The Cellular Basis of Epilepsy and Behavioural Illness Flashcards
What is SUDEP?
Sudden unexplained death in epilepsy
What causes an epileptic seizure?
Excessive, hyper-synchronous activity of populations of neurons in the brain, due to an imbalance between inhibition and excitation of cortical neurons and neuronal networks
What are the clinical manifestations of an epileptic seizure?
Varies depending on the regions of the brain involved at onset and during the secondary spread
What are the 3 broad classifications of epilepsy?
Genetic (idiopathic/primary)
Structural/metabolic (symptomatic/secondary)
Unknown (cryptogenic)
Why is it important to determine a patient’s specific epileptic syndrome?
Because prognosis, treatment and genetic implications vary greatly between the syndromes
List 4 characteristics of genetic epilepsies
Usually onset during childhood/teenage years
May remit
Usually respond well to medication
Likely to have genetic basis (e.g. mutation in ion channels)
List 3 characteristics of structural/metabolic epilepsies
More common with age (most common for a new diagnosis of epilepsy from mid-life onwards)
Uncommonly remit
Often incompletely controlled with medication
List 4 possible mechanisms for the development of epileptic neuronal networks
Alternations in neuronal network components (e.g. loss of inhibitory neurons, gain of excitatory neurons, aberrant sprouting)
Alterations in intrinsic neuronal cellular excitability
Alterations in synaptic transmission
Alterations in extra-neuronal environment (e.g. glial function)
What are the 3 main underlying molecular changes in mesial temporal sclerosis (MST)?
Cell loss in CA1, CA3 and dentate hilus regions of the hippocampus
Abnormal sprouting
Gliosis (glial cell proliferation)
What effect do seizures have on epileptogenesis?
Accelerate epileptic changes
What is the largest age demographic for new onset epilepsy?
> 60 y.o.
What is the most common aetiology of new onset epilepsy in infancy and early childhood?
Congenital/perinatal CNS insults (e.g. ischaemic insult during birth or development)
What is the most common aetiology of new onset epilepsy in late childhood and early adulthood?
Idiopathic
Genetic
What is the most common aetiology of new onset epilepsy in adults and the elderly?
Structural/metabolic (e.g. trauma, ischaemia, tumours, haemorrhage, degenerative disease)
What is the hypothesised cause of idiopathic generalised epilepsies (IGE)?
Genetically determined
List 3 broad groups of targets for mutations believed to have a role in causing epilepsy
Voltage-gated ion channels
Ligand-gated ion channels
Non-ion channel genes (involved in neural migration, other structural elements)
Describe the inheritance patterns of IGE
Most are complex
5-10% Mendelian monogenic inheritance patterns
Does genetics have a role in acquired epilepsy?
May contribute to an individual’s vulnerability to acquiring epilepsy after some insult
Those with acquired epilepsy are 3x more likely to have a family history than those without
What imaging modality is most commonly used to evaluate epilepsy?
MRI
What imaging modality is most commonly used to evaluate epilepsy? Why?
MRI; sensitive and specific, high spatial resolution and tissue contrast
In what % of cases of medically refractory focal epilepsy is MRI successful in detecting the focal lesion? What does the ability to detect this lesion mean for patient outcomes?
70%
Strongly predictive of outcome following epilepsy surgery
How is MST usually treated?
Most patients are refractory to medical therapy but have good prognosis with epilepsy surgery
List 4 features of an MRI of MST
Hippocampal atrophy
Increased T2 signal
Decreased T1 signal
Loss of cytoarchitecture
What is focal cortical dysplasia?
A focal region of disturbed cortical development and architecture with unknown aetiology (not genetic)
List 4 features of an MRI of focal cortical dysplasia
Focal thickening of the cerebral cortex
Blurring of the grey/white interface
Gyral abnormalities (e.g. polymicrogyria, macrogyria)
May be associated with a region of increased T2 signal
What is epilepsy primarily a disease of?
The grey matter
What is a periventricular nodular heterotopia? Is it bilateral or focal?
Generalised malformation due to abnormal neural migration, resulting in nodular masses of grey matter diffusely lining the ventricular walls
May be bilateral or focal
Is there a genetic basis for periventricular nodular heterotopia?
Can be inherited in the case of bilateral heterotopia
What is the most common cause of new onset partial seizures aged 35-55 years?
Low grade tumours
List 3 of the most common types of low grade tumours causing partial epilepsy
Gliomas (most common)
Meningiomas
Dysembryoplastic neuroepithelial tumour
What is the most epileptogenetic site for a low grade tumour?
Centro-temporo-parietal region
What are the 2 types of vascular lesions causing epilepsy?
Cavernomas
Arteriovenous malformations
List 3 MRI features of focal encephalomalacia
Irregular area of atrophy of the cerebral cortex and underlying white matter
Surrounding region of increased T2 signal (due to gliosis)
May be associated with a large cystic region
What is focal encephalomalacia?
A focal lesion resulting from previous destructive insult (e.g. trauma, stroke, infection)
What do anti-epileptic drugs treat?
The symptoms, not the underlying condition
List 3 non-medical treatments for epilepsy
Surgery
Neurostimulators
Diet
What are the 2 requirements for a candidate for epilepsy surgery?
Continuing uncontrolled seizures interfering with quality of life, despite trials of several appropriate AEDs
Epilepsy syndrome must be surgically remediable (must be focal, must be a brain region that can be resected with acceptably low risk)
Distinguish between psychopathology and neuropathology
Psychopathology refers to clinical symptoms
Neuropathology refers to anatomical changes underlying these symptoms
List 5 characteristics of catatonia
Motor immobility Excessive motor activity Extreme negativism or mutism Peculiarities of voluntary movement Echolalia or echopraxia (repetition of actions of words)
Describe the progression of neurodevelopment
Involves cortical grey matter thinning, which begins at the posterior regions (the sensory cortex), and finishes with the prefrontal and frontal cortex and the lateral temporal regions
What is the hypothesised defect in childhood and adolescent schizophrenia and other disorders?
Problems with synaptic formation or synaptic pruning
When does synaptic pruning begin and when does it end?
Synaptic spine density begins to decrease from age 5 and stabilises in the 3rd decade
List 3 changes of anatomical connectivity observed in schizophrenia and other behavioural disorders
Decreased neuronal size
Decreased neuronal connections
Altered cell skeleton
List 3 risk factors for the development of behavioural disorders
Genetic/epigenetic risk Perinatal risk (e.g. hypoxia during birth) Prenatal risk (e.g. pyrexia, starvation)
In which area is there notable loss of neuronal connections in schizophrenia and other behavioural disorders? What proteins involved in synaptic connections are downregulated at these sites?
Decreased connections between the thalamus and cortex
Decreased expression of synapsin, gap43 and connexins
What are the 3 broad classification of factors involved in the molecular pathology behind behavioural disorders? Give some specific examples for each
Neurochemical (e.g. dopamine, glutamate, GABA)
Anatomical (e.g. decreased dendrites via alterations in MAP2 expression, decreased glia and microglia)
Trophic/signalling (e.g. Wnt/GSK3B)
What were the findings of multiple studies measuring glial density in bipolar disorder, schizophrenia and major depressive disorder?
Decreased glial density (especially in layers 5 and 6, the deeper layers of the cortex, and especially in major depressive disorder)
What gene relating to microglial activation is upregulated in schizophrenia?
Gene for calprotectin, a pro-inflammatory marker expressed by glia
What were the findings of a study observing the behaviour of Hoxb8 mutants?
Expressed behaviour similar to OCD, which could be resolved by transplantation of wild-type bone marrow
What is one of the observed neurodevelopmental abnormalities in autism?
Early peak overgrowth in the dorsolateral prefrontal cortex
What is the HLA haplotype found to be over-expressed by activated microglia and astroglia in autism?
HLA-DR
What is the main cellular abnormality in the autistic DLPFC?
Increased microglial density and volume (due to over-activation)
What is the genetic basis of autism?
Appears to be SNPs which confer either risk or resilience factors; SNPs may be in the same gene but have different effects
