The Cellular Basis of Epilepsy and Behavioural Illness

Question 1

What is SUDEP?

Answer 1

Sudden unexplained death in epilepsy

Question 2

What causes an epileptic seizure?

Answer 2

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

Question 3

What are the clinical manifestations of an epileptic seizure?

Answer 3

Varies depending on the regions of the brain involved at onset and during the secondary spread

Question 4

What are the 3 broad classifications of epilepsy?

Answer 4

Genetic (idiopathic/primary)
Structural/metabolic (symptomatic/secondary)
Unknown (cryptogenic)

Question 5

Why is it important to determine a patient’s specific epileptic syndrome?

Answer 5

Because prognosis, treatment and genetic implications vary greatly between the syndromes

Question 6

List 4 characteristics of genetic epilepsies

Answer 6

Usually onset during childhood/teenage years
May remit
Usually respond well to medication
Likely to have genetic basis (e.g. mutation in ion channels)

Question 7

List 3 characteristics of structural/metabolic epilepsies

Answer 7

More common with age (most common for a new diagnosis of epilepsy from mid-life onwards)
Uncommonly remit
Often incompletely controlled with medication

Question 8

List 4 possible mechanisms for the development of epileptic neuronal networks

Answer 8

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)

Question 9

What are the 3 main underlying molecular changes in mesial temporal sclerosis (MST)?

Answer 9

Cell loss in CA1, CA3 and dentate hilus regions of the hippocampus
Abnormal sprouting
Gliosis (glial cell proliferation)

Question 10

What effect do seizures have on epileptogenesis?

Answer 10

Accelerate epileptic changes

Question 11

What is the largest age demographic for new onset epilepsy?

Answer 11

> 60 y.o.

Question 12

What is the most common aetiology of new onset epilepsy in infancy and early childhood?

Answer 12

Congenital/perinatal CNS insults (e.g. ischaemic insult during birth or development)

Question 13

What is the most common aetiology of new onset epilepsy in late childhood and early adulthood?

Answer 13

Idiopathic

Genetic

Question 14

What is the most common aetiology of new onset epilepsy in adults and the elderly?

Answer 14

Structural/metabolic (e.g. trauma, ischaemia, tumours, haemorrhage, degenerative disease)

Question 15

What is the hypothesised cause of idiopathic generalised epilepsies (IGE)?

Answer 15

Genetically determined

Question 16

List 3 broad groups of targets for mutations believed to have a role in causing epilepsy

Answer 16

Voltage-gated ion channels
Ligand-gated ion channels
Non-ion channel genes (involved in neural migration, other structural elements)

Question 17

Describe the inheritance patterns of IGE

Answer 17

Most are complex

5-10% Mendelian monogenic inheritance patterns

Question 18

Does genetics have a role in acquired epilepsy?

Answer 18

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

Question 19

What imaging modality is most commonly used to evaluate epilepsy?

Answer 19

MRI

Question 20

What imaging modality is most commonly used to evaluate epilepsy? Why?

Answer 20

MRI; sensitive and specific, high spatial resolution and tissue contrast

Question 21

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?

Answer 21

70%

Strongly predictive of outcome following epilepsy surgery

Question 22

How is MST usually treated?

Answer 22

Most patients are refractory to medical therapy but have good prognosis with epilepsy surgery

Question 23

List 4 features of an MRI of MST

Answer 23

Hippocampal atrophy
Increased T2 signal
Decreased T1 signal
Loss of cytoarchitecture

Question 24

What is focal cortical dysplasia?

Answer 24

A focal region of disturbed cortical development and architecture with unknown aetiology (not genetic)

Question 25

List 4 features of an MRI of focal cortical dysplasia

Answer 25

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

Question 26

What is epilepsy primarily a disease of?

Answer 26

The grey matter

Question 27

What is a periventricular nodular heterotopia? Is it bilateral or focal?

Answer 27

Generalised malformation due to abnormal neural migration, resulting in nodular masses of grey matter diffusely lining the ventricular walls May be bilateral or focal

Question 28

Is there a genetic basis for periventricular nodular heterotopia?

Answer 28

Can be inherited in the case of bilateral heterotopia

Question 29

What is the most common cause of new onset partial seizures aged 35-55 years?

Answer 29

Low grade tumours

Question 30

List 3 of the most common types of low grade tumours causing partial epilepsy

Answer 30

Gliomas (most common) Meningiomas Dysembryoplastic neuroepithelial tumour

Question 31

What is the most epileptogenetic site for a low grade tumour?

Answer 31

Centro-temporo-parietal region

Question 32

What are the 2 types of vascular lesions causing epilepsy?

Answer 32

Cavernomas | Arteriovenous malformations

Question 33

List 3 MRI features of focal encephalomalacia

Answer 33

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

Question 34

What is focal encephalomalacia?

Answer 34

A focal lesion resulting from previous destructive insult (e.g. trauma, stroke, infection)

Question 35

What do anti-epileptic drugs treat?

Answer 35

The symptoms, not the underlying condition

Question 36

List 3 non-medical treatments for epilepsy

Answer 36

Surgery Neurostimulators Diet

Question 37

What are the 2 requirements for a candidate for epilepsy surgery?

Answer 37

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)

Question 38

Distinguish between psychopathology and neuropathology

Answer 38

Psychopathology refers to clinical symptoms | Neuropathology refers to anatomical changes underlying these symptoms

Question 39

List 5 characteristics of catatonia

Answer 39

``` Motor immobility Excessive motor activity Extreme negativism or mutism Peculiarities of voluntary movement Echolalia or echopraxia (repetition of actions of words) ```

Question 40

Describe the progression of neurodevelopment

Answer 40

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

Question 41

What is the hypothesised defect in childhood and adolescent schizophrenia and other disorders?

Answer 41

Problems with synaptic formation or synaptic pruning

Question 42

When does synaptic pruning begin and when does it end?

Answer 42

Synaptic spine density begins to decrease from age 5 and stabilises in the 3rd decade

Question 43

List 3 changes of anatomical connectivity observed in schizophrenia and other behavioural disorders

Answer 43

Decreased neuronal size Decreased neuronal connections Altered cell skeleton

Question 44

List 3 risk factors for the development of behavioural disorders

Answer 44

``` Genetic/epigenetic risk Perinatal risk (e.g. hypoxia during birth) Prenatal risk (e.g. pyrexia, starvation) ```

Question 45

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?

Answer 45

Decreased connections between the thalamus and cortex | Decreased expression of synapsin, gap43 and connexins

Question 46

What are the 3 broad classification of factors involved in the molecular pathology behind behavioural disorders? Give some specific examples for each

Answer 46

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)

Question 47

What were the findings of multiple studies measuring glial density in bipolar disorder, schizophrenia and major depressive disorder?

Answer 47

Decreased glial density (especially in layers 5 and 6, the deeper layers of the cortex, and especially in major depressive disorder)

Question 48

What gene relating to microglial activation is upregulated in schizophrenia?

Answer 48

Gene for calprotectin, a pro-inflammatory marker expressed by glia

Question 49

What were the findings of a study observing the behaviour of Hoxb8 mutants?

Answer 49

Expressed behaviour similar to OCD, which could be resolved by transplantation of wild-type bone marrow

Question 50

What is one of the observed neurodevelopmental abnormalities in autism?

Answer 50

Early peak overgrowth in the dorsolateral prefrontal cortex

Question 51

What is the HLA haplotype found to be over-expressed by activated microglia and astroglia in autism?

Answer 51

HLA-DR

Question 52

What is the main cellular abnormality in the autistic DLPFC?

Answer 52

Increased microglial density and volume (due to over-activation)

Question 53

What is the genetic basis of autism?

Answer 53

Appears to be SNPs which confer either risk or resilience factors; SNPs may be in the same gene but have different effects