Sleep, ECG and Epilepsy

Question 1

Describe the state of the brain during sleep.

Answer 1

• 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).

Question 2

How does the EEG work?

Answer 2

• 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.

Question 3

Describe the normal adult brain waves on an EEG.

Answer 3

Question 4

Describe the stages of the sleep cycle.

Answer 4

Question 5

Describe a typical night sleep.

Answer 5

• 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.

Question 6

Describe non-REM sleep.

Answer 6

• 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.

Question 7

Describe REM sleep.

Answer 7

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.

Question 8

Describe the brainstem reticular formation.

Answer 8

• 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).

Question 9

Describe thalamic functions.

Answer 9

• 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.

Question 10

Describe the neural control of non-REM sleep.

Answer 10

• 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.

Question 11

What is orexin?

Answer 11

• 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.

Question 12

What is the centre of non-REM sleep promotion?

Answer 12

• 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.

Question 13

How is the VLPO inhibited?

Answer 13

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

Question 14

Describe the switch between arousal and sleep.

Answer 14

• 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.

Question 15

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

Answer 15

• 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.

Question 16

How is the clock gene in the body reset?

Answer 16

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

Question 17

What is narcolepsy?

How does it present?

Answer 17

• 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).

Question 18

What are the available treatments for narcolepsy?

Answer 18

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

Question 19

What is epilepsy?

Answer 19

• 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.

Question 20

What information is needed to make a diagnosis of epilepsy?

Answer 20

• 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..

Question 21

Describe the classification of epilepsy.

Answer 21

Question 22

Describe a simple partial seizure.

Answer 22

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

Question 23

Describe a complex partial seizure.

Answer 23

• 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.

Question 24

Describe secondarily generalised seizures.

Answer 24

• 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.

Question 25

Describe generalised seizures.

Answer 25

• 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.

Question 26

Describe absence seizures (petit mal).

Answer 26

• 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.

Question 27

Describe myoclonic seizures.

Answer 27

• 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.

Question 28

Describe atonic seizures.

Answer 28

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

Question 29

Describe tonic-clonic seizures.

Answer 29

• 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.

Question 30

Describe convulsions.

Answer 30

• 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.

Question 31

What is status epilepticus?

Answer 31

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

Question 32

What is an antiepileptic drug?

Answer 32

• 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.

Question 33

What is the current pharmacotherapy for epilepsy?

Answer 33

• 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.

Question 34

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

Answer 34

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

Question 35

Describe the cellular mechanisms of seizure generation.

Answer 35

Question 36

What are the targets for antiepileptic drugs?

Answer 36

• 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.

Question 37

Describe the role of glutamate in epilepsy.

Answer 37

• 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.

Question 38

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

Answer 38

• 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

Question 39

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

Answer 39

• Lamotrigine
• Sodium valporate
• Carbamazepine
• Oxcarbazepine
• Levetiracetam
• Topiramate

Question 40

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

Answer 40

• Phenytoin
• Ethosuxamide
• Phenobarbitone
• Vigabatrin
• Tiagabine

Question 41

Describe lamotrigine.

Answer 41

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

Question 42

Describe sodium valporate.

Answer 42

• 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)

Question 43

Describe carbamazepine.

Answer 43

• 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

Question 44

Describe oxcarbazepine.

Answer 44

• 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.

Question 45

What are the newer antiepileptic drugs?

Answer 45

• Levetiracetam
• Topiramate
• Tiagabine
• Zonisamide

Question 46

Describe levetiracetam.

Answer 46

• 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.

Question 47

Describe topiramate.

Answer 47

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

Question 48

Describe tiagabine.

Answer 48

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

Question 49

Describe zonisamide.

Answer 49

• Blocks sodium channels, can cause anorexia and somnolence.

Question 50

Describe phenytoin.

Answer 50

• 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.

Question 51

Describe ethosuximide.

Answer 51

• 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.

Question 52

Describe phenobarbitone.

Answer 52

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

Question 53

What are the first line treatments for status epilepticus?

Describe the mechanism of action.

Answer 53

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

Question 55

What is felbamate?

Answer 55

• 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.

Question 56

What is vigabatrin?

Answer 56

• 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

Question 57

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

Answer 57

• 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.

Question 58

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

Answer 58

Question 59

What is the treatment for status epilepticus?

Answer 59

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

Question 60

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

Answer 60

• 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.

Question 61

Describe baclofen.

Answer 61

• Selective agonist on GABA_B-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.