General Flashcards
(139 cards)
1
Q
What is epilepsy?
A
tendency to have recurrent, unprovoked, seizures
– A seizure is an abnormal paroxysmal synchronous discharge of a very large number of cortical neurons, causing symptoms
2
Q
Epiepsy Epidemiology
A
- commonest “serious” neurological disease
- Prevalence ~0.6% of population (~400,00 people in UK) • Annual incidence ~0.07%
- Prevalence ~0.6% of population (~400,00 people in UK) • Annual incidence ~0.07%
- Most adults with epilepsy (~70%) become seizure-free on treatment • Many enter long-term remission – ie. for many, epilepsy is a transient condition • In addition to epilepsy, single seizures are quite frequent – lifetime prevalence of one or more seizures ~5% of population – Many of these single seizures are “acute symptomatic” seizures, not epilepsy
3
Q
Common causes
n.b 50% new-onset cases in adults are not explained
A
Common causes include:
– Tumours (especially indolent / “benign”)
– Brain malformations
– Consequences of previous neurological infection
Cerebrovascular disease
– In association with learning disability and autism
4
Q
Risk Factors
A
– Known neurological disease, cerebrovascular disease risk factors, family history, childhood febrile convulsions, previous head injury, substance misuse, abnormal neurological development
5
Q
Useful indicators that Epilepsy IS the cause of LoC (loss of consciousness)
A
– Abrupt onset
– Short event ~1min
– Confused and drowsy after, several hours to fully recover
– Attacks are stereotyped (= extremely similar every time) – Specific recognisable features of certain seizure types
6
Q
Useful indicators that epilepsy is NOT the cause of LoC
A
– Gradual onset of pre-syncopal symptoms (likely neurocardiogenic syncope)
– Cardiac risk factors, palpitations, chest pain, pallor & sweating, association with exercise (likely cardiac syncope)
– Prolonged episode, other psychogenic or somatic symptoms, variable features, tends to “wax and wane” (likely dissociative convulsions)
7
Q
Seizure types
A
- Focal seizures
- Generalised seizures
- Status epilepticus
8
Q
Focal seizures
A
Seizures arise from many focal brain regions,
give rise to many different patterns
9
Q
Generalised seizures
A
Seizures may also arise in widespread bilateral brain networks,
giving rise to several different patterns
10
Q
Status Epilepticus
n.b. rare phenomenon
A
Seizures are usually brief, discrete self-limiting episodes, but sometimes may continue for hours or even days
11
Q
Generalised seizure types
A
Tonic–clonic (in any combination) Absence Typical Atypical Absence with special features Myoclonic absence Eyelid myoclonia Myoclonic Myoclonic Myoclonic atonic Myoclonic tonic Clonic Tonic Atonic
12
Q
Focal Seizure types
A
-
Simple partial seizure
- no impairment of consciousness/awareness
-
Complex Partial seizure
- has impairment of consciousness/awareness
-
Bilateral convulsive seizure
- Involves tonic, clonic or tonic & clonic components
13
Q
General principles of Management of Epilepsy
A
Be sure of the diagnosis – Clinical diagnosis supported by investigations
- Give clear and comprehensive advice and information
- Involve patient in decisions about treatment
- Treat with one antiepileptic drug, at therapeutic dose, without causing side-effects
- If first treatment fails, swap to a different drug
- Seek specialist advice if:
– Successive drugs fail to stop seizures
– Cognitive decline, neurological signs, child, psychiatric comorbidity
14
Q
Antiepileptic drugs
Info
A
- Are teratogenic - have harmful effects of development of embryo/foetus
- Often have complex interactions with other drugs
- Occasionally need blood monitoring
- Frequently cause side-effects
- Should always be commenced by a specialist
15
Q
What is medicalisation?
A
When a problem of everyday living gets taken over by medicine
• In the past doctors did the medicalising • Now, increasingly, it is the patients
16
Q
Epilepsy regulations driving
A
Group 2
During the 10 year period immediately preceding the date when the license is granted the applicant/holder should:
- be free from any epileptic attac
AND
- have not taken medication to treat epilepsy
17
Q
Excitatory Transmitters
A
- Glutamate
- Aspartate - Amino acid
18
Q
Glutamate
Many functions in the brain rely on activity of Glutamate NT
A
- major FAST excitatory transmitter in CNS
- Mediates most of fast excitatory neurotransmission
- – ~70 of CNS synapses - glutamatergic
- Principle mediator of sensory information, motor coordination, emotions, cognition (including memory)
- Acts on specific receptors
- – Ionotropic receptors (ion channels)
- – Metabotropic receptors (G protein coupled receptors) receptors (G protein coupled receptors)
19
Q
Aspartate
A
– mediates transmission at a small number of central sypnapses
20
Q
Synthesis
Glutamate & aspartate
A
- Non-essential amino acids essential amino acids
- Do not cross blood-brain barrier not supplied by circulation
- Synthesized in brain from metabolism of glucose
- Also from glutamine synthesized by astrocytes
21
Q
degradation
Glutamate
A
Released glutamate taken up primarily by ASTROCYTES
- Converted into glutamine by glutamine synthase
- Glutamine transported out of astrocytes
- Glutamine uptake by neurons (transporter)
- Converted back to glutamate by the enzyme, glutaminase
22
Q
What converta GABA to Succinic semialdehyde?
A
GABA transaminase
23
Q
what changes glutamate into GABA?
A
GAD- Glutamate decarboxylase
24
Q
Storage of Glutamate
A
- Synaptic vesicles actively accumulate glutamate
- Driven by electrical gradient created by different concentrations of H + across vesicle membrane (i.e. inside vesicle and in cytoplasm)
- Vesicle positive potential with respect to cytoplasm
- Electrical potential gradient generated by vesicle ATP proton (H +) pump
- Driven by electrical gradient created by different concentrations of H + across vesicle membrane (i.e. inside vesicle and in cytoplasm)
- Vesicle transporters highly selective (glutamate >> aspartate) –
- VGluT1-3 (vesicular glutamate transporters) glutamate inflow – driven by electrical gradient and H + 3 glutamate inflow driven by electrical gradient and H outflow
- – K m for glutamate ~1mM
25
Vesicular conc \>20mM
1,000 – 2,000 molecules per vesicle
26
Release of Glutamate
* Action potential in pre-synaptic neuron
* Depolarizes the pre-synaptic terminal synaptic terminal
* Depolarization opens voltage gated calcium channels
* Calcium flows into terminal
* High local concentration of intracellular Ca +
* Triggers exocytosis of synaptic vesicle contents
* Glutamate diffuses across synaptic cleft
* Interacts with specific receptors Multiple receptor types
* Multiple receptor types
27
Reuptake of Glutamate (and Aspartate)
* Excitatory Amino Acid Transporters (EAATs)
* Reduces the extracellular concentration
* Terminates transmitter
28
WHat leads to termination of transmitter action?
Diffusion and Active uptake of the NT
29
Uptake of glutamate terminates synaptic transmission
N.B some glutamate may diffuse to act at adjacent synapses
* Km for glutamate ~low micromolar
* – Keeps extracellular concentration low
* ~15,000 – 20,000 transporters per synaptic bouton
* – Effective uptake process
Glutamate transporters drive uptake through
* Co-transport of (2-3) Na + and H + into the cell
* Counter-transport of K +
Most transporters located on
* Glial cells (astrocytes)
* Post-synaptic neurons (lesser extent)
30
What are the two large families of GLutamae receptors?
* Ionotrophic receptors - ion channels
* Metabotrophic receptors
31
Ionotropic receptors
ion channels general info
* Binding site located on channel
* Agonist binding promotes channel opening
* Role in fast synaptic transmission
32
Ionotrophic receptors
ion channels
3 different types?
3 classes:
* **NMDA** (N-methyl-D-aspartate) receptors
* **AMPA** ( alpha-amino-3-hydroxy-5-methly-4-ilsoxazole propionic acid) receptors
* **Kainate receptors** (kainate found in some seaweeds) • Names based on ability of these drugs to selectively activate channels
***Glutamate is the natural transmitter at all receptors***
33
**_Metabotropic receptors_**
* G protein coupled receptors
* Modulatory effects on neuronal function and synaptic transmission
* i.e no/freq of AP's etc
34
Locations in brain of ionotrophic glut receptors
* AMPA & NMDA receptors often co-localise at functional excitatory synapses
* Ratios at individual synapses varies greatly
* Some can contain only one sub-type
• Only small number of kainate receptors in most CNS regions
35
Structure of ionotropic glutamate receptors
* Each subunit has 3 transmembrane spanning domains
* Large extracellular N-terminus
* Receptors made up of 4 subunits
36
What is responsible for fast exictatory transmission?
Activation of AMPA & NMDA receptors responsible for fast excitatory synaptic transmission
37
AMPA receptors
Fast synaptic current
Fast decay due to relatively low affinity (K d ~200nM)
38
NMDA receptors
* Slower onset
* Slower decay (up to several hundred msecs)
* Higher affinity glutamate binding
* ( Kd~ 5nM)
39
What explains the differences in decay speed between AMDA and NMDA receptors?
Affinity difference
40
AMPA receptors
general structure info
* Assembled from GluA1-4
* – Tetramers
* Fast synaptic current
* All permeable to Na+ & K+ (some also Ca2+- permeable)
* Depolarizes towards reversal potential, ~0mV
* Activation depolarizes neuron
41
NMDA receptor 1
* NMDA receptors are permeable to Na+, K+ and Ca2+
* – Ca2+ influx can also activate 2nd messenger systems and Ca-dependent dependent enzymes
* Slower action of NMDA receptors
* Provides mechanism for spatial & temporal summation
* Also voltage sensitive
* At membrane potentials \<-50mV blocked by Mg2+ in extracellular fluid
* So blocked at potentials near resting potential (~-70mV)
* Like a ‘plug in a plug-hole’
42
NMDA receptor 2
* NMDA receptors act as ‘co-incidence’ detectors (i.e. several inputs)
* Needs repetitive or multiple excitatory inputs from other, AMPA, receptors - depolarize the neuron and relieve the Mg2+ block
* Act to sense activity of many independent synaptic inputs on same neuron
43
Structure of NMDA receptor
* Tetramers
* 2 GluN1 subunits plus 2 GluN2 subunits
* To function NMDA receptor require:
* Glutamate binds to the GluN2 subunit
* Binding of glycine ( or D Binding of glycine ( or D -serine) to a site on GluN1 serine) to a site on GluN1
* – (not to be confused with inhibitory glycine receptors)
* Glycine concentration in brain saturating for some sub-types
* Potential site for drugs to act : drugs that prevent glycine binding will inhibit NMDA receptors
44
NMDA channel blocking drugs
Phencyclidine, Ketamine, Dextromethrophan
**Uses:**
***Dextromethorphan***: cough suppressant g
***Ketamine***: anaesthetic/analgesic - pediatric anaesthesia, emergency surgery, (usually with sedative drug e g Diazepam) e.g. Diazepam). Suppresses breathing Suppresses breathing less than most other anaesthetics and increases cardiac output.
45
Metabotropic Glutamate receptors
8 receptors known – mGluR1 - 8
7 transmembrane G-protein coupled receptors
Not formed of subunits – **One molecule = one receptor**
• Located in different regions of CNS
– Pre -synaptic – Post-synaptic
• Grouped into 3 groups according to:
– Amino acid sequence homology – Agonist pharmacology – Signal transduction pathways – Group I, II & III
46
Metabotrophic Glutamate receptors
Group I : mGluR1&5
* increases intracel. Ca2+ conc
* leads to protein phosphoryl
Group II: mGluR2 & 3
Group III: mGluR4,6-8
* group II and III inhibit adenylate cyclase - decrease cAMP levels and modifiy ion channel activity
47
**Pre-synaptic effects of mGLuRs**
* Inhibit voltage gated Ca channels – reduce transmitter release
* Primarily group II & III receptors
* Glutamatergic terminals (inhibitory autoreceptors)
* Terminals that release other transmitters
48
***_Post-synaptic effects of mGluRs_***
- variable
* Inhibit some K + channels -increase excitability
* Increase activity of some K+ channels – decrease excitability
* Effects depend on cell type involved
49
Calcium influx and Excitotoxicity
* Many ionotropic glutamate receptors are permeable calcium
* – Greatly increased glutamate release seen with a seizure or in ischaemia/reperfusion with e.g. stroke
* – Intense receptor activity
* Large Ca2+ influx
* – Overwhelms normal Ca2+ buffering & sequestration into intracellular organelles
* Increased intracellular Ca2+ concentration
* Normally used as a signalling pathway e.g. activate some enzymes
* Protein kinase C, Phospholipase C –
* BUT large Ca2+ increase
* • Activates Ca2+-dependent enzymes that cleave proteins (proteases; e.g. Calpain which activates Caspases leading to Apoptosis)
* Generates damaging molecules – Lysophospholipids compromise membrane integrity – Oxidative stress (free radicals)
* Leads to cell death
50
GABA - major inhibitory NT in the brain
* GABA: gamma-amino butyric acid
* GABA occurs in brain tissues but not in other mammalian tissues at significant concentrations
* GABA functions as major inhibitory transmitter in many CNS pathways – Functions throughout brain
* Transmitter at ~30% of all synapses in CNS
51
How is GABA formed and destroyed?
* GABA formed from glutamate by action of enzyme
* Glutamic acid decarboxylase (GAD)
* Enzyme found only in GABA-synthesizing neurons (hence not in astrocytes etc)
* GABA destroyed by GABA Transaminase within cells
52
WHat is Vigabatrin?
* – synthetic analogue of GABA
* Inhibits GABA Transaminase by irreversible covalent binding
* hence Long lasting effect despite short plasma half-life
* Increases GABA concentration in brain
* Effective in epileptic patients (resistant to other drugs)
* Generally well tolerated and relatively free from side effects
* **• Main drawback – depression and occasional psychotic episodes in minority of patients minority of patients**
* Absence seizures are paradoxically often exacerbated by drugs that enhance GABA activity
* Better treated by drugs acting by different mechanisms
53
GABA storage and uptake
* Vesicular packaging via a transporter
* Like glutamate transporter dependent on electrical potential across vesicle membrane
* Potential generated by ATP-dependent proton pump
* Released GABA taken up by transporters
* Uses energy from Na + gradient to drive uptake (co-transport)
* In pre-synaptic neurons : reutilized
* In post-synaptic neurons & glia
* **Tiagabine – inhibits GABA uptake and increases GABA concentration**
54
Types of GABA receptors
• Two main functional groups •
* **Ionotropic GABAA receptors**
* post-synaptic
* Site of action of benzodiapepine drugs
* **Metabotropic GABAB receptors**
* pre- & post-synaptic
* G protein coupled receptors
GABA receptors identified in all regions of the brain
55
GABAA RECPTORS
Donut structure
* Ionotropic GABAA receptors – post-synaptic
* Each receptor made up of 5 subunits
* Composition is 2alpha 2beta 1gamma
* Each subunits has 4 transmembrane spaning domains
* GABA binding sites (2) at interface of alpha & beta subunits
* **GABAA receptors - Cl- selective ion channels that mediate fast inhibition**
* Hyperpolarize neuron or ‘clamp’ voltage near resting potential
* Inhibit depolarization responses to excitatory inputs
56
GABA a receptor pharmacol
**Agonists**
## Footnote
• Muscimol from hallucinogenic mushrooms from hallucinogenic mushrooms
**Antagonists**
* Convulsant alkaloid *bicuculline* inhibits GABA receptors by binding to the GABA binding site
* Another convulsant - *picrotoxin* - blocks the chloride channel
**Modulatory drugs**
• Benzodiazepines • Barbiturates • Neurosteroids (e.g. pregnenelone, alphaxolone) • Ethanol • Anaesthetics
57
GABA a Benzodiazepines
– Selectively potentiate GABA effects on GABAA receptors receptors
– Bind to an accessory site – not the GABA binding site
* Located at a site of alpha subunit interaction with gamma subunit
* Facilitates binding of GABA by allosteric action
* Enhances effect of GABA
* Increase probability of channels opening – no effect on channel conductance or open time – **Agonists**
* Diazepam – long lasting as metabolized to active metabolite long lasting as metabolized to active metabolite
* Clonazepam – long lasting parent compound
* Lorazepam, Temazepam – short lasting, no active metabolite
**Antagonist**
* Flumazenil – can act as a convulsant
* Used as antidote for benzodiazepine overdoses
58
Effects of Benzo drugs
* anxiolytic
* sedative
* reduction of muscle tone
* anticonvulsant
* amnesia
59
Benzo side effects
* Drowsiness
* Confusion
* Amnesia
* Impaired coordination
* High degree of tolerance and dependence
60
Benzo
acute toxicity and withdrawal symptoms
**Acute toxicity**
– Overdose less dangerous than other anxiolytic/hypnotic drugs – Prolonged sleep without depressing respiration/cardiovascular function – With alcohol – respiratory depression
* Treated with antagonist *Flumazenil*
* **Withdrawal symptoms**
– Anxiety, increase in irritability and aggression – Tremor and dizziness
61
GABA a - BARBITURATES
Barbiturates discovered in the early 20th century
• Bind to GABAA recep p tor at different site to benzodiazepines
– Potentiate GABA effect
* Less specific receptor activity than Benzodiazepines
* Widely used as sedatives until 1960/70s
62
Barbiturates
Overdose
Overdose
death from respiratory and cardiovascular depression
– Sedative effects, impaired cognition and motor coordination
– High degree of tolerance and dependence
– Strongly induce hepatic cytochrome P450 enzyme
* Enzymes that break down many drugs
* Drug-drug interactions – therefore rarely used
63
Pentobarbitol and Thiopental
**Phentobarbitol:**
* occasionally used for sleeping pills and as an anxiolytic but less safe than benzodiazepines
* still used for anticonvulsant activity/status epilepticus (i.v) •
* **Thiopental** – used as an intravenous anaesthetic
64
How were GABA b receptors intially found?
Insensitivity to Bicuculine
65
Info GABA b receptors
**• Metabotropic G protein coupled receptor – 7TM**
Coupled to Gi – inhibit adenylate cyclase
Coupled to ion channels via beta/gammasubunits
**• 2 major sub-types**
– GABAB R1 – required for functional receptors
– GABAB R2 – not activated by GABA
– Form heterodimers
**Activation of GABAB receptors leads to long-lasting inhibition**
− Pre-synaptic (typically 1a isoform)
− Post-synaptic (typically 1b isoform)
66
GABA b Pre-synaptic inhibition
1a isoform
* – Inhibition of voltage-gated Ca2+ by beta/gamma subunits subunits
* – beta/gamma subunits also directly inhibit synaptic vesicle release
* decrease transmitter release
* Occurs on glutamate, GABA and other transmitter containing pre-synaptic terminals
67
GABA b recept Post-synaptic inhib
– Increased opening of K Increased opening of K+ channels channels by beta/gamma subunits subunits
* reduced firing of post-synaptic neuron
– Inhibition of adenylyl cyclase reduces cAMP levels and PKA activity
* ** reduced phosphorylation of other proteins including other ion channels**
68
Pharmacology of GABA b Receptors
• Muscle relaxant Baclofen is a potent agonist at GABA B receptors
– Reduces spasticity and spasm in MS and spinal cord injury patients
– Side effects: include drowsiness, dizziness, nausea, confusion
– Sudden withdrawal may cause hallucinations, psychosis, visual disturbances, and seizures disturbances, and seizures
• Saclofen, phaclofen and SCH-50911 are selective GABA B antagonists
– No therapeutic use but experimental laboratory tool compounds
* GABA metabolite gamma-hydroxybutyrate (GHB) may be a second endogenous agonist of GABAB Rs,.
* GHB –
* Marketed for the treatment of narcolepsy – Widely abused as a recreational drug.
* – Increase in endogenous concentrations of GHB to levels high enough to activate GABA BRs seen with Succinic semialdehyde dehydrogenase deficiency – Unknown whether, under non-pathological conditions, endogenous concentrations of GHB are sufficiently high to activate GABA BRs
69
Glycine -
2nd major inhib transmitter
MAJOR INHIB TRANSM IN CNA
* Especially in spinal cord and brainstem
* Critical for regulation of motoneurons
* Functions in retina, auditory system, sensory systems
* Serine -\> Glycine via *Serine hydroxymethyl transferase enzyme*
* Small pool of glycine packaged into synaptic vesicles
* – H +-dependent vesicular inhibitory amino acid transporter (VIAAT)
•Released glycine taken up by transporters (GLYT1 & GLYT2)
* Astrocytes – terminates transmitter action
* Pre -synaptic neurons synaptic neurons – replenishes pre -synaptic pool
* Driven by Na + & Cl- gradients
70
Glycine degradation
Degradation in body via enzymes in ‘glycine cleavage system’
* Highest concentrations in liver and brain – mitochonrial location –
* Defect -\>group of metabolic disorders – nonketotic hyperglycinemias
* High concentration of glycine in CSF & plasma
* Neurological defects – lethargy, hypotonia, myoclonus, seizures
71
Glycine receptors
* Like GABAA receptors – pentameric (5 subunits)
* Four types of alpha subunits; one type of beta subunit known
* Composed of alpha(3) & beta(2) subunits
Each 4 transmembrane spanning domains
* Strychnine (antagonist) and glycine (agonist) bind to alpha sub unit
* Picrotoxin – non-competitive inhibitors at glycine receptor alpha subunit
* Also binding pg sites for other compounds e.g. Antihelminthic drug, Invermectin
* Ion channels permeable to Cl-
– *Activation generates a hyperpolarizing ipsp*
• No therapeutic drugs act specifically on glycine receptors
72
Glycine receptors 2
mutations
• Mutation in human glycine receptor –
leads to Hyperekplexia
* – Increased muscle tone, increased startle reflex
* – Variable incidence of apnoea, intellectual disability and delays in speech acquisition
* – Classic startle response is characterized by forceful closure of eyes, rising of bent arms over the head and flexion of the neck, trunk, elbows, hips and knees
– Rare dominant mutations - single amino acid mutations in alpha1 subunit
* One mutation leads to 100-fold decrease in glycine affinity & greatly reduced glycine sensitivity
* Others reduce glycine receptor channel function (↓chloride flux)
73
What is Epilepsy
**Epilepsy:** A disorder of the CNS characterized by , recurrent, sudden large increases in electrical activity (electrical seizures) that may be localized or generalized.
74
What do symptoms depend on?
symptoms (i.e. the presentation of epilepsy) will depend on:
* The CNS region(s) in which the electrical seizure occurs. • Whether the seizure is localized or general. Whether the seizure is localized or general.
* If localized initially, whether the seizure then spreads to other regions of the CNS.
75
Partial seizure
| (localized, focal)
Seizure is restricted to a limited region
**Simple** if subject remains *conscious and aware*
**Complex** if *consciousness is impaired*
76
Primary Generalized
Most of the CNS is involved, but no focus can be distinguished
77
Secondary generalized
most of the CNS is involved eventually but the exictation has spread from an intial focus
78
What are seizures preceded by frequently?
AN aura,
feeling/experience that warns the subject of an impending seizure
79
Absence seizure (old name: petit mal).
* primarily generalized seizure
* common in children
* Characterized by sudden loss of awareness lasting up to about 30 sec.
80
Tonic-clonic seizure (old name: grand mal).
* generalized seizure
* lasting 2 - 5 minutes
* characterized by sudden stiffening ('tonic') of muscles, a fall, followed by jerking ('clonic') movements
81
***_Simple partial seizure (_******_old name of this example: Jacksonian)_***.
* example would be a focal cortical seizure
* characterized by jerking movements that begin in the extremities and spread throughout the body (Jacksonian march)
* May be sensory symptoms rather than motor (Jacksonian march).
82
***_Temporal lobe epilepsy (also known as psychomotor epilepsy)._***
partial seizure of the temporal lobe that may be a:
* *simple partial seizure* characterized by emotional sensory or memory-related phenomena ***OR***
* *complex partial seizure* where the seizure spreads throughout the temporal lobe impairing consciousness and may be secondarily generalized to provoke a tonic-clonic seizure.
* ***commonest form of epilpesy***
83
Status epilepticus
when the seizure doesn't stop but continues or repeats for a period of 30 min or more the condition is termed status epilepticus
is life threatening.
84
idiopathic epilepsy
unknown cause
85
Cryptogenic
Cause can't be proven
86
what percentage of cases are symptomatic?
30%
i.e. occur following head injury, stroke, infection, tumour, drug abuse etc
87
Benign febrile epilepsy
linked to mutations in KCNQ2 and KCNQ3:
genes that encode voltage-gated potassium channels.
88
Family generalised epilepsy with febrile seizure plus
linked to mutations in SCN1B, a gene that encodes an accessory subunit of the voltage-gated sodium channel.
89
Drug induced seizures
many drugs have pro-convulsant effects
90
Cellular event that causes a focal seizure?
Paroxysmal depolarizing shift (PDS)
91
Paroxysmal depolarising shift (PDS)
rise (depolarizing phase) of the cellular PDS depends on activation of ionotropic glu receptors (AMPA and NMDA), and opening of voltage- -40 mV ) pg g gated Ca2+ channels.
Curtailment of the PDS and repolarization depends on opening of voltage-gated K+ on opening of voltage gated K channels and activation of ionotropic GABA receptors.
92
Spread of seizures
Without surround inhibition:
diverging synaptic connections of neurones in a relay nucleus can lead to spreading as well as blending of information flowing out of the nucleus
With surround inhibition:
"surround inhibition" mediated by interneurons through feedback pathways has the effect of limiting spead of the input signal i.e. has a focusing effect
93
Surround inhibition effect
**surround inhibition will localize discharges (e.g. due to PDS) and prevent their spread** *but reduction or loss of surround inhibition will allow spread of excitation.*
94
What may absent seizures be a result of?
may be due to dysfunction in thalamocortical networks that control sleep/wake cycles
95
Drug Rx for:
## Footnote
**Tonic-clonic; partial; temporal lobe seizures**
* Benzodiazepines (e.g. diazepam, clonazepam)
* Barbiturates (phenobarbitone)
* Vigabatrin
* Tiagabin
96
What drugs are Contraindicated for Absence seizures?
Vigabatrin
Tiagabin
Makes them worse
97
**For tonic-clonic, partial, temporal lobe seizures – may provoke absences**
Use dependent block of voltage gated sodium channels:
Carbamazepine, phenytoin, lacosamide:
* These drugs will reduce the likelihood of action potentials firing at high frequencies but have relatively little effect at low frequencies.
* Their binding (and hence blocking action) to the voltage-gated sodium channels is state-dependent
98
Drugs for treating absence seizures only:
**Ethosuximide:** Mechanism uncertain.
Thought to work by blocking T-type volta gegated Ca2+ g channels in thalamic neurons. These channels are important for the generation of rhythmic activity in the neurons.
*Not useful for tonic-clonic seizures*
99
Drugs useful for both tonic-clonic and absence seizures:
* **Lamotrigine:**
* Use-dependent blocker of sodium channels.
* **Sodium valproate:**
* Mechanism uncertain. Combines a weak blocking action on voltage-gated sodium channels with a weak inhibition of GABA transaminase
100
Other drugs: for epilepsy
* **Gabapentin, pregabalin:**
* Mechanism is uncertain but the molecular tar get is known to be the 2 -subunit of voltage-gated Ca2+ channels so they probably work by compromising neurotransmitter release. R i bi (E bi i USA)
* **Retigabine** (Ezogabine in USA): Acts by provoking the opening of K + channels of the KCNQ type so the anticonvulsant effect is probably due to stabilization of the resting membrane potential of neurones.
* **Perampanel** (approved in EU and in USA for partial seizures in persons \>12 yo) felbamate: persons \>12 yo), felbamate: Thought to act as antagonists of AMPA receptors (ionotropic glutamate receptors).
* **Levetiracetam**, binds to a synaptic vesicle protein called SV2A so it may affect neurotransmission – briveracetam in phase III trials.
* **Topiramate, zonisamide**: Mechanism(s) uncertain.
101
What drug to give? Epilepsy
* Many drugs are useful given alone (monotherapy e.g. carbamazepine, phenobarbitone, ethosuximide, sodium valproate, topiramate)
* others are recommended for adjunctive therapy (e.g. tiagabine, vigabatrine, gabapentin, retigabine).
* Drugs that are useful for tonic clonic seizures are not always useful for absence seizures and may even make them worse (carbamazepine, phenobarbitone, phenytion).
* Conversely, ethosuximide is useful for absence seizures but is not effective for ethosuximide is useful for absence seizures but is not effective for tonic-clonic seizures.
* Sodium valproate and lamotrigine are potentially useful for both classes of seizure.
102
Other Treatments ketogenic diet
Argued that a high fat, low carbohydrate diet (normal protein) is beneficial for the control of epileptic seizures in children (at least)
Sometimes used when conventional therapy is not sufficiently effective.
103
Other Rx Vagal Stimulation
surgically implanted device stimulates the vagus nerve by applying regular electrical stimuli.
The device can also be activated by a magnet to deliver a predefined program of stimuli to abort an ongoing or impending attack.
The device is effective but the mechanism by which it works is not known.
104
Other Rx Surgery
Removal of tissue that harbours a recurrent focus or to limit spread of excitation.
105
Stigma
defn + types of characteristics that may attract a stigma
A condition, attribute or trait that sets the possessor apart and marks the individual as unacceptable or inferior.
Types of characteristics that may attract a stigma:
a) Membership of certain religious, racial or ethnic groups.
b) Behaviour regarded as morally unacceptable.
c) Medical conditions viewed as unacceptable. How regarded depends on prevailing social values.
106
Felt stigma vs Enacted Stigma
‘***_Felt stigma’ (shame & fear of enacted stigma)_***
Perceived lack of acceptability and worry how others will react to you.
***_‘Enacted stigma’_***
Experience of discrimination, avoidance & exclusion (interpersonal, work, psychosocial impacts).
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WHat do risks of enacted stigma depend upon?
depend on whether condition
is: Discreditable or Discrediting
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Psych effects of stigma
Low self-esteem
High levels of anxiety & depression
Feelings of isolation & marginalisation
Negative social impacts influenced by:
severity of condition, effectiveness of treatment personality family and community support
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What is stigma a power tool of?
***_powerful tool of social control._***
Defines boundaries of acceptable behaviour & consequences of of non-conformity through negative labelling & social rejection
e.g. homosexuals, injecting drug users, sex workers, alcoholics , suicides
Label as ‘outsiders’ Marks boundaries (acceptable/not acceptable)
**Stigmatization is the enforcement mechanism behind social norms**
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Types of Genetic disease
**• Autosomal Dominant** - disease expressed in heterozygote, *only need error in 1 gene*
* **Autosomal Recessive** - disease expressed in homozygote, heterozygote is a carrier, *need both genes for expression of the trait/disease*
* **Dominant negative** - mutant protein disrupts the function of normal protein, *abnormal disrupts activity of normal one*
* **Haploinsuffiency** - both genes required for full function, *both genes together are not producing the required amount of protein etc*
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***_Hyperekplexia (Startle disease or Stiff Baby Syndrome)_***
Symptoms:
* • muscle spasm in response to unexpected stimuli
* • become rigid & fall over
* • increased muscle tone as infant (hypertonia)
* Autosomal dominant
* Genetic linkage chromosome 5q32
* same place as the gene for the glycine receptor
* point mutation R271Q in GLRA1
result:
reduced glycinergic inhibition in the spinal cord
1) exaggerated reflexes 2) hypertonia 3) exaggerated startle response
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**_Familial Erythromelalgia (Weir Mitchell’s disease)_** •
Symptoms:
* Burning pain in extremities in response to warm stimuli or moderate exercise
* Autosomal dominant
* Linkage 2q31-32 • Gene SCN9A
* Point mutation
* F1449V (phenylalanine at 1449 to valine)
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***_Generalised Epilepsy with Febrile Seizures (GEFS)_***
Symptoms:
* convulsions • fever • 3% children under six
* proportion go on to get generalised epilepsy in later life
* Autosomal dominant
* Linkage chromosome 19q13.1
* Same place as SCN1B
* point mutation C121W
SCN1B - sodium channel beta 1 subunit gene
C121W - cysteine at 121 mutated to tryptophan
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What happens with mutated B subunits of voltage gated Na channels?
with mutated beta subunits, inactivation takes much longer and the cell depolarises more.
na current activates v quickly and switche soff v quickly
mutation is in the disulphide bond of the beta chain, makes it unable to form the disulphide bond
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***_Benign Familial Neonatal Seizures (BFNS)_*** •
Recurrent seizures in early life • Starts within first three days • Resolves spontaneously within 3 months • Increased risk of epilepsy in 10-15% of individuals in later life
Linkage 20q13.3 • Same place as KCNQ2 • Frameshift mutation • 300 amino acid deletion • Non-functional potassium channel from one allele • Haploinsufficiency leads to Hyperexcitability
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General anaesthesia
reversible drug-induced loss of consciousness that facilitates surgical procedures that consciousness that facilitates surgical procedures that would otherwise cause pain and distress.
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Inhalational G.A's
Sevoflurane (volatile liquid)
Isoflurane (volatile liquid)
Nitrous oxide (gas)
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Intravenous G.A
Propofol - most commonly use
etomiade
thiopental sodium (rarely used)
ketamine (rarely used -paeds)
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What will an ideal general anaesthetic drug have?
• Analgesia • Suppression of nocifensive reflexes and stress responses stress responses • Immobility • Amnesia
and will have:
• A rapid onset of action • A rapid recovery • Minimal after effects • Minimal drug interactions • Minimal side-effects
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What are the stages of anaesthesia?
* Stage 1: Analgesia.
* Stage 2: Disinhibited responses (delirium).
* Stage 3: Surgical anaesthesia, this stage is divided into 4 ‘planes’.
* Stage 4: overdose, medullary depression, eventually respiratory depression, eventually respiratory and circulatory failure.
Patients may pass through the Patients may pass through the ‘stages’ at different rates depending on the agent used, the dose and the route of administration route of administration
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what state does surgical anaesthetic resemble?
Non-REM sleep states
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What happens to EEG amplitude during G.A?
Increasing depth of anesthesia induces progressive changes progressive changes in the EEG :
* Mean EEG amplitude increases initially in stage 2 and early stage 3 and early stage 3
* then decreases (depicted by black area) through stage 3 into stage 4
* Mean frequency gradually decreases with increasing depth of anesthesia resembling sleep states in stage 3 and progressing to an EEG that resembles coma in stage 4
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what regions are affected most by G.A?
cortical regions and thalamus
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What is GA associated with in the cerebral cortex?
inhibition of activity in the cerebral cortex , especially in regions of parietal and occipital cortex.
Cortical inhibition during anesthesia is partly a direct effect but is also secondary to inhibition (hyperpolarization) of thalamic neurons
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What does reduced thalamic activity do?
Reduced thalamic activity turns off a thalamic arousal mechanism leading to reduced thalamocortical activity and activity and together with reduced corticothalamic feedback this slows and synchronizes thalamocortical activity leading to a sleep-like state where the cortex is isolated from sensory input isolated from sensory input.
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what happens to the arousal nuclei?
Activity originating in ‘arousal’ nuclei e.g. from the reticular activating system in the brainstem that would normally excite thalamic relay neurons is also suppressed
Thalamocortical arousal is reinforced by corticothalamic thalamus positive feedback to maintain wakeful states. GA inhibits this.
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Molecular Targets for general anaesthetics:
1 . Enhancement/activation o f GABA A receptor activity.
* **enhance the activity of GABA at GABA A ionotropic receptors and can directly activate the Cl- channel of the receptor at high concentrations.**
subunit composition of the GABAA receptor can affect the selectivity of individual agents.
This is an especially important mechanism for causing loss of consciousness and for deactivating the thalamic ‘switch‘ to isolate the cortex from sensory input.
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what reduced the efficacy of most GA's?
What do drugs do to the CNS?
introduction of specific point mutations into GABA subunits can reduce the efficacy of most general anaesthetics.
drugs increase inhibition in the CNS
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Molecular Targets for general anaesthetics:
2. Antagonism / block of NMDA receptor activity.
Some general anaesthetics decrease the activity of NMDA receptors (ionotropic glutamate receptors).
NMDA- main types of ionotropic glutamate receptors involved in glutamate receptors involved in excitatory synaptic transmission. Block of NMDA receptors causes a profound analgesia and a dissociative anaesthesia (i.e. stupor – not loss of consciousness)
evidence that anaesthetics work at the glycine glycine binding site of the NMDA receptor (as well as its role as an inhibitory neurotransmitter in its own right glycine is a co-factor for NMDA receptor activation - glycine binding is necessar y for normal function of the NMDA receptor)
especially important mechanism for the analgesic effect by blocking nociceptive sensory input at the level of the spinal cord.
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Molecular Targets for general anaesthetics: 3. Activation /opening of Two Pore domain K+ channels.
Some general anaesthetics open K + channels that stabilize the membrane potential.
effect is anticipated to have a general inhibitory effect in neurones
Two pore domain K + (2PK) channels are a large family of K + channels that stabilize the membrane potential at negati l th b i hibiti tive values there by inhibiting depolarization.
Effects of 2PK channels may also account for some effects of general anaesthetics on other systems e g is anaesthetics on other systems e.g. cardiovascular system
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Main 3 mechanisms for GA's
increase 2PK
Increase GABA
Decrease NMDA
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Combo of drugs used in surgery for best effects
**Before beginning**
• Before surgery a narcotic analgesic (e.g.an opioid such as fentanyl) and an anxiolytic/sedative/amnesic (e.g. /sedative/amnesic (e.g. midazolam midazolam) may be administered. A ) may be administered. A muscarinic muscarinic antagonist (e.g. hyoscine) may be used to reduce secretions.
**During the procedure**
• An intravenous induction agent (typically An intravenous induction agent (typically propofol propofol) Is used for rapid induction of ) Is used for rapid induction of anaesthesia • A maintenance agent (e.g. sevoflurane with nitrous oxide) • A muscle relaxant A muscle relaxant\* may be given to decrease unwanted movements including those may be given to decrease unwanted movements including those due to reflexes (typically atracurium – respiratory assistance required).
**During recovery**
• An analgesic to reduce post An analgesic to reduce post-operative pain (morphine) operative pain (morphine) • An anti-emetic • An anticholinesterase (e.g neostigmine to reverse muscle relaxant)
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Lipid theory of GA's
noted a strong correlation between lipid solubility (expressed as oil/gas partition coefficient) and anaesthetic potency (MAC – see below) for volatile anaesthetics. This led to the long-held belief that general anaesthetics work by somehow disrupting membrane function in a non-specific way.
***_FAULT:_*** But this idea cannot explain why some anaesthetics have stereospecific actions or wh th i ‘ t hy there is a ‘cu t-off’ ith t t l l i ff’ with respec t to molecular size – anaesth ti t f ll ff th etic po tency falls off after a critical molecular size.
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Protein theory
Considered better than the lipid theory
Anaesthetics bind to a lipophilic pocket in membrane proteins
most probably ion channels
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Is epilepsy a symptom or a diagnosis?
Symptom NOT a diagnosis
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what is a syndrome?
What is epilepsy syndrome?
Syndrome = a recognisable complex of concurrent symptoms, signs and investigation findings
Epilepsy Syndrome = syndrome in which recurrent seizures predominate
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What are seizures usually?
usually brief, discrete selflimiting episodes
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how can epilepsy manifest?
epilepsy can be manifest by many different patterns of seizure in many specific syndromes with a wide variety of underlying pathological causes
The investigation and treatment of different epilepsy syndromes is not the same
The two classification schemes (syndromes and seizure types) provide the framework for planning clinical management
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what is the future of epilepsy treatment?
* Focal drug delivery, to the part of the brain giving rise to seizures
* Surgery to disconnect (rather than cut out) the part of the brain giving rise to seizures
* A better understanding of epilepsy genetics will provide new avenues for drug treatment
* Treatments to prevent the initial development of epilepsy, rather than simply to stop seizures
