Browsing by Subject "epilepsy"

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  • Parmentier, Thomas; Monteith, Gabrielle; Cortez, Miguel A.; Wielaender, Franziska; Fischer, Andrea; Jokinen, Tarja S.; Lohi, Hannes; Sanders, Sean; Sammut, Veronique; Tai, Tricia; James, Fiona M. K. (2020)
    Background Ambulatory wireless video electroencephalography (AEEG) is the method of choice to discriminate epileptic seizures from other nonepileptic episodes. However, the influence of prior general anesthesia (GA), sedation, or antiseizure drug (ASD) on the diagnostic ability of AEEG is unknown. Hypothesis/Objectives The use of sedation/GA or ASD treatment before AEEG recording may affect the diagnostic ability of AEEG and the time to first abnormality on AEEG. Animals A total of 108 client-owned dogs undergoing ambulatory AEEG for paroxysmal episodes. Methods Retrospective cohort study. Proportions of diagnostic AEEG and time to first abnormality were compared between dogs that received sedation/GA or neither for instrumentation as well as dogs receiving at least 1 ASD and untreated dogs. Results Ambulatory EEG was diagnostic in 60.2% of all dogs including 49% of the sedation/GA dogs and 68% of dogs that received neither (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.02-5.00;P= .05). The AEEG was diagnostic in 51% of dogs receiving at least 1 ASD and 66% of untreated dogs (OR, 1.95; 95% CI, 0.9-4.3;P= .11). No difference was found in time to first abnormality between sedation/GA or neither or ASD-treated or untreated dogs (P= .1 andP= .3 respectively). Ninety-five percent of dogs had at least 1 abnormality within 277 minutes. Conclusion and Clinical Importance Sedation/GA and concurrent ASD administration were not identified as confounding factors for decreasing AEEG diagnostic capability nor did they delay the time to first abnormality. A 4-hour minimal recording period is recommended.
  • Hikmat, Omar; Naess, Karin; Engvall, Martin; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal M. E.; Brodtkorb, Eylert; Fiskerstrand, Torunn; Isohanni, Pirjo; Uusimaa, Johanna; Darin, Niklas; Rahman, Shamima; Bindoff, Laurence A. (2018)
    Objective: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. Methods: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries-Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF bather. Results: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). Significance: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.
  • Marshall, Pepin; Garton, Daniel R.; Taira, Tomi; Voikar, Vootele; Vilenius, Carolina; Kulesskaya, Natalia; Rivera, Claudio; Andressoo, Jaan-Olle (2021)
    Parvalbumin-positive interneurons (PV+) are a key component of inhibitory networks in the brain and are known to modulate memory and learning by shaping network activity. The mechanisms of PV+ neuron generation and maintenance are not fully understood, yet current evidence suggests that signalling via the glial cell line-derived neurotrophic factor (GDNF) receptor GFR alpha 1 positively modulates the migration and differentiation of PV+ interneurons in the cortex. Whether GDNF also regulates PV+ cells in the hippocampus is currently unknown. In this study, we utilized a Gdnf "hypermorph" mouse model where GDNF is overexpressed from the native gene locus, providing greatly increased spatial and temporal specificity of protein expression over established models of ectopic expression. Gdnf(wt/hyper) mice demonstrated impairments in long-term memory performance in the Morris water maze test and an increase in inhibitory tone in the hippocampus measured electrophysiologically in acute brain slice preparations. Increased PV+ cell number was confirmed immunohistochemically in the hippocampus and in discrete cortical areas and an increase in epileptic seizure threshold was observed in vivo. The data consolidate prior evidence for the actions of GDNF as a regulator of PV+ cell development in the cortex and demonstrate functional effects upon network excitability via modulation of functional GABAergic signalling and under epileptic challenge.
  • Tarkiainen, Virpi (Helsingfors universitet, 2013)
    Goals: The purpose of the study was to describe and analyse the content of online discussions and shared experiences among parents of children who suffer from epilepsy as well as parents' experiences with online peer support and its development. The goal was to deepen understanding of online peer support and the experiences of parents, and to develop the online activities of the Finnish Epilepsy Foundation based on the information gained. Previous studies about peer support have included group manifestations, personal experiences and peer support in community discussions. More and more peer support is available online, which has been seen in peer support studies from 2000 2009. Online peer support has been reported as both supporting and hindering empowering experiences. Previous studies have highlighted the significance of personal experiences. In this study, the concept of "experience" is defined from the standpoint of Dewey. Peer support is approached in the framework of empowerment. The study addresses four research questions. 1) What do parents of children with epilepsy write in online discussions? 2) What kind of experiences do they share in it? 3) What kind of experiences have parents had with online peer support, and which experiences further parents' empowerment? 4) How should online discussions be developed among parents? Methods: Study data was drawn from online discussions written by parents of children with epilepsy (the first message posted and the following message chain) and interviews with six (N = 6) parents who agreed to theme interviews. Web materials were written 15 June 13 December 2012. Data from theme interviews were gathered in February 2013 by interviewing parents by phone or in person. Web postings and interview content were handled using abductive content analysis, such that high rankings in the analysis utilised concepts of Siitonen's empowerment model (1999). Results and conclusions: The Internet offered parents of ill children an opportunity to share their experiences with other parents in similar life situations. In online discussions, parents shared their experiences about their children becoming ill, epilepsy treatments, support they had experienced as well as their emotions and mental images of the future. The significance of experiential data was highlighted in what parents wrote. Parents experienced the discussion environment as friendly, open, matter-of-fact and empathetic. From the standpoint of empowerment, it was significant that parents had the strength to support one another even in very difficult everyday life situations. The significance of experiences was affected by the environment of the online discussion, its content, parents' pre-conceived expectations as well as sharing emotional experiences and mental images of the future. Factors in the development of online discussions were related to briefing of the service, improved availability as well as active facilitation.
  • Laugesaar, Rael; Vaher, Ulvi; Lõo, Silva; Kolk, Anneli; Männamaa, Mairi; Talvik, Inga; Õiglane-Shlik, Eve; Loorits, Dagmar; Talvik, Tiina; Ilves, Pilvi (2018)
    Objective: With an incidence up to 63/100,000 live births, perinatal stroke is an important cause of childhood epilepsy. The aim of the study was to find the prevalence and predictive factors of epilepsy, and to describe the course of epilepsy of children with perinatal stroke with different vascular subtypes. Methods: Patients were retrieved from Estonian Paediatric Stroke Database with follow-up time at least 24 months. Patients were divided into five perinatal stroke syndromes: neonatal arterial ischemic stroke (AIS), neonatal hemorrhagic stroke, neonatal cerebral sinovenous thrombosis, presumed AIS, and presumed periventricular venous infarction. Results: Final study group included 73 children with perinatal stroke (39 boys). With median follow-up time 8.6 years, epilepsy was diagnosed in 21/73 (29%) children, most of whom had AIS (17/21, 81%). The 18-year cumulative post-stroke epilepsy risk according to Kaplan-Meier estimator was 40.8% (95%CI: 20.7–55.9%). The median age at epilepsy diagnosis was 50 months (range 1 month to 18.4 years). Children with neonatal AIS had the highest risk of epilepsy, but children with presumed AIS had more often severe epilepsy syndromes. Cortical lesions (OR 19.7; 95%CI 2.9–133), involvement of thalamus (OR 9.8; 95%CI: 1.8–53.5) and temporal lobe (OR 8.3; 95%CI: 1.8–39.6) were independently associated with post-stroke epilepsy. Significance: The risk for poststroke epilepsy after perinatal stroke depends on the vascular subtype. Patients with perinatal AIS need close follow-up to detect epilepsy and start with antiepileptic treatment on time. This article is protected by copyright. All rights reserved.
  • Leino, Teppo (Helsingfors universitet, 2013)
    Voltage-gated sodium channels play an essential role in the function of the nervous system as they are responsible for producing action potentials. Abnormal activity of sodium channels is in connection to several diseases such as epilepsy and chronic pain. Voltage-gated sodium channel blockers which are selective towards a specific isoform could provide more efficient and better tolerated drugs to treat these diseases when compared to the drugs used today. Clathrodin is an alkaloid isolated from Caribbean sea sponge Agelas clathrodes. Bioactivity studies have shown that clathrodin changes the function of voltage-gated sodium channels. The aim of this study was to synthesize two kinds of structure analogs of clathrodin and study their structure-activity relationship towards different isoforms of voltage-gated sodium channels. The study is part of the MAREX project (Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications) funded by the European Union. Intention of the project is to find new bioactive compounds in marine organisms. A four-step route was developed for synthesizing 2-aminobenzothiazole analogs. A three-step route was developed as well but the last step seemed to be problematic for some of the compounds. The three-step route provided new compounds as intermediates and some of them were sent to tests for activity. Synthesis of 1H-pyrrole-2-carboxamide analogs of clathrodin failed. 4,5-dihydrooxazole was recognized as a problem as it was formed as a result of a cyclization reaction when bromination was tried on the intermediate. The formed structure was used in synthesizing 2-(1H-pyrrol-2-yl)-4,5-dihydrooxazole analogs of clathrodin. These reactions failed to give any final products which could have been tested for activity. Eight synthesized compounds were sent to tests for activity. Results were received from two of them and they showed no activity towards the voltage-gated sodium channels in 10 µM concentrations. Discussion about structure-activity relationship is not possible based on two compounds only.
  • Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Bonifazi, Paolo; Abiega, Oihane; Diaz-Aparicio, Irune; Tegelberg, Saara; Lehesjoki, Anna-Elina; Valero, Jorge; Sierra, Amanda (2020)
    Objective Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB). Methods We used confocal imaging and stereology-based quantification of apoptosis and phagocytosis of the hippocampus ofCstbknockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduceCstbexpression, and a virtual three-dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons. Results Microglial phagocytosis was impaired in the hippocampus ofCstbKO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present inCstbKO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) inCstb-deficient mice were at close proximity to active cFos(+)neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos(+)neurons was specific forCstbKO mice. Significance These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction inCstbKO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.
  • Macharey, Georg; Väisänen-Tommiska, Mervi; Gissler, Mika; Ulander, Veli-Matti; Rahkonen, Leena; Nuutila, Mika; Heinonen, Seppo (2018)
    Purpose: To evaluate whether a trial of planned vaginal breech labor affects neurologic development in children. Methods: This is a nationwide, Finnish, population-based record linkage study. An odds ratio with 95% confidence intervals was used to estimate the relative risk that a child delivered by planned vaginal breech labor would be diagnosed with adverse neurodevelopmental outcome (cerebral palsy, epilepsy, intellectual disability, sensor neural developmental outcome, hyperactivity, speech and language problems) at the age of 4 years. The reference group were children born by planned cesarean section. Results: During a study period of 7 years, 8374 infants were delivered in breech position. Among them, 3907 (46.7%) had an attempted labor and 4467 (53.3%) infants were delivered by planned cesarean section. There were no differences in the neurodevelopmental outcome. In the planned vaginal labor group, 133 (3.4%) children had an abnormal neurodevelopmental outcome at the age of 4 years compared to 142 (3.2%) in the planned cesarean section group. Conclusion: The absolute risk of abnormal neurological outcome in breech deliveries at term was low, regardless of planned mode of birth. Planned vaginal breech labor did not increase the risk for abnormal neurological outcome compared to planned cesarean section.
  • Räty, Silja; Sallinen, Hanne; Virtanen, Pekka; Haapaniemi, Elena; Wu, Teddy Y.; Putaala, Jukka; Meretoja, Atte; Tatlisumak, Turgut; Strbian, Daniel (2021)
    Objectives Posterior location affects the clinical presentation and outcome of ischemic stroke, but little is known about occipital intracerebral hemorrhage (ICH). We studied non-traumatic occipital ICH phenotype, outcome, and post-ICH epilepsy. Materials and Methods Occipital ICH patients were retrospectively identified from the Helsinki ICH Study registry of 1013 consecutive ICH patients treated in our tertiary center in 2005-2010. They were compared to non-occipital ICH patients to evaluate the effect of location on functional outcome at discharge (dichotomized modified Rankin Scale, mRS), 3- and 12-month mortality, and incidence of epilepsy. Results We found 19 occipital ICH patients (5.3% of lobar and 1.9% of all ICH). Compared to non-occipital lobar ICHs, they were younger (median age 63 vs 71 years,P= .007) and had lower National Institutes of Health Stroke Scale on admission (1 vs 8,P<.001), smaller hematoma volume (6.3 vs 17.7 ML,P= .008), and more frequently structural etiology underlying the ICH (26% vs 7%,P= .01). Mortality at both 3 and 12 months was 6%, whereas 84% reached favorable outcome (mRS 0-2) at discharge. Occipital location was associated with favorable outcome at discharge in lobar ICH (OR 11.02, 95% CI 1.55-78.20). Incidence of post-ICH epilepsy (median follow-up 2.7 years) was 18%, equaling to that of non-occipital lobar ICH. Conclusions Occipital ICH patients are younger, have less severe clinical presentation, smaller hematoma volume, more often structural etiology, and better outcome than other ICH patients. They exhibit a similar risk of epilepsy as non-occipital ICHs.
  • EuroEPINOMICS- RES Consortium; Tang, Shan; Addis, Laura; Smith, Anna; Pal, Deb K.; Lehesjoki, Anna-Elina (2020)
    Objective We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). Methods We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. Results We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. Significance MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.
  • Issakainen, Jani (Helsingin yliopisto, 2021)
    Electroencephalography (EEG) is a non-invasive neurophysiological method for evaluating brain activity by measuring electrical potential at the scalp. The electrical potentials originate mainly from postsynaptic cortical currents created by neuronal activity. It is a valuable tool for both research and clinical practice. EEG can be used e.g. to diagnose epilepsy, focal brain disorders, brain death, and coma. Intermittent photic stimulation (IPS) is an important tool in clinical EEG. Healthcare professionals use it to induce epileptic activity in patients to help diagnose their conditions. In these tests, various IPS frequencies are used with eyes-closed, eyes-open, and eye-closure conditions. IPS test is listed in clinical practice guidelines in EEG globally, and it is mainly used to diagnose photosensitive epilepsy, i.e., to detect epilepsy-related abnormal sensitivity to flickering light. Magnetoencephalography (MEG) is a non-invasive neurophysiological method in which minute magnetic fields — produced by the same postsynaptic currents as in EEG — are measured with special superconductive sensors around the head. MEG is a valuable tool for research and clinical practice with increasing world-wide utilization. The main advantages of MEG over EEG are easier source modelling and higher resolution at cortical areas. IPS has not been introduced to MEG since the IPS stimulators used in EEG are not compatible with MEG. IPS in MEG could improve the analysis of IPS and provide better tools for diagnoses. Currently, data analysis of IPS is typically limited to healthcare professionals examining the visualization of the raw data while looking for induced epileptiform activites and lateralizing them. In this thesis, an MEG-compatible IPS stimulator is introduced and alternative ways of analyzing IPS data for both MEG and EEG are showcased. Although analysis methods were applied with decent signal-to-noise ratios, further research is needed—especially to compare responses between patients with epilepsy and healthy subjects.
  • Epi25 Consortium; Leu, Costin; Stevelink, Remi; Palotie, Aarno; Daly, Mark J.; Lehesjoki, Anna-Elina (2019)
    Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64 x 10(-15); Cleveland: P = 2.85 x 10(-4); Finnish-ancestry Epi25: P = 1.80 x 10(-4)) or population controls (Epi25: P = 2.35 x 10(-70); Cleveland: P = 1.43 x 10(-7); Finnish-ancestry Epi25: P = 3.11 x 10(-4); UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 x 10(-4)). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74 x 10(-19); Cleveland: P = 1.69 x 10(-6)). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60 x 10(-15); Cleveland: P = 1.39 x 10(-2)). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
  • Mikkonen, Era D.; Skrifvars, Markus B.; Reinikainen, Matti; Bendel, Stepani; Laitio, Ruut; Hoppu, Sanna; Ala-Kokko, Tero; Karppinen, Atte; Raj, Rahul (2020)
    Objective Posttraumatic epilepsy (PTE) is a well-described complication of traumatic brain injury (TBI). The majority of the available data regarding PTE stem from the adult population. Our aim was to identify the clinical and radiological risk factors associated with PTE in a pediatric TBI population treated in an intensive care unit (ICU). Methods We used the Finnish Intensive Care Consortium database to identify pediatric ( Results Of the 290 patients included in the study, 59 (20%) developed PTE. Median age was 15 years (interquartile range [IQR] 13-17), and 80% had an admission Glasgow Coma Scale (GCS) score Significance We showed that PTE is a common long-term complication after ICU-treated pediatric TBI. Higher age, moderate injury severity, obliterated suprasellar cisterns, seizures during ICU stay, and surgical treatment are associated with an increased risk of PTE. Further studies are needed to identify strategies to decrease the risk of PTE.
  • Hikmat, Omar; Naess, Karin; Engvall, Martin; Klingenberg, Claus; Rasmussen, Magnhild; Tallaksen, Chantal M. E.; Brodtkorb, Eylert; Ostergaard, Elsebet; de Coo, I. F. M.; Pias-Peleteiro, Leticia; Isohanni, Pirjo; Uusimaa, Johanna; Darin, Niklas; Rahman, Shamima; Bindoff, Laurence A. (2020)
    Background Variants inPOLGare one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods A multinational, retrospective study using data from 155 patients withPOLGvariants recruited from seven European countries. Results We describe the spectrum of clinical features associated withPOLGvariants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset-onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.
  • Johannesen, Katrine M.; Gardena, Elena; Encinas, Alejandra C.; Lehesjoki, Anna-Enna; Linnankivi, Tarja; Petersen, Michael B.; Lund, Ida Charlotte Bay; Blichfeldt, Susanne; Miranda, Maria J.; Pal, Deb K.; Lascelles, Karine; Procopis, Peter; Orsini, Alessandro; Bonuccelli, Alice; Giacomini, Thea; Helbig, Ingo; Fenger, Christina D.; Sisodiya, Sanjay M.; Hernandez-Hernandez, Laura; Krithika, Sundararaman; Rumple, Melissa; Masnada, Silvia; Valente, Marialuisa; Cereda, Cristina; Giordano, Lucio; Accorsi, Patrizia; Burki, Sarah; Mancardi, Margherita; Korff, Christian; Guerrini, Renzo; von Spiczak, Sarah; Hoffman-Zacharska, Dorota; Mazurczak, Tomasz; Coppola, Antonietta; Buono, Salvatore; Vecchi, Marilena; Hammer, Michael F.; Varesio, Costanza; Veggiotti, Pierangelo; Lal, Dennis; Bruenger, Tobias; Zara, Federico; Striano, Pasquale; Rohholi, Guido; Moller, Rikke S. (2019)
    Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
  • Khan, Luqman; van Lanen, Rick; Hoogland, Govert; Schijns, Olaf; Rijkers, Kim; Kapsokalyvas, Dimitrios; van Zandvoort, Marc; Haeren, Roel (2021)
    Despite extensive research, the exact pathomechanisms associated with epileptic seizure formation and propagation have not been elucidated completely. Two-photon imaging (2PI) is a fluorescence-based microscopy technique that, over the years, has been used to evaluate pathomechanisms associated with epileptic seizures and epilepsy. Here, we review previous applications of 2PI in epilepsy. A systematic search was performed in multiple literature databases. We identified 38 publications that applied 2PI in epilepsy research. These studies described models of epileptic seizure propagation; anatomical changes and functional alterations of microglia, astrocytes, and neurites; and neurometabolic effects that accompany seizures. Moreover, various neurovascular alterations that accompany seizure onset and ictal events, such as blood vessel responses, have been visualized using 2PI. Lastly, imaging and quantitative analysis of oxidative stress and the aggregation of lipofuscin in the neurovasculature have been accomplished with 2PI. Cumulatively, these papers and their reported findings demonstrate that 2PI is an especially well-suited imaging technique in the domain of epilepsy research, and these studies have significantly improved our understanding of the disorder. The application of 2PI provides ample possibilities for future research, most interestingly on human brains, while also stretching beyond the field of epilepsy.