Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.

Extended follow-up after anterior temporal lobectomy demonstrates seizure recurrence 20+ years postsurgery.

OBJECTIVE: Anterior temporal lobectomy (ATL) for medication-resistant localized epilepsy results in ablation or reduction of seizures for most patients. However, some individuals who attain an initial extended period of postsurgical seizure freedom will experience a later seizure recurrence. In this study, we examined the prevalence and some risk factors for late recurrence in an ATL cohort with extensive regular follow-up. METHODS: Included were 449 patients who underwent ATL at Austin Health, Australia, from 1978 to 2008. Postsurgical follow-up was undertaken 2-3 yearly. Seizure recurrence was tested using Kaplan-Meier analysis, log-rank test, and Cox regression. Late recurrence was qualified as a first disabling seizure >2 years postsurgery. We examined risks within the ATL cohort according to broad pathology groups and tested whether late recurrence differed for the ATL cohort compared to patients who had resections outside the temporal lobe (n = 98). RESULTS: Median post-ATL follow-up was 22 years (range = .1-38.6), 6% were lost to follow-up, and 12% had died. Probabilities for remaining completely seizure-free after surgery were 51% (95% confidence interval [CI] = 53-63) at 2 postoperative years, 36% (95% CI = 32-41) at 10 years, 32% (95% CI = 27-36) at 20 years, and 30% (95% CI = 25-34) at 25 years. Recurrences were reported up to 23 years postoperatively. Late seizures occurred in all major ATL pathology groups, with increased risk in the "normal" and "distant lesion" groups (p ≤ .03). Comparison between the ATL cohort and patients who underwent extratemporal resection demonstrated similar patterns of late recurrence (p = .74). SIGNIFICANCE: Some first recurrences were very late, reported decades after ATL. Late recurrences were not unique to any broad ATL pathology group and did not differ according to whether resections were ATL or extratemporal. Reports of these events by patients with residual pathology suggest that potentially epileptogenic abnormalities outside the area of resection may be implicated as one of several possible underlying mechanisms.

Comorbidities in newly diagnosed epilepsy: Pre-existing health conditions are common and complex across age groups.

OBJECTIVES: People with epilepsy have a higher prevalence of medical and psychiatric comorbidities compared to the general population. Comorbidities are associated with poor epilepsy outcomes, and there have been recommendations for screening and early identification to improve clinical management. Data from 'First Seizure Clinics' (FSCs) with expert epileptological review can inform about disorders already present at the point of diagnosis of epilepsy or unprovoked seizures. Here, we aimed to describe pre-existing conditions with a focus on psychiatric, substance use, cardiac, neurological, and cancer health domains. METHODS: We included 1383 adults who received a new diagnosis of epilepsy or unprovoked seizures at Austin Hospital (AH) or Royal Melbourne Hospital (RMH) (Australia) FSCs from 2000 to 2010. Data were audited from FSC records, primarily detailed interviews undertaken by epileptologists. Logistic regression examined age distribution and other risk factors. RESULTS: The median age at FSC presentation was 37 years (IQR 26-53, range 18-94). Pre-existing conditions were reported by 40 %; from 32 % in the youngest group (18-30 years) to 53 % in the oldest (65+ years). Psychiatric (18 %) and substance use (16 %) disorders were most common, with higher prevalence among patients 18 to 65 years of age compared to those older than 65 years (p < 0.001). Cardiac, neurological, or cancer conditions were reported by 3-6 %, most often amongst those older than 65 years (p < 0.01). Eight percent (n = 112) reported disorders in >1 health domain. The commonest combination was a psychiatric condition with substance use disorder. Of the sixty-two patients reporting this combination, 61 were ≤65 years of age. CONCLUSIONS: Pre-existing health conditions are present in a substantial proportion of patients diagnosed with epilepsy or unprovoked seizures. Disorders are highest amongst elders, but one-third of younger adults also reported positive histories. These are predominantly psychiatric and/or substance use disorders, conditions strongly associated with poor outcomes in the general population. These findings inform post-diagnosis planning and management, as well as research examining post-diagnostic outcomes and associations between comorbidities and epilepsy.

Monocytes mediate Salmonella Typhimurium-induced tumor growth inhibition in a mouse melanoma model.

The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH 1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+ MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer.

"Do I still have epilepsy?" Epilepsy identity 15-20 years after anterior temporal lobectomy.

OBJECTIVE: Identity is a multifaceted construct, comprising personal identity (sense of being a unique individual) and social identity (the sense-of-self derived from membership of social groups). Social identity involves explicit identification with a group ("I am …") and implicit behaviors or attitudes associated with group membership. Following successful treatment with surgery, patients with epilepsy can undergo a complex and lasting change in personal identity. To date, there has been no research into postoperative social epilepsy identity (SEI). We sought to examine SEI 15-20 years post-surgery, and the relationship between SEI and satisfaction with surgery, psychosocial improvements, mood, and health-related quality of life (HRQoL). METHODS: Thirty-two patients who underwent anterior temporal lobectomy (ATL; 19 female) were recruited, with a median follow-up of 18 years (interquartile range [IQR] = 2.5). Using a novel interactive online program, we collected data on SEI, satisfaction with surgery, and perceived psychosocial improvements, alongside standardized measures of mood (Neurological Disorders Depressio Inventory-Epilepsy; Patient Health Questionnaire-Generalised Anxiety Disorder-7 item) and HRQoL (Quality of Life in Epilepsy-31 item). Non-parametric analyses were used to analyse the data. RESULTS: Twenty-five percent of patients were free of disabling seizures since surgery, yet 65% stated they no longer had epilepsy and >90% reported satisfaction with surgery. Explicitly discarding SEI was positively associated with HRQoL at long-term follow-up, over and above seizure outcome. Implicit SEI was expressed as (a) acceptance of epilepsy, (b) a sense of belonging to the epilepsy community, and (c) difficulty disclosing and discussing epilepsy. Difficulty disclosing and discussing epilepsy was associated with increased anxiety and lower HRQoL. SIGNIFICANCE: At long-term follow-up, over half of our patients reported an explicit change in SEI, which could promote better HRQoL. In contrast, difficulty with disclosure of epilepsy was associated with increased anxiety and reduced HRQoL, possibly reflecting the ongoing effects of stigma. These findings highlight the importance of understanding changes in patient social identity for promoting long-term well-being after surgery.

Missed, mistaken, stalled: Identifying components of delay to diagnosis in epilepsy.

A substantial proportion of individuals with newly diagnosed epilepsy report prior seizures, suggesting a missed opportunity for early epilepsy care and management. Consideration of the causes and outcomes of diagnostic delay is needed to address this issue. We aimed to review the literature pertaining to delay to diagnosis of epilepsy, describing the components, characteristics, and risk factors for delay. We undertook a systematic search of the literature for full-length original research papers with a focus on diagnostic delay or seizures before diagnosis, published 1998-2020. Findings were collated, and a narrative review was undertaken. Seventeen papers met the inclusion criteria. Studies utilized two measures of diagnostic delay: seizures before diagnosis and/or a study-defined time between first seizure and presentation/diagnosis. The proportion of patients with diagnostic delay ranged from 16% to 77%; 75% of studies reported 38% or more to be affected. Delays of 1 year or more were reported in 13%-16% of patients. Seizures prior to diagnosis were predominantly nonconvulsive, and usually more than one seizure was reported. Prior seizures were often missed or mistaken for symptoms of other conditions. Key delays in the progression to specialist review and diagnosis were (1) "decision delay" (the patient's decision to seek/not seek medical review), (2) "referral delay" (delay by primary care/emergency physician referring to specialist), and (3) "attendance delay" (delay in attending specialist review). There were few data available relevant to risk factors and virtually none relevant to outcomes of diagnostic delay. This review found that diagnostic delay consists of several components, and progression to diagnosis can stall at several points. There is limited information relating to most aspects of delay apart from prevalence and seizure types. Risk factors and outcomes may differ according to delay characteristics and for each of the key delays, and recommendations for future research include examining each before consideration of interventions is made.

Understanding long-term changes in patient identity 15-20 years after surgery for temporal lobe epilepsy.

OBJECTIVE: Following epilepsy surgery, patients can experience complex psychosocial changes. We recently described a longer term adjustment and reframing ("meaning-making") process 15-20 years following surgery for temporal lobe epilepsy, which could involve an ongoing sense of being a "different" person for some patients. Here, we quantitatively examine identity at long-term follow-up and how this relates to meaning-making and postoperative seizure outcome. METHODS: Eighty-seven participants were included: 39 who underwent anterior temporal lobectomy (ATL) 15-20 years ago (59% female; median age = 49.2 years, interquartile range [IQR] = 10; median follow-up = 18.4 years, IQR = 4.4) and 48 surgically naïve focal epilepsy patients (56% female; median age = 34.5 years, IQR = 19). We captured approach to meaning-making by coding for key narrative features identified in our previous qualitative work. Nonparametric tests and correspondence analysis were then used to explore relationships between a quantitative measure of identity and meaning-making, as well as seizure outcome, mood, and health-related quality of life (HRQOL). RESULTS: Patients 15-20 years post-ATL demonstrated a shift toward increasing identity commitment and exploration compared to the surgically naïve cohort, with this shift significantly linked to seizure outcome. Examining the relationship between identity and meaning-making also revealed three groups: (1) those who embraced self-change (29%), (2) those who continued to struggle with this process (60.5%), and (3) those who showed minimal engagement (10.5%). Those who "embraced change" were significantly younger at regular seizure onset and demonstrated a trend toward higher HRQOL. SIGNIFICANCE: Findings suggest that ATL patients show a more developed identity profile compared to surgically naïve controls; however, the majority still struggled with postoperative identity change at long-term follow-up. Approximately one third of patients demonstrated positive psychological growth following surgery, reflected in the ability to embrace change. Findings highlight the importance of understanding the impact of surgery on patient identity to maximize the psychosocial benefits.

Metabolic patterns and seizure outcomes following anterior temporal lobectomy.

OBJECTIVE: We investigated the relationship between the interictal metabolic patterns, the extent of resection of 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) hypometabolism, and seizure outcomes in patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection. METHODS: Eighty-two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant 18 FDG-PET hypometabolism, and at least 2 years of postoperative follow-up were included in this 2-center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre- and postoperative MRI scans coregistered with interictal 18 FDG-PET. RESULTS: Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). INTERPRETATION: The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1-10 ANN NEUROL 2019;85:241-250.

A patient-centered approach to understanding long-term psychosocial adjustment and meaning-making, 15 to 20 years after epilepsy surgery.

OBJECTIVE: Different psychosocial trajectories have been identified following treatment with epilepsy surgery, as patients adjust to possible changes in seizure frequency and the subsequent impact on their psychosocial functioning. Qualitative research has been key to understanding this adjustment process, particularly in the short-term (2-5 years). Currently, however, there is a lack of qualitative research examining longer-term (>15 years) outcomes, precluding the same rich, detailed understanding of longer-term psychosocial outcomes. Using a grounded theory approach, we explored how patients reflected on and made sense of their adjustment trajectories, 15 to 20 years after surgery. This included the impact of surgery on their sense of self and broader psychosocial functioning. METHODS: We recruited 40 adult patients who had undergone anterior temporal lobectomy (ATL) 15 to 20 years ago (24 females; 26 left-sided). Median age at habitual seizure onset was 9.7 years (Interquartile range; IQR = 13.8), and at surgery was 31 years (IQR = 12). Median length of follow-up was 18.4 years (IQR = 4.3). Comprehensive one-on-one interviews (median time = 86 min, IQR = 28) were used to elicit patient experiences of their surgery and subsequent psychosocial outcomes. Data were analyzed using a grounded theory inductive-deductive process. RESULTS: Patient narratives revealed a common process of psychosocial change and meaning-making triggered by surgery, which was often perceived as a major turning point in life. Patients reflected on moving through an early postsurgical period (<5 years) of upheaval and psychological disequilibrium. While this period was often remembered as stressful, difficulties were softened and/or reframed in hindsight. Through this process of reframing and meaning-making, patients were able to reestablish equilibrium and a sense of normality. Differences were evident in how patients navigated the process of meaning-making, and the extent to which they felt surgery had changed their self-identity. DISCUSSION: We propose a model of postsurgical meaning-making, evident in the narratives of patients who have undergone ATL, providing a new perspective on long-term psychosocial outcomes. This model contributes to our understanding of patient well-being and quality of life, by acknowledging the active role that patients play in seeking to create their own sense of normality after epilepsy surgery.

Familial mesial temporal lobe epilepsy and the borderland of déjà vu.

OBJECTIVE: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly diagnosed nonlesional MTLE actually represents familial MTLE (FMTLE). METHODS: We identified all consecutive patients presenting to the Austin Health First Seizure Clinic with MTLE and normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by 2 epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious for epilepsy; or unaffected. Physiological déjà vu was noted. RESULTS: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9 of 121 relatives versus 0 of 121 controls (p = 0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences that were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives versus none of the controls (p = 0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%). INTERPRETATION: FMTLE accounts for almost one-fifth of newly diagnosed nonlesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena that clinically lie in the "borderland" between epileptic seizures and physiological déjà vu. Ann Neurol 2017;82:166-176.

SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection.

Salmonella invasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or other Salmonella pathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in an ex vivo intestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag for in vivo tracking of individual effectors.

Mind the gap: Multiple events and lengthy delays before presentation with a "first seizure".

OBJECTIVE: Up to half of patients assessed for suspected new-onset epileptic seizures report previous undiagnosed events. This suggests that delay to timely and expert assessment is a major issue. Very little is known about the degree of delay or nature of the undiagnosed events, impacting on our understanding of new-onset epilepsy. In this study we aimed to examine events that occur before presentation, as well as the extent and risk factors for delay to assessment. METHOD: Included in this retrospective study were 220 patients diagnosed at the First Seizure Clinic (Austin Health, Australia) between 2003 and 2006 with an epileptic index seizure. Patients with a prior diagnosis of epileptic seizures were excluded. Chart review was undertaken, including detailed interviews conducted by an epileptologist at first assessment. Logistic regression assessed risk factors for delay from first event to presentation, including event characteristics, socioeconomic disadvantage, employment, and distance to medical facility. RESULTS: Forty-one percent (n = 90) of patients had one or more event before their index seizure. Of these, 50% had multiple or more than five prior events and 28% experienced one or more convulsive event before the index seizure. Of the total 220 patients, 36% had delayed presentation >4 weeks, 21% delayed >6 months, and 14% delayed >2 years. First events without convulsions or features likely to disrupt behaviour were strongly associated with delay (p = <0.001). Relative socioeconomic disadvantage was also associated with delay to presentation (p = 0.04). SIGNIFICANCE: Our findings suggest a gap in early diagnosis and care in a sizable proportion of new-onset cases, despite a "first world" urban environment and the availability of free basic medical care. Delay appears particularly likely when events are nonconvulsive or low-impact, suggesting that these seizure types may be underrepresented in studies of new-onset epilepsy. This has implications for our understanding of the incidence, evolution, impact, and treatment response of new-onset epilepsy.

The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia.

OBJECTIVE: Epilepsy surgery is the most effective treatment for select patients with drug-resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. METHODS: We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. RESULTS: Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis (MTS) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] -27.3% to -67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 ± 0.07% in the performance of invasive electroencephalography (EEG) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. SIGNIFICANCE: These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well-established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed.

Common experiences of patients following suboptimal treatment outcomes: implications for epilepsy surgery.

Few studies have investigated the patient experience of unsuccessful medical interventions, particularly in the epilepsy surgery field. The present review aimed to gain insight into the patient experience of seizure recurrence after epilepsy surgery by examining the broader literature dealing with suboptimal results after medical interventions (including epilepsy surgery). To capture the patient experience, the literature search focused on qualitative research of patients who had undergone medically unsuccessful interventions, published in English in scholarly journals. Twenty-two studies were found of patients experiencing a range of suboptimal outcomes, including seizure recurrence, cancer recurrence and progression, unsuccessful joint replacement, unsuccessful infertility treatment, organ transplant rejection, coronary bypass graft surgery, and unsuccessful weight-loss surgery. In order of frequency, the most common patient experiences included the following: altered social dynamics and stigma, unmet expectations, negative emotions, use of coping strategies, hope and optimism, perceived failure of the treating team, psychiatric symptoms, and control issues. There is support in the epilepsy surgery literature that unmet expectations and psychiatric symptoms are key issues for patients with seizure recurrence, while other common patient experiences have been implied but not systematically examined. Several epilepsy surgery specific factors influence patient perceptions of seizure recurrence, including the nature of postoperative seizures, the presence of postoperative complications, and the need for increased postoperative medications. Knowledge of common patient experiences can assist in the delivery of patient follow-up and rehabilitation services tailored to differing outcomes after epilepsy surgery.

Effect of visual presentation format and recall direction on letter span and error patterns in Deaf signing and hearing adults.

Deaf signers consistently show shorter memory spans than hearing nonsigners, but the scope and nature of this difference remain unclear. The present study tested whether Deaf signers are biased toward flexible use of visual aspects of linguistic items. Matched samples of adult Deaf signers (N = 33) and hearing nonsigners (N = 32) performed a letter-span task with visual serial presentation, to bias phonological processing, and a simultaneous presentation, to bias visuospatial processing. We also manipulated short-term memory by varying recall direction (forward, backward). Analyses revealed reduced spans for Deaf signers compared with hearing nonsigners, backward compared with forward recall, and sequential compared with simultaneous presentation. Item-level responses indicated that Deaf signers made more errors than hearing nonsigners across three error types. Deaf signers also showed reduced item position binding compared with hearing nonsigners, which indicates differences related to item order and sequencing in tasks with printed, linguistic stimuli. Deaf signers were the only group who demonstrated reduced omission errors when switching from sequential to simultaneous presentation, suggesting flexible processing mechanisms. No group differences were found for a secondary spatial span test, indicating the scope of group differences for ordered information was limited to verbal items. Overall, results are consistent with flexible use of different memory cues in Deaf signers. A core area for future research includes evaluating reduced activation of phonological representations of linguistic items in Deaf signers. These results amplify a novel M3 model approach for evaluating how errors contribute to short-term memory differences in Deaf signers.

Verbal and visual serial-order memory in deaf signers and hearing nonsigners: A systematic review and meta-analysis.

Previous research suggests Deaf signers may have different short-term and working memory processes compared with hearing nonsigners due to prolonged auditory deprivation. The direction and magnitude of these reported differences, however, are variable and dependent on memory modality (e.g., visual, verbal), stimulus type, and research design. These discrepancies have made consensus difficult to reach which, in turn, slows progress in areas such as education, medical decision-making, and cognitive sciences. The present systematic review and meta-analysis included 35 studies (N = 1,701 participants) that examined verbal (n = 15), visuospatial (n = 10), or both verbal and visuospatial (n = 10) serial-memory tasks comparing nonimplanted, Deaf signers to hearing nonsigners across the life span. Multivariate meta-analyses indicated a significant, negative effect of deafness on verbal short-term memory (forward recall), g = -1.33, SE = 0.17, p < .001, 95% CI [-1.68, -0.98], and working memory (backward recall), g = -0.66, SE = 0.11, p < .001, 95% CI [-0.89, -0.45], but no significant effect of deafness on visuospatial short-term memory, g = -0.055, SE = 0.17, p = 0.75, 95% CI [-0.39, 0.28]. Visuospatial working memory was not analyzed due to limited power. Population estimates for verbal and visuospatial short-term memory were moderated by age wherein studies with adults demonstrated a stronger hearing advantage than studies with children/adolescents. Quality estimates indicated most studies were of fair quality, with only 38% of studies involving Deaf authors. Findings are discussed in the context of both Deaf equity and models of serial memory.

Long-term seizure outcome and risk factors for recurrence after extratemporal epilepsy surgery.

PURPOSE: We aimed to assess long-term seizure outcome and risk factors for seizure recurrence in a cohort of patients who have undergone extratemporal resection for management of refractory seizures. METHODS: Eighty-one patients underwent extratemporal resection at Austin Health, Melbourne, Australia (1991-2004). Seizure recurrence was any postoperative disabling seizure (complex partial seizure [CPS] ± secondary generalization). Multivariate Cox proportional hazards regression models examined potential preoperative and perioperative risk factors and the risk associated with early postoperative seizures (≤ 28 days postsurgery). The change between preoperative and postoperative seizure frequency was also measured. KEY FINDINGS: Median follow-up was 10.3 years (range 1-17.7). The probabilities of freedom from disabling seizures (on or off antiepileptic medication) were 40.7% (95% confidence interval [CI] 30-51) at 1 month, 23.5% (95% CI 15-33) at 1 year, and 14.7% (95% CI 8-23) at 5 years postoperative. Reduction of disabling seizures to at least 20% of preoperative frequency was attained by 57% of patients at 5 postoperative years. Of the preoperative/perioperative factors, focal cortical dysplasia (FCD) type 1 (hazard ratio [HR] 1.90, 95% CI 1.08-3.34, p = 0.025) and incomplete resection (HR 1.71, 95% CI 1.06-2.76, p = 0.028) were independent recurrence risks. After surgery, an early postoperative seizure was the only factor associated with higher risk (HR 4.28 [2.42-7.57], p = 0.00). SIGNIFICANCE: Distinction between subtypes of focal cortical dysplasia, which can be made using magnetic resonance imaging (MRI) criteria, may be useful for preoperative prognostication. Early seizures after surgery are not benign and may be markers of factors that contribute to seizure recurrence. Most patients achieve substantial reduction in seizure frequency. Further study of the significance of this reduction in terms of surgical "success" or otherwise is required.

Significance of post-operative auras after temporal lobectomy: a surprising methodological trap.

We aimed to examine post-operative auras/simple partial seizures and the associated risk of seizure recurrence after temporal lobectomy. Included were 159 patients who underwent anterior temporal lobectomy (1995-2006) at Austin Health, Australia. Initial analyses used Cox regression. Post-hoc, exploratory analyses of aura and seizure patterns were undertaken. Initial analyses indicated that post-operative auras were not associated with subsequent disabling seizures (HR 0.65, 95%CI 0.4-1.1 p=0.08). However, post-hoc examination found data patterns that suggest that post-operative auras may have been under-reported when medical contact between these events was absent. These findings are relevant to current research, as similar methodology is commonly employed in post-operative outcome studies. Important implications include potential underestimation of seizure risk associated with auras. Carefully planned prospective studies are required to assess the risk associated with post-operative auras.

Diagnostic delay in focal epilepsy: Association with brain pathology and age.

PURPOSE: Between 16-77% of patients with newly diagnosed epilepsy report seizures before diagnosis but little is known about the risk factors for diagnostic delay. Here, we examined the association between prior seizures and neuroimaging findings in newly diagnosed focal epilepsy. METHODS: Adults diagnosed with focal epilepsy at First Seizure Clinics (FSC) at the Royal Melbourne Hospital or Austin Health, Melbourne, Australia, between 2000 and 2010 were included. Medical records were audited for seizure history accrued from the detailed FSC interview. Potentially epileptogenic brain abnormality type, location and extent was determined from neuroimaging. Statistical analysis comprised multivariate logistic regression. RESULTS: Of 735 patients, 44% reported seizure/s before the index seizure. Among the 260 individuals with a potentially epileptogenic brain imaging abnormality, 34% reported prior seizures. Of 475 individuals with no abnormality, 50% reported prior seizures (p < 0.001). Patients with post-stroke changes had lower odds of prior seizures (n = 24/95, OR 0.5, p = 0.005) compared to patients without abnormalities, as did patients with high-grade tumors (n = 1/10, OR 0.1, p = 0.04). Abnormality location or extent was not associated with seizures. Prior seizures were inversely associated with age, patients aged >50 years had lower odds compared to those 18-30 years (OR 0.5, p = 0.01). CONCLUSIONS: A history of prior seizures is less common in patients with newly diagnosed focal epilepsy associated with antecedent stroke or high-grade tumor than in those without a lesion, and is also less common in older individuals. These findings may be related to age, biological mechanisms or aspects of diagnosis and assessment of these events.

Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance.

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T2 signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants.