Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Sc 28 Epilepsy > General > Flashcards

General Flashcards

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Seizure types

A
  • Focal seizures
  • Generalised seizures
  • Status epilepticus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Focal seizures

A

Seizures arise from many focal brain regions,

give rise to many different patterns

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Generalised seizures

A

Seizures may also arise in widespread bilateral brain networks,

giving rise to several different patterns

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Excitatory Transmitters

A
  • Glutamate
  • Aspartate - Amino acid
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Aspartate

A

– mediates transmission at a small number of central sypnapses

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What converta GABA to Succinic semialdehyde?

A

GABA transaminase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

what changes glutamate into GABA?

A

GAD- Glutamate decarboxylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Vesicular conc >20mM

A

1,000 – 2,000 molecules per vesicle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Release of Glutamate

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Reuptake of Glutamate (and Aspartate)

A
  • Excitatory Amino Acid Transporters (EAATs)
  • Reduces the extracellular concentration
  • Terminates transmitter
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

WHat leads to termination of transmitter action?

A

Diffusion and Active uptake of the NT

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Uptake of glutamate terminates synaptic transmission

N.B some glutamate may diffuse to act at adjacent synapses

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What are the two large families of GLutamae receptors?

A
  • Ionotrophic receptors - ion channels
  • Metabotrophic receptors
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Ionotropic receptors

ion channels general info

A
  • Binding site located on channel
  • Agonist binding promotes channel opening
  • Role in fast synaptic transmission
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Ionotrophic receptors

ion channels

3 different types?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

Metabotropic receptors

A
  • G protein coupled receptors
  • Modulatory effects on neuronal function and synaptic transmission
    • i.e no/freq of AP’s etc
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Locations in brain of ionotrophic glut receptors

A
  • 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Structure of ionotropic glutamate receptors

A
  • Each subunit has 3 transmembrane spanning domains
  • Large extracellular N-terminus
  • Receptors made up of 4 subunits
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is responsible for fast exictatory transmission?

A

Activation of AMPA & NMDA receptors responsible for fast excitatory synaptic transmission

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

AMPA receptors

A

Fast synaptic current

Fast decay due to relatively low affinity (K d ~200nM)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

NMDA receptors

A
  • Slower onset
  • Slower decay (up to several hundred msecs)
  • Higher affinity glutamate binding
    • ( Kd~ 5nM)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

What explains the differences in decay speed between AMDA and NMDA receptors?

A

Affinity difference

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

AMPA receptors

general structure info

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

NMDA receptor 1

A
  • 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’
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

NMDA receptor 2

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Structure of NMDA receptor

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

NMDA channel blocking drugs

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

Metabotropic Glutamate receptors

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Metabotrophic Glutamate receptors

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Pre-synaptic effects of mGLuRs

A
  • Inhibit voltage gated Ca channels – reduce transmitter release
    • Primarily group II & III receptors
  • Glutamatergic terminals (inhibitory autoreceptors)
  • Terminals that release other transmitters
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Post-synaptic effects of mGluRs

A
  • variable
  • Inhibit some K + channels -increase excitability
  • Increase activity of some K+ channels – decrease excitability
  • Effects depend on cell type involved
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

Calcium influx and Excitotoxicity

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

GABA - major inhibitory NT in the brain

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

How is GABA formed and destroyed?

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

WHat is Vigabatrin?

A
  • – 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

GABA storage and uptake

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

Types of GABA receptors

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

GABAA RECPTORS

Donut structure

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

GABA a receptor pharmacol

A

Agonists

• 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
Q

GABA a Benzodiazepines

A

– 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
Q

Effects of Benzo drugs

A
  • anxiolytic
  • sedative
  • reduction of muscle tone
  • anticonvulsant
  • amnesia
59
Q

Benzo side effects

A
  • Drowsiness
  • Confusion
  • Amnesia
  • Impaired coordination
  • High degree of tolerance and dependence
60
Q

Benzo

acute toxicity and withdrawal symptoms

A

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
Q

GABA a - BARBITURATES

A

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
Q

Barbiturates

Overdose

A

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
Q

Pentobarbitol and Thiopental

A

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
Q

How were GABA b receptors intially found?

A

Insensitivity to Bicuculine

65
Q

Info GABA b receptors

A

• 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
Q

GABA b Pre-synaptic inhibition

1a isoform

A
  • – 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
Q

GABA b recept Post-synaptic inhib

A

– 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
Q

Pharmacology of GABA b Receptors

A

• 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
Q

Glycine -

2nd major inhib transmitter

A

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
Q

Glycine degradation

A

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
Q

Glycine receptors

A
  • 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
Q

Glycine receptors 2

mutations

A

• 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
Q

What is Epilepsy

A

Epilepsy: A disorder of the CNS characterized by , recurrent, sudden large increases in electrical activity (electrical seizures) that may be localized or generalized.

74
Q

What do symptoms depend on?

A

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
Q

Partial seizure

(localized, focal)

A

Seizure is restricted to a limited region

Simple if subject remains conscious and aware

Complex if consciousness is impaired

76
Q

Primary Generalized

A

Most of the CNS is involved, but no focus can be distinguished

77
Q

Secondary generalized

A

most of the CNS is involved eventually but the exictation has spread from an intial focus

78
Q

What are seizures preceded by frequently?

A

AN aura,

feeling/experience that warns the subject of an impending seizure

79
Q

Absence seizure (old name: petit mal).

A
  • primarily generalized seizure
  • common in children
  • Characterized by sudden loss of awareness lasting up to about 30 sec.
80
Q

Tonic-clonic seizure (old name: grand mal).

A
  • generalized seizure
  • lasting 2 - 5 minutes
  • characterized by sudden stiffening (‘tonic’) of muscles, a fall, followed by jerking (‘clonic’) movements
81
Q

Simple partial seizure (old name of this example: Jacksonian).

A
  • 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
Q

Temporal lobe epilepsy (also known as psychomotor epilepsy).

A

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
Q

Status epilepticus

A

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
Q

idiopathic epilepsy

A

unknown cause

85
Q

Cryptogenic

A

Cause can’t be proven

86
Q

what percentage of cases are symptomatic?

A

30%

i.e. occur following head injury, stroke, infection, tumour, drug abuse etc

87
Q

Benign febrile epilepsy

A

linked to mutations in KCNQ2 and KCNQ3:

genes that encode voltage-gated potassium channels.

88
Q

Family generalised epilepsy with febrile seizure plus

A

linked to mutations in SCN1B, a gene that encodes an accessory subunit of the voltage-gated sodium channel.

89
Q

Drug induced seizures

A

many drugs have pro-convulsant effects

90
Q

Cellular event that causes a focal seizure?

A

Paroxysmal depolarizing shift (PDS)

91
Q

Paroxysmal depolarising shift (PDS)

A

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
Q

Spread of seizures

A

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
Q

Surround inhibition effect

A

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
Q

What may absent seizures be a result of?

A

may be due to dysfunction in thalamocortical networks that control sleep/wake cycles

95
Q

Drug Rx for:

Tonic-clonic; partial; temporal lobe seizures

A
  • Benzodiazepines (e.g. diazepam, clonazepam)
  • Barbiturates (phenobarbitone)
  • Vigabatrin
  • Tiagabin
96
Q

What drugs are Contraindicated for Absence seizures?

A

Vigabatrin

Tiagabin

Makes them worse

97
Q

For tonic-clonic, partial, temporal lobe seizures – may provoke absences

Use dependent block of voltage gated sodium channels:

A

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
Q

Drugs for treating absence seizures only:

A

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
Q

Drugs useful for both tonic-clonic and absence seizures:

A
  • 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
Q

Other drugs: for epilepsy

A
  • 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
Q

What drug to give? Epilepsy

A
  • 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
Q

Other Treatments ketogenic diet

A

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
Q

Other Rx Vagal Stimulation

A

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
Q

Other Rx Surgery

A

Removal of tissue that harbours a recurrent focus or to limit spread of excitation.

105
Q

Stigma

defn + types of characteristics that may attract a stigma

A

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
Q

Felt stigma vs Enacted Stigma

A

‘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).

107
Q

WHat do risks of enacted stigma depend upon?

A

depend on whether condition

is: Discreditable or Discrediting

108
Q

Psych effects of stigma

A

 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

109
Q

What is stigma a power tool of?

A

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

110
Q

Types of Genetic disease

A

• 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
111
Q

Hyperekplexia (Startle disease or Stiff Baby Syndrome)

A

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

112
Q

Familial Erythromelalgia (Weir Mitchell’s disease) •

A

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)
113
Q

Generalised Epilepsy with Febrile Seizures (GEFS)

A

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

114
Q

What happens with mutated B subunits of voltage gated Na channels?

A

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

115
Q

Benign Familial Neonatal Seizures (BFNS) •

A

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

116
Q

General anaesthesia

A

reversible drug-induced loss of consciousness that facilitates surgical procedures that consciousness that facilitates surgical procedures that would otherwise cause pain and distress.

117
Q

Inhalational G.A’s

A

Sevoflurane (volatile liquid)

Isoflurane (volatile liquid)

Nitrous oxide (gas)

118
Q

Intravenous G.A

A

Propofol - most commonly use

etomiade

thiopental sodium (rarely used)

ketamine (rarely used -paeds)

119
Q

What will an ideal general anaesthetic drug have?

A

• 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

120
Q

What are the stages of anaesthesia?

A
  • 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

121
Q

what state does surgical anaesthetic resemble?

A

Non-REM sleep states

122
Q

What happens to EEG amplitude during G.A?

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
123
Q

what regions are affected most by G.A?

A

cortical regions and thalamus

124
Q

What is GA associated with in the cerebral cortex?

A

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

125
Q

What does reduced thalamic activity do?

A

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.

126
Q

what happens to the arousal nuclei?

A

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.

127
Q

Molecular Targets for general anaesthetics:

1 . Enhancement/activation o f GABA A receptor activity.

A
  • 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.

128
Q

what reduced the efficacy of most GA’s?

What do drugs do to the CNS?

A

introduction of specific point mutations into GABA subunits can reduce the efficacy of most general anaesthetics.

drugs increase inhibition in the CNS

129
Q

Molecular Targets for general anaesthetics:

  1. Antagonism / block of NMDA receptor activity.
A

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.

130
Q

Molecular Targets for general anaesthetics: 3. Activation /opening of Two Pore domain K+ channels.

A

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

131
Q

Main 3 mechanisms for GA’s

A

increase 2PK

Increase GABA

Decrease NMDA

132
Q

Combo of drugs used in surgery for best effects

A

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)

133
Q

Lipid theory of GA’s

A

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.

134
Q

Protein theory

Considered better than the lipid theory

A

Anaesthetics bind to a lipophilic pocket in membrane proteins

most probably ion channels

135
Q

Is epilepsy a symptom or a diagnosis?

A

Symptom NOT a diagnosis

136
Q

what is a syndrome?

What is epilepsy syndrome?

A

Syndrome = a recognisable complex of concurrent symptoms, signs and investigation findings

Epilepsy Syndrome = syndrome in which recurrent seizures predominate

137
Q

What are seizures usually?

A

usually brief, discrete selflimiting episodes

138
Q

how can epilepsy manifest?

A

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

139
Q

what is the future of epilepsy treatment?

A
  • 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

Sc 28 Epilepsy (1 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions