Abstract:The management of shoulder injuries resulting from epileptic seizures presents a particular challenge. These injuries often present complex patterns, ranging from dislocations and fractures to damage to the rotator cuff. Recurrent seizures can significantly impact the outcome and must be considered a central risk factor when choosing the therapeutic approach. Accordingly, these injuries require close multidisciplinary cooperation between orthopaedics/trauma surgery, neurology/epileptology and physiotherapy, both in diagnosis and treatment. Despite their clinical relevance, standardised treatment algorithms are currently lacking, and the available scientific evidence remains limited. This review article addresses the specific characteristics of seizure-related shoulder injuries within a multidisciplinary approach. Epidemiological aspects, including pathomechanical principles, diagnostic challenges, and current conservative and surgical treatment options, are discussed.

Psychische Erkrankungen treten bei Menschen mit Epilepsie häufiger auf, umgekehrt haben psychiatrische Patient*innen ein erhöhtes Epilepsierisiko. Psychosoziale Faktoren, Medikamenteneffekte, peri- und interiktale Symptome spielen ebenso wie gemeinsame genetische Mechanismen eine Rolle, insbesondere bei seltenen monogenetischen Epilepsiesyndromen. Der Übersichtsartikel behandelt exemplarisch GRIN2A-assoziierte Syndrome, entwicklungsbedingte und epileptische Enzephalopathien einschließlich Dravet-Syndrom sowie tuberöse Sklerose. Zusammengefasst werden neuropsychiatrische Manifestationen, pathophysiologische Grundlagen und zielgerichtete Therapien. Schwerpunkt ist die systematische Erfassung psychiatrischer Symptome und die präzise klinische Phänotypisierung zur Beurteilung krankheitsmodifizierender Therapieeffekte jenseits der Anfallskontrolle. Ziel ist es, klinische Implikationen, Versorgungsdefizite und offene Fragen aufzuzeigen und interdisziplinäre neurologisch-psychiatrische Betreuung zu fördern.

Abstract Educational initiatives that address the gap between basic/preclinical and clinical practices are important to effectively translate basic science discoveries to benefit patients. The ILAE Neurobiology Commission conducted a pilot project aimed at exposing basic and preclinical scientists engaged in epilepsy research to general clinical issues pertaining to the diagnosis and care of people with epilepsy. This aim was addressed through a two‐week‐long, on‐site clinical training program for 50 basic scientists in 21 epilepsy centers across 18 countries in the six ILAE regions (with a maximum of 3 basic scientists per center). The learning objectives and the training module were discussed and defined by the project organizing committee, which consisted of Neurobiology Commission members and a team of epileptologists representing different geographical regions. The training activities were conducted at each epilepsy center under the local supervision of clinical tutors. Each basic scientist was exposed to 50.3 ± 23.3 (range 16–89) hours of intensive and dedicated clinical training, coordinated by 2–3 tutors per center, assisted by 6.8 ± 3.6 colleagues. A structured test consisting of 17 general clinical epilepsy questions was completed by the trainees before and after the training activity. The learning assessment was based on the comparison between responses to the exit and entry tests. After the on‐site clinical exposure, the proportion of correct answers increased to 87% compared to 61% in the entry test. Structured post‐training questionnaires demonstrated very high satisfaction of trainees and all involved tutors across the different aspects of the training module. This global pilot study demonstrated that on‐site attendance by basic scientists in specialized clinical settings up‐scaled their knowledge of clinical epileptology and facilitated networking with clinicians. Expansion of this pilot to further centers should be considered to understand how exposure to clinical practice affects research direction and quality of translational epilepsy research. Plain Language Summary Epilepsy research has long benefitted from collaboration between scientists and clinicians. Early exposure of researchers to people with epilepsy and their care teams may strengthen future impact. This pilot study tested a two‐week immersive experience where small teams of basic scientists shadowed clinicians during their work at hospitals around the world. Questionnaires showed high satisfaction among both groups. Results support expanding such training, with the backing of the International League Against epilepsy and aligned centers, to build understanding, interest, and long‐term commitment, ensuring bench research is informed by and translates to clinical practice and improved quality of life for patients.

Der kurzzeitige Bewusstseinsverlust ist ein häufiges Symptom in der Notfallversorgung. Differenzialdiagnostisch müssen Synkopen u. a. von epileptischen oder psychogenen Anfällen unterschieden werden, Fehleinschätzungen sind nicht selten. Dieser Artikel soll dazu befähigen, entscheidende klinische Kernsymptome systematisch zu erheben und so die Ursache des kurzzeitigen Bewusstseinsverlustes mit hoher Sicherheit abzuleiten.

Psychiatric disorders are more common in people with epilepsy and vice versa psychiatric patients have an increased risk of epilepsy. Psychosocial factors, medication effects, peri-ictal or interictal symptoms play a role as do shared genetic mechanisms, particularly in rare monogenic epilepsy syndromes. This review article exemplary discusses GRIN2A-associated disorders, development-related and epileptic encephalopathies including Dravet syndrome and tuberous sclerosis complex. Neuropsychiatric manifestations, pathophysiological foundations and targeted treatment are summarized. Emphasis is placed on the systematic assessment of psychiatric symptoms and detailed clinical phenotyping to evaluate disease-modifying effects of emerging therapies beyond seizure control. The article highlights the clinical implications, gaps in care and to present open questions and to promote interdisciplinary neurological psychiatric management.

Background/Objectives: Consanguine families are helpful to identify recessive candidate genes for inherited diseases, but can also show an unusual inheritance pattern of pathogenic mutations. In this case series, we demonstrate this in five consanguine families with epilepsy from Pakistan. Methods: We performed whole exome sequencing of respective index patients, analyzed the data using two different models for inheritance of mutations and determined the segregation pattern of relevant mutations in the families by bi-directional Sanger sequencing. Results: Apart from mutations in classical dominant epilepsy genes (TSC2, DEPDC5, and CACNA1I), pathogenic mutations in rare recessive epilepsy-related genes (PGAP2, NOVA2, and CCDC88C) were also identified. Interestingly, we were able to provide evidence that GALR2 is potentially an additional gene associated with a recessive form of epilepsy. In one family, a homozygous 'pathogenic' TRAF3IP1 p. Gly387* nonsense mutation was identified, which, most probably due to stop-codon read-through, did not contribute to the phenotype. Conclusions: Our case series of consanguine families with epilepsy exemplifies the inheritance pattern of mutations in rare recessive epilepsy genes, and shows that mutations in classical epilepsy genes showing dominant or sporadic inheritance can also be relevant. That requires the analysis of whole exome data on the basis of different inheritance models.

Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters. We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort. Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated. These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.

OBJECTIVE:We investigated the presence and potential functional relevance of antimitochondrial autoantibodies in patients suspicious for autoimmune encephalitis (AIE) associated with psychiatric symptoms and/or seizures, who were negative for known antineuronal autoantibodies. METHODS:We screened serum samples from 387 patients autoantibody-negative for known antineuronal autoantibodies with psychiatric disturbances and/or epileptic seizures, including patients with temporal lobe epilepsy of unknown etiology. Various techniques, including immunoblotting, immunoprecipitation, mass spectrometry, immunohistochemistry, and in vitro assays assessing neuronal autoantibody uptake, neuronal viability, pyruvate dehydrogenase (PDH) enzyme activity, and mitochondrial DNA levels in biofluids were applied. RESULTS:Mass spectrometry detected all three subunits of the intramitochondrial PDHc-pyruvate dehydrogenase, dihydrolipoyl acetyltransferase, and dihydrolipoyl dehydrogenase-as targets of antibodies present in serum samples from three index patients suspicious for AIE with psychiatric symptoms or seizures. The presence of the anti-PDHc autoantibodies was confirmed by immunoblotting in 12 of 387 patients. Exposure of cultured primary neurons to commercial anti-PDH antibodies resulted in neuronal uptake and loss of neuronal viability. Patient-derived autoantibodies also impaired PDH enzyme activity in vitro. Additionally, cell-free mitochondrial DNA fragment levels were elevated in the serum and cerebrospinal fluid of PDH-positive patients compared to controls. SIGNIFICANCE:Anti-PDH autoantibodies were detected in patients suspicious for AIE with seizures and/or psychiatric symptoms as core manifestation in the absence of known antineuronal autoantibodies. These autoantibodies bind neuronal structures and reduce PDH enzyme activity under experimental conditions, supporting mechanistic plausibility of a functional role in disease.

Objective Conceptualizing functional/dissociative seizures (FDS) as resulting from dissociation, or conversion, we hypothesized that, compared to epileptic seizures (ES), FDS should carry more symbolic or communicative content and that this would allow observers to distinguish FDS from ES.Methods Three independent, epileptologically naive raters evaluated home videos of patients with confirmed diagnoses of either FDS or ES using a standardized form. The focus of the ratings was explicitly not on seizure semiology, but on verbal and nonverbal behavior, the role of proxies, interaction patterns, communication, emotional tone, symbolic content, and situational context.Results Of 598 home videos available from 183 patients, 215 ES and 95 FDS videos were suitable for analysis. No explicit symbolic communication was identified. FDS showed more passive, withdrawn behavior, and the postictal phase-captured more often than the ictal period-was particularly helpful for distinguishing FDS from ES. Interrater reliability was moderate. Features observed more commonly in FDS included closed eyes, recumbent posture, repetitive movements, reduced eye contact, responses to caring behavior, and occurrence in private settings. Raters perceived greater emotional distress in FDS and reported more distress watching these videos. Logistic regression based on all ratings correctly classified 94% of ES but only 32% of FDS.Significance Home video analysis captures important contextual and behavioral features of FDS and ES. The differential diagnostic reliability of lay raters' perceptions is limited. Findings suggest that FDS comprise passive rather than active appellative communication, likely reflecting emotional regulation processes. In contrast, in the home videos studied, ES patients exhibit greater postictal awareness and interaction than FDS patients, pointing to the relevance of the postictal phase for discriminating both seizure types. The results emphasize integrating environmental context and patient-caregiver interactions before, during, and after seizures to understand the functional significance of FDS in naturalistic, nonclinical settings.

BACKGROUND AND OBJECTIVES:Autoimmune encephalitis (AIE) with anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies typically manifests with subacute cognitive deficits, seizures, and psychiatric symptoms, mostly in older adults. Immunotherapy (IT) leads to the cessation of seizures in most patients, yet some develop AIE-associated epilepsy (AEAE) and persistent cognitive deficits. The aim of this large multicentric retrospective observational cohort study was to assess long-term outcomes of patients with anti-LGI1 encephalitis regarding seizures and AEAE and to identify associated factors. METHODS:We included patients with anti-LGI1 encephalitis from 3 national referral centers/consortia meeting the following inclusion criteria: (I) definite LGI1 limbic encephalitis (Graus criteria); (II) occurrence of seizures; and (III) follow-up period ≥24 months. We aimed to (1) determine the risk of seizure recurrence (ROSR) on remission, (2) investigate clinical and paraclinical biomarkers for an effect on time to seizure remission using Cox proportional hazard modeling (n = 188), and (3) assess the risk of AEAE and determine associated factors (n = 236). RESULTS:AEAE was observed in 5.9% (16/271) of the full cohort. Both AEAE (16/16 vs 129/215, p = 0.001) and longer time to seizure remission (OR 1.36 per year, p = 0.025) were associated with persistent cognitive impairment. Patients with pilomotor seizures had a lower rate of seizure remission (hazard ratio [HR] 0.58, 95% CI 0.55-0.60, p < 0.001) while patients under IT administration had a higher rate of seizure remission over time (HR 12.4, 95% CI 9.67-16.0, p < 0.001). In addition, patients receiving second-line IT tended to achieve earlier seizure remission (log-rank test, p = 0.019). The ROSR at 12, 60, and 120 months on seizure remission was 9% (95% CI 4.5%-13%), 20% (95% CI 11%-28%), and 53% (95% CI 14%-74%), respectively. DISCUSSION:In conclusion, our results demonstrate that AEAE in anti-LGI1 encephalitis is rare and suggest that the diagnosis of epilepsy is inappropriate in patients reaching seizure remission because of a relatively low ROSR. Accordingly, on seizure remission, the diagnosis of acute symptomatic seizures would be appropriate. Moreover, we validate and quantify the importance of IT for seizure remission and identify biomarkers associated with lower rates of seizure remission. Late remission of seizures and AEAE were associated with persistent cognitive impairment.

Autoantibodies targeting the intracellular 65-kDa isoform of glutamic acid decarboxylase (anti-GAD65) have been associated with a variety of autoimmune-related syndromes involving a spectrum of difficult-to-treat neurological disorders. However, the pathophysiological role of anti-GAD65 in neuroinflammation remains vague. Its understanding may be complicated by the possible pathogenic interaction between anti-GAD65 and potentially coexisting autoantibodies. We combined a broad spectrum of approaches ranging from antibody-antigen identification, immunoblotting, immunoprecipitation, mass-spectrometry, cell-based assays, subcellular binding pattern analysis in primary neuronal cultures, and immunohistochemistry to in vitro assays of neuronal uptake, viability, and multi-electrode arrays. In anti-GAD65-positive neurological patients, mass-spectrometric analysis revealed cytosolic 5’-nucleotidase 1 A (CN1A syn. NT5C1A) as the most abundant antigen. Subsequent screening of 118 anti-GAD65-positive patients revealed that 32 of them had additional autoantibodies targeting CN1A, which were also present in all available corresponding CSF samples. Limbic encephalitis was more often diagnosed in anti-CN1A/anti-GAD65-positive compared to the anti-GAD65-positive patients. Functionally, incubation of primary hippocampal neurons with anti-GAD65, but not with anti-CN1A, resulted in uptake into GABAergic neurons, neuronal cell death, and increased neuronal network activity. Moreover, simultaneous incubation with both antibodies (anti-CN1A/anti-GAD65) resulted in concomitant intraneuronal uptake in a concentration-dependent manner, which correlated with enhanced autophagy followed by massive neuronal death. GAD65 antibodies directly affect neuronal viability and network activity. Co-existing autoantibodies against CN1A, present in anti-GAD65-positive patients, enhance autophagy and subsequent neuronal death in vitro. Clinically, anti-GAD65-positive patients should be screened for anti-CN1A-associated diseases, and evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions may clarify links between systemic autoimmunity and epilepsy. What is already known on this topic– Even though autoantibodies against GAD65 protein have been identified in several autoimmune disorders their direct pathogenic effects are highly controversial and patients are often difficult to treat. What this study adds– Anti-GAD65-positive patients often have coexisting CN1A autoantibodies, leading to higher incidence of limbic encephalitis, increased neuronal activity, with combined autoantibody uptake enhancing neuronal death rate correlated with enhanced autophagy. How this study might affect research, practice or policy– Patients positive for anti-GAD65 should be screened for anti-CN1A-associated diseases, and broader evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions (e.g., type 1 diabetes, vitiligo, Hashimoto’s thyroiditis) may clarify links between systemic autoimmunity and epilepsy. Anti-GAD65-positive neurological patients show a high prevalence of coexisting autoantibodies against CN1A. CN1A/GAD65 autoantibody-positive patients are more often diagnosed with limbic encephalitis. Patient-derived GAD65 autoantibodies increase network activity in cultured neurons. Interneuronal dendritic uptake of anti-CN1A combined with anti-GAD65 leads to aggravated neurodegeneration associated with enhanced autophagy.

Objective Stereotactic radiosurgery (SRS) emerges as a non-surgical treatment option for drug-resistant non-neoplastic focal epilepsy. Previous studies have reported that in about 20% of patients treated with radiotherapy, however, subsequent salvage surgery is required, among other because of symptomatic radiation necrosis (RN). We propose a novel and radiobiologically substantiated dose-fractionation regimen which minimizes the RN risk while aiming to preserve efficacy and report our first-in-human experience. Methods From February 2021 to April 2024, three patients (aged 42, 45, and 47 years) with different underlying etiologies were treated, including a post-hemorrhagic lesion, Rasmussen encephalitis, and focal cortical dysplasia. We applied linac-based frameless fractionated stereotactic radiotherapy (fSRT) to a total dose of 50 Gy in 10 fractions over 2 weeks. Each epileptogenic zone was defined by a multidisciplinary team, including a radiation oncologist, epileptologist, neurosurgeon, and neuroradiologist. Results The irradiated volumes were 10.3, 11.3, and 16.5 cm 3 . After a follow-up of 12, 29, and 36 months, all three patients experienced an improvement in both seizure frequency and severity (two already during or shortly after fSRT). One patient achieved complete seizure freedom. All patients reported improvements in quality of life and regained independence or displayed functional recovery. Tolerability was excellent, with radiation-induced side effects being mild (grade 1 only) and transient. RN was not observed. One patient died 29 months after radiotherapy most likely from a ruptured aneurysm of a vertebral artery, unrelated to the treatment. Significance Frameless fSRT of 50 Gy in 10 fractions was feasible and might be safe and effective in selected patients with drug-resistant non-neoplastic focal epilepsy and large suspected epileptogenic zones. A prospective single-arm evaluation with structured long-term follow-up including assessment of patient-reported outcome measures is currently being conducted.

Background and Objectives Autoimmune encephalitis (AIE) with anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies typically manifests with subacute cognitive deficits, seizures, and psychiatric symptoms, mostly in older adults. Immunotherapy (IT) leads to the cessation of seizures in most patients, yet some develop AIE-associated epilepsy (AEAE) and persistent cognitive deficits. The aim of this large multicentric retrospective observational cohort study was to assess long-term outcomes of patients with anti-LGI1 encephalitis regarding seizures and AEAE and to identify associated factors. Methods We included patients with anti-LGI1 encephalitis from 3 national referral centers/consortia meeting the following inclusion criteria: (I) definite LGI1 limbic encephalitis (Graus criteria); (II) occurrence of seizures; and (III) follow-up period >= 24 months. We aimed to (1) determine the risk of seizure recurrence (ROSR) on remission, (2) investigate clinical and paraclinical biomarkers for an effect on time to seizure remission using Cox proportional hazard modeling (n = 188), and (3) assess the risk of AEAE and determine associated factors (n = 236). Results AEAE was observed in 5.9% (16/271) of the full cohort. Both AEAE (16/16 vs 129/215, p = 0.001) and longer time to seizure remission (OR 1.36 per year, p = 0.025) were associated with persistent cognitive impairment. Patients with pilomotor seizures had a lower rate of seizure remission (hazard ratio [HR] 0.58, 95% CI 0.55-0.60, p < 0.001) while patients under IT administration had a higher rate of seizure remission over time (HR 12.4, 95% CI 9.67-16.0, p < 0.001). In addition, patients receiving second-line IT tended to achieve earlier seizure remission (log-rank test, p = 0.019). The ROSR at 12, 60, and 120 months on seizure remission was 9% (95% CI 4.5%-13%), 20% (95% CI 11%-28%), and 53% (95% CI 14%-74%), respectively. DiscussionIn conclusion, our results demonstrate that AEAE in anti-LGI1 encephalitis is rare and suggest that the diagnosis of epilepsy is inappropriate in patients reaching seizure remission because of a relatively low ROSR. Accordingly, on seizure remission, the diagnosis of acute symptomatic seizures would be appropriate. Moreover, we validate and quantify the importance of IT for seizure remission and identify biomarkers associated with lower rates of seizure remission. Late remission of seizures and AEAE were associated with persistent cognitive impairment.

BackgroundAutoantibodies targeting the intracellular 65-kDa isoform of glutamic acid decarboxylase (anti-GAD65) have been associated with a variety of autoimmune-related syndromes involving a spectrum of difficult-to-treat neurological disorders. However, the pathophysiological role of anti-GAD65 in neuroinflammation remains vague. Its understanding may be complicated by the possible pathogenic interaction between anti-GAD65 and potentially coexisting autoantibodies.MethodsWe combined a broad spectrum of approaches ranging from antibody-antigen identification, immunoblotting, immunoprecipitation, mass-spectrometry, cell-based assays, subcellular binding pattern analysis in primary neuronal cultures, and immunohistochemistry to in vitro assays of neuronal uptake, viability, and multi-electrode arrays.ResultsIn anti-GAD65-positive neurological patients, mass-spectrometric analysis revealed cytosolic 5'-nucleotidase 1 A (CN1A syn. NT5C1A) as the most abundant antigen. Subsequent screening of 118 anti-GAD65-positive patients revealed that 32 of them had additional autoantibodies targeting CN1A, which were also present in all available corresponding CSF samples. Limbic encephalitis was more often diagnosed in anti-CN1A/anti-GAD65-positive compared to the anti-GAD65-positive patients. Functionally, incubation of primary hippocampal neurons with anti-GAD65, but not with anti-CN1A, resulted in uptake into GABAergic neurons, neuronal cell death, and increased neuronal network activity. Moreover, simultaneous incubation with both antibodies (anti-CN1A/anti-GAD65) resulted in concomitant intraneuronal uptake in a concentration-dependent manner, which correlated with enhanced autophagy followed by massive neuronal death.ConclusionGAD65 antibodies directly affect neuronal viability and network activity. Co-existing autoantibodies against CN1A, present in anti-GAD65-positive patients, enhance autophagy and subsequent neuronal death in vitro. Clinically, anti-GAD65-positive patients should be screened for anti-CN1A-associated diseases, and evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions may clarify links between systemic autoimmunity and epilepsy.

INTRODUCTION:Patients with epilepsy often sustain uncommon shoulder injuries, including bilateral lesions and posterior dislocations. Increased glenoid retroversion is associated with posterior instability, although it remains unclear whether this is a cause or an adaptation. During tonic-clonic seizures, the humeral head is driven cranially and posteriorly against the glenoid by muscle contractions, potentially leading to acute dislocation or plastic deformation, which can be particularly relevant during skeletal development, even without instability episodes. This cross-sectional study aimed to evaluate whether the cumulative frequency of tonic-clonic seizures affects glenoid anatomy in patients with epilepsy who have not experienced shoulder instability. METHODS:Patients with epilepsy referred to a tertiary epilepsy center were enrolled sequentially. The duration of epilepsy and the frequency of tonic-clonic seizures were recorded and the glenoid version, the glenoid vault angle and the scapulohumeral subluxation index were measured on axial magnetic resonance imaging scans. The cumulative Burden of Recurrent Seizures over Time (BuRST) was calculated multiplying the duration of epilepsy by the number of yearly tonic-clonic seizures to compare patients with no BuRST, with those with a low BuRST (<40) and with a high BuRST (≥40). Statistical tests, including one-way analysis of variance with post hoc Tukey's test for multiple comparisons, were used to assess variable differences, correlations, and measurement reliability. RESULTS:Data were collected for 91 epileptic patients, 34 of which with a low and 28 with a high BuRST. A significant difference between the 3 BuRST groups emerged for all investigated parameters, with higher BuRST correlated with more pronounced changes (glenoid version angle: -1.93 ± 4.02°; -3.80 ± 4.34°; -6.67 ± 4.73°; glenoid vault angle: -12.78 ± 3.81°; -16.58 ± 4.02°; -20.66 ± 4.35°; subluxation index: 51.2% ± 4.7%; 54.6% ± 5.2%; 55.9% ± 5.1%). Intra- and interrater reliability was good to excellent for angular measurements and moderate to good for subluxation measurements. CONCLUSIONS:Patients with epilepsy who experience frequent tonic-clonic seizures, but have not yet had a shoulder instability episode, show increased glenoid retroversion, a more retroverted vault, and a higher scapulohumeral subluxation index compared to those with none or rare tonic-clonic seizures. These findings may suggest a possible link between recurrent tonic-clonic seizures and plastic deformation of the glenoid during growth, potentially influenced by repeated, powerful posteriorly directed muscular contractions. Although causality cannot be established, these results may pave the way for prospective studies aimed at better understanding the increased incidence of posterior shoulder instability observed in patients with epilepsy and recurrent tonic-clonic seizures.

Focal cortical dysplasia (FCD) type 2 is the most common malformation of cortical development associated with pharmaco-resistant focal epilepsy and frequently located in the frontal cortex. Neuropathological hallmarks comprise abnormal cortical layering and enlarged, dysmorphic neuronal elements. Fundamentally altered local neuronal activity has been reported in human FCD type 2 epilepsy surgical biopsies. Of note, FCD type 2 emerges during brain development and forms complex connectivity architectures with surrounding neuronal networks. Local cortical microcircuits, particularly in frontal localization, are extensively modulated by monoaminergic axonal projections originating from the brainstem. Previous analysis of monoaminergic modulatory inputs in human FCD type 2 biopsies suggested altered density and distribution of these monoaminergic axons; however, a systematic investigation is still pending. Here, we perform a comprehensive analysis of dopaminergic (DA) innervation, in human FCD type 2 biopsies and in the medial prefrontal cortex (mPFC) of an FCD type 2 mouse model [mechanistic target of rapamyin (mTOR) hyperactivation model] during adolescent and adult stages. In addition, we analyse the expression of dopamine receptor transcripts via multiplex fluorescent RNA in situ hybridization in human specimens and the mPFC of this mouse model. In the mTOR hyperactivation mouse model, we observe a transient alteration of DA innervation density during adolescence and a trend towards decreased innervation in adulthood. In human FCD type 2 areas, the overall DA innervation density is decreased in adult patients compared with control areas from these patients. Moreover, the DA innervation shows an altered lamination pattern in the FCD type 2 area compared with the control area. Dopamine receptors 1 and 2 appear to be differentially expressed in the dysmorphic neurons in human samples and mTOR-mutant cells in mice compared with normally developed neurons. Intriguingly, our results suggest complex molecular and structural alterations putatively inducing impaired DA neurotransmission in FCD type 2. We hypothesize that this may have important implications for the development of these malformations and the manifestation of seizures.

ABSTRACT Background Pharmacoresistance imposes a high burden on people with epilepsy (PWE). Recently authorized cenobamate (CNB) offers new hope with high efficacy reported in phase III and early real‐world studies. Here, we present data from a reasonably sized monocentric cohort, complementing the knowledge derived from clinical practice. Methods We retrospectively analyzed medical records of all PWE treated with CNB from market entry to July 31, 2023. Results After an average of 1.1 years, follow‐up data were available for 262 out of 280 PWE, who received at least one dose of CNB. The average CNB dose was 183 ± 98 mg/d, with a mean number of anti‐seizure medications (ASM) of 2.9 ± 1 per patient. A total of 36% of the patients showed ≥ 50% reduction in seizure frequency (10.7% were seizure‐free), whilst 12.3% reported increased seizure frequency. Seizure freedom was associated with concomitant perampanel or GABA receptor modulators. No predictors of treatment response were found. Side effects were reported by 38%, alertness issues being most prevalent (19%). The retention rate amounted to 72% and was associated with response status, dose of CNB, side effects, and age at CNB introduction. Among those who discontinued CNB, 55% experienced side effects and 89% showed no meaningful seizure reduction. Regarding co‐medication, the withdrawal of lamotrigine, brivaracetam, clobazam, or lacosamide was associated with higher rates of non‐response. Conclusions In this large cohort of 262 PWE, CNB proved very efficient with a high retention rate over one year. Co‐medication with perampanel or GABA receptor modulators was linked to seizure‐freedom. The overall positive impression of CNB is further supported.

OBJECTIVE:This study aims to report human performance in the detection of Focal Cortical Dysplasias (FCDs) using an openly available dataset. Additionally, it defines a subset of this data as a "difficult" test set to establish a public baseline benchmark against which new methods for automated FCD detection can be evaluated. METHODS:The performance of 28 human readers with varying levels of expertise in detecting FCDs was originally analyzed using 146 subjects (not all of which are openly available), we analyzed the openly available subset of 85 cases. Performance was measured based on the overlap between predicted regions of interest (ROIs) and ground-truth lesion masks, using the Dice-Soerensen coefficient (DSC). The benchmark test set was chosen to consist of 15 subjects most predictive for human performance and 13 subjects identified by at most 3 of the 28 readers. RESULTS:Expert readers achieved an average detection rate of 68%, compared to 45% for non-experts and 27% for laypersons. Neuroradiologists detected the highest percentage of lesions (64%), while psychiatrists detected the least (34%). Neurosurgeons had the highest ROI sensitivity (0.70), and psychiatrists had the highest ROI precision (0.78). The benchmark test set revealed an expert detection rate of 49%. SIGNIFICANCE:Reporting human performance in FCD detection provides a critical baseline for assessing the effectiveness of automated detection methods in a clinically relevant context. The defined benchmark test set serves as a useful indicator for evaluating advancements in computer-aided FCD detection approaches. PLAIN LANGUAGE SUMMARY:Focal cortical dysplasias (FCDs) are malformations of cortical development and one of the most common causes of drug-resistant focal epilepsy. Once found, FCDs can be neurosurgically resected, which leads to seizure freedom in many cases. However, FCDs are difficult to detect in the visual assessment of magnetic resonance imaging. A myriad of algorithms for automated FCD detection have been developed, but their true clinical value remains unclear since there is no benchmark dataset for evaluation and comparison to human performance. Here, we use human FCD detection performance to define a benchmark dataset with which new methods for automated detection can be evaluated.

The detection of transient peri-ictal magnetic resonance imaging (MRI) abnormalities has been variable after epileptic seizures. The most common reason for this variability is that abnormalities may disappear if the interval between seizure and scan acquisition is prolonged using conventional high-field systems. Here, we deployed a portable ultra-low-field MRI system in the presurgical evaluation at the bedside of individuals with epilepsy. We hypothesized that this novel technology enables rapid postictal scans and reliably shows focal peri-ictal MRI abnormalities in the seizure onset zone. A .064-T Swoop Portable MR Imaging System was used. Postictally, an axial diffusion-weighted sequence was acquired. The interictal MRI consisted of the diffusion-weighted and three-dimensional T1-weighted sequences. Postictal-interictal difference maps of diffusion-weighted volumes were calculated. Three individuals were included. Two individuals with focal aware seizures scanned 29 s and 19 min after the seizure, respectively, showed focal restrictions in diffusivity in the seizure onset zone, and a third individual scanned 5 h 45 min after a focal to bilateral tonic-clonic seizure showed global restrictions of diffusivity. Portable ultra-low-field MRI opens a new line of inquiry with the aim to establish postictal seizure imaging as part of the presurgical evaluation of people with epilepsy.