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There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic.
Methods:
We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre’s epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable.
Results:
In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable.
Conclusion:
We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.
The insular cortex is an extensively connected brain region that has recently gained considerable interest due to its elusive role in several pathological conditions and its involvement in a variety of functions. Structural connectivity studies have identified connections to the frontal, temporal, and parietal cortices, with both a rostro-caudal and a dorso-ventral organizational pattern. The insula is also widely connected to subcortical structures. The use of diffusion-weighted imaging in insular epilepsy has not yet reached its full potential; however, it may still provide some insights into its pathophysiology, assess long-term consequences, and help prevent operative complications. This chapter explores the insula’s structural connectivity and promising applications in the field of insular epilepsy.
Epilepsy surgery patients played a pioneering role in our early understanding of the insula in Penfield’s stimulation studies. Following the advent of functional imaging, epilepsy patients are once again helping us understand the role of this critical structure in human behavior. The insular cortex is involved in a wide range of complex human functions, including auditory processing, language function, attention, emotional processing, social cognition, and decision-making. In this chapter, we review this literature and report new data on the postoperative neuropsychological function of a series of 31 patients who have undergone partial or complete insular resections at the Centre Hospitalier de l’Université de Montréal (CHUM). Standard neuropsychological assessments reveal few cognitive impairments specific to insular epilepsy or its surgery. Specialized assessments are required to fully assess the impact of insular resection on socio-emotional processing and behavioral features of executive function that can be compromised following surgery.
The role of the insular cortex in epilepsy has been largely neglected until very recently. With growing interest in insular epilepsies, this book provides unique, in-depth coverage of the condition from childhood to adulthood. Detailed description of the anatomy, vascularization, connectivity, and functions of the insula along with complete description of the semiology, neurophysiology, and neuroimaging of insular epilepsy helps clinicians better recognize the condition. Up-to-date treatment avenues are explored, guiding the management of patients, including drug-resistant cases suitable for neurosurgery. Authors come from a range of backgrounds, providing a multidisciplinary perspective essential to all health professionals involved in epilepsy diagnosis and treatment. A scratch-off code in the inside cover allow users access to an online equivalent of the book, featuring videos illustrating the semiology of the various forms of insular seizures. This authoritative overview provides clinicians with the necessary information to treat this under-recognized condition.
Insular epilepsy has come into focus quite late in the field of epileptology. This entity was forgotten between the 1960s and 1980s by the last generation of epileptologists who were busy leading the fight for a localization approach and anatomo-electro-clinical correlations. This lengthy period is well documented in the first chapter of this work. This drift may be attributed to various restrictions, mostly technical: the insular cortex does not appear on the surface of the brain but is the seat of a plethoric vascularization that supplies blood to motor fibers in the centrum ovale through its network of perforating arteries. Therefore, it could not be operated without exposing the patient to unreasonable risks for the goal intended. It could not also be explored invasively without the risk of causing a hemorrhage due to the necessity of crossing a triple curtain of pial arteries. The condemnation was heard: “exploring the insula, at best, is useless, and at worst, dangerous.”
Insular lobe seizures (ILS) may present with several subjective and objective symptoms. Somatosensory and viscerosensory symptoms, notably paresthesia and laryngeal constriction, are symptoms frequently encountered with ILS. Other manifestations may become only evident after the ictal discharge spreads to extra-insular structures. Depending on propagation pathways, ILS exhibit two main clinical patterns: (1) a perisylvian /temporo-perisylvian pattern and (2) a frontal-like pattern. Other miscellaneous clinical presentations include epileptic spasms, ecstatic, gelastic, reflex, and autonomic seizures.
The insular cortex is gaining attention in the epilepsy literature; however, characteristics of insular epilepsy on non-invasive electrophysiological studies are still being defined. In this chapter, we review this emerging literature with a focus on electroencephalography and present the ictal and interictal findings of 106 patients collected in the literature. Despite the location of the insula in the depth of the Sylvian fissure, a majority of patients have ictal and interictal epileptiform abnormalities on scalp EEG, which are most commonly found in the frontal or fronto-temporal electrodes. The distribution of these findings follows an antero-posterior gradient in keeping with the connectivity pathways of the insular cortex. Multifocal abnormalities are common in the pediatric population and should not preclude surgical evaluation. Evidence is increasingly favoring magnetoencephalography as a complementary modality to EEG and its use will likely be more prominent. Scarce data is available on the utility of high-density EEG, and more studies are thus needed.
Uncontrolled epilepsy creates a constant source of worry for patients and puts them at a high risk of injury. Identifying recurrent “premonitory” symptoms of seizures and using them to recalibrate seizure prediction algorithms may improve prediction performances. This study aimed to investigate patients’ ability to predict oncoming seizures based on preictal symptoms.
Methods:
Through an online survey, demographics and clinical characteristics (e.g., seizure frequency, epilepsy duration, and postictal symptom duration) were collected from people with epilepsy and caregivers across Canada. Respondents were asked to answer questions regarding their ability to predict seizures through warning symptoms. A total of 196 patients and 150 caregivers were included and were separated into three groups: those who reported warning symptoms within the 5 minutes preceding a seizure, prodromes (symptoms earlier than 5 minutes before seizure), and no warning symptoms.
Results:
Overall, 12.2% of patients and 12.0% of caregivers reported predictive prodromes ranging from 5 minutes to more than 24 hours before the seizures (median of 2 hours). The most common were dizziness/vertigo (28%), mood changes (26%), and cognitive changes (21%). Statistical testing showed that respondents who reported prodromes also reported significantly longer postictal recovery periods compared to those who did not report predictive prodromes (P < 0.05).
Conclusion:
Findings suggest that patients who present predictive seizure prodromes may be characterized by longer patient-reported postictal recovery periods. Studying the correlation between seizure severity and predictability and investigating the electrical activity underlying prodromes may improve our understanding of preictal mechanisms and ability to predict seizures.
This study was conducted to examine whether the nuclear to cytoplasmic (N/C) ratio had any influence on the timing of embryo compaction and blastocoel formation, as well as formation rate and quality of blastocyst. First, we produced embryos with increased N/C ratio by removal of approximately one-third of the cytoplasm and with decreased N/C ratio by doubling the oocyte cytoplasm with an enucleated oocyte. The initiation of compaction and cavitation in reduced cytoplasm group was significantly earlier (P < 0.05) compared with the control and doubled cytoplasm groups. The rate of blastocysts in the reduced cytoplasm and doubled cytoplasm groups was significantly lower (P < 0.05) compared with the control group. Blastocyst quality in terms of total cell number in the reduced cytoplasm group was significantly lower (P < 0.05) compared with the doubled cytoplasm group, but not different from the control group. Next, we produced embryos with various N/C ratios by oocyte fusion combined with cytochalasin D treatment. The onset of compaction and cavitation in the 2N/2C group (decreased N/C ratio) was significantly delayed (P < 0.05) or had the tendency to be delayed (P = 0.064), respectively, compared with the control group (2N/1C). A significantly higher rate of blastocyst was observed in the 4N/2C group compared with the 1N/1C group (P < 0.05) but not different from the remaining groups. These results demonstrated that an increase in N/C ratio caused an earlier occurrence of morula compaction and blastocyst formation in both in vitro fertilization (IVF) and parthenogenetically activated pig embryos.
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Part IV
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Multilateral Rule-Making in Asia on Trade and Investment: From ASEAN to the Comprehensive and Progressive Agreement for Trans-Pacific Partnership
The EU-Vietnam Investment Protection Agreement (‘EVIPA’) includes the new trend of a two-tier permanent dispute resolution system called the ‘Investment Tribunal System’ (‘ITS’). The inclusion of the untested ITS in the EVIPA has unsurprisingly been met with mixed opinion from scholars and practitioners all over the world. A number of new issues, such as the constitution and operation of the tribunal system, the dispute resolution procedure, and the transparency of the dispute resolution process, is foreign to the traditional model that Vietnam usually follows. Furthermore, the enforcement of the awards rendered through the ITS, which are primarily to be enforced as the judgment of the contracting states’ courts and shall be also deemed as arbitral awards falling within the scope of the 1958 New York Convention on Recognition and Enforcement of Foreign Arbitral Awards, also poses a challenge for Vietnam and has given rise to serious concern in the community. Notwithstanding these matters, Vietnam should be well prepared for its participation in the EVIPA. This chapter reviews the procedure of the new system and critically analyse the situation of Vietnam, as well as some challenges that Vietnam may face when dealing with the new mechanism of investment dispute resolution under the EVIPA.