There is an urgent need for more informative quantitative techniques that non-invasively and obje... more There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies—limited spatial sampling and the implici...
Volumetric MRI permits acquisition of fine, contiguous slices with excellent tissue contrast, and... more Volumetric MRI permits acquisition of fine, contiguous slices with excellent tissue contrast, and is ideal for detailed morphometric studies of the hippocampus.
Fibre- and sphere-based microcapsules have been developed, exhibiting controllable uniform morpho... more Fibre- and sphere-based microcapsules have been developed, exhibiting controllable uniform morphologies, predictable drug release profiles, and neuro-cytocompatibility.
The serendipitous discovery of triggered autobiographical memories and eventual memory improvemen... more The serendipitous discovery of triggered autobiographical memories and eventual memory improvement in an obese patient who received fornix deep brain stimulation in 2008 paved the way for several phase I and phase II clinical trials focused on the safety and efficacy of this potential intervention for people with Alzheimer's disease. In this article, we summarize clinical trials and case reports on fornix deep brain stimulation for Alzheimer's disease and review experiments on animal models evaluating the physiological or behavioral effects of this intervention. Based on information from these reports and studies, we identify potential translational challenges of this approach and determine practical and ethical considerations for clinical trials, focusing on issues regarding selection criteria, trial design, and outcome evaluation. Based on initial results suggesting greater benefit for those with milder disease stage, we find it essential that participant expectations are ...
Diabetes/metabolism research and reviews, Jan 10, 2015
This study assesses the autonomic function of patients who have regained awareness of hypoglycaem... more This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant. Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age and gender matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness, and five healthy control participants without diabetes. All participants underwent: i. A battery of five cardiovascular autonomic function tests, ii. Quantitative sudomotor axonal reflex testing (QSART), and iii. Sympathetic skin response (SSR) testing. Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0-3 months post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97% to 69% at 0-3 months (p<0.001, Fisher's Exact Test) and to 20% after 12 months (p<0.0001, Fis...
Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin precondi... more Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin preconditioning of muscle following plasmid injection. We investigated in vivo delivery of naked DNA to mdx mouse muscle, utilising enhanced green fluorescent protein reporter vector (pEGFP) and a corrective nucleic acid to promote targeted corrective gene conversion at the mutant mdx mouse dystrophin (DMDmdx) locus. Electroporation, myoablation with bupivacaine and a combined protocol, were applied to mdx muscle. We report up to 90% EGFP expression in electroporated mdx tibialis anterior muscle. Muscles preconditioned with bupivacaine showed low transgene expression with or without EP. Single EGFP+ve muscle fibre explants showed EGFP expression in mature fibres in preference to satellite cells. We observed a two-fold increase (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.005; t) in dystrophin protein, accompanied by wild-type (wt) DMD transcript in muscles injected with corrective nucleic acid over contralateral saline-injected TAs. By targeting the muscle fibres in preference to the satellite cells, plasmid-bourne transgenes delivered to dystrophic muscle will not penetrate the regenerative component of muscle. Whether in the context of targeted corrective gene conversion or therapeutic non-viral transgenes, under these conditions periodic re-administration will be required to promote phenotypic benefits in dystrophic muscle.
Abstract Researchers have emphasized a need for ongoing rehabilitation and support for individual... more Abstract Researchers have emphasized a need for ongoing rehabilitation and support for individuals with traumatic brain injury FBI), yet there are few detailed descriptions of long-term outcome, and many people with long-standing TBI do not or cannot access support services. HB and NL, two men who sustained severe TBI, presented for neuropsychological consultation for the first time more than 20 years post-injury. Referral was prompted by significant mood and relationship disturbances, and ongoing mnemonic and cognitive ...
ABSTRACTBACKGROUND AND PURPOSEThe difficulty of distinguishing disorders of consciousness from ce... more ABSTRACTBACKGROUND AND PURPOSEThe difficulty of distinguishing disorders of consciousness from certain disorders of communication leads to the possibility of false diagnosis. Our aim is to communicate with patients with disorders of consciousness through asking them to answer questions with “yes/no” by performing mental imagery tasks using functional magnetic resonance imaging (fMRI).METHODSA 1.5 T fMRI study with 5 patients and a control group is presented. Speech comprehension, mental imagery, and question–answer tests were performed.RESULTSThe imagery task of mental calculation produced equally distinct activation patterns when compared to navigation and motor imagery in controls. For controls, we could infer answers to questions based on imagery activations. Two patients produced activations in similar areas to controls for certain imagery tasks, however, no activations were observed for the question–answer task.CONCLUSIONSThe results from 2 patients provide independent support ...
Temporal lobe epilepsy (TLE), the most common form of partial epilepsy in adults is often refract... more Temporal lobe epilepsy (TLE), the most common form of partial epilepsy in adults is often refractory to medical treatment and in these patients epilepsy surgery is considered. Successful surgery is dependent on accurate localisation and lateralisation of the epileptogenic zone. The preoperative evaluation involves a series of assessments and investigations including detailed clinical history, interictal EEG, video-EEG monitoring, MRI, PET, SPECT, and neuropsychology and neuropsychiatric assessment. The role of each of these investigations and assessments in the preoperative evaluation is discussed. Advanced MR techniques including magnetic resonance spectroscopy, MR diffusion and MR perfusion have recently been assessed and are likely to enhance the pre-surgical evaluation of patients with TLE. The surgical outcome and preoperative investigations performed of 80 consecutive patients who underwent temporal lobe surgery between 1993 and 2002 at Royal Melbourne Hospital were reviewed. All patients had MRI, video-EEG monitoring and neuropsychology assessment and 56% a PET scan. During a mean follow-up of 5.9 years 75% had Class 1 outcome, 22% non-Class 1 outcome and 3% were lost to follow-up. The results of preoperative investigations were correlated with outcome. For interictal EEG, seizure semiology, ictal EEG, PET and neuropsychology assessment the surgical outcome of patients in whom results were concordant to side of surgery was compared with those discordant or nonlateralising. There was no significant difference. In 78 of 80 patients MRI revealed mesial temporal sclerosis or a foreign tissue lesion. The outcome was no different between these two groups. Results suggest that in patients with unilateral temporal lobe lesion on MRI and where ictal EEG is either concordant or non-lateralising, other investigations including PET, provide little additional prognostic information.
defined as 1 and 2 above, plus a response to anti-TB treatment and exclusion of other causes of m... more defined as 1 and 2 above, plus a response to anti-TB treatment and exclusion of other causes of meningitis. Results: 104 patients with TB meningitis (71 definite, 33 probable) presented between 1965 and 2004. On average, 2-3 new cases presented each year. 33% were Pacific people, 28% Maori, 28% European and 9% Asian. The frequency of complications was hyponatraemia 48%, hydrocephalus 37%, epileptic seizures 28%, cerebral infarcts 25%, coma 14%, tuberculoma 5%, diabetes insipidus 4%, intracranial haemorrhage 2%, paraplegia 2% and syringomyelia 1%. Delays in performing a lumbar puncture in 11 patients and incorrectly attributing CSF abnormalities to bacterial meningitis in 12 patients led to a delay in starting anti-TB treatment in 24% of the patients. The Glasgow Outcome Score (GOS) at discharge was 1 (death) 19%, 2 (persistent vegetative state) 2%, 3 (severe disability) 19%, 4 (moderate disability) 22% and 5 (good recovery) 37%. Conclusions: Pacific people, Maori and Asians have a higher risk of developing TB meningitis. The advent of HIV infection has not affected the incidence of TB meningitis in Auckland. Delays in starting anti-TB treatment occurred in 25% of the patients. Serious neurological and systemic complications were common and 40% of patients had a poor outcome (GOS 1-3).
Journal of Clinical and Experimental Neuropsychology, 2006
Controversy surrounds the question of whether there is a specific pattern of psychopathology or p... more Controversy surrounds the question of whether there is a specific pattern of psychopathology or personality style observed in patients with temporal lobe epilepsy (TLE) or whether the symptoms of psychological distress reflect a common disorder such as depression. Measurement equivalence was examined to test the hypothesis that the latent variable model underlying scores on the Beck Depression Inventory (BDI) was equivalent across samples of patients with TLE (n = 187) and patients with heterogeneous neurological disorders (n = 150). A well-replicated model of depression or psychological distress comprising three related variables, negative attitude, performance difficulty, and somatic elements, displayed a pattern of strict metric invariance. This result suggests that the same set of latent variables is measured with the same metric relationship between item scores and latent variables in patients with TLE and in patients with heterogeneous neurological disorders.
Communicated by Mireille Claustres Targeted corrective gene conversion (TCGC) holds much promise ... more Communicated by Mireille Claustres Targeted corrective gene conversion (TCGC) holds much promise as a future therapy for many hereditary diseases in humans. Mutation correction frequencies varying between 0.0001% and 40% have been reported using chimeraplasty, oligoplasty, triplex-forming oligonucleotides, and small corrective PCR amplicons (CPA). However, PCR technologies used to detect correction events risk either falsely indicating or greatly exaggerating the presence of corrected loci. This is a problem that is considerably exacerbated by attempted improvement of the TCGC system using high corrective nucleic acid (CNA) to nuclear ratios. Small fragment homologous replacement (SFHR)-mediated correction of the exon 23 dystrophin (DMD) gene mutation in the mdx mouse model of DMD has been used in this study to evaluate the effect of increasing CPA amounts. In these experiments, we detected extremely high levels of apparently corrected loci and determined that at higher CNA to nuclear ratios the extent of locus correction was highly exaggerated by residual CNA species in the nucleic acids extracted from the treated cells. This study describes a generic locus-specific detection protocol designed to eradicate residual CNA species and avoid the artifactual or exaggerated detection of gene correction. Hum Mutat 28(8), 816-823, 2007.
Epilepsy is characterised by recurrent seizures, which are manifestations of aberrant cortical ne... more Epilepsy is characterised by recurrent seizures, which are manifestations of aberrant cortical neuronal firing. It is unclear whether oxidative stress is a cause or consequence of seizure-related hippocampal neuronal loss or whether it occurs concomitantly with the initiation of cell death pathways. We utilised the rapid electrical amygdala kindling (REAK) model which does not induce cell death to examine early seizure-induced oxidative stress in wildtype and superoxide dismutase 2 (Sod2) +/- mice, which lack 50% of Sod2 activity and are therefore known to be more susceptible to mitochondrial oxidative stress. A significant increase in lipid peroxidation and superoxide production was noted in the hippocampi of wildtype mice and a more delayed response observed in Sod2 +/- mice at early time-points post-seizures, but protein carbonylation levels appeared unchanged. A 10-fold increase in superoxide production was seen in the Sod2 +/- CA2 neurons, indicating that Sod2 plays an important role in protecting the CA2 region of the hippocampus from seizure-induced free radical damage. Early hippocampal cell death was undetectable in wildtype or Sod2 +/- mice post-seizures. We were able to demonstrate that hippocampal oxidative stress occurred as a direct consequence of seizures rather than downstream of activation of cell death pathways. We were also able to show that this increase in oxidative stress was not sufficient to cause cell death within the time window investigated. Our data indicates that a possible upregulation of endogenous antioxidant activity might exist within selective hippocampal sectors in the Sod2 +/- mice that are as yet unknown.
Patients with psychogenic nonepileptic seizures (PNES) are common in tertiary epilepsy centers, e... more Patients with psychogenic nonepileptic seizures (PNES) are common in tertiary epilepsy centers, emergency departments, and neurological practices. Psychiatric discussion of patients with PNES has emphasized the role of trauma and dissociation. Personality disorder has been considered, but its extensive implications for neurological management have not been fully appreciated. We propose that the most difficult aspects of management stem not from the convulsive episodes, but from the personality disorder that frequently accompanies them. Although it is not the neurologist's role to treat personality disorder, the conduct of the physician-patient relationship can have potent consequences for good or ill on the outcome. We present a brief guide to current concepts of personality disorder; discuss the literature concerning its association with PNES, and offer practical guidelines for the conduct of the neurologist-patient relationship. This perspective offers resolutions to longstanding controversies, including how to communicate the diagnosis, discontinuing medication, and ongoing neurological contact.
The pathophysiologic basis for the [ 'sF]fluorodeoxyglucose positron-emission tomography (FDG-PET... more The pathophysiologic basis for the [ 'sF]fluorodeoxyglucose positron-emission tomography (FDG-PET) temporal lobe hypometabolism in patients with hippocampal sclerosis (HS) is uncertain. We tested the hypothesis that hippocampal atrophy, which is strongly correlated with hippocampal cell loss, is largely responsible for the regional hypometabolism in HS. Methods: Regions of interest (ROIs) on FJlG-PET scanning were determined in the medial, lateral, and posterior temporal lobe, thalamus, and basal ganglia. A righaeft asymmetry index for each ROI was calculated. These results were correlated with hippocampal magnetic resonance imaging (MRI) volume ratios. Results: There was no correlation between the magnitudes of the FDG-PET asymmetry index and the MRI volume ratio for
SummaryThe incidence of constipation as an adverse effect of pregabalin has previously been repor... more SummaryThe incidence of constipation as an adverse effect of pregabalin has previously been reported as low, with all cases described as either mild or moderate. From the experience of a tertiary referral epilepsy hospital center, we report several cases of severe and disabling constipation after initiating pregabalin, and resolving only on drug withdrawal. Of 80 consecutive patients, six (7.5%) developed significant constipation within 1–2 weeks of commencing pregabalin. Constipation was the most frequent adverse effect that required pregabalin to be withdrawn (6.3% of patients). The severity of symptoms was dose dependent. Pregabalin can cause marked constipation in some patients, and can lead to multiple unnecessary investigations and procedures if the clinician is not aware of this entirely reversible side effect.
Summary: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We r... more Summary: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We report a patient with an unusual form of reflex epilepsy in whom seizures are induced by tooth brushing. Magnetic resonance imaging (MRI) demonstrated a right posterior frontal low‐grade tumor predominantly involving the precentral gyrus. Video‐telemetry demonstrated right‐sided epileptiform activity during a typical induced complex partial seizure. An ictal single photon emission computed tomography (SPECT) scan showed an area of hyperfusion that corresponded to the MRI lesion on coregistration with a surface‐matching technique. A subsequent coregistered interictal SPECT scan demonstrated hypoperfusion in the same region. Ours is the first report to demonstrate a structural focus in this unusual form of reflex epilepsy. Possible mechanisms to explain the induction of the seizures are discussed.
Inpatient video-EEG monitoring (VEM) is widely used for the diagnosis, seizure classification, an... more Inpatient video-EEG monitoring (VEM) is widely used for the diagnosis, seizure classification, and presurgical evaluation of patients with seizure disorders. It is resource intensive and relatively expensive, so its utility continues to be debated. Few studies have specifically evaluated the utility of inpatient VEM in altering diagnosis or management of patients with seizure disorders. We sought to assess the proportion of patients for whom the preadmission diagnosis and management were altered after inpatient VEM of patients admitted for diagnostic and presurgical evaluation of seizure disorders. Data from a consecutive cohort of patients admitted over a 3-year period to an inpatient VEM unit in a tertiary referral hospital were retrospectively analyzed. The preadmission diagnosis and management by the referring neurologist was compared with the diagnosis and management after the VEM. Of 131 patients, 91 (70%) were admitted for diagnostic evaluation and 39 (30%) for a presurgical workup. Mean evaluative period was 5.6 days. Mean number of seizures recorded was 2.9. No seizures were recorded in 31% of patients. Interictal EEG showed epileptiform changes in 56 (43%). In 76 (58%), the diagnosis was altered as a result of the VEM, with the greatest change being an increase in the nonepileptic diagnosis group (7% to 31%) and the generalized diagnosis group (5% to 11%). Management was changed after the VEM in 95 (73%). The results of this study demonstrate that inpatient VEM has a high yield in changing diagnosis and management. Future long-term cost-benefit studies of the management changes resulting from VEM evaluation will aid in further reinforcing its role.
There is an urgent need for more informative quantitative techniques that non-invasively and obje... more There is an urgent need for more informative quantitative techniques that non-invasively and objectively assess strategies for epilepsy surgery. Invasive intracranial electroencephalography (iEEG) remains the clinical gold standard to investigate the nature of the epileptogenic zone (EZ) before surgical resection. However, there are major limitations of iEEG, such as the limited spatial sampling and the degree of subjectivity inherent in the analysis and clinical interpretation of iEEG data. Recent advances in network analysis and dynamical network modeling provide a novel aspect toward a more objective assessment of the EZ. The advantage of such approaches is that they are data-driven and require less or no human input. Multiple studies have demonstrated success using these approaches when applied to iEEG data in characterizing the EZ and predicting surgical outcomes. However, the limitations of iEEG recordings equally apply to these studies—limited spatial sampling and the implici...
Volumetric MRI permits acquisition of fine, contiguous slices with excellent tissue contrast, and... more Volumetric MRI permits acquisition of fine, contiguous slices with excellent tissue contrast, and is ideal for detailed morphometric studies of the hippocampus.
Fibre- and sphere-based microcapsules have been developed, exhibiting controllable uniform morpho... more Fibre- and sphere-based microcapsules have been developed, exhibiting controllable uniform morphologies, predictable drug release profiles, and neuro-cytocompatibility.
The serendipitous discovery of triggered autobiographical memories and eventual memory improvemen... more The serendipitous discovery of triggered autobiographical memories and eventual memory improvement in an obese patient who received fornix deep brain stimulation in 2008 paved the way for several phase I and phase II clinical trials focused on the safety and efficacy of this potential intervention for people with Alzheimer's disease. In this article, we summarize clinical trials and case reports on fornix deep brain stimulation for Alzheimer's disease and review experiments on animal models evaluating the physiological or behavioral effects of this intervention. Based on information from these reports and studies, we identify potential translational challenges of this approach and determine practical and ethical considerations for clinical trials, focusing on issues regarding selection criteria, trial design, and outcome evaluation. Based on initial results suggesting greater benefit for those with milder disease stage, we find it essential that participant expectations are ...
Diabetes/metabolism research and reviews, Jan 10, 2015
This study assesses the autonomic function of patients who have regained awareness of hypoglycaem... more This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant. Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age and gender matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness, and five healthy control participants without diabetes. All participants underwent: i. A battery of five cardiovascular autonomic function tests, ii. Quantitative sudomotor axonal reflex testing (QSART), and iii. Sympathetic skin response (SSR) testing. Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0-3 months post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97% to 69% at 0-3 months (p<0.001, Fisher's Exact Test) and to 20% after 12 months (p<0.0001, Fis...
Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin precondi... more Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin preconditioning of muscle following plasmid injection. We investigated in vivo delivery of naked DNA to mdx mouse muscle, utilising enhanced green fluorescent protein reporter vector (pEGFP) and a corrective nucleic acid to promote targeted corrective gene conversion at the mutant mdx mouse dystrophin (DMDmdx) locus. Electroporation, myoablation with bupivacaine and a combined protocol, were applied to mdx muscle. We report up to 90% EGFP expression in electroporated mdx tibialis anterior muscle. Muscles preconditioned with bupivacaine showed low transgene expression with or without EP. Single EGFP+ve muscle fibre explants showed EGFP expression in mature fibres in preference to satellite cells. We observed a two-fold increase (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.005; t) in dystrophin protein, accompanied by wild-type (wt) DMD transcript in muscles injected with corrective nucleic acid over contralateral saline-injected TAs. By targeting the muscle fibres in preference to the satellite cells, plasmid-bourne transgenes delivered to dystrophic muscle will not penetrate the regenerative component of muscle. Whether in the context of targeted corrective gene conversion or therapeutic non-viral transgenes, under these conditions periodic re-administration will be required to promote phenotypic benefits in dystrophic muscle.
Abstract Researchers have emphasized a need for ongoing rehabilitation and support for individual... more Abstract Researchers have emphasized a need for ongoing rehabilitation and support for individuals with traumatic brain injury FBI), yet there are few detailed descriptions of long-term outcome, and many people with long-standing TBI do not or cannot access support services. HB and NL, two men who sustained severe TBI, presented for neuropsychological consultation for the first time more than 20 years post-injury. Referral was prompted by significant mood and relationship disturbances, and ongoing mnemonic and cognitive ...
ABSTRACTBACKGROUND AND PURPOSEThe difficulty of distinguishing disorders of consciousness from ce... more ABSTRACTBACKGROUND AND PURPOSEThe difficulty of distinguishing disorders of consciousness from certain disorders of communication leads to the possibility of false diagnosis. Our aim is to communicate with patients with disorders of consciousness through asking them to answer questions with “yes/no” by performing mental imagery tasks using functional magnetic resonance imaging (fMRI).METHODSA 1.5 T fMRI study with 5 patients and a control group is presented. Speech comprehension, mental imagery, and question–answer tests were performed.RESULTSThe imagery task of mental calculation produced equally distinct activation patterns when compared to navigation and motor imagery in controls. For controls, we could infer answers to questions based on imagery activations. Two patients produced activations in similar areas to controls for certain imagery tasks, however, no activations were observed for the question–answer task.CONCLUSIONSThe results from 2 patients provide independent support ...
Temporal lobe epilepsy (TLE), the most common form of partial epilepsy in adults is often refract... more Temporal lobe epilepsy (TLE), the most common form of partial epilepsy in adults is often refractory to medical treatment and in these patients epilepsy surgery is considered. Successful surgery is dependent on accurate localisation and lateralisation of the epileptogenic zone. The preoperative evaluation involves a series of assessments and investigations including detailed clinical history, interictal EEG, video-EEG monitoring, MRI, PET, SPECT, and neuropsychology and neuropsychiatric assessment. The role of each of these investigations and assessments in the preoperative evaluation is discussed. Advanced MR techniques including magnetic resonance spectroscopy, MR diffusion and MR perfusion have recently been assessed and are likely to enhance the pre-surgical evaluation of patients with TLE. The surgical outcome and preoperative investigations performed of 80 consecutive patients who underwent temporal lobe surgery between 1993 and 2002 at Royal Melbourne Hospital were reviewed. All patients had MRI, video-EEG monitoring and neuropsychology assessment and 56% a PET scan. During a mean follow-up of 5.9 years 75% had Class 1 outcome, 22% non-Class 1 outcome and 3% were lost to follow-up. The results of preoperative investigations were correlated with outcome. For interictal EEG, seizure semiology, ictal EEG, PET and neuropsychology assessment the surgical outcome of patients in whom results were concordant to side of surgery was compared with those discordant or nonlateralising. There was no significant difference. In 78 of 80 patients MRI revealed mesial temporal sclerosis or a foreign tissue lesion. The outcome was no different between these two groups. Results suggest that in patients with unilateral temporal lobe lesion on MRI and where ictal EEG is either concordant or non-lateralising, other investigations including PET, provide little additional prognostic information.
defined as 1 and 2 above, plus a response to anti-TB treatment and exclusion of other causes of m... more defined as 1 and 2 above, plus a response to anti-TB treatment and exclusion of other causes of meningitis. Results: 104 patients with TB meningitis (71 definite, 33 probable) presented between 1965 and 2004. On average, 2-3 new cases presented each year. 33% were Pacific people, 28% Maori, 28% European and 9% Asian. The frequency of complications was hyponatraemia 48%, hydrocephalus 37%, epileptic seizures 28%, cerebral infarcts 25%, coma 14%, tuberculoma 5%, diabetes insipidus 4%, intracranial haemorrhage 2%, paraplegia 2% and syringomyelia 1%. Delays in performing a lumbar puncture in 11 patients and incorrectly attributing CSF abnormalities to bacterial meningitis in 12 patients led to a delay in starting anti-TB treatment in 24% of the patients. The Glasgow Outcome Score (GOS) at discharge was 1 (death) 19%, 2 (persistent vegetative state) 2%, 3 (severe disability) 19%, 4 (moderate disability) 22% and 5 (good recovery) 37%. Conclusions: Pacific people, Maori and Asians have a higher risk of developing TB meningitis. The advent of HIV infection has not affected the incidence of TB meningitis in Auckland. Delays in starting anti-TB treatment occurred in 25% of the patients. Serious neurological and systemic complications were common and 40% of patients had a poor outcome (GOS 1-3).
Journal of Clinical and Experimental Neuropsychology, 2006
Controversy surrounds the question of whether there is a specific pattern of psychopathology or p... more Controversy surrounds the question of whether there is a specific pattern of psychopathology or personality style observed in patients with temporal lobe epilepsy (TLE) or whether the symptoms of psychological distress reflect a common disorder such as depression. Measurement equivalence was examined to test the hypothesis that the latent variable model underlying scores on the Beck Depression Inventory (BDI) was equivalent across samples of patients with TLE (n = 187) and patients with heterogeneous neurological disorders (n = 150). A well-replicated model of depression or psychological distress comprising three related variables, negative attitude, performance difficulty, and somatic elements, displayed a pattern of strict metric invariance. This result suggests that the same set of latent variables is measured with the same metric relationship between item scores and latent variables in patients with TLE and in patients with heterogeneous neurological disorders.
Communicated by Mireille Claustres Targeted corrective gene conversion (TCGC) holds much promise ... more Communicated by Mireille Claustres Targeted corrective gene conversion (TCGC) holds much promise as a future therapy for many hereditary diseases in humans. Mutation correction frequencies varying between 0.0001% and 40% have been reported using chimeraplasty, oligoplasty, triplex-forming oligonucleotides, and small corrective PCR amplicons (CPA). However, PCR technologies used to detect correction events risk either falsely indicating or greatly exaggerating the presence of corrected loci. This is a problem that is considerably exacerbated by attempted improvement of the TCGC system using high corrective nucleic acid (CNA) to nuclear ratios. Small fragment homologous replacement (SFHR)-mediated correction of the exon 23 dystrophin (DMD) gene mutation in the mdx mouse model of DMD has been used in this study to evaluate the effect of increasing CPA amounts. In these experiments, we detected extremely high levels of apparently corrected loci and determined that at higher CNA to nuclear ratios the extent of locus correction was highly exaggerated by residual CNA species in the nucleic acids extracted from the treated cells. This study describes a generic locus-specific detection protocol designed to eradicate residual CNA species and avoid the artifactual or exaggerated detection of gene correction. Hum Mutat 28(8), 816-823, 2007.
Epilepsy is characterised by recurrent seizures, which are manifestations of aberrant cortical ne... more Epilepsy is characterised by recurrent seizures, which are manifestations of aberrant cortical neuronal firing. It is unclear whether oxidative stress is a cause or consequence of seizure-related hippocampal neuronal loss or whether it occurs concomitantly with the initiation of cell death pathways. We utilised the rapid electrical amygdala kindling (REAK) model which does not induce cell death to examine early seizure-induced oxidative stress in wildtype and superoxide dismutase 2 (Sod2) +/- mice, which lack 50% of Sod2 activity and are therefore known to be more susceptible to mitochondrial oxidative stress. A significant increase in lipid peroxidation and superoxide production was noted in the hippocampi of wildtype mice and a more delayed response observed in Sod2 +/- mice at early time-points post-seizures, but protein carbonylation levels appeared unchanged. A 10-fold increase in superoxide production was seen in the Sod2 +/- CA2 neurons, indicating that Sod2 plays an important role in protecting the CA2 region of the hippocampus from seizure-induced free radical damage. Early hippocampal cell death was undetectable in wildtype or Sod2 +/- mice post-seizures. We were able to demonstrate that hippocampal oxidative stress occurred as a direct consequence of seizures rather than downstream of activation of cell death pathways. We were also able to show that this increase in oxidative stress was not sufficient to cause cell death within the time window investigated. Our data indicates that a possible upregulation of endogenous antioxidant activity might exist within selective hippocampal sectors in the Sod2 +/- mice that are as yet unknown.
Patients with psychogenic nonepileptic seizures (PNES) are common in tertiary epilepsy centers, e... more Patients with psychogenic nonepileptic seizures (PNES) are common in tertiary epilepsy centers, emergency departments, and neurological practices. Psychiatric discussion of patients with PNES has emphasized the role of trauma and dissociation. Personality disorder has been considered, but its extensive implications for neurological management have not been fully appreciated. We propose that the most difficult aspects of management stem not from the convulsive episodes, but from the personality disorder that frequently accompanies them. Although it is not the neurologist's role to treat personality disorder, the conduct of the physician-patient relationship can have potent consequences for good or ill on the outcome. We present a brief guide to current concepts of personality disorder; discuss the literature concerning its association with PNES, and offer practical guidelines for the conduct of the neurologist-patient relationship. This perspective offers resolutions to longstanding controversies, including how to communicate the diagnosis, discontinuing medication, and ongoing neurological contact.
The pathophysiologic basis for the [ 'sF]fluorodeoxyglucose positron-emission tomography (FDG-PET... more The pathophysiologic basis for the [ 'sF]fluorodeoxyglucose positron-emission tomography (FDG-PET) temporal lobe hypometabolism in patients with hippocampal sclerosis (HS) is uncertain. We tested the hypothesis that hippocampal atrophy, which is strongly correlated with hippocampal cell loss, is largely responsible for the regional hypometabolism in HS. Methods: Regions of interest (ROIs) on FJlG-PET scanning were determined in the medial, lateral, and posterior temporal lobe, thalamus, and basal ganglia. A righaeft asymmetry index for each ROI was calculated. These results were correlated with hippocampal magnetic resonance imaging (MRI) volume ratios. Results: There was no correlation between the magnitudes of the FDG-PET asymmetry index and the MRI volume ratio for
SummaryThe incidence of constipation as an adverse effect of pregabalin has previously been repor... more SummaryThe incidence of constipation as an adverse effect of pregabalin has previously been reported as low, with all cases described as either mild or moderate. From the experience of a tertiary referral epilepsy hospital center, we report several cases of severe and disabling constipation after initiating pregabalin, and resolving only on drug withdrawal. Of 80 consecutive patients, six (7.5%) developed significant constipation within 1–2 weeks of commencing pregabalin. Constipation was the most frequent adverse effect that required pregabalin to be withdrawn (6.3% of patients). The severity of symptoms was dose dependent. Pregabalin can cause marked constipation in some patients, and can lead to multiple unnecessary investigations and procedures if the clinician is not aware of this entirely reversible side effect.
Summary: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We r... more Summary: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We report a patient with an unusual form of reflex epilepsy in whom seizures are induced by tooth brushing. Magnetic resonance imaging (MRI) demonstrated a right posterior frontal low‐grade tumor predominantly involving the precentral gyrus. Video‐telemetry demonstrated right‐sided epileptiform activity during a typical induced complex partial seizure. An ictal single photon emission computed tomography (SPECT) scan showed an area of hyperfusion that corresponded to the MRI lesion on coregistration with a surface‐matching technique. A subsequent coregistered interictal SPECT scan demonstrated hypoperfusion in the same region. Ours is the first report to demonstrate a structural focus in this unusual form of reflex epilepsy. Possible mechanisms to explain the induction of the seizures are discussed.
Inpatient video-EEG monitoring (VEM) is widely used for the diagnosis, seizure classification, an... more Inpatient video-EEG monitoring (VEM) is widely used for the diagnosis, seizure classification, and presurgical evaluation of patients with seizure disorders. It is resource intensive and relatively expensive, so its utility continues to be debated. Few studies have specifically evaluated the utility of inpatient VEM in altering diagnosis or management of patients with seizure disorders. We sought to assess the proportion of patients for whom the preadmission diagnosis and management were altered after inpatient VEM of patients admitted for diagnostic and presurgical evaluation of seizure disorders. Data from a consecutive cohort of patients admitted over a 3-year period to an inpatient VEM unit in a tertiary referral hospital were retrospectively analyzed. The preadmission diagnosis and management by the referring neurologist was compared with the diagnosis and management after the VEM. Of 131 patients, 91 (70%) were admitted for diagnostic evaluation and 39 (30%) for a presurgical workup. Mean evaluative period was 5.6 days. Mean number of seizures recorded was 2.9. No seizures were recorded in 31% of patients. Interictal EEG showed epileptiform changes in 56 (43%). In 76 (58%), the diagnosis was altered as a result of the VEM, with the greatest change being an increase in the nonepileptic diagnosis group (7% to 31%) and the generalized diagnosis group (5% to 11%). Management was changed after the VEM in 95 (73%). The results of this study demonstrate that inpatient VEM has a high yield in changing diagnosis and management. Future long-term cost-benefit studies of the management changes resulting from VEM evaluation will aid in further reinforcing its role.
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Papers by Mark J Cook