Faculty Bibliography

[This corrects the article DOI: 10.7759/cureus.113024.].

INTRODUCTION/BACKGROUND:In patients with tuberous sclerosis complex (TSC), seizure onset can be as early as in the neonatal period. Recent studies showed that earlier treatment of TSC positively improves epilepsy and neurodevelopmental outcomes. METHODS:This is an international retrospective study on neonates with TSC monitored with long-term video-EEG. RESULTS:Six of ten neonates with a perinatal diagnosis of TSC were found to have electrographic-only seizures within the first 10 days of life on long-term video-EEG. All patients in this series were found to have TSC2 variants and, except for 1 patient, had difficult-to-treat seizures requiring multiple anti-seizure medications. CONCLUSION/CONCLUSIONS:Our study suggests that early video-EEG for electrographic-only seizures may be valuable in neonates with TSC who otherwise would go untreated.

In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine in Lennox-Gastaut syndrome (LGS), patients in fenfluramine treatment groups (0.2 mg/kg/day, 0.7 mg/kg/day) experienced greater reduction from baseline in frequency of seizures associated with a fall versus placebo, which was sustained in the open-label extension (OLE) study (NCT03355209). In this post hoc analysis, trajectories of fenfluramine effectiveness and safety, along with dose changes over time, are described for patients with LGS randomized to placebo in RCT who switched to fenfluramine in OLE (PBO-FFA) and those who received fenfluramine in both RCT/OLE (FFA-FFA). Among patients who completed 12 months in OLE (N = 151), numerical improvements in effectiveness outcomes were seen in the PBO-FFA group (n = 59) after initiating fenfluramine and were similar to those in the FFA-FFA group (n = 92). Regression to the mean was not observed in the PBO-FFA group, suggesting that changes were due to fenfluramine. Incidence of the most commonly reported treatment-emergent adverse events increased in the PBO-FFA group after fenfluramine initiation but decreased in the FFA-FFA group in OLE. These data demonstrate rapid improvement in seizure frequency and global functioning in both groups with continued clinical improvement as the mean fenfluramine dose was increased. These results confirm that sustained fenfluramine treatment is effective and tolerable. PLAIN LANGUAGE SUMMARY: This study assessed the change over time in the number of seizures, overall improvement, and side effects in patients with LGS receiving placebo (no active medicine) or fenfluramine in a 14-week study; all patients later received fenfluramine in the extension study. Overall, the number of seizures (associated with a fall) decreased once patients initially receiving placebo changed to fenfluramine (optimal effect around Month 4 while receiving a higher dose), but as expected, common side effects were reported more frequently once patients began fenfluramine treatment. Patients, parents, and doctors should be aware of this time course to allow fenfluramine enough time to work.

BACKGROUND:There are limited data to guide antiseizure medication (ASM) prophylaxis in patients with aneurysmal subarachnoid hemorrhage (SAH). This results in practice variation in the use and duration of ASM prophylaxis. METHODS:We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with aneurysmal SAH. The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM or no ASM be used in patients hospitalized for aneurysmal subarachnoid hemorrhage who have no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam or phenytoin/fosphenytoin be preferentially used? (3) If an ASM is used, should a long (> 3 days) or short (≤ 3 days) duration of prophylaxis be used? The main outcomes were early seizure (≤ 14 days), late seizures (> 14 days), adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1988 articles, of which 10 formed the basis of the recommendations: Regarding PICO 1, we did not find a significant difference in outcomes of early seizure, adverse events, mortality, or functional outcomes when comparing ASM to no ASM. In regard to PICO 2, we found fewer early seizures with phenytoin/fosphenytoin and lower risk for neurologic decline with levetiracetam; however, there was low certainty of evidence. There was no significant difference in mortality between the different treatment types. Regarding PICO 3, we found extended use of ASM may be associated with lower seizure risk, but at the same time be associated with higher risk for adverse effects. CONCLUSIONS:Overall, the quality of evidence is low, precluding strong recommendations. We suggest that ASM or no ASM may be used in patients hospitalized with aneurysmal subarachnoid hemorrhage (conditional recommendation, low quality of evidence). If used, we suggest either levetiracetam or phenytoin/fosphenytoin (conditional recommendation, very low quality of evidence) for a short or long duration (conditional recommendation, moderate quality of evidence).

BACKGROUND:Psychological resilience predicts better outcomes in persons with multiple sclerosis (pwMS), yet factors which sustain it over time remain poorly understood, particularly in diverse populations. Personality traits may represent stable determinants of resilience. OBJECTIVES/OBJECTIVE:To examine the influence of personality on resilience in Black and Non-Hispanic White pwMS (BpwMS/WpwMS) and their healthy counterparts (BHCs/WHCs). METHODS:Psychological resilience and personality were assessed in a matched cohort of 120 pwMS and 80 HCs using the Connor-Davidson Resilience Scale and NEO-Five Factor Inventory-3. Personality and resilience were compared across groups. In pwMS, cross-sectional regression and longitudinal mixed-effects models evaluated personality-resilience associations; sensitivity analyses adjusted separately for depressive symptoms, psychiatric history, and subjective social status to evaluate the robustness of these associations. RESULTS:PwMS and HCs reported similar levels of Neuroticism, Agreeableness, and Conscientiousness; Extraversion and Openness were lower in pwMS. PwMS had worse resilience compared to HCs at follow-up. Higher Neuroticism predicted lower resilience, with a stronger association observed in BpwMS; higher Extraversion and Conscientiousness predicted better resilience. Higher Conscientiousness was associated with less longitudinal decline in resilience. Adjustment for depression attenuated the Conscientiousness and Neuroticism × Race associations, whereas Neuroticism and Extraversion associations remained significant. In prospective models, Conscientiousness continued to predict follow-up resilience independent of baseline depression. CONCLUSIONS:Personality traits may identify pwMS susceptible to reduced psychological resilience; Conscientiousness in particular may help sustain it over time. Although depression contributes to personality-resilience relationships, Neuroticism and Extraversion remain independently associated with resilience. Our findings support personality-informed approaches to strengthen psychological resilience in pwMS and identify depression as a clinically actionable target for future intervention.

Humans are the only species with the ability to systematically combine words to convey an unbounded number of complex meanings. This process is guided by combinatorial processes whose underlying neural mechanisms remain obscured by inherent limitations of noninvasive brain measures and a near-total focus on comprehension paradigms. Here, we address these limitations with high-resolution neurosurgical recordings (electrocorticography) and a controlled sentence production experiment. We uncover distinct cortical networks encoding word-level and higher-order information. These networks exhibited a hybrid spatial organization: broadly distributed across traditional language areas but with focal concentrations of sensitivity to semantic and structural contrasts in canonical language regions. In contrast to previous comprehension-based findings, we find that these networks are largely nonoverlapping. Most notably, higher-order linguistic information showed an unexpected dissociation from local activity magnitude. This result establishes an operational dissociation between activity magnitude and information content, pointing toward a potentially distinct neural coding scheme for higher-order language, with important implications for the neurobiology of language.

Consciousness science is fragmented, and empirical investigations are largely confined within the framework of each theory of consciousness (ToC). Proliferating ToCs accumulate anomalies without progress, operating orthogonally. The principle of recurrency, functional and architectural, specifies a unifying, mechanistic scaffold for consciousness to arise. We show that all theories tacitly invoke feedback loops and can be re-expressed along a single axis of recursion. Four nested levels, viz., cellular, local inter-areal, global, and lateral, map onto state consciousness, phenomenal (P) content, conscious access (A), and phenomenal character, respectively, thus tying evolved anatomy to phenomenality. The classical P-A distinction dissolves into a graded cascade wherein deeper recursion expands the set of reportable, behaviour-driving variables. Recurrency, defined as structural, causal, and/or functional feedforward and feedback connections between elements within a system, is favoured in biological architectures, and supports the closed-loop interactions between brain, body, and environment that underlie adaptive behaviour and self-related processing. Disparities in the explanatory mechanisms across theories of consciousness can thus be resolved by converging onto this shared principle on the implementation axis, rather than deal with phenomenal-first or functional-first ontologies. The field urgently requires this implementation-first distillation that is biologically plausible, mechanistic, and empirically testable.