epilepsy

Question 1

what percentage of the population does epilepsy effect?

Answer 1

1%

Question 2

how many patients with epilepsy continue to have seizures despite appropriate medication?

Answer 2

one third

Question 3

What is a seizure?

Answer 3

a seizure is not a disorder, its a symptom of disorders

a seizure is an event wherein localized or distributed populations of brain neurons discharge synchronously and excessively

*note that a seizure is a symptom of brain dysfunction rather than a disease because it can be induced manually as well

Question 4

What is epilepsy?

Answer 4

epilepsy is a chronic disorder characterized by recurrent, unprovoked seizures (not caused by something external)

the epileptic brain has a lot of alterations in its structure that predispose it to seizures

Question 5

What can cause a seizure?

Answer 5

almost any local or global insult resulting in disturbance of the brain’s cortex

Question 6

What are acute cerebral insults? or “provoking factors” which can give rise to a seizure

Answer 6

acute cerebral insults are situations where any normal brain under the right circumstances could have a seizure. These include

1. metabolic disturbances (hypoatremia–> low sodium, or hypocalcemia –> low calcium)
2. Toxins (e.g. EtOH, illicit drugs, antibiotics, antidepressants)
3. Infections (e.g. encephalitis) or fever (e.g. “febrile seizure)
4. acute head trauma or acute stroke

acute means severe

Question 7

what are two enduring epileptic alterations in the brain that can cause a seizure?

Answer 7

1. remote causes: i.e. malformations occurring during embryogenesis OR scars or tutors occurring later in life
2. idiopathic/cryptogenic causes (unknown causes): occurs when neuroimaging is normal, and increasingly recognized to have genetic aetiologies

Question 8

What happens in a seizure?

Answer 8

large groups of neurons over one or both hemispheres fire abnormally and synchronously

this can be viewed in an electroencephalogram (EEG)

Question 9

How are seizures classified?

Answer 9

they are classified by location

you can have a partial (aka focal/localized) or generalized seizure

Question 10

What is a partial seizure? What are some of the ways it manifests depending on the location?

Answer 10

a partial seizure is located to a focal area of the cortex (specific area)

if its in the frontal lobe –> motor manifestations
if its in the parietal or occipital lobe –> sensory or visual
if its in the temporal lobe –> sensory, psychological and emotional

Question 11

What are generalized seizures? what are two types?

Answer 11

generalized seizures are widespread and diffuse

primary generalized seizures occur in both hemispheres involved synchronously at onset

secondary seizures occur in a localized area of the cortex AND THEN spread throughout both hemispheres (i.e. starting in the temporal lobe and u get the focal side effects and then suddenly to the whole brain)

Question 12

What is a generalized tonic-clonic seizure?

Answer 12

its generalized meaning that it affects both hemispheres. it involves intense shaking and loss of consciousness followed by confusion and exhaustion (usually sleep right after)

Question 13

what is a complex partial seizure (especially stemming from temporal lobe)?

Answer 13

partial seizure means that its localized in the temporal lobe. First an aura occurs before the seizure (this could be in the form of deja vu, smell, taste…or any type of limbic symptoms) and then the person gets the seizure in the form of temporal lobe disturbances

Question 14

What is simple vs. complex seizures?

Answer 14

simple seizures show no alteration in consciousness (person is still able to interact normally throughout seizure or do actions like grasp the wall etc…)

complex seizures come with impaired consciousness

examples include: simple motor seizure, or complex partial seizure

Question 15

what is convulsive vs. non-convulsive seizures?

Answer 15

convulsive/convulsion seizures involve involuntary muscle contractions
non- convulsive seizures show no discernible muscle contractions

examples include: generalized tonic clonic convulsions, or absence seizure

Question 16

does a simple generalized seizure exist?

Answer 16

this is when you have a seizure spread between both hemispheres but the person is still conscious

NO. you can’t. alternation of consciousness is caused by disruptions in the brain stem (reticular activating system) that spreads to both hemispheres

Question 17

what are four important causes of epilepsy?

Answer 17

1. genetic defects causing channelopathies
2. disorders of cortical formation occurring during embryogenesis
3. epileptogenic neuronal networks acquired later in life
4. dysregulation of physiological neuronal networks

Question 18

what is one way we can look at epilepsy on a neuronal level?

Answer 18

its an imbalance between neuronal excitation and inhibition

Question 19

which drugs are used to prevent seizures at a molecular level?

Answer 19

drugs that are used to promote brain inhibition or dampen brain excitation by either:

1. blocking sodium channels
2. inhibiting release of glutamate
3. blocking NMDA or non-NMDA receptor
4. enhancing GABA receptors mediated inhibition

overall they reduce excitation and enhance gabenergic inhibition

Question 20

What are channelopathies?

Answer 20

they are mutations in genes that cause ion channel synthesizing gene to be mutated

Question 21

What is severe Myoclonic Epilepsy of Infancy?

Answer 21

SMEI

• starts in the first year of life for the baby who was previously developing normally
• usually followed by a fever, babies then develop semi (half of body) clonic convulsions (shaking) or generalized tonic clonic seizures
• seizures occur within months are often provoked by fever
• within one year children developmentally regress (i.e. don’t learn language)
• children often survive into adulthood with intractable epilepsy and developmental delay

Question 22

What is the genetics behind Severe Myoclonic Epilepsy of Infancy?

Answer 22

SMEI associated with over 100 different mutations in NaV1.1 (sodium channel) encoded by SCN1A gene

95% of these were not passed on by parents

Question 23

what are NaV1.1 mutations and how do they cause epilepsy?

Answer 23

these cause loss of functions in sodium channels

even though sodium channels are supposed to cause excitation, this particular channel is expressed primarily on cortical inhibitory interneurons

therefore, overall if you have this mutation, you have more brain excitation than inhibition

Question 24

what is SCN1A and Vaccine Encephalopathy?

Answer 24

“vaccine-induced epileptic encephalopathy”
is a case where casual claims by parents and physicians were made for vaccine-induced neurological dysfunction
- similar to autism and measles/mumps/rubella vaccine
- a condition called epileptic encephalopathy (VEE) has been thought to be caused by vaccines
- children with VEE reported to have severe epilepsy and developmental delay 72 hours after the pertussis vaccination at time of a fever

Question 25

What is the evidence of children in VEE done by Bercovic et al?

Answer 25

showed that severity of epilepsy and intellectual handicap was no different than patients with SMEI and concluded that VEE does not differ from SMEI

Question 26

When does normal neuronal proliferation occur (in the ventricular zone)?

Answer 26

2-4 months of gestational age

Question 27

when does neuronal migration occur (close to pial surface)?

Answer 27

3-5 months gestational age

Question 28

when does neuronal organization occur? (synapses are created)

Answer 28

gestational age of 4 months until birth age of 2 years

Question 29

What are types of disorders of neuronal proliferation? involving decreased, increased and localized?

Answer 29

- decreased proliferation is called lissencephaly (smooth brain) - increased proliferation is called megalencephaly (big head) - localized increased proliferation is called focal cortical dysplasia (only one small area of localized space has increased proliferation and theres typically no developmental disorders but they have focal seizures from that area)

Question 30

What are the disorders of neuronal Migration?

Answer 30

1. periventricular (near ventricle) Nodular (nodule shaped) Heterotopia (wrong spot) --> neurons don't migrate to pial surface during embryogenesis 2. Subcortical Band Heterotopia (aka "double cortex syndrome") --> some neurons migrated but some didn't.... neurons stop in between white matter and make it seem like another cortex layer

Question 31

What are disorders of neuronal organization?

Answer 31

- polymicrogyria: normal migration but cannot organize into gyrus and instead they form tiny microgyrus (small gyri) on the surface of the brain. - schizencephaly: a cut in the cortex resulting in abnormal organization of neurons in the cortical layer

Question 32

what causes these abnormalities in embryogenesis?

Answer 32

1. genetic abnormalities caused by genes such as Lis1, DoubleCortin, ARFGEF2, Filimin A that encode for proteins involved in microtubule stabilization, cell migration 2. Prenatal infections (TORCH infections) such as Toxoplasmosis, Rubella, Cytomegalovirus and Herpes Simplex 3. Prenatal hypoxic-ischemic injury (increase blood pressure during pregnancy) 4. unknown/cryptogenic

Question 33

Why are proliferation, migration and organization lesions epileptogenic?

Answer 33

because they cause local distortions of circuitry: - loss of normal feedback inhibition - abnormal excitatory projections and they result in electrically unstable and epileptogenic regions of cortex

Question 34

what is focal cortical dysplasia?

Answer 34

a common cause for focal epilepsy - the onset of seizures is in the first or second decade of life - usually mild developmental delay but they have frequent seizures - seizure types are dictate by the location of the dysplasia (which lobe) in diagnosing these, an MRI often doesn't show it but EEG shows this (shows very active in that region) treatment: these epilepsies are often resistant to anti-epileptic medications and often surgery is required to remove these

Question 35

What are acquired epilepsies? what are common acquired epilepsy stemming from?

Answer 35

any process that permanently damages the cortex can become a cause of epilepsy later on some acquired epilepsy roots: 1. stroke 2. vascular malformation 3. tumors 4. traumatic brain injury 5. other causes of brain scarring (sclerosis)

Question 36

What is the most common focal epilepsy? Which structures does it affect and what functions does it affect?

Answer 36

the most common focal epilepsy is medial temporal lobe epilepsy - the mesial temporal lobe includes structures like the amygdala, hippocampal formation, parahippocampus - these structures form part of the limbic system and are important for laying down memories

Question 37

what structures are involved in the hippocampal formation?

Answer 37

consists of the dentate gyrus, hippocampus proper (CA1, 2, 3, 4), subiculum, and entorhinal cortex

Question 38

what is the preferment pathway?

Answer 38

stems from enterorhinal cortex to the dentate gyrus

Question 39

What are the steps of synchrony in hippocampal circuit?

Answer 39

- largely a feed forward excitation 1. performant pathway to entorhinal cortex to dentate gyrus 2. mossy fibers extend from granule cells in GF to CA3 pyramidal cells in the hippocampus proper 3. CA3 pyramidal cells excite other pyramidal cells in the CA1 4. CA1 pyramidal cells excite neurons in the subiculum and in turn the Entorhinal cortex 5. inhibitory interneurons in the dentate gyrus provide some control over the circuit if there was no inhibitory interneurons then the system would be a run-away system where theres constant excitation the interneurons in the dentate gyrus interact with the hippocampus to create stability

Question 40

What can cause damage to the mesial temporal lobe neurons?

Answer 40

neurons in that area are vulnerable in early life | damage can occur from hypoxic injury, infections (TORCH), prolonged febrile seizures (neurotoxicity)

Question 41

What occurs to the neurons in the mesial temporal cortex in epilepsy?

Answer 41

selective neuronal loss in CA1 and CA3, inhibitory interneurons in dentate gyrus - the mossy fibres sprout to innervate neighbouring dentate gyrus cells

Question 42

What are the symptoms of mesial temporal lobe epilepsy? (i.e. what does it look like)

Answer 42

patients have prolonged febrile generalized tonic clonic seizures during infancy or early childhood or from traumatic birth - they develop complex-partial seizures (loss of consciousness) later in childhood, adolescence or adulthood

Question 43

What do MRI scans and EEG scans show in patients with mesial temporal lobe epilepsy?

Answer 43

MRI scans show atrophy and scarring in the mesial temporal lobe EEG shows unilateral or bilateral temporal lobe spikes between seizures and during seizures it shows rhythmic activity over one temporal lobe

Question 44

what is the treatment for mesial temporal lobe epilepsy?

Answer 44

initially anti epileptic medication occasionally surgery to remove temporal lobe required

Question 45

What is Absence Epilepsy?

Answer 45

its a common cause of epilepsy in previously healthy children - patients have normal birth, development and no past medical history - seizures start in childhood or adolescence - the seizures are sudden staring and possibly eyelid fluttering that last 5-10 seconds - often children are thought to be daydreaming, start preforming poorly in school their MRI scans show normal

Question 46

what does an EEG of someone who has absence seizure show and what is a possible treatment?

Answer 46

deg shows characteristics of generalized, rhythmic pattern treatment includes responsiveness to medical therapies but sometimes require lifelong medications children usually outgrow this

Question 47

What is the pathogenesis of absence epilepsy? what happens in the brain?

Answer 47

theres dysregulation in thalamic relay neurons and abnormal transitions between the tonic mode (awk) and the burst mode (non-REM sleep) control of mode occurs via interactions with nucleus reticular thalami (NRT) so the person enters an almost sleep-like state during these seizures