Newly diagnosed seizures assessed at two established first seizure clinics: Clinic characteristics, investigations, and findings over 11 years.

Objective: 'First seizure' clinics (FSCs) aim to achieve early expert assessment for individuals with possible new-onset epilepsy. These clinics also have substantial potential for research into epilepsy evolution, outcomes, and costs. However, a paucity of FSCs details has implications for interpretation and utilization of this research. Methods: We reviewed investigation findings over 11 years (2000-2010) from two established independent FSCs at Austin Health (AH) and Royal Melbourne Hospital (RMH), Australia. These adult clinics are in major public hospitals and operate with similar levels of expertise. Organizational differences include screening and dedicated administration at AH. Included were N = 1555 patients diagnosed with new-onset unprovoked seizures/epilepsy (AH n = 901, RMH n = 654). Protocol-driven interviews and investigations had been recorded prospectively and were extracted from medical records for study. Results: Median patient age was 37 (IQR 26-52, range 18-94) years (AH 34 vs RMH 42 years; P < .001). Eighty-six percent of patients attended FSC within three weeks postindex seizure (median AH 12 vs RMH 25 days; P < .01). By their first appointment, 42% had experienced ≥2 seizures. An EEG was obtained within three weeks postindex seizure in 73% of patients, demonstrating epileptiform discharges in 25% (AH 33% vs RMH 15%). Seventy-six percent of patients had an MRI within 6 weeks. Of those with imaging (n = 1500), 19% had potentially epileptogenic abnormalities (RMH 28% vs AH 12%; P < .01). At both sites, changes due to previous stroke/hemorrhage were the commonest lesions, followed by traumatic brain injury. ≥WHO level 1 brain tumors diagnosed at presentation comprised a very small proportion (<1%) at each clinic. At both sites, epilepsy type could be determined in 60% of patients; RMH had more focal and AH more generalized epilepsy diagnoses. Significance: Differences between the clinics' administrative and screening practices may contribute to differences in investigation findings. Insight into these differences will facilitate interpretation and utilization, and planning of future research.

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.

A targeted resequencing gene panel for focal epilepsy.

OBJECTIVES: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. METHODS: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. RESULTS: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases. We searched for both germline and somatic mutations in 251 patients with unsolved sporadic or familial focal epilepsy and identified 11 novel or very rare missense variants in 5 different genes: CHRNA4, GRIN2B, KCNT1, PCDH19, and SCN1A. Of these, 2 were predicted to be pathogenic or likely pathogenic, explaining ∼0.8% of the cohort, and 8 were of uncertain significance based on available data. CONCLUSIONS: We have developed and validated a targeted resequencing panel for focal epilepsies, the most important clinical class of epilepsies, accounting for about 60% of all cases. Our application of MIP technology is an innovative approach that will be advantageous in the clinical setting because it is highly sensitive, efficient, and cost-effective for screening large patient cohorts. Our findings indicate that mutations in known genes likely explain only a small proportion of focal epilepsy cases. This is not surprising given the established clinical and genetic heterogeneity of these disorders and underscores the importance of further gene discovery studies in this complex syndrome.

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.

Oxidative stress and nephrolithiasis: a comparative pilot study evaluating the effect of pomegranate extract on stone risk factors and elevated oxidative stress levels of recurrent stone formers and controls.

Previous studies have linked oxidative stress and nephrolithiasis. Animal studies have demonstrated that pomegranate juice may play a role in preventing stone formation. We examined differences between recurrent stone formers (RSFs) and non-stone formers (NSFs) regarding oxidative stress and the effect of pomegranate administration on risk factors for nephrolithiasis. RSFs were recruited prospectively and matched to a group of NSFs. Subjects submitted urine and blood samples prior to and after receiving pomegranate polyphenol extract (1,000 mg) for 90 days. Serum and urine samples were analyzed for stone risk and oxidative stress. Thirty subjects completed the study. RSFs had significantly higher levels of oxidative stress at baseline as measured by urinary 8-hydroxy-deoxyguanosine (p < 0.0001), 2.2'-azobis (2-amidinopropane) hydrochloride-induced serum lipid peroxidation [increased levels of lipid peroxides (p = 0.0002), and thiobarbituric acid reactive substances (p = 0.002)], but not by serum paraoxonase1 (PON1) arylesterase activity (p > 0.99), or by highly sensitive C-reactive protein (p > 0.99). Following pomegranate supplementation, there was a 10 % increase in PON1 activity in RSFs (p = 0.007), which correlated with a trend toward decreasing values of supersaturation of calcium oxalate (SSCaOx; p = 0.05). RSFs have markedly higher levels of oxidative stress than NSFs. While the ability to prevent stone formation through supplementation cannot be determined in this pilot study, supplementation with pomegranate extract does not increase the risk of stones and may confer some benefit in lowering SSCaOX in those patients with increased PON-1 levels following supplementation, confirming findings of previous animal models.

Tonic seizures of Lennox-Gastaut syndrome: periictal single-photon emission computed tomography suggests a corticopontine network.

PURPOSE: Lennox-Gastaut syndrome (LGS) is a severe epileptic disorder with characteristic electroclinical features but diverse etiologies. The shared electroclinical characteristics suggest that common cerebral networks are involved in generating seizures. We sought to reveal these networks by comparing ictal and interictal single-photon emission computed tomography (SPECT). METHODS: We identified 10 ictal-interictal SPECT pairs from seven patients with LGS (median age 11 years; range 1-38) who were studied during video electroencephalography (EEG)-confirmed tonic seizures. We performed a voxel-wise comparison of ictal and interictal SPECT studies across the group. The evolution of blood flow changes was explored by examining early and late injection groups. KEY FINDINGS: Median duration of tonic seizures was 10 s (range 6-29 s), and injection latency from seizure offset was -8 to 48 s. In the early injection group (<10 s; three studies), there was hyperperfusion over pons and cerebellar hemispheres (p < 0.05 cluster corrected family wise error), and hypoperfusion bilaterally over the pericentral region, with a trend toward hyperperfusion over bilateral superior and middle frontal gyri, and lateral parietal cortex. In the late injection group, there was hyperperfusion over midline and lateral cerebellar regions, with hypoperfusion widely over bilateral frontal regions. SIGNIFICANCE: This study suggests that the tonic seizures of LGS result from activity in a network, containing bilateral frontal and parietal association areas and the pons. We postulate that tonic seizures recruit the corticoreticular system, which connects frontal attentional areas to the pontine reticular formation, and is normally responsible for postural tone and orienting behavior.

Morbidity and mortality of octogenarians following open radical cystectomy using a standardized reporting system.

INTRODUCTION: Recent evidence suggests that radical cystectomy may be underutilized in elderly patients, despite literature supporting acceptable morbidity/mortality in this population. However, there is a paucity of literature reporting complications in a standardized manner. Therefore, we evaluated the morbidity and mortality of octogenarians treated with radical cystectomy using the modified Clavien complication reporting system. MATERIALS AND METHODS: We retrospectively reviewed 443 consecutive patients undergoing radical cystectomy at our institution between January 2000 and April 2010. Patients who underwent cystectomy for benign conditions were excluded, leaving 359 for analysis. Baseline demographic and perioperative data were reviewed and all complications were graded. We compared the outcomes of our octogenarian population (n = 43) against our younger population (n = 316). RESULTS: There was no difference between octogenarians and the younger cohort for overall complication rates (86% versus 83%, p = 0.91), or major (33% versus 30%, p = 0.93) or minor (81% versus 80%, p = 0.91) complications. The younger group was more likely to encounter a late complication (41.5% versus 23.3%, p = 0.03). Those 80 years and older trended toward more intraoperative complications (21% versus 10%, p = 0.07). The older group also had a greater propensity for neurological complications (26% versus 11%, p = 0.02), but there was no difference in CVA (2% versus 3%, p = 0.22). There was no difference in mortality rates between the older and younger cohort (2.3% versus 0.9%, p = 0.95). CONCLUSIONS: Radical cystectomy is a morbid procedure regardless of patient age. Age alone should not preclude radical cystectomy in the elderly.

Novel use of the capio urethral anastomotic suturing device: a 50-case assessment.

OBJECTIVE: Robotic laparoscopic assisted prostatectomy (RALP) has become the predominant technique for prostatectomy despite significant expense and no robust evidence supporting better cancer control, erectile function, or continence. Several studies have demonstrated lower bladder neck contracture (BNC) rates with RALP, believed to be related to improved visualization and control of the urethrovesical anastomosis. We evaluated the Capio™ radical prostatectomy (RP) suture capturing device for improving anastomotic precision during urethrovesical anastomosis in open radical prostatectomy. MATERIALS AND METHODS: We performed a retrospective review on a single-surgeon series of 50 consecutive patients undergoing radical retropubic prostatectomy (RRP) with utilization of the Capio™ RP device at an academic hospital (February 2010 to May 2012). Patient demographics, pathology, and outcomes data including rates of anastomotic leak, BNC, erectile function, and continence were collected. RESULTS: Mean age of patients at the time of procedure was 60.4 ± 6.43 years. Patients were stratifed by D'Amico criteria into low (14.3%), intermediate (67.4%), and high (18.4%) risk groups. Mean follow-up for all patients was 13.1 ± 7.29 months. No patients were diagnosed with BNC within 90 days after surgery. Two patients (4%) were subsequently diagnosed and treated for BNC, one of whom was asymptomatic prior to diagnosis. CONCLUSION: Utilizing the Capio™ RP device during RRP, we were able to achieve a BNC rate equivalent to rates reported for RALP. Use of the Capio™ RP device appears to be a cost-effective method for improving RRP urethrovesical anastomotic results.

Psychological trajectories in the year after a newly diagnosed seizure.

PURPOSE: Underdiagnosed depression and anxiety are well-recognized issues in chronic epilepsy, but the evolution of these symptoms after diagnosis is not well understood. We aimed to identify mood trajectories after a first seizure, and to examine factors impacting these trajectories. METHODS: Seventy-four patients were evaluated at 1, 3, and 12 months with (1) the Hospital Anxiety and Depression Scale, and (2) a semistructured interview assessing patients' initial psychological reaction to the seizure at 1 month (limited vs. pervasive loss of control). The SAS Institute's TRAJ data modelling procedure was employed to delineate trajectories. KEY FINDINGS: Two depression and three anxiety trajectories were identified, with significant overlap. The majority of patients (≈ 74%) followed a trajectory with low depression throughout the study, and either low or moderate anxiety. A minority followed trajectories with high depression and anxiety from diagnosis (≈ 16%). Patients with high levels of distress were adversely affected by seizure recurrence and antiepileptic drugs (AEDs), whereas those with low levels were not. Trajectories were predicted by the patient's sense of loss of control early after diagnosis and were weakly related to demographic and medical variables (age, gender, education, relationship status, psychiatric history, and prior epileptic events). SIGNIFICANCE: Methods that account for heterogeneity in patient responses are critical for developing a clinically relevant understanding of adjustment after a newly diagnosed seizure. Most patients appear to be resilient in the face of early seizures, whereas those at risk of longer-term psychological difficulties may be evident from diagnosis. Early screening for depression and anxiety is warranted.

Bladder Cancer Immunotherapy: BCG and Beyond.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1) immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.

Familial Lennox-Gastaut syndrome in male siblings with a novel DCX mutation and anterior pachygyria.

Lennox-Gastaut syndrome (LGS) has numerous causes,but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike-wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin (DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling.

Smaller prostate size predicts high grade prostate cancer at final pathology.

PURPOSE: Prostate size may influence the likelihood of detecting high grade prostate cancer at final pathology. We evaluated the association between prostate size and high grade (Gleason score 7 or greater) cancer. MATERIALS AND METHODS: We analyzed data from 2,880 patients who underwent surgical treatment of prostate cancer between January 2000 and June 2008. Prostate size measured at prostatectomy was compared across a strata of clinical variables (age, body mass index, prostate specific antigen, biopsy Gleason score, clinical stage and year of surgery) and pathological outcomes (final Gleason score, extraprostatic extension, positive surgical margin, seminal vesicle invasion and lymph node involvement). Multivariate logistic regression was used to assess prostate size as a predictor of high grade cancer. RESULTS: Older age, higher prostate specific antigen and later year of surgery were associated with larger gland size. Small prostate size was associated with high grade prostate cancer as well as extraprostatic extension and positive surgical margins on univariate and adjusted analysis. The probability of high grade disease decreased approximately 15% across the lowest vs highest prostate sizes. On multivariate analysis adjusted for age, race, prostate specific antigen, clinical stage, biopsy Gleason score and date of surgery prostate size was an important predictor of high grade disease (OR 0.94; 95% CI 0.92, 0.97 per 2 gm increments, p <0.001). The area under the ROC curve was 0.82 (95% CI 0.81, 0.84). CONCLUSIONS: Prostate size was inversely associated with the risk of high grade cancer at final pathology. The ability to predict high grade disease could have implications for the management of prostate cancer.

Predicting seizure control: cortical excitability and antiepileptic medication.

OBJECTIVE: Approximately 30% of patients with newly diagnosed epilepsy do not respond to antiepileptic drugs (AEDs), but this is not predictable. We used transcranial magnetic stimulation to determine the effect of AEDs on cortical excitability in patients with epilepsy and correlated this with a successful response to treatment. METHODS: Ninety-nine drug-naïve patients with newly diagnosed epilepsy (55 idiopathic generalized epilepsy, 44 focal epilepsy) were evaluated. Motor threshold and cortical excitability on recovery curve analysis were measured before and 4 to 16 weeks after starting medication. After 1 year of treatment, 43 of 55 idiopathic generalized epilepsy and 26 of 44 focal epilepsy patients were seizure free. RESULTS: A decrease in cortical excitability occurred in the seizure-free group as indicated by an increase in motor threshold (p < 0.05) and intracortical inhibition on recovery curve analysis, maximum at the 250-millisecond interstimulus interval (p < 0.01) compared with pretreatment values. These changes were not present in the group with ongoing seizures. INTERPRETATION: Seizure freedom is marked by a reduction in transcranial magnetic stimulation measures of cortical excitability, evident shortly after beginning therapy. This virtual normalization of cortical excitability occurred regardless of the seizure characteristics or AED used. Failure to show this response to AED treatment may be valuable as an early predictor of pharmacoresistance in individual patients.

Cognitive complaints after a first seizure in adulthood: Influence of psychological adjustment.

PURPOSE: To examine the nature and determinants (biologic and psychological) of cognitive complaints in first-seizure patients. We analyzed this in the context of our previous findings that a sense of loss of control after a newly diagnosed seizure (limited or pervasive) predicts subsequent psychological adjustment trajectories. METHODS: Eighty-five consecutive First Seizure Clinic patients were assessed at 1 and 3 months. Cognitive complaints were evaluated qualitatively, with a semistructured interview, and quantitatively, with the A-B Neuropsychological Assessment Schedule (ABNAS). Objective attentional processing was assessed with reaction time tasks and the Wechsler Adult Intelligence Scale-3rd edition (WAIS-III) Processing Speed Index. Mood was assessed with the Hospital Anxiety and Depression Scale (HADS). Psychological adjustment trajectories were represented by previous classification of patients into limited and pervasive groups, as derived from semistructured interview. RESULTS: Cognitive complaints at 1 and 3 months were strongly associated with mood, and unrelated to objective attentional processing. Psychological adjustment trajectories influenced the longitudinal course of cognitive complaints, and these effects were partially mediated by mood differences between the limited and pervasive groups. The course of cognitive complaints was also altered by commencing antiepileptic drugs. Patients experiencing seizure recurrence reported greater cognitive complaints, even before their seizure recurred. Mediation analyses showed this effect was likely attributable to increased mood disturbance in the seizure recurrence group, and was unrelated to objective attentional processing. DISCUSSION: Understanding cognitive complaints in first-seizure patients requires a longitudinal perspective that takes into account the patients' changing psychological and medical contexts. Patients presenting with extensive cognitive complaints may warrant assessment for mood and adjustment issues.

The psychological impact of a newly diagnosed seizure: losing and restoring perceived control.

This study aimed to characterize the process of psychosocial adjustment following a newly diagnosed seizure. Eighty-five adult patients were assessed 1 and 3 months after a first seizure presentation with a purpose-developed semistructured interview, the NEWQOL, and the COPE. Among a broad range of patient concerns, psychological issues were paramount, representing a process of losing and restoring perceived control. Two psychological adjustment trajectories were identified, which hinged on the experience of a limited (n=37) or pervasive (n=48) loss of control. These adjustment trajectories were predicted by demographic and clinical factors. The pervasive group described a more extensive process of reevaluation, leading to an improved sense of self at 3 months. Pervasive loss of control, anxiety, and depression predicted subsequent seizure recurrence. Overall, a first seizure can trigger a complex adjustment process, which might require therapeutic management in some patients.

EEG in adult-onset idiopathic generalized epilepsy.

PURPOSE: It remains controversial whether adult-onset idiopathic generalized epilepsy (IGE) is a distinct syndrome or a continuum among IGE syndromes. EEG is the only known biologic marker of IGE and helps differentiate many of its classic subsyndromes. In this study, we looked for the differences in the EEG findings of IGE of classic adolescent onset versus adult onset that may suggest syndromic heterogeneity. METHODS: Seventy-six patients (47 adolescent-onset IGE, 29 adult-onset IGE) with a clinical and EEG diagnosis of IGE were included. We defined IGE with age at onset of 11-20 years as adolescent-onset IGE and age at onset of 20 years or after as adult-onset IGE. Patients with first-decade onset of seizures, delayed EEGs, and no EEG available for review were excluded. The first EEG was performed within 24 h of the seizure, and if negative, a sleep-deprived EEG was done. All EEGs were reviewed in detail with respect to the background activity and the generalized spike-wave (GSW) characteristic. RESULTS: EEGs (87; 56 adolescent-onset IGE, 31 adult-onset IGE) were systematically reviewed. Background was normal in all patients. The morphology, amplitude, duration, frequency, occurrence, or activation of the GSW pattern did not differ between these two groups. CONCLUSIONS: No differences of EEG features were found between the classic adolescent-onset and the adult-onset IGE. This supports the hypothesis that they share common biologic determinants and exist along a life-long age spectrum of classic IGE.