Latin: sacire "to take posession of"
- Paroxysmal, abnormal, excessive, hypersynchronous discharge of cortical neurons, resulting in a change in behavior or in an EEG discharge
- Can be “provoked” or “unprovoked"
- Recurrent unprovoked seizures
- ...or one unprovoked seizure and high likelihood of more based on history/exam/studies
- ... or provoked by something that shouldn’t provoke seizures (“reflex epilepsy”)
Potential differential diagnoses for seizures?
- Gastroesophageal reflux
- Breath-holding spells
- Sleep myoclonus
- Night terrors
- Movement disorders
- Transient ischemic attacks
- Vertebrobasilar insufficiency
- Psychogenic seizures
What percentage of the population will experience seizures/epilepsy?
- Single seizure lifetime prevalence = 9-10%
- Epilepsy lifetime prevalence = 0.5-1% (3% by age 75)
(no racial/gender/geographic preference for epilepsy)
ILAE Classification History (pic)
Two division of seizure based on onset
Focal Onset seizure
- “initial activation of a system of neurons limited to one cerebral hemisphere.”
- Previously called "partial" or "localization-related"
Generalized Onset seizure
- “first clinical changes indicate involvement of both hemispheres.”
Focal seizures further divided based on what? Details?
Level of consciousness:
- No alteration of consciousness (“auras” or focal motor seizures); previously "simple partial seizures"
- Impaired or altered, but no loss of consciousness = “dyscognitive”; previously "complex partial seizures"
- Both types may evolve into generalized seizures ("secondarily generalized")
Generalized seizures include?
- Absence seizures
- Atypical substance seizure
- Clonic seizure
- Tonic seizure
- Tonic-clonic seizure
- Myoclonic seizure
- Atonic seizure
- Infantile spasms
Aura- definition and characteristics?
Brief stereotypic prodrome that precedes the more obvious clinical event by seconds to minutes
- Does not impair cognition
- Ex) taste, smell, fear, dissociation, deja vu
- Is actually a FOCAL SEIZURE
(Latin- "to strike")
The "seizure" itself
Automatisms (def) and examples?
Semipurposeful or non-purposeful “automatic” behaviors during the seizure
- Ex) picking at clothes, lipsmacking, swallowing
- Can occur in both partial and generalized epilepsies
- In partial epilepsies tend to be unilateral
Postictal state (def) and examples?
- Confusion, somnolence & fatigue (complex partial and some generalized seizures)
- Aphasia (partial seizures affecting language areas)
- Focal weakness- "Todd's paralysis" (partial seizures)
Behavioral change reflecting the anatomic location of abnormal discharge for frontal lobe?
- Clonic mvts, tonic posturing, or atonia
- Contralateral tonic posturing or bizarre bilateral hyperkinetic mvts
Behavioral change reflecting the anatomic location of abnormal discharge for temporal lobe?
- Aura of smell, taste, emotion
- Followed by confusion and staring
Behavioral change reflecting the anatomic location of abnormal discharge for parietal lobe?
- Somatosensory changes
Behavioral change reflecting the anatomic location of abnormal discharge for occipital lobe?
- Flashing lights
- Visual distortions
- Eye movements
- Not everything that shakes is a seizure
- Not every seizure is epileptic
- Note very epileptic seizure involves shaking
In a broad sense, normal CNS function is determined by what?
Balance between excitation (glutamate) and inhibition (GABA)
- Modulated by: ACh, serotonin, DA, somatostatin, CCK, dynorphin, nitric oxide, arachidonic acid, endocanabinoids...
Examples of provoked seizures (NOT epilepsy!)
- Alcohol withdrawal seizures
Exceptions- "reflex epilepsy" (typically genetic)
- Photosensitive epilepsy
- Rarely: bath (hot water), eating, music-induced epilepsy
What is the process of developing epilepsy (epileptogenesis)?
- Sequence of events leading to abnormal activity sufficient to convert a normal neuronal network into an abnormally hyperexcitable and hypersynchronous one
- A “clinically silent period” between an initial injury or insult and the development of epilepsy
Pathophysiology of epilepsy: what goes wrong (broad)?
- Loss of inhibition
- Intrinsic excitability
- Abnormal excitation (and excessive synchronization)
Pathophysiology of loss of inhibition? Examples?
Loss of inhibition
- Some interneurons are particularly vulnerable to cell death
- Disinhibition of primary neurons -> hyperexcitability and excessive neuronal activity
- Axons may sprout and synapse on other principal cells
Examples: Generalized epilepsy with febrile seizures plus (GEFS+)
Characteristics of Generalized Epilepsy with Febrile Seizures plus (GEFS+)?
Onset usually in 1st decade Clinically heterogeneous
- Febrile seizures that persist beyond 5 yrs of age
- Afebrile generalized seizures (tonic-clonic, absence, myoclonic, atonic, others)
Severity ranges from mild to severe
EEG: generalized spike and wave
Some of the mutations described are in the GABA-A recepetor
Pathophysiology of intrinsic excitability? Example?
- Decreased hyperpolarizing current
- Increased depolarizing current
Ex) decreased K conductance with Benign Familial Neonatal Convulsions
Characteristics of decreased K conductance with Benign Familial Neonatal Convulsions?
- Associated with 2 K channel genes (KCNQ2 and KCNQ3)
- Both subunits form a heterodimeric complex underlying a slow potassium conductance which regulates excitability (the M current)
- Though to be loss of function mutations
- Example of a "channelopathy"
Childhood Absence Epilepsy Circuit caused by what underlying biochemistry?
- Bursting mediated by T-type Ca channels
- Blocked by Ethosuximide
Categorizing Causes of Epilepsy?
- Evident (usually structural) cause
- For example: cortical dysplasia
- Previously “Symptomatic” Genetic
- Known or presumed genetic cause
- For example: Childhood absence epilepsy or one of the “channelopathies”
- Previously “Idiopathic” Unknown
- Previously “Cryptogenic”
- “Hidden cause” (practically: “I don’t know”)
Classification schemes can be combined as far as etiology of epilepsy and onset of seizure
- Structural epilepsy with focal onset seizures due to cortical dysplasia
- Genetic generalized epilepsy
Approach to diagnosis?
- Medical and Family Hx
- Complete description of typical events
- Complete neurological exam
- Depending on the above: Lab studies (first seizure with chemistries and tox screne, recurrents seizures with possible genetic testing), Neuroimaging (usually MRI), electroencephalography
What is this?
Electroencephalogram (EEG) "recording squiggles" of interictal discharges
What is this?
Electroencephalogram (EEG) "recording squiggles" of generalized seizure
What is this?
Electroencephalogram (EEG) "recording squiggles" of focal seizure
What are the recurrence rates following a 1st unprovoked seizure?
- 30% for pt with normal EEG, MRI, and exam - > 90% when all three are abnormal
- Multiple seizures in the same 24 hr period have same risk as a single seizure
Treatment for seizures?
New guidelines for first seizures: treat first unproviked seizure with an anti-epileptic drug. Treatment depends on:
- Syndrome classification (e.g. Childhood Absence Epilepsy, use ethosuximide)
- Type of seizures (focal-onset use narrow-spectrum agents; generalized onset use broad spectrum agents)
- Other medical problems
What is the general principle underlying AEDs (antiepileptic drugs)? Examples?
Act by restoring balance:
- Valproic acid
Mechanisms of action of AEDs with examples?
- Block Na channels: Carbamazepine
- Block Ca channels: Ethosuximide
- Block AMPA/NMDA Rs: Perampanel
- Enhance GABA receptors: Clobazam
- Enhance K channel conductance: Ezogabine
- Block NT release: Levetiracetam
Adverse effects of AEDs?
- All AEDs can cause drowsiness, dizziness, and rash
- Drugs which act on GABA system tend to be more sedating
- Not antiepileptic has been shown to be entirely safe in pregnancy (older drugs have clear teratogenic effects [2-4x increase] while newer are more likely safe, but less experience)
Serious and specific adverse effects for Valproic acid?
Acute hemorrhagic pancreatitis, hepatic failure
(1/50,000 but 1/500 for kids under 2)
Serious and specific adverse effects for Felbamate?
(up to 1/5000 adults; not seen in kids)
Serious and specific adverse effects for Carabamazepine?
Serious and specific adverse effects for Phenytoin?
Hepatotoxicity, aplastic anemia
Which drug used to treat epilepsy with focal-onset seizures?
- First line: oxcarbazepine, levetiracetam, carbamazepine, phenytoin
- Second line: lacosamide, lamotrigine, topiramate, zonisamide
Which drug used to treat epilepsy with generalized-onset seizures?
- Absence: ethosuximide, lamotrigin, valproate
- Others: lamotrigine, levetiracetam, valproate, topiramate, zonisamide, pregabalin
Success with AED Regimens?
- 47% seizure free with 1st drug
- 13% seizure free with 2nd drug
- 4% seizure free with 3rd/multiple drugs
- 36% not seizure free
Treatments for medically refractory patients?
- Ketogenic diet (an extremes Atkins: high fat low carb diet induces ketosis which has anticonvulsant effects for unclear reasons)
- Epilepsy surgery
- Vagus nerve stimulator
- Responsive focal cortical stimulation
Types of epilepsy surgery?
- Lesionectomy: take out the lesion
- Lobectomy: take out the offending lobe
- Hemispherectomy: take out the whole hemisphere
- Corpus callosotomy: cut the corpus collosum
Outcomes of epilepsy surgery depend on what?
- Type of epilepsy
- Type of surgery
For whom is epilepsy surgery considered?
Patients with intractable epilepsy
(done on about 250,000)
Mechanism of action of Carbamazepine?
Block Na channels
Mechanism of action of Ethosuximide?
Block Ca channels
Mechanism of action of Perampanel?
Mechanism of action of Clobazam?
Enhance GABA receptors
Mechanism of action of Ezogabine?
Enhance K channel conductance
Mechanism of action of Levetiracetam?
Block NT release