| | Epilepsy
Comprehensive Epilepsy Program
The Royal Melbourne Hospital Comprehensive Epilepsy Program research is focussed on clinically relevant research. The clinical service has 4 in-patient beds for comprehensive assessment of patients with epilepsy and related disorders, including video-EEG monitoring, neuropsychology, neuropsychiatry and neuroimaging Over 200 patients per year are admitted. Additionally, 3 specialist outpatient clinics are run focusing respectively on newly diagnosed, chronic, and difficult to treat epilepsy.
Our objectives are to always
improve the care and quality of life of patients with newly diagnosed and chronic epilepsy and
improve clinical quality feedback and practice in the video-EEG monitoring unit.
Research Activity in Epilepsy
We undertook a clinical audit of the number of patients who bit their tongue or were incontinent during inpatient video-EEG monitoring. Tongue biting occurred in 26% of patients who had a convulsive epileptic seizure, but no patient who had a non epileptic seizure. Incontinence occurred in 23% of patients who had an epileptic seizures and 6% of those with a non-epileptic seizure. Data from this audit has been accepted for publication in the leading international epilepsy journal, Epilepsia.
The RMH Epilepsy Program conducts a wide range of clinical and basic translational research programs, particularly focused on the areas of new anti-epileptic drug development, brain imaging, neuropsychiatric co-morbidies and evaluating the long-term outcomes of epilepsy and its treatment. Some of the highlights of the clinical research this year have been:
Publication in the high impact psychiatric journal, The British Journal of Psychiatry, of a large study comprehensively evaluating the incidence and nature of psychiatric co-morbidities in 319 patients with chronic epilepsy. This is the largest such study published, and documents that these patients have a high incidence of psychiatric disorders (58%), particularly mood disorders, psychosis and personality disorders. This work was conducted in collaboration with the Drs. Sophie Adams and Dennis Velakoulis from Neuropsychiatry.
Pharmacogenetic research has derived and validated a multigenic model that is predictive of the outcome of newly treated epilepsy with respect to seizure control, the first such model reported for the treatment of any diseases. This novel model, for which a provisional patent has been lodged, has great scientific and clinical value and is generating significant commercial interest for its potential application as a diagnostic test in clinical practice. A paper reporting will be shortly submitted to a leading general medical journal.
Publication in the leading international imaging journal, The Journal of Nuclear Medicine, of a paper reporting a decision tree analysis which evaluates the sensitivity, specificity and cost-effectiveness of clinical algorithms which incorporate FDG-PET in the work-up of patients for epilepsy surgery. This is the first time that decision tree analysis methods has been used to objectively assess the cost effectiveness of different clinical algorithms for the use of investigations in the epilepsy surgery evaluation. The increasing number of different and expensive tests advocated for use in the epilepsy surgery evaluation makes such an evaluation particularly opportune. The results conclusively demonstrate that FDG-PET is cost effective in the pre-surgical evaluation, particularly when employed in patients with a non-localizing or non-concordant VEM and/or MRI result. Other research projects include:
Investigation into the effect of neuropeptide Y-related mechanisms in a genetic model of absence epilepsy.
The neuropharmacological mechanisms underlying the aggravation of absence seizures by carbamazepine utilising a genetic rat model.
Development of a mouse model to investigate the mechanisms underlying the adverse weight and bone effects of treatment with the anti-epileptic drug valproate. The effect of stress, hypercortisolaemia and early life exposures on epileptogenesis in a rat model of temporal lobe epilepsy. Serial functional (PET) and structural (MRI) neuroimaging of changes occurring during epileptogenesis in a rat model of temporal lobe epilepsy. Saturation ENU mutagenesis screen for novel anti-epileptic and anti-epileptogenic genes. Role of proteases in the mechanisms of acquired limbic epileptogenesis. Study of clinical, neurocognitive, neuropsychiatric and QOL outcomes following first seizure; evaluating a cohort of about 600 patients who attended first seizure clinic at the Royal Melbourne Hospital. Cross sectional and longitudinal study of prevalence and determinants of psychiatric, neurocognitive and QOL issues in people admitted to Video EEG monitoring unit. KONQUEST: Study of neurocognitive, neuropsychiatric and Quality of life outcomes with treatment with Keppra versus older standard anti epileptic medication monotherapy in patients who failed their first anti epileptic medication. New MRI imaging techniques in subtypes of temporal lobe epilepsy Functional imaging (PET @ SPECT) and surgical outcome in temporal lobe epilepsy. The Effect of Stress and Early Life Experiences on Vulnerability to Temporal Lobe Epilepsy & Mood Disorders
Anxiety and depression are common co-morbidities in temporal lobe epilepsy (TLE), the most prevalent form of medical refractory epilepsy in the community, occurring in up to 50% of patients. Until relatively recently it had been widely assumed that this was a consequence of the chronic epileptic condition. However, recent evidence suggests that there is a bi-directional relationship, with the psychiatric conditions and stress also acting to aggravate the seizures and even predispose to the development of the epilepsy itself. Conversely there is now emerging evidence of the protective effects of positive early life experiences. Apart from gaining insights into causes of TLE, anxiety and depression, this framework has potential public health relevance suggesting approaches to the eventual primary and secondary prevention of both TLE and its associated psychiatric co-morbidities, a neglected area at present. We are utilizing a rat model that allows investigation of aetiological processes that extend over the lifetime, which is exceptionally difficult to achieve in humans. Retrospective clinical studies, such as case-control studies, although an indispensable research methods, are subject to bias and imprecision when it comes to measuring remote past exposures to stress, abuse, and deprivation. If the results of these experiments are consistent with our hypotheses, a very strong case would exist for exploring this relationship in human studies. The data would also provide a strong rationale for more aggressive detection and treatment of these psychiatric co-morbidities in TLE patients, in order to potentially modify the progression of the disorder as well as improve the quality of life of sufferers. The results of intervention studies may suggest specific mode of treatment to achieve this.
Pharmacogenomics of Anti-Epileptogenic Drugs (Epilepsy)
Epilepsy is the most common serious chronic neurological disease, affecting up to 3% of the population. Currently treatments for patients with epilepsy, antiepileptic drugs (AEDs), are prescribed essentially on a “trial and error” basis, with little rational basis for the specific AED chosen. Somewhere between 20-40% of patients with epilepsy will fail to have their seizures controlled by the first AED prescribed, and 40% or more will have a significant adverse drug reaction (ADR) – either major or minor. As a result, many patients are subjected to a series of trials of different AEDs and combinations until one is found to be the most effective and tolerated. There are currently a large number of AEDs available in Australia, making this practice extremely costly and exposes the patients to increased risk of suffering a serious ADR which can even on occasions lead to death. The emerging field of pharmacogenomics holds the promise of safer and more effective drug therapy with the potential to individualise and optimise drug therapy, and would be particularly applicable to the treatment of epilepsy. However, in order to make this individualisation of medication prescribing a future reality, prospective clinical information needs to be collected regarding the outcome of AED therapy in individuals that can be then correlated with their genetic information.
Candidate genes for pharmacogenetic testing are those in which there are variations (polymorphisms) that affect AED transport, metabolism, site of action or the immune response. The polymorphism also needs to be carried in the population with a high enough gene frequency to logically explain, or partly explain the frequencies of ADR or pharmacoresistance. An increasing number of studies have attempted to identify such polymorphisms, with many reporting significant associations. However, replication attempts have almost all failed to definitively confirm this association. The most illustrative example of this is with a polymorphism (3435 TT/CC) in the multidrug resistance 1 (MDR1) gene. MDR proteins have been proposed to play a role in brain transport of AEDs, and genetic variations in these may affect the rate of drug efficacy and side effects. A several high profile publications have reported an association between this MDR1 gene polymorphism with pharmacoresistance in patients with chronic epilepsy, but more recent studies have refuted this. However, almost all studies of pharmacogenomics of AEDs have been limited by multiple confounders and retrospective clinical data. Our research group have initiated an international collaboration that prospectively collects a database of clinical, drug response, adverse drug reaction and genetic information from patients newly treated for epilepsy. Relevant factors that may differ between the centres are examined, including the distribution of genotype frequencies, ethnicity, medication usage and seizure types. This collaboration now has treatment outcomes and genotype correlations form 525 newly treated patients. Yes, I want to fight against Epilepsy and make a donation. |
