Sleep, Wakefulness, Epilepsy and EEG Flashcards
What is sleep?
Usually described in relation to consciousness as an easily reversible state of inactivity with a lack of interaction with the environment
What is unconsciousness?
Inconsistant term - can be coma (depressed state of neural activity, absence of wakefulness), sleep (variation in neural activity)
What is consciousness?
Having awareness; with perceptions, thoughts and feelings - philosophical and biological aspects
What are the 2 main forms of easily discernable sleep?
- When the eyes move rapidly from side to side (REM sleep)
- When they do not (non REM, slow wave, deep sleep)
What can neuronal activity during different stages of wakefulness be measured by?
EEG (Electroencephalogram)
How does the EEG work?
- Post synaptic activity of individual neurons not picked up
- Post synaptic activity of synchronised dendritic activity can be picked up
- Synchronisation is either by neuronal interconnections or by pacemaker
- The more neurons that are synchronised, the bigger the peaks on the ECG
How many EEG electrodes are there?
19
What are the different types of brain wave?
- Beta - Awake with mental activity (14-30Hz)
- Alpha - Awake and resting (8-13Hz)
- Theta - Sleeping (4-7Hz)
- Delta - Deep sleep (<3.5Hz)
What are the 5 stages of sleep?
Stage 1-4 + REM
- Waves get longer through each stage until REM where Hz increase and fast beta waves are present. After about 1 hour
What stage of sleep is associated with penile erection?
REM
After the first cycle of sleep what is the deepest sleep stage attained?
Stage 3 and increasing time spent in REM
What are slow waves thought to be involved in?
Inhibiting sections of the relevant cortex
What happens during REM sleep?
- Brain is very active and is most likely to be dreaming (95% likelihood), but the body is effectively paralysed
- One source of activity is concerened with inhibiting motor output (excepting breathing and eye movement)
- Body temperature drops as metabolism is inhibited
What is the reticular formation a diffuse collection of?
At least 100 networks of neuromodulatory neurons spanning all 3 divisions of the brainstem. It is not homogenous, main NTs are NAdr, 5HT, Ach and has diverse functions (posture, rep, HR and sleep arousal)
What is the reticular formation has projections to what?
- Thalamus
- Hypothalamus
- Brainstem nuclei
- Cerebellum
- Spinal cord
- Cerebral cortex
What does the reticular formation receive input from?
Cerebra (collaterals from the corticospinal pathways), the visual and auditory systems, sensory spinal systems, the cerebellum, certai brainstem nuclei
Sleep mechanisms rely on communication between what 2 places?
Reticular formation and thalamus (being the main relay station to and from the cortex)
Inhibiting and exciting the thalamus does what?
Inhibiting:
- Decreases sensory throughput
Exciting
- Increases sensory throughput
What is nonREM sleep characterised by?
Synchronised cortical slow waves caused by a hyperpolarised thalamus and decreased activity in the arousal centres of the reticulum
What are Sleep spindles and K complexes?
- Caused in part by inherent rythmicity of thalamic neurons as they hyperpolarise due to reduced ascending reticular formation input. Seen in Non REM stage 2 sleep
What happens as thalamic cells hyperpolarise further?
Develop slow wave rhythmicity (due to thalamic interconnections) which serves to block ascending sensory input. This rhythmicity is transmitted to the cortex and due to a strong reciprocity between these two areas, the waves becomes synchronised across the cortex
Where are orexinergic neurons situated?
Lateral hypothalamus
When are orexinergic neurons active?
During wakefullness
Where do orexinergic neurons project to?
The cerebra, the arousal nuclei and the Ventro-lateral pre-optic nucleus in the anterior hypothalamus (VLPO) however the VLPO has no orexin receptors
What do VLPO lesions cause?
Insomnia
What is orexin pivotal in?
The sleep/awake switch circuitry and adds stability to the mechanism
What nuclei do orexinergic neurons enhance?
Arousal nuclei and by doing so cause indirect inhibition of the VLPO via reciprocal inhibition pathways between the arousal centres and the VLPO
Where is the VLPO situated?
Anterior hypothalamus
What is the centre of non-REM sleep promotion?
VLPO
What does the VLPO have inhibitory projections to?
Major direct arousal centres (red), and is active during sleep
What does the VLPO innervate?
Neurons in the lateral hypothalamus (including the orexin neurons (green)), and inter-neurons in the MRF cell groups (yellow) (PPT and LDT)
What does the extended VLPO (eVLPO) promote?
REM sleep
What is the VLPO reciprocally inhibited by?
Projections (NA GABA and 5-HT) from the arousal centres
What does the suprachiasmatic nucleus (in the hypothalamus) control?
- Circadian cycles
- Influences many physiological and behavioral rhythms occuring over a 24 hour period, including the sleep/wake cycle
What receptors in the retina react to light and synapse directly onto the SCN resetting the clock gene?
Melanopsin
How long is the “free running” of the SCN clock gene?
Gives a periodicity of about 24.5 hours
What is the circadian cycle re-set by?
A variey of zeitgebers (time givers in German), the most dominant of which is the light dark cycle
What is narcolepsy due to?
- Due to specific loss of the orexin containing neurons in the lateral hypothalamus
- Though to be an inherited auto-immune condition linked to chromosome 6
What are the tetrad of symptoms associated with sleep disorders?
- Repeatedly falling asleep during the day, regardless of current activity (go straight into REM sleep)
- Limb weakness during emotional episodes (mild to extreme cataplexy)
- Night time or morning wakening accompanied by muscular paralysis (sleep paralysis)
- Vivid dream recollection just prior to wakening (hypanagogic hallucinations)
How is Narcolepsy treated?
- Modafanil
- Amphetamines
- Methylphenidate
- Sodium oxybate (GHB)
- SSRIs and tricyclic antidepressants suppress REM sleep
- Venlafaxine may help cataplexy
What are some sleep disorders?
- Narcolepsy
- Insomnia
- Sleep apnoea (XS daytime sleepiness)
- REM sleep disorder
- Somnambulism
- Epilepsies
How is sleep apnoea treated?
Respiratory support overnight with increased oxygen pressure
What is REM sleep disoreder associated with?
PArkinsons
How common is epilepsy?
0.5% of the population
What is the overall lifetime risk of seizure?
1 in 50
What is epilepsy?
Continuing tendency to have seizures
What are seizures?
Sudden discharges of abnormal electrical activity
What is the risk of sudden death in epileptics?
1 in 1000 epileptics
What is the DVLA rule for driving with seizures?
Cannot drive within 6 months of having a seizure
- 2 attacks = 1 year off driving
What is the most important part of an epilepsy diagnosis?
History
What is the commonest lobe to have abnormal electrical activity?
Temporal lobes - control sense of smell, taste and emotion
- Abnormal taste or smell or feeling of fear may precede a seizure
What factors are important in diagnosing epilepsy?
- History (patient and witness)
- Aura/warning
- Abnormal movements (myoclonic jerks esp morning)
- colour
- Position
- When?
- After effects?
How is epilepsy diagnosed?
- Examination usually normal
- Investigations include ECG, EEG, MRI
- Put all information together to come up with best diagnosis, seizure semiology
- Partial, simple or complex
- Generalised, primary or secondary
What can cause the abnormal electrical activity that can cause a seizure?
- Areas of abnormal neuronal migration
- Islands of nerve cells in white matter
What cells control memory?
Temporal lobes contain very big cells called pyramidal cells - can cause hippocampal sclerosis
What is the difference between a partial and simple seizure?
Partial: Abnormal electrical activity from one spot of the brain
Generalised: Abnormal electrical activity from all over the brain
What is a todds paralysis?
Seizure is followed by a brief period of temporary paralysis
What is the difference between partial simple and partial complex seizures?
- Simple partial seizures, patients retain awareness
- Complex partial seizures, they lose awareness
What is a simple secondary seizure?
Partial seizure that becomes generalised
What lobe is the most common site of complex partial seizures?
Temporal (presence common)
Describe generalised seizures?
- Both hemispheres are widely involved from the outset
- Manifestations of the seizure are determined by the cortical site at which the seizure arises
How common are generalised seizures?
Present in 40% of all epileptic syndromes
What are the different types of generalised seizures?
- Absence seizure
- Mycolonic seizure
- Atonic seizures
- Tonic-clonic seizures
What is an absence seizure?
Type of generalised seizure. Sudden onset abrupt cessation; brief duration, consciousness is altered; attack may be associated with mild clonic jerking of the eyelids or extremities, postural tone changes, autonomic phenomena and automatisms (difficult diagnosis from partial); characteristic 2.5-3.5 Hz spike-and wave pattern
What is a myoclonic seizure?
Type of generalised seizure
Myoclonic jerking is seen in a wide variety of seizures but when this is the major seizure type it is treated differently to some extent from partial leading to generalised
What are atonic seizures?
Sudden loss of postural tone; most often in children but may be seen in adults
What are tonic-clonic seizures?
Major convulsions with rigidity (tonic) and jerng (clonic), this slows over 60-120 sec followed by stuporous state (post-ictal depression)
What are the major two phases of generalised tonic-clonic seizures?
Tonic phase:
- Muscles will suddenly tense up, causing the person to fall to the ground if they are standing
Clonic phase:
- Muscles will start to contract and relax rapidly, causing convulsions
What are convulsions?
- Motor manifestations
- May or may not be present during seizures
- Excessive neuronal discharge
In what seizures do convulsions appear?
Simple partial and complex partial focal neuronal discharge includes motor centres; they occur in all generalised tonic-clonic seizures regardless of the site of origin
WHat type of seizures are non-convulsive?
Atonic and absence seizures
What is status epilepticus?
- More than 30mins of continous seizure activity
- Two or more sequential seizures spanning this period without full recovery between seizures
- Medical emergency
What are antiepileptic drugs?
- Drug which decreases the frequency and/or severity of seizures in people with epilepsy
- Treats the symptoms of seizures, not the underlying epileptic condition
- Goal - maximise quality of life by minimising seizures and adverse drug effects
- Currently no “anti-epileptogenic” drugs available
What percentage of people with epilepsy can become seizure free with drug therapy?
Just under 60% - in another 20% the seizures can be drastically reduced
- 20% of epileptics seizures are refractory to currently available AEDs
What should be considered when choosing an antiepileptic drug?
- Seizure type
- Epilepsy syndrome
- Pharmacokinetic profile
- Interactions/other medical conditions
- Efficacy
- Expected adverse effects
- Cost
What are the targets of AEDs?
- Increase GABA (inhibitory NT)
- Decrease Glutamate (excitatory NT)
- Block voltage-gated inward positive currents - Na+ or Ca2+
- Increase outward positive current - K+
- Many AEDs pleiotropic - act via multiple mechansims
What is the brain’s main excitatory NT?
Glutamate
What are the 2 groups of glutamate receptors?
- Ionotropic - fast synaptic transmission
- Metabotropic - slow synaptic transmission
What are the 2 major glutamate receptors?
NMDA and AMPA
- work through Na+ K+ interaction
What AEDs act primarily on Na+ channels?
Phenytoin, carbamazepine
- Block voltage-dependant Na+ channels at high firing frequencies - use dependant
Oxcarbazepine
- Blocks voltage-dependant Na+ channles at high firing frequencies
- Also effects K+ channels
Zonisamide
- Blocks voltage-dependant Na+ channels and T-type Calcium channel
Lamotrigine
What is the commonest AED?
Lamotrigine
What is phentoin effective in?
Many forms of epilepsy but not absence seizures
- Also used as antidysrhythmic
What are current commonly used AEDs?
- Lamotrigine
- Sodium Valproate
- Carbamazepine
- Oxcarbazepine
- Levetiracetam
- Topiramate
What are older AEDs less used?
- Phenytoin
- Ethosuxamide
- Phenobarbitone
- Vigabatrin
- Tiagabine
What are the features of Lamotrigine?
- Inhibits Na+ channels
- Broad therapeutic profile
- Main s0de-effects are hypersensitivity reactions
What are the features of sodium Valproate?
- Chemically unrelated to other antiepileptic drugs
- MOA not clear, causses GABA increase in brain. Weak inhibition of GABA transaminase, some effect of Na+ channels
- Side effects: Tetratogenicity and foeatla syndrome AVOID IN PREGNANCY, liver damage
What AED must be avoided in pregnancy?
Sodium Valproate
What are the features of Carbamazepine?
- Derivative of tricyclic antidepressants
- Effective particularly in partial seizures; also useful in trigeminal neuralgia
- Strong enzyme-inducing agent; therefore, many drug interactions
- Unwanted side effects principally sedation, ataxia, mental disturbances, water retention
What are the features of Oxacarbazepine?
- Newer drug, closely related to Carbamazapine, approved for monotherpay, or add-on therapy in aprtial seizures
- May also augment K+ channels
- Some induction of P450 but much less than that seen with CBZ
- Sedating but otherwise less toxic than Carbamazapine
What ar ethe features of Levetriacetam?
- Probably inhibits presynaptic CA
- Analogue of piracetam, a drug used to improve cognitive function
- Useful in partial seizures and generalised seizures now
- Can use psychiatric side effects
What are the features of Topiramate?
- Compex actions not fully understood
- Risk of teratogenesis
- Need to slow titration to avoid cognitive side effects
What are the features of tigabine?
- GABA uptak inhibitor
- Side-effwects are dizziness and confusion
- Licensed for partial seizures
What are the feautures of Zonisamide?
Blocks Na+ channels, can cause anorr=exia and somnolence
How does Phenytoin (old) act?
- Mainly by use-dependant block of Na+ channles
- Interactions are common
- Plasma conc varies needs to be monitored
- Unwanted side-effects of confusion, gum hyperplasia, skin rashes, anaemia, teratogenesis, cerebellar syndrome, osteoperosis
What was ethmosuximide (old) used to treat?
Absense seizures in children, may exacerbate other forms
- Acts by blocking T-type Calcium channels
What are the side-effects of ethosuximide (old)?
Relatively few unwanted side-effects, mainly nausea and anorexia
Features of phenobarbitone?
- Rarely used, but ppl stil on it
- Enzyme inducing
- Very long half life
- Osteoperosis
What is the treatment for status epilepticus?
- First line: IV benzodiazepines
- Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established
- If still not working pateint to be paralysed and ventilated
- Medical emergency
What are some rarely used AEDs?
Felbamate
- Use limited to intractable disease high risk of hypersensitivity reactions, aplastic anaemia
Vigabatrin
- Inhibits GABA transaminase
- Effective in patients who are unresponsive to conventional drugs
- Side-effects of drowsiness, behavioural and mood swings, retinal loss, now rarely used
What are gabapentin and its second generation derivative Pregabalin used to treat?
- Act specifically on Calcium channel subunits called alph2delt1. Unclear how this action leads to antiepileptic effects, but inhibition of NT release may be one mechanism
- Used in add-on therapy for partial seizures and tonic-clonic seizures
- Less sedating than classic AEDs
- Now mainly used in neuropathic pain
When is neurosurgery considered in treatment for epilepsy?
- Partial seizures
- When at least 3 AEDs have been tried
- Temporal lobe lesions or tumour causing attack
- Work-up includes detailed electrophysiology
- Certain seizure comes from lesion
- Ideally non-dominant hemisphere
- fMRI, specialist centre
What is Baclofen?
- Selective agonsit on GABA(B) receptor occur in spinal cord
- Reduces spasticity
- Effective in spinal cord lesions and MS NOT epilepsy
What are scars on the brain most commonly due to?
Lack of O2 probably pre-natally or around time of birth
