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Flashcards in Sleep, ECG and Epilepsy Deck (61)
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1
Q

Describe the state of the brain during sleep.

A
  • The true function of sleep is unknown:
    • Suggested functions include the processing and storage of memories, recuperation of the body’s immune system and to conserve energy.
  • During sleep the neurons of the brain are active, but display a different type of activity from wakefullness.
  • The sleeping brain consumes as much oxygen as the wakeful brain, and sometimes more.
  • There are 2 main forms of externally discernable sleep, they are either:
    1. when the eyes move rapidly from side to side (REM sleep) or
    2. when they do not (non REM, slow wave or deep sleep), however there are other determinants also.
  • Neuronal activity during different stages of wakefullness (including sleep) can be measured using an electroencephalogram (EEG).
2
Q

How does the EEG work?

A
  • 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 EEG.
3
Q

Describe the normal adult brain waves on an EEG.

A
4
Q

Describe the stages of the sleep cycle.

A
5
Q

Describe a typical night sleep.

A
  • Consists of several cycles through the 5 stages of sleep. Note that stage 4 is only reached in the initial cycles, thereafter the deepest sleep is attained in stage 3. Not increasing time spent in REM sleep.
  • Eye movement is slow and rolling in the 1st stage and rapid in REM, muscle activity (head) decreases with depth of sleep.
  • REM is also characterised by increases in heart rate, neural activity and respiration and oxygen consumption.
  • Penile erection is associated with REM sleep and this characteristic can be used in discrimination between different types of erectile dysfunction.
6
Q

Describe non-REM sleep.

A
  • Non-REM sleep = waves during slow wave or non-REM sleep.
  1. As the subject goes deeper into non-REM sleep, movement and breathing is depressed however movement is still possible.
  2. At stage 4, the brain shows slow waves of synchronised firing of large groups of neurons.
  • Slow waves are thought to be involved with inhibiting sections of the relevant cortex.
7
Q

Describe REM sleep.

A
  1. The brain is very active and is most likely to be dreaming (95% likelihood), but the body is effectively paralysed.
  2. One source of activity is concerned with inhibiting motor output (excepting breathing and eye movement).
  3. Body temperature drops as metabolism is inhibited.
8
Q

Describe the brainstem reticular formation.

A
  • Diffuse collection of at least 100 networks of neuromodulatory neurons spanning all three divisions of the brainstem.
  • It is not homogeneous and has diverse functions (posture, respiration, HR and sleep / arousal). The main neurotransmitters are noradrenaline, 5HT, ACh.
  • It has projections to: thalamus, hypothalamus, some brainstem nuclei, cerebellum, spinal cord and cerebral cortex.
  • It receives input from the cerebra (collaterals from the corticospinal pathways), the visual and auditory systems, sensory spinal systems, the cerebellum, certain brainstem nuclei.
  • Sleep mechanisms rely on communication between the reticular formation and the thalamus (being the main relay station to and from the cortex).
9
Q

Describe thalamic functions.

A
  • Broadly speaking, inhibiting the thalamus decreases the sensory throughput and exciting the thalamus increases the sensory throughput.
  • Specific site, and general excitability of the thalamus can be controlled by the reticular formation via a number of pathways.
  • The thalamus acts as a major relay between the sensory ststems (including sight) and the cerebral cortex.
10
Q

Describe the neural control of non-REM sleep.

A
  • Non-REM is characterised by synchronised cortical slow waves caused by a hyperpolarised thalamus and decreased activity in the arousal centres of the reticulum.
  • Sleep spindles and K complexes are caused in part by the inherent rhythmicity of thalamic neurons as they hyperpolarise due to reduced ascending reticular formation input. Seen in non-REM stage 2 sleep.
  • As thalamic cells hyperpolarise further, they 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 2 areas, the waves become synchronised across the cortex.
11
Q

What is orexin?

A
  • Orexinergic neurons are normally active during wakefulness, situated in the lateral hypothalamus.
  • These neurons project into the cerebra, the arousal nucleu and the ventro-lateral pre-optic nucleus in the anterior hypothalamus (VLPO), however, the VLPO has no orexin receptors.
  • Therefore these neurons enhance the arousal nucleu and by doing so cause indirect inhibition of the VLPO via reciprocal inhibition pathways between the arousal centres and the VLPO.
  • VLPO lesions cause insomnia.
  • Orexin is therefore pivotal in the sleep / awake switch circuitry and adds stability to the mechanism.
12
Q

What is the centre of non-REM sleep promotion?

A
  • The ventrolateral pre-optic nucleus (VLPO).
  • It has inhibitory projections to all the major direct arousal centres and is active during sleep.
  • The VLPO also innervates neurons in the lateral hypothalamus (including the orexin neurons), and inter-neurons in the MRF cell groups.
  • The extended VLPO (eVLPO) (area around the VLPO) promotes REM sleep, and the VLPO cluster promotes NREM sleep.
13
Q

How is the VLPO inhibited?

A

The VLPO is reciprocally inhibited by projections (NA GABA and 5-HT) from the arousal centres.

14
Q

Describe the switch between arousal and sleep.

A
  • When orexin is released it stimulates the arousal centres and so causes inhibition of the VLPO.
  • As long as Orexin is released, the balance is shifted towards full wakefullness.
  • When the VPLO begins to fire, it inhibits both the orexinergic neurons and the arousal centres.
    • This
    1. removes the inhibition of VLPO by the arousal centre, and
    2. cuts off the excitation from the orexinergic neurons thus pushing the balance quickly towards sleep.
15
Q

Where is the suprachiasmatic nucleus found and what does it control?

A
  • The suprachiasmatic nucleus (SCN) is located in the hypothalamus and controls:
    1. Circadian cycles
    2. Influences many physiological and behavioural rhythms occurring over a 24-hour period, including the sleep / wake cycle.
  • In humans ‘free-running’ of the SCN clock gene gives a periodicity of about 24.5 hours.
  • This cycle is therefore re-set each day by a variety of zeitgebers (time givers in German), the most dominant of which is the light dark cycle.
16
Q

How is the clock gene in the body reset?

A

Receptors in the retina (not rods or cones) containing melanopsin react to light and synapse directly onto the SCN resetting the clock gene.

17
Q

What is narcolepsy?

How does it present?

A
  • Onset due to specific loss of the Orexin containing neurons in the lateral hypothalamus.
  • Thought to be an inherited autoimmune condition linked to chromosome 6 - immune system attacks the orexin pathway.
  • Presents as a tetrad of symptoms:
    • 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 (hypnagogic hallucinations).
18
Q

What are the available treatments for narcolepsy?

A
  • Modafanil
  • Amphetamines
  • Methylphenidate
  • Sodium oxybate (GBH)
  • SSRIs and tricyclic antidepressants suppress REM sleep
  • Venlafaxine may help cataplexy
19
Q

What is epilepsy?

A
  • Epilepsy is a continuing tendency to have seizures.
  • Seizures are sudden discharges of abnormal electrical activity.
  • Classification of seizure type is important - mixture of description of attack and investigations. Rare risk of sudden death (SUDEP, 1 in 1,000 epileptics).
  • Overall lifetime risk of seizure is 1 in 50.
  • Affects ~0.5% of the population.
20
Q

What information is needed to make a diagnosis of epilepsy?

A
  • History is most important, both from patient and witness.
  • ?Aura / warning
  • Abnormal movements
  • Colour
  • Position
  • When?
  • After effects?
  • Examination is usually normal.
  • Investigations include ECG, EEG, MRI.
  • Put all information together to come up with best diagnosis, seizure seminology.
  • Partial, simple or complex.
  • Generalised, primary or secondary..
21
Q

Describe the classification of epilepsy.

A
22
Q

Describe a simple partial seizure.

A
  • Focal with minimal spread of abnormal discharge.
  • Normal consciousness and awareness are maintained.
23
Q

Describe a complex partial seizure.

A
  • Local onset, then spreads.
  • Impaired consciousness.
  • Clinical manifestations vary with site of origin and degree of spread.
    • Presence and nature of aura.
    • Automatisms
    • Other motor activity
  • Temporal lobe epilepsy most common.
24
Q

Describe secondarily generalised seizures.

A
  • Begins focally, with or without focal neurological symptoms.
  • Variable symmetry, intensity, and duration of tonic (stiffeninc and clonic (jerking) phases.
  • Typical duration up to 1-2 minutes.
  • Postictal confusion and somnolence.
25
Q

Describe generalised seizures.

A
  • In 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.
  • Present in 40% of all epileptic syndromes.
26
Q

Describe absence seizures (petit mal).

A
  • Sudden onset and abrupt cessation.
  • Brief duration, consciousness is altered; attack may be associated with mild clonic jerking of the eyelids or extremities, postural tone changes, autonimic phenomena and automatisms (difficult diagnosis from partial seizures); characteristic 2.5-3.5Hz spike-and wave pattern.
27
Q

Describe myoclonic seizures.

A
  • 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.
28
Q

Describe atonic seizures.

A
  • Sudden loss of postural tone; most often in children but may be seen in adults.
29
Q

Describe tonic-clonic seizures.

A
  • Tonic-clonic seizures (grand mal): major convulsions with rigidity (tonic) and jerking (clonic), this slows over 60-120 seconds followed by stuporous state (post-ictal depression).
  • Recruitment of neurons throughout the cortex.
  • Major convulsions, usually with 2 phases:
    1. Tonic phase: muscles will suddenly tense up, causing the person to fall to the ground if they are standing.
    2. Clonic phase: muscles will start to contract and relax rapidly, causing convulsions.
30
Q

Describe convulsions.

A
  • Convulsions:
    • ​motor manifestations
    • may or may not be present during seizures
    • excessive neuronal discharge
  • Convulsions appear in simple partial and complex partial; focal neuronal discharge includes motor centres; they occur in generalised tonic-clonic seizures regardless of the site of origin.
  • Atonic and absence seizures are non-convulsive.
31
Q

What is status epilepticus?

A
  • More than 30 minutes of continuous seizure activity.
  • 2 or more sequential seizures spanning this period without full recovery between seizures.
  • Medical emergency.
32
Q

What is an antiepileptic drug?

A
  • A drug which decreases the frequency and / or severity of seizures in people with epilepsy.
  • Treats the symptom of seizures, not the underlying epileptic condition.
  • Goal - maximise quality of life by minimising seizures and adverse drug effects.
  • Currently no ‘anti-epileptogenic’ drugs are available.
33
Q

What is the current pharmacotherapy for epilepsy?

A
  • Just under 60% of all people with epilepsy can become seizure free with drug therapy.
  • In another 20%, the seizures can be drastically reduced.
  • ~20% epileptic patients, seizures are refractory to curently available AEDs.
34
Q

What factors must be taken into consideration when choosing antiepileptic drugs?

A
  • Seizure type
  • Epilepsy syndrome
  • Pharmacokinetic profile
  • Interactions / other medical conditions
  • Efficacy
  • Expected adverse effects
  • Cost
35
Q

Describe the cellular mechanisms of seizure generation.

A
36
Q

What are the targets for antiepileptic drugs?

A
  • Increase inhibitory neurotransmitter system - GABA.
  • Decrease excitatory neurotransmitter system - glutamate.
  • Block voltage-gated inward positive currents - Na+ or Ca2+.
  • Increase outward positive current - K+.
  • Many antiepileptic drugs are pleiotropic - act via multiple mechanisms.
37
Q

Describe the role of glutamate in epilepsy.

A
  • Glutamate = the brain’s major excitatory neurotransmitter.
  • Two groups of glutamate receptors:
    • Ionotropic - fast synaptic transmission
      • NMDA, AMPA, kainate.
      • Gated Ca2+ and gated Na+ channels.
    • Metabotropic - slow synaptic transmission
      • Regulation of second messengers (cAMP and Inositol).
      • Modulation of synaptic activity.
  • Modulation of glutamate receptors:
    • Glycine, polyamine sites, zinc, redox site.
38
Q

What are the antiepileptic drugs which act primarily on Na+ channels?

A
  • Phenytoin, carbamazepine
    • Block voltage-gated sodium channels at high firing frequencies - use dependent.
  • Oxcarbazepine
    • Blocks voltage-dependent sodium channels at high firing frequencies.
    • Also affects K+ channels.
  • Zonisamide
    • Blocks voltage-dependent sodium channels and T-type calcium channels.
  • Lamotrigine
39
Q

What are the major antiepileptic drugs which are currently commonly used?

A
  • Lamotrigine
  • Sodium valporate
  • Carbamazepine
  • Oxcarbazepine
  • Levetiracetam
  • Topiramate
40
Q

What are the major antiepileptic drugs which are currently used less?

A
  • Phenytoin
  • Ethosuxamide
  • Phenobarbitone
  • Vigabatrin
  • Tiagabine
41
Q

Describe lamotrigine.

A
  • Acts by inhibiting sodium channels.
  • Broad therapeutic profile.
  • Main side effects are hypersensitivity reactions (especially skin rashes).
42
Q

Describe sodium valporate.

A
  • Chemically unrelated to other antiepileptic drugs.
  • Mechanism of action is not clear. Is causes significant increase in the GABA content of the brain. It is a weak inhibitor of GABA transaminase. It has some effect on sodium channels.
  • Relatively few adverse effects:
    • Teratogenicity and fetal syndrome (avoid in pregnancy)
    • Liver damage (very rare, but serious)
43
Q

Describe carbamazepine.

A
  • Derivative of tricyclic antidepressants.
  • Effective particularly in partial seizures; also useful in trigeminal neuralgia.
  • Strong enzyme-inducing agent; therefore, many drug interactions.
  • Unwanted effects, principally:
    • sedation
    • ataxia
    • mental disturbances
    • water retention
44
Q

Describe oxcarbazepine.

A
  • Newer drug, closely related to carbamazepine, approved for monotherapy, or add-on therapy in partial seizures.
  • May also augment K+ channels.
  • Some induction of P450 but much less than that seen with CBZ.
  • Sedating but otherwise less toxic than carbamazepine.
45
Q

What are the newer antiepileptic drugs?

A
  • Levetiracetam
  • Topiramate
  • Tiagabine
  • Zonisamide
46
Q

Describe levetiracetam.

A
  • Mechanism of action is unknown, probably inhibits presynaptic Ca2+.
    • Analogue of piracetam, a drug used to improve cognitive function.
    • Useful in partial seizures and generalised seizures now.
    • Can cause psychiatric side effects.
47
Q

Describe topiramate.

A
  • Complex actions, not fully understood.
  • Risk of teratogenesis.
  • Need slow titration to avoid cognitive side effects.
48
Q

Describe tiagabine.

A
  • GABA-uptake inhibitor.
  • Side-effects are dizziness and confusion.
  • Licensed for partial seizures.
49
Q

Describe zonisamide.

A
  • Blocks sodium channels, can cause anorexia and somnolence.
50
Q

Describe phenytoin.

A
  • Acts mainly by use-dependent block of sodium channels.
  • Effective in many forms of epilepsy, but not absence seizures.
  • Metabolism shows saturation kinetics; therefore, plasma concentration can vary widely and monitoring is needed.
  • Drug interactions are common.
  • Main unwanted effects are confusion, gum hyperplasia, skin rashes, anaemia, teratogenesis, cerebellar syndrome, osteoporosis.
  • Widely used in treatment of epilepsy; also used as antidysrhythmic agent.
51
Q

Describe ethosuximide.

A
  • Was the main drug used to treat absence seizures in children, may exacerbate other forms.
  • Acts by blocking T-type calcium channels.
  • Retatively few unwanted effects, mainly nausea and anorexia.
52
Q

Describe phenobarbitone.

A
  • Rarely used, but some patients are still on it.
  • Enzyme inducing, very long half life.
  • Increased risk of osteoporosis.
53
Q

What are the first line treatments for status epilepticus?

Describe the mechanism of action.

A
  • Benzodiazepines used as first-line treatment for status epilepticus (delivered IV - fast-acting).
  • Sedating.
  • Lorazapam and Diazepam.
54
Q
A
55
Q

What is felbamate?

A
  • A rarely-used antiepileptic drug.
  • Mechanisms of action unknown.
  • Broad therapeutic profile.
  • Use limited to intractable disease because of the risk of severe hypersensitivity reactions, aplastic anaemia.
56
Q

What is vigabatrin?

A
  • A rarely-used antiepileptic drug.
  • Acts by inhibiting GABA transaminase.
  • Effective in patients unresponsive to conventional drugs.
  • Main side effects:
    • Drowsiness
    • Behavioural and mood changes
    • Retinal loss
57
Q

Describe the use of gabapentin and its second generation derivative pregabalin in the treatment of epilepsy.

A
  • Act specifically on calcium channel subunits called α2δ1.
  • It is unclear how this action leads to their antiepileptic effects, but inhibition of neurotransmitter release may be one mechanism.
  • Used in add-on therapy for partial seizures and tonic-clonic seizures.
  • Less sedating than classic antiepileptic drugs.
  • Now main uses in neuropathic pain.
58
Q

What are the antiepileptic drug treatment options for the different types of seizures?

A
59
Q

What is the treatment for status epilepticus?

A
  • Treatment
    • Diazepam, lorazapam IV (fast, short-acting).
    • Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established.
60
Q

What is the role of neurosurgery in the treatment of epilepsy?

A
  • Most commonly used for partial seizures.
  • Only considered when 3 AEDs have been tried.
  • Work-up includes detailed electrophysiology.
  • Best results when lesion correlates with EEG.
  • Certain seizure comes from lesion.
  • Ideally non-dominant hemisphere.
  • Functional MRI, specialist centre.
61
Q

Describe baclofen.

A
  • Selective agonist on GABAB-receptors.
  • Action exerted mainly at the level of the spinal cord to inhibit motorneurons.
  • Effective orally and is given widely for the treatment of spasticity associated with MS or spinal injury. Ineffective for cerebral spasticity caused by birth injury.
  • Side effects are drowsiness, motor incoordination and nausea. Many behavioural effects.
  • Not useful in epilepsy.