Challenges and needs in cerebrovascular disease pathway: A qualitative descriptive study from the patients' and healthcare professionals' perspectives.

AIM(S): To understand patients' and healthcare professionals' experiences to improve care in and across different domains of the cerebrovascular disease pathway. DESIGN: A qualitative descriptive study. METHODS: Semi-structured in-person interviews were conducted among 22 patients diagnosed with acute cerebrovascular disease and 26 healthcare professionals taking care of them in a single tertiary-level hospital from August 2021 to March 2022. Data were analysed using deductive and inductive content analysis. The consolidated criteria for reporting qualitative research was used to ensure reliable reporting. RESULTS: Overall, 19 generic and 79 sub-categories describing perceived challenges with 17 generic and 62 sub-categories describing perceived needs were identified related to primary prevention, organization of stroke services, management of acute stroke, secondary prevention, rehabilitation, evaluation of stroke outcome and quality assessment, and life after stroke. CONCLUSION: Several challenges and needs were identified in and across the different domains of the cerebrovascular disease pathway. There is a requirement for adequate resources, early initiation of treatment, early diagnostics and recanalization, dedicated rehabilitation services, long-term counselling and support, and impact evaluation of services to improve cerebrovascular disease care. Future research on caregivers', and clinical leadership experiences in and across the cerebrovascular disease pathway is needed to explore the provision of services. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The results of this study can be applied by organizations, managers and research for developing and improving services in the cerebrovascular disease pathway. IMPACT: This study identified several patient-related, organizational and logistical needs and challenges, with suggestions for required actions, that can benefit the provision of effective, high-quality cerebrovascular disease care. REPORTING METHOD: We have adhered to relevant EQUATOR guidelines with the COREQ reporting method. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement.

Patient experiences on the quality of cerebrovascular diseases counselling using digital solutions in hospital-A qualitative research study.

AIM: To describe patients' experiences of the quality of counselling to develop new digital counselling solutions for patients with cerebrovascular disease. DESIGN: A descriptive, qualitative approach. METHODS: Semi-structured in-person interviews were conducted among 22 patients diagnosed with acute cerebrovascular disease and treated as inpatients at a single university hospital in Finland between September 2021 and February 2022. Data were analysed using deductive and inductive content analysis. RESULTS: The identified facilitators, barriers and possible solutions for the development of new digital counselling solutions were deductively categorized into five main categories: (1) background factors, (2) resources, (3) implementation, (4) sufficiency, and (5) effects and 12 generic categories. Patients with cerebrovascular diseases worry about symptoms affecting their ability to receive information and valued a supportive atmosphere. Staff should have more time for counselling and use motivational digital counselling solutions in plain language, moderate length and with multimedia content. Patients desired reminders, easy search functions and possibilities for two-way communication. CONCLUSION: New digital counselling solutions could be beneficial in supporting the patients' knowledge, emotions and adherence. For the success of such solutions, patients' special needs concerning different levels of cognitive impairment need to be considered. IMPACT: The results of this study may benefit healthcare organizations in the development of digital counselling solutions that meet the patients' needs. REPORTING METHOD: We have adhered to relevant EQUATOR guidelines with the COREQ reporting method. PATIENT OR PUBLIC CONTRIBUTION: Patients were involved as the study population.

Validation of the Finnish Version of the Unified Dyskinesia Rating Scale.

INTRODUCTION: The Unified Dyskinesia Rating Scale (UDysRS) was developed to provide a comprehensive rating tool of dyskinesia in Parkinson's disease (PD). Because dyskinesia therapy trials involve multicenter studies, having a scale that is validated in multiple non-English languages is pivotal to international efforts to treat dyskinesia. The aim of the present study was to organize and perform an independent validation of the UDysRS Finnish version. METHODS: The UDysRS was translated into Finnish and then back-translated into English using 2 independent teams. Cognitive pretesting was conducted on the Finnish version and required modifications to the structure or wording of the translation. The final Finnish version was administered to 250 PD patients whose native language is Finnish. The data were analyzed to assess the confirmatory factor structure to the Spanish UDysRS (the reference standard). Secondary analyses included an exploratory factor analysis (EFA), independent of the reference standard. RESULTS: The comparative fit index (CFI), in comparison with the reference standard factor structure, was 0.963 for Finnish. In the EFA, where variability from sample to sample is expected, isolated item differences of factor structure were found between the Finnish and Reference Standard versions of the UDysRS. These subtle differences may relate to differences in sample composition or variations in disease status. CONCLUSION: The overall factor structure of the Finnish version was consistent with that of the reference standard, and it can be designated as the official version of the UDysRS for Finnish speaking populations.

Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial.

BACKGROUND: The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. METHODS: Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. RESULTS: Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, - 1.9 [- 3.25, - 0.47]; P = 0.009; monthly fremanezumab, - 3.0 [- 4.39, - 1.59]; P < 0.001), the United States (quarterly fremanezumab, - 3.7 [- 5.77, - 1.58]; P < 0.001; monthly fremanezumab, - 4.2 [- 6.23, - 2.13]; P < 0.001), and Finland (quarterly fremanezumab, - 3.0 [- 5.32, - 0.63]; P = 0.014; monthly fremanezumab, - 3.9 [- 6.27, - 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from - 5.6 to - 2.4 with quarterly fremanezumab and from - 5.3 to - 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups. CONCLUSIONS: Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03308968 .

Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized, placebo-controlled, phase 3b FOCUS study.

BACKGROUND: Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18-45 years and > 45 years) and sex. METHODS: In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18-45 and > 45 years) and sex subgroups. RESULTS: The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18-45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18-45 years: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.7 days; placebo, - 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.7 days; placebo, - 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, - 4.1 days; monthly fremanezumab, - 4.6 days; placebo, - 0.3 days; P < 0.001; female: quarterly fremanezumab, - 3.6 days; monthly fremanezumab, - 3.9 days; placebo, - 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups. CONCLUSIONS: These results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03308968 (FOCUS), registered October 13, 2017.

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.

Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease.

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate-induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy.

OBJECTIVE: Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA-induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. METHODS: Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. RESULTS: A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. SIGNIFICANCE: POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

Mutation m.15923A>G in the MT-TT gene causes mild myopathy - case report of an adult-onset phenotype.

BACKGROUND: Only five patients have previously been reported to harbor mutations in the MT-TT gene encoding mitochondrial tRNA threonine. The m.15923A > G mutation has been found in three severely affected children. One of these patients died within days after birth and two had a phenotype of myoclonic epilepsy with ragged red fibers (MERRF) in early childhood. We have now found the mutation in an adult patient with mild myopathy. CASE PRESENTATION: The patient is a 64-year-old Finnish man, who developed bilateral ptosis, diplopia and exercise intolerance in his fifties. Family history was unremarkable. Muscle histology showed cytochrome c-oxidase (COX) negative and ragged red fibres. The m.15923A > G mutation heteroplasmy was 33% in the skeletal muscle and 2% in buccal epithelial cells. The mutation was undetectable in the blood. Single-fibre analysis was performed and COX-negative fibres had a substantially higher heteroplasmy of 92%, than the normal fibres in which it was 43%. CONCLUSIONS: We report the fourth patient with m. 15923A > G and with a remarkably milder phenotype than the previous three patients. Our findings and recent biochemical studies suggest that the mutation m.15923A > G is a definite disease-causing mutation. Our results also suggest that heteroplasmy of the m.15923A > G mutation correlates with the severity of the phenotype. This study expands the catalog of the phenotypes caused by mutations in mtDNA.

A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease.

BACKGROUND: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. METHODS: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions. RESULTS: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered. CONCLUSIONS: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations.

Molecular Epidemiology of Charcot-Marie-Tooth Disease in Northern Ostrobothnia, Finland: A Population-Based Study.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder with a population prevalence of 9.7-82.3/100,000. In this study, we have estimated the prevalence of CMT and its subtypes in Finland and examined the frequency of molecular etiologies. METHODS: A population-based survey included adult patients with peripheral neuropathy from the province of Northern Ostrobothnia, Finland. Secondary causes of peripheral polyneuropathy were excluded and patients with clinical and neurophysiological features pertinent with CMT were included. Molecular diagnostics was carried out when DNA was available. RESULTS: We found 107 subjects with CMT yielding a prevalence 34.6/100,000 in Northern Ostrobothnia. The heterozygous point mutation p.His123Arg in ganglioside induced differentiation associated protein 1 (GDAP1) was found in 31.5% and peripheral myelin protein 22 (PMP22) duplication in 16.9% of the affected. Point mutations in myelin protein zero, mitofusin 2, and gap junction protein beta 1 accounted for 6.7% of the cases. In addition, 18 persons had hereditary neuropathy with liability to pressure palsies and 15 of them carried the PMP22 deletion. CONCLUSIONS: The prevalence of CMT in Northern Ostrobothnia, Finland, seems to be slightly higher than those in previous studies in European populations. Founder mutation in the GDAP1 gene accounts for a large part of the genetically defined CMT2 in Finland.

Case report: a novel frameshift mutation in the mitochondrial cytochrome c oxidase II gene causing mitochondrial disorder.

BACKGROUND: Mitochondrial cytochrome c oxidase 2, MT-CO2, encodes one of the three subunits, which form the catalytic core of cytochrome c oxidase (COX), complex IV. Mutations in MT-CO2 are rare and the associated phenotypes are variable including nonsyndromic and syndromic forms of mitochondrial diseases. CASE PRESENTATION: We describe a 30-year-old man with cognitive decline, epilepsy, psychosis, exercise intolerance, sensorineural hearing impairment, retinitis pigmentosa, cataract and lactic acidosis. COX-deficient fibers and ragged red fibers were abundant in the muscle. Sequencing of mitochondrial DNA (mtDNA) revealed a novel frameshift mutation m.8156delG that was predicted to cause altered C-terminal amino acid sequence and to lead to truncation of the COX subunit 2. The deletion was heteroplasmic being present in 26% of the mtDNA in blood, 33% in buccal mucosa and 95% in muscle. Deletion heteroplasmy correlated with COX-deficiency in muscle histochemistry. The mother and the siblings of the proband did not harbor the deletion. CONCLUSIONS: The clinical features and muscle histology of the proband suggested a mitochondrial disorder. The m.8156delG deletion is a new addition to the short list of pathogenic mutations in the mtDNA-encoded subunits of COX. This case illustrates the importance of mtDNA sequence analysis in patients with an evident mitochondrial disorder.

Myocardial glucose uptake in patients with the m.3243A > G mutation in mitochondrial DNA.

Mitochondrial mutations impair glucose oxidation and increase glucose uptake in cell cultures and lead to cardiomyopathy in patients. Here we characterize cardiac glucose uptake in 14 patients with the m.3243A > G mutation in mitochondrial DNA. The 14 patients with m.3243A > G and 13 controls were similar in age, physical activity and body mass index. Ten patients had diabetes. Left ventricular glucose uptake per tissue mass (LVGU) was measured with 2-[(18) F]fluoro-2-deoxyglucose positron emission tomography during euglycemic hyperinsulinemia. Cardiac morphology and function were assessed with magnetic resonance imaging. We found that the LVGU was 25% lower in the patients than that in the controls (P = 0.029). LVGU was inversely correlated with mutation heteroplasmy, glycated haemoglobin and fasting lactate in patients. The seven patients with mutation heteroplasmy ≥ 49% had 44% lower LVGU than the seven patients with heteroplasmy < 49%. This difference remained significant after adjustment for concurrent free fatty acid concentration or glycated haemoglobin or glucose uptake in skeletal muscle or all (p < 0.048 [All]). Patients with m.3243A > G had a lower stroke volume and a higher heart rate than the controls, whereas cardiac output and work were similar. Myocardial glucose uptake is not increased but decreased with a threshold effect pattern in patients with the m.3243A > G mutation. The glucose hypometabolism adds to the impaired cardiac energetics and likely contributes to the progression of the mitochondrial cardiomyopathy.

Atypical phenotypes in titinopathies explained by second titin mutations.

OBJECTIVE: Several patients with previously reported titin gene (TTN) mutations causing tibial muscular dystrophy (TMD) have more complex, severe, or unusual phenotypes. This study aimed to clarify the molecular cause of the variant phenotypes in 8 patients of 7 European families. METHODS: Clinical, histopathological, and muscle imaging data of patients and family members were reanalyzed. The titin protein was analyzed by Western blotting and TTN gene by reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing. RESULTS: Western blotting showed more pronounced C-terminal titin abnormality than expected for heterozygous probands, suggesting the existence of additional TTN mutations. RT-PCR indicated unequal mRNA expression of the TTN alleles in biopsies of 6 patients, 3 with an limb-girdle muscular dystrophy type 2J (LGMD2J) phenotype. Novel frameshift mutations were identified in 5 patients. A novel A-band titin mutation, c.92167C>T (p.P30723S), was found in 1 patient, and 1 Portuguese patient with a severe TMD phenotype proved to be homozygous for the previously reported Iberian TMD mutation. INTERPRETATION: The unequal expression levels of TTN transcripts in 5 probands suggested severely reduced expression of the frameshift mutated allele, probably through nonsense-mediated decay, explaining the more severe phenotypes. The Iberian TMD mutation may cause a more severe TMD rather than LGMD2J when homozygous. The Finnish patient compound heterozygous for the FINmaj TMD mutation and the novel A-band titin missense mutation showed a phenotype completely different from previously described titinopathies. Our results further expand the complexity of muscular dystrophies caused by TTN mutations and suggest that the coexistence of second mutations may constitute a more common general mechanism explaining phenotype variability.

Hereditary myopathy with early respiratory failure: occurrence in various populations.

OBJECTIVE: Several families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying cause in these families, and to characterise the phenotype in our large cohort. METHODS: DNA samples of all currently known families with HMERF without molecular genetic cause were obtained from 12 families in seven different countries. Clinical, histopathological and muscle imaging data were collected and five biopsy samples made available for further immunohistochemical studies. Genotyping, exome sequencing and Sanger sequencing were used to identify and confirm sequence variations. RESULTS: All patients with clinical diagnosis of HMERF were genetically solved by five different titin mutations identified. One mutation has been reported while four are novel, all located exclusively in the FN3 119 domain (A150) of A-band titin. One of the new mutations showed semirecessive inheritance pattern with subclinical myopathy in the heterozygous parents. Typical clinical features were respiratory failure at mid-adulthood in an ambulant patient with very variable degree of muscle weakness. Cytoplasmic bodies were retrospectively observed in all muscle biopsy samples and these were reactive for myofibrillar proteins but not for titin. CONCLUSIONS: We report an extensive collection of families with HMERF with five different mutations in exon 343 of TTN, which establishes this exon as the primary target for molecular diagnosis of HMERF. Our relatively large number of new families and mutations directly implies that HMERF is not extremely rare, not restricted to Northern Europe and should be considered in undetermined myogenic respiratory failure.

Status epilepticus in POLG disease: a large multinational study.

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.

Feasibility and patient acceptability of a commercially available wearable and a smart phone application in identification of motor states in parkinson's disease.

In the quantification of symptoms of Parkinson's disease (PD), healthcare professional assessments, patient reported outcomes (PRO), and medical device grade wearables are currently used. Recently, also commercially available smartphones and wearable devices have been actively researched in the detection of PD symptoms. The continuous, longitudinal, and automated detection of motor and especially non-motor symptoms with these devices is still a challenge that requires more research. The data collected from everyday life can be noisy and frequently contains artefacts, and novel detection methods and algorithms are therefore needed. 42 PD patients and 23 control subjects were monitored with Garmin Vivosmart 4 wearable device and asked to fill a symptom and medication diary with a mobile application, at home, for about four weeks. Subsequent analyses are based on continuous accelerometer data from the device. Accelerometer data from the Levodopa Response Study (MJFFd) were reanalyzed, with symptoms quantified with linear spectral models trained on expert evaluations present in the data. Variational autoencoders (VAE) were trained on both our study accelerometer data and on MJFFd to detect movement states (e.g., walking, standing). A total of 7590 self-reported symptoms were recorded during the study. 88.9% (32/36) of PD patients, 80.0% (4/5) of DBS PD patients and 95.5% (21/22) of control subjects reported that using the wearable device was very easy or easy. Recording a symptom at the time of the event was assessed as very easy or easy by 70.1% (29/41) of subjects with PD. Aggregated spectrograms of the collected accelerometer data show relative attenuation of low (<5Hz) frequencies in patients. Similar spectral patterns also separate symptom periods from immediately adjacent non-symptomatic periods. Discriminative power of linear models to separate symptoms from adjacent periods is weak, but aggregates show partial separability of patients vs. controls. The analysis reveals differential symptom detectability across movement tasks, motivating the third part of the study. VAEs trained on either dataset produced embedding from which movement states in MJFFd could be predicted. A VAE model was able to detect the movement states. Thus, a pre-detection of these states with a VAE from accelerometer data with good S/N ratio, and subsequent quantification of PD symptoms is a feasible strategy. The usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients. Finally, the usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients.

Phenotype of Patients With Charcot-Marie-Tooth With the p.His123Arg Mutation in GDAP1 in Northern Finland.

BACKGROUND AND OBJECTIVES: Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene cause autosomal dominant or autosomal recessive forms of Charcot-Marie-Tooth disease (CMT). Our aim was to study the clinical phenotype of patients with CMT caused by heterozygous p.His123Arg in GDAP1. METHODS: Twenty-three Finnish patients were recruited from a population-based cohort and through family investigation. Each patient was examined clinically and electrophysiologically. The Neuropathy Symptom Score and the Neuropathy Disability Score (NDS) were used in clinical evaluation. RESULTS: The median age at onset of symptoms was 17 years among patients with p.His123Arg in GDAP1. Motor symptoms were markedly more common than sensory symptoms at onset. All patients had distal weakness in lower extremities, and 17 (74%) patients had proximal weakness. Muscle atrophy and pes cavus were also common. Nineteen (82%) patients had sensory symptoms such as numbness or pain. The disease progressed with age, and the NDS increased 8.5 points per decade. Electrodiagnostic testing revealed length-dependent, sensory and motor axonal polyneuropathy. EDx findings were asymmetrical in 14 patients. Genealogic study of the families suggested a founder effect. DISCUSSION: We found that CMT in patients with p.His123Arg in GDAP1 is relatively mild and slow in progression.

Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial.

OBJECTIVE/BACKGROUND: Lemborexant is a dual orexin receptor antagonist approved in the United States, Japan, and Canada for the treatment of insomnia in adults. We report effectiveness and safety outcomes in subjects with insomnia who received up to twelve months of continuous lemborexant treatment in Study E2006-G000-303 (Study 303; SUNRISE-2). PATIENTS/METHODS: Study 303 was a twelve-month, global, multicenter, randomized, double-blind, parallel-group, Phase 3 study divided into two treatment periods. In Treatment Period 1 (first six months), subjects (n = 949, Full Analysis Set) were randomized to daily placebo, lemborexant 5 mg (LEM5) or lemborexant 10 mg (LEM10). In Treatment Period 2 (second six months), placebo subjects were rerandomized to LEM5 or LEM10, and subjects randomized to lemborexant continued their assigned treatment (LEM5, n = 251; LEM10, n = 226). Sleep onset and sleep maintenance endpoints were analyzed from daily electronic sleep diary data. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: For all sleep parameters, the significant benefits observed with LEM5 and LEM10 versus placebo over six months were maintained at twelve months in subjects who received twelve continuous months of treatment. There was no evidence of rebound insomnia or withdrawal in either lemborexant group following treatment discontinuation. Over twelve months of lemborexant treatment, most TEAEs were mild/moderate; the most common TEAEs were nasopharyngitis, somnolence and headache. CONCLUSIONS: LEM5 and LEM10 had significant benefit on sleep onset and sleep maintenance compared with placebo, and importantly, lemborexant effectiveness persisted at twelve months, suggesting that lemborexant may provide long-term benefits for subjects with insomnia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02952820; ClinicalTrialsRegister.eu, EudraCT Number 2015-001463-39.

POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype.

BACKGROUND: The c.2447G>A (p.R722H) mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease. METHODS: Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced. RESULTS: An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic. CONCLUSIONS: The recessive c.2447G>A (p.R722H) mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.