RESUMEN
Precision medicine is an old concept, but it is not widely applied across human health conditions as yet. Numerous attempts have been made to apply precision medicine in epilepsy, this has been based on a better understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope of precision medicine is to provide effective strategies for treating individual patients with specific agent(s) that are likely to work best based on the causal biological make-up. We provide an overview of the main applications of precision medicine in epilepsy, including the current limitations and pitfalls, and propose potential strategies for implementation and to achieve a higher rate of success in patient care. Such strategies include establishing a definition of precision medicine and its outcomes; learning from past experiences, from failures and from other fields (e.g. oncology); using appropriate precision medicine strategies (e.g. drug repurposing versus traditional drug discovery process); and using adequate methods to assess efficacy (e.g. randomised controlled trials versus alternative trial designs). Although the progress of diagnostic techniques now allows comprehensive characterisation of each individual epilepsy condition from a molecular, biological, structural and clinical perspective, there remain challenges in the integration of individual data in clinical practice to achieve effective applications of precision medicine in this domain.
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Oncología Médica , Medicina de Precisión , Humanos , Medicina de Precisión/métodosRESUMEN
Valproate (VPA) is an effective treatment for epilepsy and also used in bipolar disorder. However, VPA is associated with a significant risk of birth defects and developmental disorders if used during pregnancy. This has led to the introduction of measures to reduce the use of valproate in women of childbearing potential such as the 'Prevent' pregnancy prevention program (PPP) and the completion of an annual risk acknowledgement form (ARAF). The aim of the current audit was to assess compliance with the guidance. An audit tool was made available to neurologists registered with the Association of British Neurologists (ABN) and to epilepsy nurse specialists via the Epilepsy Nurses Association (ESNA) in the UK. Data were collected between November 2020 and March 2021. The main indication for valproate was generalised epilepsy (55.8%), followed by focal (22.5%). For most, there was documentation that the woman had been informed about the risks associated with taking valproate during pregnancy (93.1%) and the need to be on highly effective contraception or that this was not deemed appropriate (92.2%). A signed ARAF was available in the notes for 81.2% although only 66% were <12 months old. Although information had been made available for most women, there were still individuals where this was not documented. Further work is needed to facilitate identification of women taking valproate and implementation of a digital ARAF. For clinicians, the audit highlights a need to carefully counsel women about the teratogenic risks of continuing to take valproate versus the risk of deteriorating seizure control if the drug is withdrawn. This is particularly true of women with focal epilepsy, where there may be safer, equally effective, alternative anti-seizure medication (ASM). The aim should be to create a partnership of trust between the patient and clinician in order to arrive at the best clinical decision for that individual.
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Epilepsias Parciales , Epilepsia , Anticonvulsivantes/efectos adversos , Epilepsias Parciales/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Lactante , Embarazo , Reino Unido , Ácido Valproico/efectos adversosRESUMEN
The course of established epilepsy in late life is not fully known. One key question is whether the resolution of an epileptic diathesis is a natural outcome in some people with long-standing epilepsy. We investigated this with a view to generating a hypothesis. We retrospectively explored whether terminal seizure-freedom occurs in older people with previous drug-resistant epilepsy at the Chalfont Centre for Epilepsy over twenty years. Of the 226 people followed for a median period of 52 years, 39 (17%) achieved late-life terminal seizure-freedom of at least two years before death, which occurred at a median age of 68 years with a median duration of 7 years. Multivariate analysis suggests that a high initial seizure frequency was a negative predictor (p < 0.0005). Our findings indicate that the 'natural' course of long-standing epilepsy in some people is one of terminal seizure freedom. We also consider the concept of "remission" in epilepsy, its definition challenges, and the evolving terminology used to describe the state of seizure freedom. The intersection of ageing and seizure freedom is an essential avenue of future investigation, especially in light of current demographic trends. Gaining mechanistic insights into this phenomenon may help broaden our understanding of the neurobiology of epilepsy and potentially provide targets for therapeutic intervention.
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Epilepsia , Preparaciones Farmacéuticas , Anciano , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Libertad , Humanos , Estudios Retrospectivos , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
AIMS: Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. METHODS: Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. RESULTS: Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P < 0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P < 0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P < 0.05). CONCLUSIONS: Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.
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Muerte Súbita/patología , Epilepsia/patología , Imagen por Resonancia Magnética , Muerte Súbita e Inesperada en la Epilepsia/patología , Tronco Encefálico/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , Convulsiones/patologíaRESUMEN
AIMS: Understanding the spatiotemporal dynamics of reactive cell types following brain injury is important for future therapeutic interventions. We have previously used penetrating cortical injuries following intracranial recordings as a brain repair model to study scar-forming nestin-expressing cells. We now explore the relationship between nestin-expressing cells, PDGFRß+ pericytes and Olig2+ glia, including their proliferation and functional maturation. METHODS: In 32 cases, ranging from 3 to 461 days post injury (dpi), immunohistochemistry for PDGFRß, nestin, GFAP, Olig2, MCM2, Aquaporin 4 (Aq4), Glutamine Synthetase (GS) and Connexin 43 (Cx43) was quantified for cell densities, labelling index (LI) and cellular co-expression at the injury site compared to control regions. RESULTS: PDGFRß labelling highlighted both pericytes and multipolar parenchymal cells. PDGFRß LI and PDGFRß+ /MCM2+ cells significantly increased in injury Zones at 10-13 dpi with migration of pericytes away from vessels with increased co-localization of PDGRFß with nestin compared to control regions (P < 0.005). Olig2+ /MCM2+ cell populations peaked at 13 dpi with significantly higher cell densities at injury sites than in control regions (P < 0.01) and decreasing with dpi (P < 0.05). Cx43 LI was reduced in acute injuries but increased with dpi (P < 0.05) showing significant cellular co-localization with nestin and GFAP (P < 0.005 and P < 0.0001) but not PDGFRß. CONCLUSIONS: These findings indicate that PDGFRß+ and Olig2+ cells contribute to the proliferative fraction following penetrating brain injuries, with evidence of pericyte migration. Dynamic changes in Cx43 in glial cell types with dpi suggest functional alterations during temporal stages of brain repair.
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Encéfalo/metabolismo , Gliosis/metabolismo , Traumatismos Penetrantes de la Cabeza/metabolismo , Pericitos/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Adolescente , Adulto , Anciano de 80 o más Años , Encéfalo/patología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/patología , Traumatismos Penetrantes de la Cabeza/patología , Humanos , Masculino , Persona de Mediana Edad , Pericitos/patología , Adulto JovenRESUMEN
BACKGROUND: People with epilepsy have more concomitant medical conditions than the general population; these comorbidities play an important role in premature mortality. We sought to generate explanatory hypotheses about the co-occurrence of somatic comorbidities and epilepsy, avoiding causal and treatment-resultant biases. METHODS: We collected clinical, demographic and somatic comorbidity data for 2016 consecutive adults with epilepsy undergoing assessment at a tertiary centre and in 1278 people with epilepsy in the community. Underlying causes of epilepsy were not classed as comorbidities. RESULTS: Somatic comorbidities were more frequent in the referral centre (49%) where people more frequently had active epilepsy than in the community (36%). Consistent risk factors for comorbidities were found in both cohorts. Using multivariable ordinal regression adjusted for age, longer epilepsy duration and an underlying brain lesion were independently associated with a smaller burden of somatic conditions. The treatment burden, measured by the number of drugs to which people were exposed, was not an independent predictor. Shorter epilepsy duration was a predictor for conditions that conceivably harbour significant mortality risks. CONCLUSIONS: Somatic comorbidities do not occur randomly in relation to epilepsy; having more severe epilepsy seems to be a risk factor. Independently from age, the early period after epilepsy onset appears to be at particular risk, although it is not clear whether this relates to an early mortality or to a later decrease in the burden of comorbidities. These results suggest that, for some people, epilepsy should be considered a systemic condition not limited to the CNS.
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Epilepsia/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: Previous studies suggest that ictal panic symptoms are common in patients with psychogenic nonepileptic seizures (PNES). This study investigates the frequency of panic symptoms in PNES and if panic symptoms, just before or during episodes, can help distinguish PNES from the other common causes of transient loss of consciousness (TLOC), syncope and epilepsy. METHODS: Patients with secure diagnoses of PNES (n=98), epilepsy (n=95) and syncope (n=100) were identified using clinical databases from three United Kingdom hospitals. Patients self-reported the frequency with which they experienced seven symptoms of panic disorder in association with their episodes. A composite panic symptom score was calculated on the basis of the frequency of symptoms. RESULTS: 8.2% of patients with PNES reported "never" experiencing any of the seven panic symptoms in their episodes of TLOC. Patients with PNES reported more frequent panic symptoms in their attacks than those with epilepsy (p<0.001) or syncope (p<0.001), however, patients with PNES were more likely "rarely" or "never" to report five of the seven-ictal panic symptoms than "frequently" or "always" (45-69% versus 13-29%). A receiver operating characteristic analysis demonstrated that the composite panic symptom score distinguished patients with PNES from the other groups (sensitivity 71.1%, specificity 71.2%), but not epilepsy from syncope. CONCLUSIONS: Patients with PNES report TLOC associated panic symptoms more commonly than those with epilepsy or syncope. Although panic symptoms are reported infrequently by most patients with PNES, a composite symptom score may contribute to the differentiation between PNES and the other two common causes of TLOC.
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Epilepsia/diagnóstico , Trastorno de Pánico/etiología , Convulsiones/diagnóstico , Síncope/diagnóstico , Inconsciencia/diagnóstico , Adulto , Diagnóstico Diferencial , Epilepsia/complicaciones , Epilepsia/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pánico , Convulsiones/complicaciones , Convulsiones/psicología , Autoinforme , Encuestas y Cuestionarios , Síncope/complicaciones , Síncope/psicología , Inconsciencia/complicaciones , Inconsciencia/psicologíaRESUMEN
OBJECTIVES: There are very few data available in the literature on the use of stiripentol in adults with Dravet syndrome (DS). DS cases are increasingly recognized in adulthood, and more children with DS now survive to adulthood. The aim of the study was to document the effectiveness and tolerability of stiripentol in adults with DS. MATERIAL AND METHODS: We conducted an observational clinical audit in the epilepsy service of the National Hospital for Neurology and Neurosurgery, London (UK). RESULTS: We included 13 adult subjects with DS (eight females, five males). The responder (defined as more than 50% reduction in all seizure types) rate was 3/13 (23%) at 36 months. The following other outcomes were reported: seizure exacerbation (3/13, 23%), no change (3/13, 23%), less than 50% reduction in seizures (2/13, 15%), more than 50% reduction in generalized tonic-clonic seizures but no other seizure types (1/13, 8%), undefined response (1/13, 8%). The retention rate was 62% after 1 year and 31% after 5 years. Adverse effects were reported in 7/13 (54%): the most frequent were anorexia, weight loss, unsteadiness and tiredness. Withdrawal due to adverse effects occurred in 3/13 (23%). CONCLUSIONS: Compared with previous studies on children with DS, our results show a lower responder rate and a similar tolerability profile. Stiripentol can be effective with a good tolerability profile. Our audit is small, but supports the use of stiripentol in adults with DS when first-line treatments are ineffective or not tolerated, in keeping with published guidelines.
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Anticonvulsivantes/uso terapéutico , Dioxolanos/uso terapéutico , Epilepsias Mioclónicas/tratamiento farmacológico , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Niño , Preescolar , Dioxolanos/efectos adversos , Epilepsias Mioclónicas/genética , Femenino , Humanos , Masculino , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genéticaRESUMEN
AIMS: Hippocampal sclerosis (HS) is long-recognized in association with epilepsy (HSE ) and more recently in the context of cognitive decline or dementia in the elderly (HSD ), in some cases as a component of neurodegenerative diseases, including Alzheimer's disease (AD) and fronto-temporal lobe dementia (FTLD). There is an increased risk of seizures in AD and spontaneous epileptiform discharges in the dentate gyrus of transgenic AD models; epilepsy can be associated with an age-accelerated increase in AD-type pathology and cognitive decline. The convergence between these disease processes could be related to hippocampal pathology. HSE typically shows re-organization of both excitatory and inhibitory neuronal networks in the dentate gyrus, and is considered to be relevant to hippocampal excitability. We sought to compare the pathology of HSE and HSD , focusing on re-organization in the dentate gyrus. METHODS: In nine post mortem cases with HSE and bilateral damage, 18 HSD and 11 controls we carried out immunostaining for mossy fibres (dynorphin), and interneuronal networks (NPY, calbindin and calretinin) on sections from the mid-hippocampal body. Fibre sprouting (FS) or loss of expression in the dentate gyrus was semi-quantitatively graded from grade 0 (normal) to grade 3 (marked alteration). RESULTS: Significantly more re-organization was seen with all four markers in the HSE than HSD group (P < 0.01). Mild alterations were noted in HSD group with dynorphin (FS in 3 cases), calretinin (FS in 6 cases), NPY (FS in 11 cases) and calbindin (loss in 10 cases). In eight HSD cases, alteration was seen with more than one antibody but in no cases were the highest grades seen. We also noted NPY and, to a lesser extent, calretinin labelling of Hirano bodies in CA1 of AD cases and some older controls, but not in HSE . CONCLUSION: Reorganization of excitatory and inhibitory networks in the dentate gyrus is more typical of HSE . Subtle alterations in HSD may be a result of increased hippocampal excitability, including unrecognized seizure activity. An unexpected finding was the identification of NPY-positive Hirano bodies in HSD but not HSE , which may be a consequence of the relative vulnerabilities of interneurons in these conditions.
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Demencia/patología , Giro Dentado/patología , Epilepsia/patología , Hipocampo/patología , Anciano , Enfermedad de Alzheimer/patología , Femenino , Demencia Frontotemporal/patología , Humanos , Masculino , EsclerosisRESUMEN
Reorganisation of the dentate gyrus, including granule cell dispersion (GCD) and mossy fibre sprouting, typically accompany hippocampal sclerosis (HS) in temporal lobe epilepsy. Calbindin (CB) expression in granule cells increases during infancy, influences granule cell excitability, vulnerability to excitotoxicity in addition to important physiological functions in memory. Our aim was to study CB patterns in relation to dentate gyrus re-organisation, epilepsy history and memory function. Forty-five surgical cases and 11 post mortems were examined from patients with drug-resistant epilepsy in addition to three post mortem controls. In the surgical cases, CB expression, and the degree of GCD and mossy fibre sprouting were measured. In post mortem cases, CB expression was assessed in relation to the pattern of HS along the rostral-caudal axis of the hippocampus, and compared to PM controls. Three patterns were identified. In Group 1 (40%), the most dispersed granule cells were CB-positive and basal cells negative imitating developmental patterns. In Group 2 (47%), normal CB expression was retained and in Group 3 (13%), CB was predominantly lost in granule cells. These patterns correlated with GCD, the presence of mossy fibre sprouting and the pattern of HS. Group 1 was associated with early onset of seizures but not independently predictive of outcome. In post mortem cases, altered CB expression lateralised to the side of HS and persisted despite seizure remission in some patients. No significant correlation between CB expression and memory function was identified. CB expression patterns in HS may indicate developmental dysmaturation and are associated with the extent of GCD and mossy fibre sprouting in HS. The functional significance of CB loss, in terms of epileptogenesis and effects on memory, remain uncertain.
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Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Neuronas/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Calbindina 1 , Calbindinas , Epilepsia del Lóbulo Temporal/patología , Femenino , Hipocampo/patología , Humanos , Masculino , Memoria/fisiología , Trastornos de la Memoria/patología , Persona de Mediana Edad , Fibras Musgosas del Hipocampo/patología , Neuronas/patología , Esclerosis/metabolismo , Esclerosis/patologíaAsunto(s)
Anticonvulsivantes/efectos adversos , Vigabatrin/efectos adversos , Trastornos de la Visión/inducido químicamente , Campos Visuales/efectos de los fármacos , Adulto , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Retina/patología , Células Ganglionares de la Retina/patología , Factores de Tiempo , Tomografía de Coherencia Óptica , Trastornos de la Visión/patologíaAsunto(s)
Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Convulsiones Febriles/genética , Canales de Sodio/genética , Estudios de Cohortes , Femenino , Humanos , Desequilibrio de Ligamiento , Masculino , Canal de Sodio Activado por Voltaje NAV1.1 , Oportunidad Relativa , Convulsiones Febriles/clasificaciónRESUMEN
BACKGROUND: Hippocampal sclerosis (HS) is the most common surgical pathology associated with mesial temporal lobe epilepsy (MTLE). HS is typically characterized by mossy fiber sprouting (MFS) and reorganization of neuropeptide Y (NPY) fiber networks in the dentate gyrus. One potential cause of postoperative seizure recurrence following temporal lobe surgery may be the presence of seizure-associated bilateral hippocampal damage. We aimed to investigate patterns of hippocampal abnormalities in a postmortem series as identified by NPY and dynorphin immunohistochemistry. METHODS: Analysis of dentate gyrus fiber reorganization, using dynorphin (to demonstrate MFS) and NPY immunohistochemistry, was carried out in a postmortem epilepsy series of 25 cases (age range 21-96 years). In 9 patients, previously refractory seizures had become well controlled for up to 34 years prior to death. RESULTS: Bilateral MFS or abnormal NPY patterns were seen in 15 patients including those with bilateral symmetric, asymmetric, and unilateral HS by conventional histologic criteria. MFS and NPY reorganization was present in all classical HS cases, more variably in atypical HS, present in both MTLE and non-MTLE syndromes and with seizure histories of up to 92 years, despite seizure remission in some patients. CONCLUSION: Synaptic reorganization in the dentate gyrus may be a bilateral, persistent process in epilepsy. It is unlikely to be sufficient to generate seizures and more likely to represent a seizure-induced phenomenon.
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Giro Dentado/patología , Giro Dentado/fisiología , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/fisiopatología , Lateralidad Funcional/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Dinorfinas/metabolismo , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Fibras Musgosas del Hipocampo/metabolismo , Neuropéptido Y/metabolismo , Esclerosis , Adulto JovenRESUMEN
AIMS: Glial fibrillary acidic protein (GFAP)-delta is a novel isoform that differs in its C-terminal sequence from other GFAP isoforms. Previous studies suggest restriction of expression to the subpial layer, subventricular zone and the subgranular zone astrocytes, with an absence in pathological conditions causing reactive gliosis. GFAP-delta is speculated to have roles in regulation of astrocyte size and motility and a subpopulation of GFAP-delta-positive glia may be multipotent stem cells. The aim of this study was to investigate its expression in common causes of lesion-related refractory epilepsy. METHODS: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD) type IIB, cortical tuberous sclerosis (TSC) lesions, gangliogliomas, grey matter heterotopias and hemimegalencephaly from a wide age range of patients using both surgical and post mortem tissue specimens were studied. RESULTS: GFAP-delta expression was observed in CA4 and CA1 astrocytes in HS with less frequent labelling in the granule cell layer, even where granule cell dispersion was present. No significant labelling was noted in the subiculum in HS cases or in any subfields in non-HS epilepsy cases. Balloon cells in FCDIIB and hemimegalencephaly, giant cells in TSC and the astrocytic component of gangliogliomas showed immunoreactivity, colocalizing with conventional GFAP. No neuronal expression for GFAP-delta was seen in any of the pathologies. Quantitative analysis in 10 FCDIIB and five TSC cases revealed greater numbers of GFAP-delta-positive balloon cells than conventional GFAP. There was no GFAP-delta expression within nodular heterotopia. CONCLUSIONS: GFAP-delta expression patterns in HS overall appears to mirror regional reactive gliosis. It is a useful marker for the demonstration of balloon cells in FCD and TSC, which may be relevant to their abnormal size and localization. The lack of GFAP-delta within heterotopia supports their composition from cells destined for deeper cortical layers.
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Encefalopatías/metabolismo , Encéfalo/metabolismo , Epilepsia/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Astrocitos/metabolismo , Encéfalo/anomalías , Niño , Ganglioglioma/metabolismo , Células Gigantes/metabolismo , Humanos , Lactante , Malformaciones del Desarrollo Cortical/metabolismo , Persona de Mediana Edad , Neuronas/metabolismo , Isoformas de Proteínas/metabolismo , Esclerosis/metabolismo , Esclerosis Tuberosa/metabolismoRESUMEN
Voxel-based morphometry (VBM) is commonly used to study systematic differences in brain morphology from patients with various disorders, usually by comparisons with control subjects. It has often been suggested, however, that VBM is also sensitive to variations in composition in grey matter. The nature of the grey matter changes identified with VBM is still poorly understood. The aim of the current study was to determine whether grey matter histopathological measurements of neuronal tissue or gliosis influenced grey matter probability values that are used for VBM analyses. Grey matter probability values (obtained using both SPM5 and FSL-FAST) were correlated with neuronal density, and field fraction of NeuN and GFAP immunopositivity in a grey matter region of interest in the middle temporal gyrus, in 19 patients undergoing temporal lobe resection for refractory epilepsy. There were no significant correlations between any quantitative neuropathological measure and grey matter probability values in normal-appearing grey matter using either segmentation program. The lack of correlation between grey matter probability values and the cortical neuropathological measures in normal-appearing grey matter suggests that intrinsic cortical changes of the type we have measured do not influence grey matter probability maps used for VBM analyses.
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Epilepsia del Lóbulo Temporal/patología , Neuronas/patología , Probabilidad , Lóbulo Temporal/patología , Adulto , Mapeo Encefálico , Electroencefalografía , Epilepsia del Lóbulo Temporal/cirugía , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/metabolismo , Fosfopiruvato Hidratasa/metabolismo , Estadística como Asunto , Adulto JovenRESUMEN
Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.
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Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Predisposición Genética a la Enfermedad , Glicoproteínas de Membrana/genética , Proteínas del Tejido Nervioso/genética , Piracetam/análogos & derivados , Adulto , Estudios de Cohortes , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/genética , Femenino , Variación Genética , Genotipo , Hipocampo/patología , Humanos , Irlanda , Levetiracetam , Masculino , Piracetam/uso terapéutico , Polimorfismo Genético/genética , Vesículas Sinápticas/genética , Reino UnidoRESUMEN
INTRODUCTION: Guidelines from the National Institute for Health and Clinical Excellence (NICE) and the International League Against Epilepsy recommend long term EEG monitoring (LTM) in patients for whom seizure or syndrome type is unclear, and in patients for whom it is proving difficult to differentiate between epilepsy and non-epileptic attack disorder (NEAD). The purpose of this study was to evaluate this recommended use of LTM in the setting of an epilepsy tertiary referral unit. METHODS: This study reviewed the case notes of all admissions to the Sir William Gowers Unit at the National Society for Epilepsy in the years 2004 and 2005. A record was made of the type, duration and result of all LTM performed both prior to and during the admission. Pre- and post-admission diagnoses were compared, and patients were divided according to whether LTM had resulted in a change in diagnosis, refinement in diagnosis or no change in diagnosis. The distinction between change and a refinement in the diagnosis was made on the basis of whether or not this alteration resulted in a change in management. RESULTS: 612 patients were admitted during 2004 and 2005, 230 of whom were referred for diagnostic clarification. Of these, LTM was primarily responsible for a change in diagnosis in 133 (58%) and a refinement of diagnosis in 29 (13%). In 65 (29%) patients the diagnosis remained the same after LTM. In those patients in whom there was a change in diagnosis, the most common change was in distinguishing epilepsy from NEAD in 73 (55%) and in distinguishing between focal and generalised epilepsy in 47 (35%). LTM was particularly helpful in differentiating frontal lobe seizures from generalised seizures and non-epileptic attacks. Inpatient ambulatory EEG proved as effective as video telemetry in helping to distinguish between NEAD, focal and generalised epilepsy. DISCUSSION: The study revealed that LTM led to an alteration in the diagnosis of 71% of patients referred to a tertiary centre for diagnostic clarification of possible epilepsy. Although LTM is relatively expensive, time consuming and of limited availability, this needs to be balanced against the considerable financial and social cost of misdiagnosed and uncontrolled seizures. This service evaluation supports the use of performing LTM (either video or ambulatory) in a specialist setting in patients who present diagnostic difficulty.
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Electroencefalografía , Epilepsias Parciales/diagnóstico , Epilepsia del Lóbulo Frontal/diagnóstico , Epilepsia Generalizada/diagnóstico , Telemetría , Grabación en Video , Anticonvulsivantes/economía , Anticonvulsivantes/uso terapéutico , Estudios de Cohortes , Costos y Análisis de Costo , Diagnóstico Diferencial , Electroencefalografía/economía , Epilepsias Parciales/tratamiento farmacológico , Epilepsias Parciales/economía , Epilepsia del Lóbulo Frontal/tratamiento farmacológico , Epilepsia del Lóbulo Frontal/economía , Epilepsia Generalizada/tratamiento farmacológico , Epilepsia Generalizada/economía , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/economía , Hospitales Universitarios/economía , Humanos , Londres , Cuidados a Largo Plazo/economía , Auditoría Médica , Monitoreo Ambulatorio/economía , Admisión del Paciente/economía , Derivación y Consulta/economía , Telemetría/economía , Grabación en Video/economíaRESUMEN
Granule cell dispersion (GCD) is a common finding in hippocampal sclerosis in patients with intractable focal epilepsy. It is considered to be an acquired, post-developmental rather than a pre-existing abnormality, involving dispersion of either mature or newborn neurones, but the precise factors regulating it and its relationship to seizures are unknown. We present two cases of GCD with associated CD34-immunopositive balloon cells, a cell phenotype associated with focal cortical dysplasia type IIB, considered to be a developmental cortical lesion promoting epilepsy. This observation opens up the debate regarding the origin of balloon cells and CD34 expression and their temporal relationship to seizures.
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Giro Dentado/patología , Neuronas/clasificación , Neuronas/patología , Adulto , Antígenos CD34/metabolismo , Epilepsias Parciales/complicaciones , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Neuronas/metabolismo , Esclerosis/etiologíaRESUMEN
Newer MRI methods can detect cerebral abnormalities not identified on routine imaging in patients with focal epilepsy. Correlation of MRI with histopathology is necessary to understand the basis of MRI abnormalities and subsequently predict histopathology from in vivo MRI. The aim of this study was to determine if particular quantitative MR parameters were associated with particular histological features. Nine patients with temporal lobe epilepsy were imaged at 1.5 T using standard presurgical volumetric and quantifiable sequences: magnetization transfer and FFT2. The resected temporal lobe was registered with the volumetric MRI data according to our previously described method to permit correlation of the modalities. Stereologically measured neuronal densities and field fraction of GFAP, MAP2, synaptophysin and NeuN immunohistochemistry were obtained. Analyses were performed in the middle temporal gyrus and compared with quantitative MRI data from the equivalent regions. There was a significant Spearman Rho negative correlation between NeuN field fraction and the T2 value in gray matter (correlation coefficient -0.72, p=0.028). There were no significant correlations between any neuropathological and MR measures in white matter. These preliminary findings suggest that T2 in gray matter is sensitive to the proportion of neuronal tissue. Novel quantitative MRI measures acquired with higher field strength magnets, and so with superior signal to noise ratios, may generate data that correlate with histopathological measures. This will enable better identification and delineation of the structural causes of refractory focal epilepsy, and will be of particular benefit in patients in whom current optimal MRI does not identify a relevant abnormality.