001 one year after MI). The CHA2DS2-VASc score is a simple tool used to estimate the long-term risk of NOAF and IS after MI in patients without baseline AF. Coronary bypass surgery is associated with an increased NOAF incidence after MI.

Fractionation of Technical Lignin from Enzymatically Treated Steam-Exploded Poplar Using Ethanol and Formic Acid.

Lignocellulosic biorefineries produce lignin-rich side streams with high valorization potential concealed behind their recalcitrant structure. Valorization of these residues to chemicals, materials, and fuels increases the profitability of biorefineries. Fractionation is required to reduce the lignins' structural heterogeneity for further processing. We fractionated the technical biorefinery lignin received after steam explosion and saccharification processes. More homogeneous lignin fractions were produced with high ß-O-4' and aromatic content without residual carbohydrates. Non-toxic biodegradable organic solvents like ethanol and formic acid were used for fractionation and can be adapted to the existing biorefinery processes. Macromolecular properties of the isolated fractions were carefully characterized by structural, chemical, and thermal methods. The ethanol organosolv treatment produced highly soluble lignin with a reasonable yield, providing a uniform material for lignin applications. The organosolv fractionation with formic acid and combined ethanol-formic acid produced modified lignins that, based on thermal analysis, are promising as thermoresponsive materials.

Comorbidities in patients with Unverricht-Lundborg disease (EPM1).

BACKGROUND: Unverricht-Lundborg disease (EPM1) typically leads to accumulating disability. Disability may also be caused by comorbidities but there are no data available on these. AIMS OF THE STUDY: To investigate the frequency of comorbidities in EPM1. METHODS: Comorbidity data of a previously described cohort of 135 Finnish patients with EPM1 were retrieved from neurological, surgical (including subspecialities), internal medicine (including subspecialities) and intensive care patient charts of the treating hospitals. RESULTS: Mean follow-up time was 31.4 years (SD 12.4 years, range 6.8-57.8 years), during which at least one comorbidity was observed in 107 patients (79%) and three or more in 53 (39%). The most common diagnostic categories were external injuries, mental and behavioural disorders and endocrine, nutritional and metabolic diseases. The most common single comorbid diagnosis was a fracture of the ankle (in 19% of all patients). The second most common single comorbid diagnosis in the cohort was diabetes (in 13% of all patients), and the third was depression, recorded for 13% of the cohort. Malignancies and cardiovascular end-organ damage were rare, whereas phimosis/paraphimosis appeared more common than in general population. CONCLUSIONS: Patients with EPM1 often have comorbidities. Trauma and mental health risks should be especially followed and acted upon. Further studies are needed to more accurately comorbidity risks, characteristics and patient needs.

Age Is Only a Number Also in Hyperacute Stroke Care-But Not an Irrelevant One.

"It is difficult to make predictions, especially about the future [...].