ORCID Profile
0000-0003-1224-4101
Current Organisations
Florey Institute of Neuroscience and Mental Health
,
Monash University
,
Austin Health
,
University of Melbourne
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-06-2010
Publisher: Oxford University Press (OUP)
Date: 17-03-2015
DOI: 10.1093/BRAIN/AWV052
Publisher: Wiley
Date: 22-09-2015
DOI: 10.1111/DMCN.12593
Abstract: Dravet syndrome, a severe infantile epilepsy syndrome, is typically resistant to anti-epileptic drugs (AED). Lamotrigine (LTG), an AED that is effective for both focal and generalized seizures, has been reported to aggravate seizures in Dravet syndrome. Therefore, LTG is usually avoided in Dravet syndrome. We describe two adults and a child with Dravet syndrome in whom LTG resulted in decreased seizure duration and frequency. This benefit was highlighted in each patient when LTG was withdrawn after 6 to 15 years, and resulted in an increased frequency of convulsive seizures together with longer seizure duration. A 25-year-old male required hospital admission for frequent seizures for the first time in 7 years, 6 weeks after ceasing LTG. Reintroduction of LTG improved seizure control, suggesting that in some patients with Dravet syndrome, LTG may be beneficial.
Publisher: Hindawi Limited
Date: 06-09-2022
DOI: 10.1002/HUMU.24454
Abstract: Tuberous sclerosis complex (TSC) is a multi-system genetic disorder. Most patients have germline mutations in TSC1 or TSC2 but, 10%-15% patients do not have TSC1/TSC2 mutations detected on routine clinical genetic testing. We investigated the contribution of low-level mosaic TSC1/TSC2 mutations in unsolved sporadic patients and families with TSC. Thirty-one sporadic TSC patients negative on routine testing and eight families with suspected parental mosaicism were sequenced using deep panel sequencing followed by droplet digital polymerase chain reaction. Pathogenic variants were found in 22/31 (71%) unsolved sporadic patients, 16 were mosaic (median variant allele fraction [VAF] 6.8% in blood) and 6 had missed germline mutations. Parental mosaicism was detected in 5/8 families (median VAF 1% in blood). Clinical testing laboratories typically only report pathogenic variants with allele fractions above 10%. Our findings highlight the critical need to change laboratory practice by implementing higher sensitivity assays to improve diagnostic yield, inform patient management and guide reproductive counseling.
Publisher: Wiley
Date: 28-11-2017
DOI: 10.1111/BPH.13658
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-10-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-07-2015
Publisher: Elsevier BV
Date: 10-2023
Publisher: Elsevier BV
Date: 05-2011
Publisher: Wiley
Date: 09-05-2018
DOI: 10.1111/EPI.14042
Abstract: The genetic generalized epilepsies (GGEs) are mainly genetically determined disorders. Although inheritance in most cases appears to be complex, involving multiple genes, variants of a number of genes are known to contribute. Pathogenic variants of SLC2A1 leading to autosomal-dominant GLUT1 deficiency account for up to 1% of cases, increasing to 10% of those with absence seizures starting before age 4 years. Copy number variants are found in around 3% of cases, acting as risk alleles. Copy number variation is much more common in those with comorbid learning disability. Common variant associations are starting to emerge from genome-wide association studies but do not yet explain a large proportion of GGEs. Although currently genetic testing is not likely to yield a diagnosis for most patients with GGEs, it can be of great importance in specific clinical situations. Providers should consider the in idual patient's history in determining the utility of genetic testing.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.PHARMTHERA.2014.06.001
Abstract: Metabolic dysfunction leading to epilepsy is well recognised. Dietary therapy, in particular the ketogenic diet, is now considered an effective option. Recent genetic studies have highlighted the central role that metabolism can play in setting seizure susceptibility. Here we discuss various metabolic disorders implicated in epilepsy focusing on energy deficiency due to genetic and environmental causes. We argue that low, uncompensated brain glucose levels can precipitate seizures. We will also explore mechanisms of disease and therapy in an attempt to identify common metabolic pathways involved in modulating seizure susceptibility. Finally, newer therapeutic approaches based on diet manipulation in the context of energy deficiency are discussed.
Publisher: Wiley
Date: 11-2012
DOI: 10.1002/ANA.23702
Abstract: We examined whether glucose transporter 1 (GLUT1) deficiency causes common idiopathic generalized epilepsies (IGEs). The IGEs are common, heritable epilepsies that usually follow complex inheritance currently little is known about their genetic architecture. Previously considered rare, GLUT1 deficiency, due to mutations in SLC2A1, leads to failure of glucose transport across the blood-brain barrier and inadequate glucose for brain metabolism. GLUT1 deficiency was first associated with an encephalopathy and more recently found in rare dominant families with epilepsy and paroxysmal exertional dyskinesia (PED). Five hundred four probands with IGEs and 470 controls underwent SLC2A1 sequencing. Glucose transport was assayed following expression of SLC2A1 variants in Xenopus oocytes. All available relatives were phenotyped, and SLC2A1 was sequenced. Functionally validated mutations in SLC2A1 were present in 7 of 504 (1.4%) probands and 0 of 470 controls. PED, undiagnosed prior to study, occurred in 1 proband and 3 of 13 relatives with mutations. The IGEs in probands and relatives were indistinguishable from typical IGE. Three cases (0.6%) had mutations of large functional effect and showed autosomal dominant inheritance or were de novo. Four (0.8%) cases had a subtle functional effect 2 showed possible dominant inheritance, and 2 did not. These alleles leading to subtle functional impairment may contribute to complex, polygenic inheritance of IGE. SLC2A1 mutations contribute to approximately 1% of IGE both as a dominant gene and as a susceptibility allele in complex inheritance. Diagnosis of GLUT1 deficiency has important treatment (ketogenic diet) and genetic counseling implications. The mechanism of restricted glucose delivery differs from the current focus on IGEs as ion channel disorders.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.YEBEH.2018.12.026
Abstract: Psychogenic nonepileptic seizures (PNES) resemble seizures but are psychological in origin. The etiology of PNES remains poorly understood, yet several theories argue for the importance of autonomic dysregulation in its pathophysiology. We therefore conducted a retrospective study to investigate autonomic dynamics leading up to a seizure to inform their mechanistic relevance. One hundred one patients with PNES and 45 patients with epileptic seizure (ES) were analyzed for preictal heart rate (HR) and respiratory rate (RR) at baseline and at minute intervals from 5 min to onset. Patients with PNES showed rising HR (p < 0.001, repeated-measures analysis of variance (ANOVA)) and rising RR (p = 0.012, repeated-measures ANOVA) from baseline to the onset of their seizures. Patients with ES did not exhibit significant preictal HR or RR increase. Patients with PNES had nonsignificantly higher preictal HR and RR than patients with ES. Patients with PNES exhibit increasing autonomic arousal prior to seizure events unlike patients with epilepsy. This may reflect increasing levels of preictal anxiety, and future studies could study patients' subjective experiences of the preictal period, and more definitive measures of ventilation to see if this supported a model of PNES as "panic without panic".
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2016
Publisher: Wiley
Date: 13-01-2012
DOI: 10.1111/J.1528-1167.2011.03379.X
Abstract: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.
Publisher: BMJ
Date: 20-09-2019
Abstract: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippoc us are aetiologically important. Despite decades of investigation, it is unclear whether hippoc al volume is reduced in POE, perhaps due to small s le sizes and methodological limitations of past research. In this study, we examined the volume of the total hippoc us, and the hippoc al head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippoc al volumes were manually traced and compared between (1) POE and EC (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). Compared with EC the POE group had smaller total left hippoc us volume (13.5% decrease, p .001), and smaller left hippoc al body (13.3% decrease, p=0.002), and left (41.5% decrease, p .001) and right (36.4% decrease, p .001) hippoc al tail volumes. Hippoc al head volumes did not differ between groups. Posterior hippoc al volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippoc al head. Posterior hippoc al atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippoc al atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.
Publisher: Springer Science and Business Media LLC
Date: 04-2001
Abstract: To quantitatively assess subjects' ability to detect hedonic (palatability), sensory and nutritional differences between covertly manipulated high-fat (HF) and low-fat (LF) diets. SUBJECTS AND DIETS: This study examined the response of 16 subjects (eight men, eight women) to 20 LF and 20 HF versions of manipulated foods. Average percentage protein:fat:carbohydrate (by energy) and energy density (ED) of the two diets were 13:25:62, 371 kJ/100 g and 13:50:37, 672 kJ/100 g, respectively. Subjects were asked to simultaneously assess the HF and LF versions of each food in terms of (i) subjective pleasantness of each food, (ii) perceived differences in appearance, smell, taste and texture of the foods, and (iii) for each s le to assess whether it was high or low in energy, protein, carbohydrate, fat, fibre, sugar and salt. Perceived pleasantness of HF and LF versions of the foods was compared by analysis of variance. Comparisons used chi-squared tests of independence to assess departure from the null hypothesis of no perceived difference in remaining parameters (ii-iii). On average, subjects exhibited no significant preference for LF or HF versions of the foods (no difference 15 foods, three HF foods more pleasant, two LF foods more pleasant (P<0.03)). On average there were no general differences in comparison of sensory attributes that were consistently ascribable to the LF or HF foods, although there were numerous significant differences for in idual foods. Subjects appeared unable to distinguish the HF foods as being HF (66% of estimates) and guessed correctly 33% of the time. They were better able to categorize the LF foods correctly (53% correct). On aggregate 43% of HF and LF foods were correctly identified. Subjects appeared able to detect sensory differences between foods but not to relate them to energy or nutrient content of these foods. These data suggest that subjects are on average not able to perceive large differences in the fat content of diets manipulated in this manner. In general the assumption that the manipulation of such foods is covert appears to hold, but subjects were far better at correctly identifying certain food types (dairy-based) over others.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2018
DOI: 10.1212/NXG.0000000000000297
Abstract: To examine the genotype to phenotype connection in glucose transporter type 1 (GLUT1) deficiency and whether a simple functional assay can predict disease outcome from genetic sequence alone. GLUT1 deficiency, due to mutations in SLC2A1 , causes a wide range of epilepsies. One possible mechanism for this is variable impact of mutations on GLUT1 function. To test this, we measured glucose transport by GLUT1 variants identified in population controls and patients with mild to severe epilepsies. Controls were reference sequence from the NCBI and 4 population missense variants chosen from public reference control databases. Nine variants associated with epilepsies or movement disorders, with normal intellect in all in iduals, formed the mild group. The severe group included 5 missense variants associated with classical GLUT1 encephalopathy. GLUT1 variants were expressed in Xenopus laevis oocytes, and glucose uptake was measured to determine kinetics (V max ) and affinity (K m ). Disease severity inversely correlated with rate of glucose transport between control (V max = 28 ± 5), mild (V max = 16 ± 3), and severe (V max = 3 ± 1) groups, respectively. Affinities of glucose binding in control (K m = 55 ± 18) and mild (K m = 43 ± 10) groups were not significantly different, whereas affinity was indeterminate in the severe group because of low transport rates. Simplified analysis of glucose transport at high concentration (100 mM) was equally effective at separating the groups. Disease severity can be partly explained by the extent of GLUT1 dysfunction. This simple Xenopus oocyte assay complements genetic and clinical assessments. In prenatal diagnosis, this simple oocyte glucose uptake assay could be useful because standard clinical assessments are not available.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.SEIZURE.2018.05.007
Abstract: Psychogenic Non-Epileptic Seizures (PNES) are events that appear epileptic but are instead thought to have a psychological origin. Increased rates of several psychiatric disorders have been reported in PNES, including anxiety and panic disorders. Some theories suggest panic and/or hyperventilation have aetiological roles in PNES, though these remain unproven. We conducted a systematic review of associations of panic and hyperventilation with PNES using Ovid Medline and PubMed, and a meta-analysis where appropriate. We found eighteen studies reporting rates of panic in PNES and eight studies reporting hyperventilation. The reported rate of panic attacks in PNES ranged from 17% to 83%, with physical symptoms more commonly reported, and affective symptoms less so. 'Dizziness or light-headedness' was found to be more prevalent than 'fear of dying' by random-effects meta-analysis (68% vs. 23%). A proportion meta-analysis found a weighted occurrence of 20% of panic disorder in PNES. A pooled meta-analytic rate of PNES events following voluntary hyperventilation induction was 30%, while the clinically observed rates of peri-ictal hyperventilation in PNES without induction varied from 15 to 46%. Previous studies have reported moderate rates of association of panic in PNES, though the proportions varied considerably across the literature, with physical symptoms more commonly reported than affective. Hyperventilation is an effective inducer of PNES events in a minority, and can be observed occurring in a minority of patients without induction. These results support an important, albeit not essential, role for panic and hyperventilation in the pathogenesis of PNES events.
Publisher: Cold Spring Harbor Laboratory
Date: 29-09-2021
DOI: 10.1101/MCS.A006127
Abstract: Maffucci syndrome is a rare, highly variable somatic mosaic condition, and well-known cancer-related gain-of-function variants in either the IDH1 or IDH2 genes have been found in the affected tissues of most reported in iduals. Features include benign enchondroma and spindle-cell hemangioma, with a recognized increased risk of various malignancies. Fewer than 200 affected in iduals have been reported therefore, accurate estimates of malignancy risk are difficult to quantify and recommended surveillance guidelines are not available. The same gain-of-function IDH1 and IDH2 variants are also implicated in a variety of other benign and malignant tumors. An adult male presented with several soft palpable lesions on the right upper limb. Imaging and histopathology raised the possibility of Maffucci syndrome. DNA was extracted from peripheral blood lymphocytes and tissue surgically resected from a spindle-cell hemangioma. Sanger sequencing and droplet digital polymerase chain reaction (PCR) analysis of the IDH1 gene were performed. We identified a somatic mosaic c.394C T (p.R132C) variant in exon 5 of IDH1 , in DNA derived from hemangioma tissue at ∼17% variant allele fraction. This variant was absent in DNA derived from blood. This variant has been identified in the affected tissue of most reported in iduals with Maffucci syndrome. Although this in idual has a potentially targetable variant, and there is a recognized risk of malignant transformation in this condition, a decision was made not to intervene with an IDH1 inhibitor. The reasons and prospects for therapy in this condition are discussed.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
DOI: 10.1212/WNL.0000000000004769
Abstract: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 . A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 ided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial. Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3–5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10–18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval −1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction. Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks. Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151). This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1 , quinidine does not significantly reduce seizure frequency.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2013
DOI: 10.1038/NRNEUROL.2012.272
Abstract: Research on epilepsies in 2012 has substantially advanced our knowledge of these often devastating conditions. From important discoveries that revealed causative factors and the molecular basis of disease, to major implications for surgical decision-making, these studies set the scene for future advances in the field.
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1111/EPI.16475
Publisher: Wiley
Date: 02-2010
DOI: 10.1002/ANA.21968
Publisher: Wiley
Date: 08-2018
Abstract: Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome in which affected in iduals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures plus with a good outcome to severe epileptic encephalopathies. Here, we review the spectrum of epilepsy phenotypes, the genetic architecture of GEFS+, and the implicated genes. Using an illustrative clinical case study, we describe important steps in managing patients with GEFS+: making the diagnosis of GEFS+, appropriate genetic testing, and counselling.
Publisher: Wiley
Date: 25-10-2012
DOI: 10.1111/EPI.12007
Abstract: Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike-waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE.
Publisher: BMJ
Date: 30-04-2201
Publisher: Wiley
Date: 18-11-2015
DOI: 10.1002/ANA.24520
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.SEIZURE.2022.04.012
Abstract: Functional seizures (FS) are heterogenous, with no agreed way to sub ide them. One FS subtype frequently observed during EEG is those whose seizures are provoked by hyperventilation. We wished to see whether this subtype might reflect a different seizure mechanism. We analysed the video-EEG/ECGs of all patients with FS from two hospitals in Melbourne from 2010-6. We identified 120 patients during the study period, 107 of whom had usable recordings. Examining those 11 (10%) whose seizures had been induced by hyperventilation, we compared the heart rates of those where the seizure occurred during the hyperventilation, and those where they occurred afterwards. The during-hyperventilation group had a higher baseline heart rate which increased prior to their seizure the after-hyperventilation group had a lower baseline heart rate and no pre-ictal increase. In those patients whose seizures were not hyperventilation-induced, the same two heart rate patterns could be found: those with a higher baseline heart rate showed increasing heart rate prior to seizure onset, while those with a lower baseline heart rate did not. Cluster analysis showed the s le was optimally ided into these two groups based on their pre-onset heart rate alone. Patients with FS show two distinct patterns of pre-ictal heart rate, which may reflect two distinct seizure mechanisms.
Publisher: Wiley
Date: 31-08-2023
DOI: 10.1002/ANA.26765
Abstract: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippoc al sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in in iduals with FMTLE. We studied 134 families with ≥ 2 first or second‐degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one in idual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13–28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug‐resistance and/or hippoc al sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007) in contrast, no enrichment for the febrile seizure PRS was observed. FMTLE is a generally mild drug‐responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub‐genome‐wide significant focal epilepsy genome‐wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.SEIZURE.2022.09.006
Abstract: To explore the cortical morphological associations of the psychoses of epilepsy. Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10). POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall. The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Wiley
Date: 17-05-2013
DOI: 10.1002/AJMG.A.35946
Publisher: American Medical Association (AMA)
Date: 09-2011
DOI: 10.1001/ARCHNEUROL.2011.102
Abstract: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Genetic analysis. Ambulatory and hospitalized care. Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe lification. Any identified mutations were then screened in controls. Any SLC2A1 mutations. Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe lification analysis did not reveal any genomic rearrangements in 75 of the remaining cases 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder.
Location: Australia
No related grants have been discovered for Saul Mullen.