epilepsy Flashcards
what percentage of the population does epilepsy effect?
1%
how many patients with epilepsy continue to have seizures despite appropriate medication?
one third
What is a seizure?
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
What is epilepsy?
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
What can cause a seizure?
almost any local or global insult resulting in disturbance of the brain’s cortex
What are acute cerebral insults? or “provoking factors” which can give rise to a seizure
acute cerebral insults are situations where any normal brain under the right circumstances could have a seizure. These include
- metabolic disturbances (hypoatremia–> low sodium, or hypocalcemia –> low calcium)
- Toxins (e.g. EtOH, illicit drugs, antibiotics, antidepressants)
- Infections (e.g. encephalitis) or fever (e.g. “febrile seizure)
- acute head trauma or acute stroke
acute means severe
what are two enduring epileptic alterations in the brain that can cause a seizure?
- remote causes: i.e. malformations occurring during embryogenesis OR scars or tutors occurring later in life
- idiopathic/cryptogenic causes (unknown causes): occurs when neuroimaging is normal, and increasingly recognized to have genetic aetiologies
What happens in a seizure?
large groups of neurons over one or both hemispheres fire abnormally and synchronously
this can be viewed in an electroencephalogram (EEG)
How are seizures classified?
they are classified by location
you can have a partial (aka focal/localized) or generalized seizure
What is a partial seizure? What are some of the ways it manifests depending on the location?
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
What are generalized seizures? what are two types?
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)
What is a generalized tonic-clonic seizure?
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)
what is a complex partial seizure (especially stemming from temporal lobe)?
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
What is simple vs. complex seizures?
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
what is convulsive vs. non-convulsive seizures?
convulsive/convulsion seizures involve involuntary muscle contractions
non- convulsive seizures show no discernible muscle contractions
examples include: generalized tonic clonic convulsions, or absence seizure
does a simple generalized seizure exist?
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
what are four important causes of epilepsy?
- genetic defects causing channelopathies
- disorders of cortical formation occurring during embryogenesis
- epileptogenic neuronal networks acquired later in life
- dysregulation of physiological neuronal networks
what is one way we can look at epilepsy on a neuronal level?
its an imbalance between neuronal excitation and inhibition
which drugs are used to prevent seizures at a molecular level?
drugs that are used to promote brain inhibition or dampen brain excitation by either:
- blocking sodium channels
- inhibiting release of glutamate
- blocking NMDA or non-NMDA receptor
- enhancing GABA receptors mediated inhibition
overall they reduce excitation and enhance gabenergic inhibition
What are channelopathies?
they are mutations in genes that cause ion channel synthesizing gene to be mutated
What is severe Myoclonic Epilepsy of Infancy?
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
What is the genetics behind Severe Myoclonic Epilepsy of Infancy?
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
what are NaV1.1 mutations and how do they cause epilepsy?
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
what is SCN1A and Vaccine Encephalopathy?
“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
What is the evidence of children in VEE done by Bercovic et al?
showed that severity of epilepsy and intellectual handicap was no different than patients with SMEI and concluded that VEE does not differ from SMEI
When does normal neuronal proliferation occur (in the ventricular zone)?
2-4 months of gestational age
when does neuronal migration occur (close to pial surface)?
3-5 months gestational age
when does neuronal organization occur? (synapses are created)
gestational age of 4 months until birth age of 2 years
What are types of disorders of neuronal proliferation? involving decreased, increased and localized?
- 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)
What are the disorders of neuronal Migration?
- periventricular (near ventricle) Nodular (nodule shaped) Heterotopia (wrong spot) –> neurons don’t migrate to pial surface during embryogenesis
- 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
What are disorders of neuronal organization?
- 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
what causes these abnormalities in embryogenesis?
- genetic abnormalities caused by genes such as Lis1, DoubleCortin, ARFGEF2, Filimin A that encode for proteins involved in microtubule stabilization, cell migration
- Prenatal infections (TORCH infections) such as Toxoplasmosis, Rubella, Cytomegalovirus and Herpes Simplex
- Prenatal hypoxic-ischemic injury (increase blood pressure during pregnancy)
- unknown/cryptogenic
Why are proliferation, migration and organization lesions epileptogenic?
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
what is focal cortical dysplasia?
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
What are acquired epilepsies? what are common acquired epilepsy stemming from?
any process that permanently damages the cortex can become a cause of epilepsy later on
some acquired epilepsy roots:
- stroke
- vascular malformation
- tumors
- traumatic brain injury
- other causes of brain scarring (sclerosis)
What is the most common focal epilepsy? Which structures does it affect and what functions does it affect?
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
what structures are involved in the hippocampal formation?
consists of the dentate gyrus, hippocampus proper (CA1, 2, 3, 4), subiculum, and entorhinal cortex
what is the preferment pathway?
stems from enterorhinal cortex to the dentate gyrus
What are the steps of synchrony in hippocampal circuit?
- 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
What can cause damage to the mesial temporal lobe neurons?
neurons in that area are vulnerable in early life
damage can occur from hypoxic injury, infections (TORCH), prolonged febrile seizures (neurotoxicity)
What occurs to the neurons in the mesial temporal cortex in epilepsy?
selective neuronal loss in CA1 and CA3, inhibitory interneurons in dentate gyrus
- the mossy fibres sprout to innervate neighbouring dentate gyrus cells
What are the symptoms of mesial temporal lobe epilepsy? (i.e. what does it look like)
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
What do MRI scans and EEG scans show in patients with mesial temporal lobe epilepsy?
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
what is the treatment for mesial temporal lobe epilepsy?
initially anti epileptic medication
occasionally surgery to remove temporal lobe required
What is Absence Epilepsy?
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
what does an EEG of someone who has absence seizure show and what is a possible treatment?
deg shows characteristics of generalized, rhythmic pattern
treatment includes responsiveness to medical therapies but sometimes require lifelong medications
children usually outgrow this
What is the pathogenesis of absence epilepsy? what happens in the brain?
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
