Epilepsy

benzodiazapines

Valium (diazepm), Ativan (lorazepam) -agonists of GABAA receptor (These used in ER, Valium not used today for chronic epilepsy due to development of tolerance, Ativan more powerful, subject to abuse)

during interictal period, abnormal activity is confined to

focus by the afterhyperpolarization This is dependent on GABAergic inhibition, GABA circuits provide 'inhibitory surround'.

electrophysiology of partial seizure: motor cortex focus

focus causes twitching/jerking of limb, other motor manifestation.

Seizure onset, neurons depolarize as in beginning of PDS. Depolarization persists

for secs. to mins. GABA inhibition fails while AMPA and NMDA-mediated excitation continues (tonic phase of muscle contraction). As GABAergic inhibition returns, neurons begin to oscillate (clonic phase).

benign neonatal convulsions

potassium channelopathies

Normal EEG in awake subject: normal frequencies

range 1-30 Hz, amplitudes of 20-100µV

epilepsy and pregnancy: AEDs

"Older" or classical AEDs are teratogenic (benzodiazepines, carbamazepine, phenobarbitol) Exposure in utero associated with: -minor facial dysmophisms, digital abnormalities. These may be subtle and can be 'outgrown' -major malformations include cleft palate, cardiac defects (atrial septal defect, teratology of Fallot, pulmonary stenosis,...) urogenital defects, neural tube defects (spina bifida, anencephaly), learning disabilities,...

tonic/clonic

"classical seizures", tonic phase starts with stiffening muscles, forced air produces cry/groan Consciousness lost, may bite tongue Clonic phase displays rapids jerks of limbs. Bowl/Bladder control lost. Lasts several minutes, consciousness slowly returns

epileptic seizure

"is a transient behavioral change that might be objective signs or subjective symptoms"

mechanisms of GABA modulation in seizure medication: benzodiazepines for acute treatment

(Valium, Atavan, Librium); class used in acute treatments, not suitable for chronic treatment due to tolerance and dependency developing over time

generalized seizure

(convulsive or nonconvulsive) begin without aura

non-pharmacological interventions for seizures: neurostimulation

-This is an exciting and growing field. Many patients have experienced relief through vagus nerve stimulation. Expanded late-stage trials are underway.

antiepileptic drugs

-primarily intended to prevent seizures -multiple other uses; migraine, neuropathic pain, bipolar disorder, myotonia, anxiety disorders, schizophrenia, restless leg, social phobia, PTS, alcohol dependence

Mechanisms of Ca channel modulation in seizure medication: HVA Ca 2+ channels

-transmitter release -α1 subunit makes up pore & voltage sensors -α2δ subunits are binding site for Gabapentin

delta waves in EEG

0.5-4 Hz; drowsiness, slow-wave sleep

antiepileptic drugs categories

1) Modulation of Voltage-gated Channels 2) Enhancement of Inhibition 3) Inhibition of Excitation

theta waves in EEG

4-7 Hz; drowsiness, slow-wave sleep

electrophysiology of partial seizure: phases of development

1. inter-ictal period 2. neuronal synchronization 3. seizure spread 4. secondary generalization Different factors underlie each phase

beta waves in EEG

13-30 Hz; frontal areas, associated with intense thought

mechanisms of GABA modulation in seizure medication: Bromide

1st effective AED, worked through enhancing GABAa receptor sensitivity, has since been replaced due to side effects & toxicity

alpha waves in EEG

8-13 Hz; parietal and occipital areas, associated with relaxed wakefulness

brain slice technique: electrophysiology rig

A brain slice (300-700µm) is placed in a 'physiology chamber', stimulating and recording electrodes are positioned, output goes to amplifier, then PC for analysis

'Generalized epilepsy with febrile seizures plus' for example, produces febrile seizures, "plus" at least one other type of seizure (absence, myoclonic, ...).

A mutation in the beta-1 subunit of the Na channel has been identified, which changes the gating and inactivation of the channel

epilepsy

Chronic neurological condition characterized by reoccurring seizures

antiepileptic drugs and their molecular targets: Na channel modulators with some Ca channel effects

Dilatin, Tegretol, Tripetal, Lamictal, Zonegran

Childhood absence epilepsy and febrile seizures

GABAa receptor subunit channelopathy

generation of primary generalized seizures:powerful feedback inhibition through

GABAergic interneurons which hyperpolarizes the cell for 100 to 200 ms The summation of the bursts and inhibition produces the spike-wave EEG pattern

mechanisms of GABA modulation in seizure medications: GAD and GABAT

GAD (glutamate decarboxylase) & GABAT (GABA transaminase) break down GABA

Mechanisms of Ca channel modulation in seizure medication: originally intended to be GABAa antagonist

Gabapentin found to bind to subunits of the HVA (high voltage-activation) subunits of the Ca channel- this is the channel for the Ca current responsible for initiating transmitter release

non-pharmacological interventions for seizures: dietary therapies

Many patients have been successfully treated with ketogenic diets. Some patients have found this unsustainable, but have managed with variations of the Atkins diet.

Mechanisms of Na+ Channel Modulation in Seizure Medications:

Na channel modulators work by blocking high frequency spike firing without overly affecting normal ongoing neuronal activity- is necessary if the intention is to stop seizures without generalized inhibition and/or impairment of brain function

Antiepileptic drugs and their molecular targets: ca channel

Neurontin Gabapentin is a example. Marketed as Neurontin, also used in treatment of neuropathic pain, bipolar disorder*, mood stabilizer/depression*, anxiety*,..(*off-label)

electrophysiology of partial seizure: Intracellular trace of paroxysmal depolarization shift

PDS are rhythmic depolarizations PDS is sudden large depolarization lasting 50-200ms. Train of APs rides on depolarizing envelope. PDS is followed by 'afterhyperpolarization'. In lower trace, cell hyperpolarized to reveal PDS waveform

epilepsy and pregnancy

Pregnancy presents difficult complications for epilepsy treatment. -Of women with pre-existing epilepsy, 35% report increased seizures, 55% report no change, 10% decrease -Seizures in pregnancy increase the chances of miscarriage -drug concentrations change during pregnancy and are difficult to maintain at specific dose. May be due to several reasons; decreased gastric motility, increased plasma volume, increased renal clearance,...

paroxysmal

Refers to a sudden outburst or attack

ictal

Relating to or caused by a stroke or seizure. An EEG recording of a seizure is said to be

electrophysiology of partial seizure: characteristic of neurons in the focus

Rhythmic depolarizations- "paroxysmal depolarization shift" PDSs of groups of cells synchronize, producing 'interictal spikes'.

mechanisms of ca channel modulation in seizure medication: underlie bursting and intrinsic oscillations

T-type Ca channel In the thalamus, these channels are believed to be responsible for thalamo-cortical generalized absence seizures. They are inactivated at Em, and are released from inactivation by hyperpolarization. generate low threshold Ca-spikes when depolarized after being released from inactivation. These Ca spikes then trigger Na-mediated Action Potentials

Intrinsic Firing Properties of TC Neurons Located at Ventrobasal Complex

T-type Ca channel is a 'low voltage' channel current is thought to be the underlying mechanism responsible for the burst-firing among thalamocortical relay neurons knockouts for T-type channel fail to show burst

non-pharmacological interventions for seizures: resective surgery

The problem here is that only a subset of patients are appropriate candidates

Partial seizure events: reorganization in hippocampus after hippocampal sclerosis

The pyramidal cells of the hippocampus are susceptible to excitotoxicity. In response to loss of pyramidal cell targets, the axons of the dentate gyrus cells- the mossy fibers of the granule cells- sprout collaterals which project back onto the parent population

partial seizure events: reorganization in the hippocampus (dentate gyrus)

The pyramidal cells of the hippocampus are susceptible to excitotoxicity. In response to loss of pyramidal cell targets, the axons of the dentate gyrus cells- the mossy fibers of the granule cells- sprout collaterals which project back onto the parent population

synchronization results from

a breakdown in surround inhibition

electrophysiology of partial seizure

abnormal activity originating from a seizure focus, produces 'epileptiform' excitability Location determines symptoms. Motor cortex focus causes twitching/jerking of limb, other motor manifestation. Limbic system focus can produce unusual behaviors, altered consciousness

Seizures occur when the balance of excitation and inhibition is disrupted, which may occur through

abnormal membrane properties and/or through abnormal communication among neuronal populations

generalized seizures 6 types

absence myoclonic clonic tonic tonic/clonic atonic

inhibition of thalamic reticulat cells diminishes

absence seizures mechanisms of GABA modulation

focal seizure: A seizure pattern characterized by a prevalent excitatory network activation at onset (that is, hypersynchronous pattern in mesial temporal lobe epilepsy). In this pattern, synchronized principal neurons are

active and recruit other principal neurons and interneurons into a larger seizure network At the same time, extracellular space alterations can enhance neuronal excitability.

Large amplitude 8-10Hz activity develops over occipital region -known as

alpha rhythm of relaxed wakeful state

electrophysiology of partial seizure: limbic focus

an produce unusual behaviors, altered consciousness

dilantin and tegretol

anticonvulsants, reduces neuronal excitability by blocking voltage-gated Na+ channels, promoting Na+ efflux, reducing Na+ gradient, stabilizing AP threshold Acts in motor cortex to stop seizure progression

Examples of inherited ion-channel dysfunction associated with epilepsy: SCN1B

associated with "generalized epilepsy with febrile seizures +", the inward Na current fails to inactivate, allowing a prolonged Na current to keep the cell depolarized longer, which in turn results in multiple action potentails

generation of primary generalized seizures: Thalamic cells have a Calcium channel that is inactive

at resting membrane potential but is made available for activation by hyperpolarization, and becomes transiently active upon depolarization (T-channel) This works in a manner similar to the activation and inactivation of Na channels You have to hyperpolarize the Ca channel first to remove the inactivation, then depolarize to open the activation gate

PDS determined by Intrinsic Membrane Properties of Neurons: anticonvulsants

benzodiazepines dilantin tegretol

myoclonic seizure

brief, shock-like jerks of a muscle or a group of muscles

mechanisms of GABA modulation in seizure medication: mutation in gamma subunit

childhood epilepsy, GEFS+ type 3

12 yr old pt with typical absence seizure. Seizure shows sudden onset of synchronous spike (3/sec)and wave activity:

clinical manifestation was staring spell and eye blinks. Note the abrupt onset with no buildup prior to seizure, abrupt offset and return to normal patterns.

mechanisms of GABA modulation in seizure medication: benzodiazepines for absence

clonazepan by inhibiting reticular neurons in thalamus These in turn inhibit thalamic relay neurons, thereby releasing the T-type channels in the relay neurons from inactivation Inhibiting the reticular neurons keeps the T-type channels in an inactivated state.

Focal seizures include seizures that progress to bilateral

clonic seizures (formerly referred to as secondarily generalized tonic-clonic seizures).

EEG Bipolar montage

compares the response between two active electrodes

tonic

continuous tension or contraction

What causes breakdown of Inhibitory Surround?: chronic changes in

dendritic structure, receptor or channel density, local circuitry,... -APs from focus are projected to distal locations. These are sometimes projected back (back-propagation) to the focus -It remains poorly understood what initiates a seizure, and actually what brings it to a stop. After seizure there is a period of decreased electrical activity (postictal period), pt may be confused, drowsy

PDS determined by Intrinsice Membrane Properties of Neurons: depolarization phase

due largely to glutamate-mediated channels: AMPA & NMDA (NMDA important due to voltage-dependence, plus opens voltage-gated Ca2+ channels).

PDS determined by Intrinsic Membrane Properties of Neurons: afterhypolarization

due to combination of voltage-dependent calcium and potassium conductances, and GABAergic IPSPs (GABAA; chloride current, GABAB; potassium current) limits PDS, gradual loss is responsible for progression into clinical seizure.

Mechanisms of Na+ Channel Modulation in Seizure Medications: lamotrigine => blocks bursts

during depolarization CA1 neurons responding to Schaffer collateral stimulation. Note in 50 uM Lamotrigne, the repetitive burst of action potentials is blocked. Washing out the drug allowed for recovery of the burst response

Neuronal and thalamic relay neurons synchronize

during primary generalized seizure Depolarizations are by AMPA receptors and T-channel currents

EEG output compares the

electrical activity between electrode pairs

Hypothetical neocortical focus. Cell 'A' displaying PDS, activates cell 'B'. If enough cells synchronize

event is recorded on EEG. Activity in 'A' and 'B' also excite GABAergic inhibitory interneurons. Feedback inhibition reduces excitability in 'A' and 'B', as well as cells outside focus (cell 'C'), producing 'Inhibitory Surround

PDS determined by Intrinsic Membrane Properties of Neurons: cortical circuitry

feed-forward and feedback inhibitory pathways Normal pyramidal cell responds with ESPS/IPSP sequence. PDS is 'exaggeration' of this Many anticonvulsants work to enhance inhibition

Cortical pyramidal neurons activate the thalamic reticular neurons in a

feed-forward loop. Ascending noradrenergic, serotonergic, and dopaminergic inputs from brain-stem structures appear to modulate this circuit.

Tonic/clonic (grand mal) has abrupt onset

frequently with groan or cry from tonic contraction of diaphragm Pt falls, becomes rigid, clench jaw, lose bladder and bowel control, become cyanotic ... After 10-30 sec., tonic phase evolves into clonic jerking of extremities for 1 -2 min. This followed by postictal phase. most common generalized seizure

EEG monopolar montage

have active electrodes being compared to a single indifferent electrode (ground), typically attached to ear lobe

generation of primary generalized seizures: Animal models using weak GABA antagonists (penicillin)

have shown thalamic and cortical cells will synchronize through thalamocortical connections It is unclear which synchronizes first, but cortical cells will show rhythmic depolarizations which will begin to fire trains of APs.

non-pharmacological interventions for seizures: anti-seizure drug side effects

have unpleasant side effects, primarily sedation, dizziness, blurred vision, diplopia, tremor, depression, anxiety, impaired concentration, just to name a few. Suicide is significantly higher among the epileptic population. Compliance with a drug regime is a serious issue. Additionally, many epileptics do not respond to medication

mode of thalamocortical activation is controlled largely by input from the thalamic reticular neurons, which

hyperpolarize the relay neurons through g-aminobutyric acid type B (GABAB) receptors and are themselves inhibited by neighboring reticular neurons through activation of GABA type A (GABAA) receptors

mechanisms of GABA modulation in seizure medications: vigabtrin

inhibits GABAT, enhances GABA inhibition. Believed to act by resisting fading of GABAergic inhibition in the face of repeated stimulation

mechanisms of GABA modulation in seizure medications: tiagabine

inhibits GAT1 (GABA transporter), prevents reuptake

chronic long-term seizures are the result of an

injury or insult (such as trauma of an induced seizure) that reduces inhibition through loss of inhibitory cells, and increases excitation through co-lateral sprouting of the remaining excitatory cells loss of GABAergic interneurons, decreased inhibition

What causes breakdown of Inhibitory Surround? -most important factor is

loss of GABA-mediated inhibition GABAergic transmission is labile, eventually fails in face of intense challenge

mechanisms of GABA modulation in seizure medication: GABAa

ionotropic, open Cl- channels Blocking GABAa receptors pharmacologically, as with bicuculline, will induce seizures

generation of primary generalized seizures: are by AMPA receptors and T-channel currents and repolarization is

is by GABAergic inhibition, voltage and calcium dependent K conductance (gK).

mechanisms of GABA modulation in seizure medication: mutation in alpha subunit

juvenile monoclonic epilepsy

autosomal dominant partial epilepsy with auditroy features

leucine rich transmembrane protein channelopathy

mechanisms of GABA modulation in seizure medication: GABAb

metabotropic (GPCR)

Examples of inherited ion-channel dysfunction associated with epilepsy: KCNQ2 and Q3

mutations result in decreased K currents, which inhibit the cell's ability to reporalize after an action potential. This also prolongs the depolarization and permits the cell to fire multiple action potentails benign familial neonatal convulsions

autosomal dominant nocturnal frontal-lobe epilepsy

neuronal nicotinic acetylcholine receptor channelopathy

If focus is limited to @1000 neurons, there are

no clinical manifestations Such an event can be seen in EEG as 'interictal spikes

voltage-gated Na channels sense depolarization and reconfigure themselves from a

non-conducting to conducting state, allows Na to flow into the cell. thereafter, they are inactivated and the membrane must be repolarized before re-activation can occur.

Mechanisms of Na+ Channel Modulation in Seizure Medications: lamotrigine => voltage dependent inhibition

of Na current Whole-cell clamp experiments on Chinese Hamster cells expressing typeII Na channels. Currents were activated by step-depolarization to 0mV from a 30s conditioning pre-pulse at the indicated potentials

focal seizure: Seizure pattern characterized by a prevalent network involvement of γ-aminobutyric acid (GABA)-ergic interneurons at onset (that is, low-voltage fast activity pattern in temporal lobe epilepsy). The initial hyperactivation

of inhibitory interneurons and the associated extracellular space modifications recruit synchronous firing of principal neurons. Extracellular changes can contribute either to seizure maintenance and progression (increase in potassium levels, decrease in calcium levels and alterations in pH) or to seizure termination (increase in adenosine and ATP

pathways for seizure propagation: secondary generalization

of partial seizure activity spreads to subcortical centers via thalamic projections. Widespread thalamo-cortical interconnections bring rapid activation in both hemispheres

partial focal seizures

originate in small group of neurons (focus), symptoms depend on local of focus. Symptoms preceding partial seizures are known as 'Auras', such as experience of a smell, emotional state (e.g. fear or anxiety)...thought to originate as electrical discharges from focus

during development of focal seizure, the surround inhibition is

overcome, afterhyperpolarization gradually fades away, and seizure spreads from original location

complex partial seizures

partial seizure progressing to point of loss of consciousness

Focal seizures are divided into seizures with or without

preserved awareness. (previously 'simple partial seizures', and 'complex partial seizures'.

absence seizure

prototype of nonconvulsive generalized seizure 1. Typical: seen in children (petit mal), abrupt onset, last 3-10 sec., involves cessation of motor activity & loss of consciousness, pt does not fall or have tonic/clonic but may show eye blinking, lip smacking,... These seizure have distinct electroencephalogram pattern 2. Atypical

complex partial seizure evolving to secondarily generalized seizure

pt losses consciousness, usually falls, experiences rigid extension of extremities (tonic phase), followed by jerking of extremities (clonic phase) -formerly known as 'grand mal seizure

clonic

rapidly alternating contraction/relaxation (excitation/relaxation).

Mechanisms of Na+ Channel Modulation in Seizure Medications: lamotrigine => accumulation of block of Na current with

repetitive depolarization These responses are due to drug binding to and prolonging the inactivation conformation of the Na channel

clonic seizure

rhythmic jerking of arms & legs. Sometimes bilateral. Rare form of the disease

voltage gated Na channels are responsible for the

rising phase of action potentials

tonic/clonic seizure (grand mal) is difficult to distinguish from

secondary generalized tonic/clonic seizure with brief or unremarkable aura, but distinction important for treatment choice and discerning origin of seizure

pathways for seizure propagation: partial seizure

seizure activity spreads from focus to adjacent cortex, homotopic contralateral cortex, and subcortical centers.

partial seizure events:

seizure events occurring varying periods of time after the initial insult, from months to years The reviews noted that among the most common involve the mesial temporal lobe, which includes the hippocampus

If seizure activity is sufficiently intense, electrical activity spreads to other brain areas along same pathways as 'normal' cortical activity. As cortex and thalamus are intimately interconnected

seizures spread along thalamocortical connections. They can also cross to opposite cortex via corpus callosum. Once other hemisphere involved, seizure becomes "secondary" generalized, and pt will lose conciousness

As inhibition fails, neurons fire synchronously

sending trains of APs to distant neurons, spreading the seizure.

partial (focal) seizures 3 types

simple partial complex partial complex partial evolving to secondarily generslized

pathways for seizure propagation: primary seizure

such as typical absence seizure, diffuse interconnections between thalamus and cortex are primary route of seizure propagation.

atonic seizure

sudden lost of muscle tone or strength. Pt may drop objects, fall to ground, eyelids and head droop. Consciousness not lost.

EEG recording shows focal sharp waves in electrodes over right temporal areas

suggesting seizure focus located in right temporal lobe

generation of primary generalized seizures: Pyramidal cells in cortex reciprocally excite

thalamic relay neurons as well as reticular thalamic neurons Thalamic reticular neurons inhibit thalamic relay neurons

generation of primary generalized seizures:thought that GABAergic interneurons may inhibit

thalamic relay neurons, thus removing inactivation of the T-channel, leading to a oscillating depolarization

EEG Wakefulness

the cortex is activated by the thalamus in a tonic mode, allowing for processing of external sensory inputs desynchronized appearance of the EEG

EEG of non-REM sleep

the cortex is activated in a burst mode, resulting in the EEG appearance of rhythmic sleep spindles

EEG of absence seizure

the normal thalamocortical circuit becomes dysfunctional, allowing burst activation of the cortex to occur during wakefulness, which results in the EEG appearance of rhythmic spike-wave discharges and interrupts responsiveness to external stimuli 3-per second spike wave

generalized epilepsies have complex inheritance patterns, but there are a few channel mutations which are passed on in Mendelian fashion

these are called channelopathies 'Generalized epilepsy with febrile seizures plus' for example, produces febrile seizures, "plus" at least one other type of seizure (absence, myoclonic, ...).

generation of primary generalized seizures: depakote (valproic acid)

thought to block T channels

Thalamic relay neurons can activate the cortical pyramidal neurons in either a

tonic mode or a burst mode- burst mode is made possible by T-type calcium channels

sequence of neuronal network activity during ictogenesis of focal seizures. Interictal epileptiform spikes are characterized by

transient synchronous hyperexcitability of glutamatergic principal neurons, followed by recurrent interneuron activation.

mechanisms of ca channel modulation in seizure medication: ethosuximide

treats absence seizures by blocking T-type currents, no effect on HVA currents, not effective against other types of seizures

Timm's stain of dentate gyrus from temporal lobe epileptic patient

visualizes the axons of the dentate granule cells- the "Mossy Fibers". staining in supragranular layer of dentate reveals aberrant excitatory pathway has formed. Similar sprouting is seen in animals after drug-induced seizures or electrical stimulation of the hippocampus.

Mechanisms of Na+ Channel Modulation in Seizure Medications: lamotrigine

weak inhibition of Na current at resting Em, but shows stronger Na current inhibition after depolarization

hyperventilation and induction of absence seizure

will lower CO2 and elevate pH, having the effect of increasing neuronal excitability

simple partial seizures

without alteration or loss of consciousness, may involve localized motor movements (jerking), starting at one point and expanding (e.g. start with hand, expand to include arm)