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 Available Finnish data are outdated and there are no data from eastern parts of the country nor concerning the occurrence autoimmune encephalitides.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.

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.

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.

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 [...].

Impact of Oral Anticoagulation and Adenosine Diphosphate Inhibitor Therapies on Short-term Outcome of Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Usage of oral anticoagulants (OACs) or adenosine diphosphate inhibitors (ADPi) is known to increase the risk of bleeding. We aimed to investigate the impact of OAC and ADPi therapies on short-term outcomes after traumatic brain injury (TBI). METHODS: All adult patients hospitalized for TBI in Finland during 2005-2018 were retrospectively studied using a combination of national registries. Usage of pharmacy-purchased OACs and ADPi at the time of TBI was analyzed with the pill-counting method (Social Insurance Institution of Finland). The primary outcome was 30-day case-fatality (Finnish Cause of Death Registry). The secondary outcomes were acute neurosurgical operation (ANO) and admission duration (Finnish Care Register for Health Care). Baseline characteristics were adjusted with multivariable regression, including age, sex, comorbidities, skull or facial fracture, OAC/ADPi treatment, initial admission location, and the year of TBI admission. RESULTS: The study population included 57,056 persons (mean age 66 years) of whom 0.9% used direct OACs (DOACs), 7.1% vitamin K antagonists (VKA), and 2.3% ADPi. Patients with VKAs had higher case-fatality than patients without OAC (15.4% vs 7.1%; adjusted hazard ratio [aHR] 1.35, CI 1.23-1.48; p < 0.0001). Case-fatality was lower with DOACs (8.4%) than with VKAs (aHR 0.62, CI 0.44-0.87; p = 0.005) and was not different from patients without OACs (aHR 0.93, CI 0.69-1.26; p = 0.634). VKA usage was associated with a higher neurosurgical operation rate compared with non-OAC patients (9.1% vs 8.3%; adjusted odds ratio 1.33, CI 1.17-1.52; p < 0.0001). There was no difference in operation rate between DOAC and VKA. ADPi was not associated with case-fatality or operation rate in the adjusted analyses. VKAs and DOACs were not associated with longer admission length compared with the non-OAC group, whereas the admissions were longer in the ADPi group compared with the non-ADPi group. DISCUSSION: Preinjury use of VKA is associated with increases in short-term mortality and in need for ANOs after TBI. DOACs are associated with lower fatality than VKAs after TBI. ADPi were not independently associated with the outcomes studied. These results point to relative safety of DOACs or ADPi in patients at risk of head trauma and encourage to choose DOACs when oral anticoagulation is required. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among adults with TBI, mortality was significantly increased in those using VKAs but not in those using DOACs or ADPi.

Prognosis of patients with operated chronic subdural hematoma.

Chronic subdural hematoma (cSDH), previously considered fairly benign and easy to treat, is now viewed a possible sign of incipient clinical decline. We investigated case-fatality, excess fatality and need for reoperations following operated cSDH in a nationwide setting focusing on patient-related characteristics. Finnish nationwide databases were searched for all admissions with operated cSDH as well as later deaths in adults (≥ 16 years) during 2004-2017. There were 8539 patients with an evacuated cSDH (68% men) with a mean age of 73.0 (± 12.8) years. During the follow-up, 3805 (45%) patients died. In-hospital case-fatality was 0.7% (n = 60) and 30-day case-fatality 4.2% (n = 358). The 1-year case-fatality was 14.3% (95% CI = 13.4-15.2%) among men and 15.3% (95% CI = 14.0-16.7%) among women. Comorbidity burden, older age, and alcoholism were significantly associated with fatality. One-year excess fatality rate compared to general Finnish population was 9.1% (95% CI = 8.4-9.9) among men and 10.3% (95% CI = 9.1-11.4) among women. Highest excess fatality was observed in the oldest age group in both genders. Reoperation was needed in 19.4% (n = 1588) of patients. Older age but not comorbidity burden or other patient-related characteristics were associated with increased risk for reoperation. The overall case-fatality and need for reoperations declined during the study era. Comorbidities should be considered when care and follow-up are planned in patients with cSDH. Our findings underpin the perception that the disease is more dangerous than previously thought and causes mortality in all exposed age groups: even a minor burden of comorbidities can be fatal in the post-operative period.

Finnish multiple sclerosis patients treated with cladribine tablets: a nationwide registry study.

BACKGROUND: Cladribine tablets for adult patients with highly active relapsing multiple sclerosis (MS) have been available in Finland since 2018. Real-world data from different genetic and geographical backgrounds are needed to complement data from clinical trials. METHODS: We investigated the use of cladribine tablets in Finland in a non-interventional cohort study, based on real-world data from the nationwide Finnish MS registry. All eligible patients who had initiated treatment with cladribine tablets in 2018-2020 were included. Descriptive analyses for outcomes were conducted using summary statistics. Time-dependent endpoints were analyzed using cumulated events analysis based on 1-Kaplan-Meier estimates and curves. Subgroups were analyzed separately according to the number of previous disease-modifying therapies (DMTs) and the most common last preceding therapies. RESULTS: Data of 179 patients were analyzed. Median follow-up time was 19.0 months (interquartile range [IQR] 12.0-26.2). Of the 134 patients who were followed for at least 12 months, 112 patients (83.6%) remained relapse-free during follow-up. Mean annualized relapse rate (ARR) was 1.0 (standard deviation [SD] 0.89) at baseline, and 0.1 (SD 0.30) at follow-up. Patients with two or more previous DMTs had shorter time to first relapse (median 2.5 months, IQR 0.6-9.3) when compared to patients with 0-1 previous DMTs (median 11.4 months, IQR 8.7-13.1) (p=0.013). After excluding patients switching from fingolimod (n=33), a statistically significant difference in time to first relapse was no longer observed between the two groups (p=0.252). Adverse events (AEs) were reported in 30 patients (16.8%). The most frequent AE was headache (n=14, 7.8%). One patient (0.6%) died of cardiac arrest. Discontinuation of cladribine tablets was reported in nine patients (5.0%). CONCLUSION: The mean ARR observed in this cohort was similar to what has been reported in clinical trials. Approximately half of the patients had used two or more previous DMTs before cladribine tablets. These patients had a shorter time to first relapse when compared to patients with 0-1 previous DMTs, mostly driven by early relapses in patients switching from fingolimod.

Changing epidemiology of traumatic brain injury among the working-aged in Finland: Admissions and neurosurgical operations.

BACKGROUND: Recent studies from Finland have highlighted an increase in the incidence of traumatic brain injuries (TBI) in older age groups and high overall mortality. We performed a comprehensive study on the changing epidemiology of TBI focusing on the acute events in the Finnish working-age population. METHODS: Nationwide databases were searched for all emergency ward admissions with a TBI diagnosis for persons of 16-69 years of age during 2004-2018. RESULTS: In the Finnish working-age population, there were 52,487,099 person-years, 38,810 TBI-related hospital admissions, 4664 acute neurosurgical operations (ANO), and 2247 cases of in-hospital mortality (IHM). The TBI-related hospital admission incidence was 94/100,000 person-years in men, 44/100,000 in women, and 69/100,000 overall. The incidence rate of admissions increased in women, while in men and overall, the rate decreased. The incidence rate increased in the group of 60-69 years in both genders. Lowest incidence rates were observed in the age group of 30-39 years. Occurrence risk for TBI admission was higher in men in all age groups. Trends of ANOs decreased overall, while decompressive craniectomy was the only operation type in which a rise in incidence was found. Evacuation of acute subdural hematoma was the most common ANO. Mean length of stay and IHM rate halved during the study years. CONCLUSIONS: In Finland, the epidemiology of acute working-aged TBI has significantly changed. The rates of admission incidences, ANOs, and IHM nowadays represent the lower end of the range of these acute events reported in the western world.

Anterior circulation large vessel occlusion outcomes in patients transferred from a peripheral primary stroke centre.

OBJECTIVES: To identify predictors of functional outcome in patients with an anterior circulation large-vessel occlusion (LVO) in a setting of long transfer distances. METHODS: Outcomes of LVO patients transferred for an endovascular thrombectomy (EVT) from North Karelia Central Hospital to Kuopio University Hospital between January 2018 and October 2019 were analysed using retrospective patient chart review. RESULTS: Three months after the stroke, modified Rankin Scale (mRS) was 0-2 in 20 of the 41 transferred patients. They were younger (66.7 vs. 74.2 years, p = 0.032) and had less severe stroke symptoms (National Institutes of Health Stroke Scale, NIHSS, 11.5 vs. 16.5, p = 0.029) than those with mRS 3-6. They also had the occlusion less often in M1 and more often in M2. EVT was performed in 32 patients (no differences between those treated with EVT and those not treated with EVT). Their median age was 73.0 years (interquartile range 65.5, 79.8; range 32-86; 25% over 80), mean NIHSS score 14.0 (standard deviation 5.9) and mRS eventually 0-2 in 44%. Only NIHSS was associated with mRS (OR = 1.16; p = 0.016) in the EVT-treated patients. mRS was 0 in 38% of all EVT-treated octogenarians but 4-6 in 83% of those with an internal carotid artery and/or M1 occlusion. DISCUSSION: Outcomes depended on stroke severity, age and vessel of occlusion. Prognosis was worse if the occlusion included M1, especially in octogenarians. Mothership and Drip-n-ship strategies should be compared in patients from remote locations stratified by stroke severity and patient age.

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients.

BACKGROUND: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. OBJECTIVES: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. METHODS: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. RESULTS: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. CONCLUSIONS: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Adult onset epilepsy incidence in Finland over 34 years: A nationwide registry study.

BACKGROUND AND PURPOSE: The incidence of epilepsy is decreasing among the working-aged in high-income countries, but previous studies have reported conflicting results in Finland. METHODS: A nationwide population-based cross-sectional analysis was made of annual epilepsy drug reimbursement rights frequency data from the Social Insurance Institution of Finland, the national authority, between 1986 and 2019. All persons at least 20 years of age living in Finland during the study period were included. RESULTS: Based on the analysis of 77,939 new reimbursement rights, crude incidence was 57.4/100,000 (95% confidence interval [CI] = 57.0-57.8) person-years, and age-standardized (to the European Standard Population 2013) incidence was 51.6/100,000 person-years. Both crude (r = 0.62, p = 0.00009) and standardized (r = 0.65, p = 0.00003) incidence increased over time. Incidence increased in both men (from 66.4 to 71.6/100,000, r = 0.51, p = 0.002) and women (from 51.5 to 55.3/100,000, r = 0.68, p < 0.00001). The mean male to female incidence rate ratio was 1.28 (95% CI = 1.26-1.30, range = 1.15-1.41), but decreased during the study period (r = -0.47, p = 0.006). Incidence decreased in those 20-59 years old but increased in all older age groups. This development was similar between sexes. CONCLUSIONS: The incidence of adult onset epilepsy in Finland increased in people older than 60 years and decreased in the 20-59-year age group during the study period. These trends were similar between sexes. Therefore, etiological epilepsy trends in the elderly need to be studied further to plan public health measures to prevent epilepsy in this age group.