epliepsy case Flashcards
what is the normal physiology of sleep
Our bodies all require long periods of sleep in order to restore and rejuvenate, to grow muscle, repair tissue, and synthesize hormones. Memory is formed, and the brain is able to react to events of the previous day(s).
what is meant by entrainment
Entrainment is the process by which an environmental rhythm, such as the light-dark cycle, regulates the period and phase relationship of a self-sustained oscillator.
what is meant by circaidan (slave) oscillator
can drive a rhythmic output but requires other oscillators (known as pacemakers) for its entrainment and/or function. A slave oscillator can therefore be self-sustained but cannot operate properly independently of other oscillators.
what is meant by A zeitgeber
is any external or environmental cue that entrains, or synchronizes, an organism’s biological rhythms to the Earth’s 24-hour light-dark cycle and 12-month cycle. Regular meal times and light are zeitgebers.
describe the circadian rhythm
2am - deepest sleep 4-5am - lowest body temp 6-7am - sharp rise in BP 7-8am - secretion of melatonin stops 9am - high level of testosterone secretion (in males) 10am - high alertness 2-4pm - optimal coordination & reaction time 6-7pm - highest BP and body temp 9pm - melatonin secretion starts
what disturbs the circadian rhythm
The circadian rhythm is disturbed by exposure to 450-500nm light at night or lack of light exposure in the morning.
what regulates the body clock
Many areas of the body are involved in regulating the body’s clock. The primary mechanisms involve the timing of food consumption and the natural light-dark cycle. The following have roles in maintaining the circadian rhythms: cardiovascular tissue, liver, kidney, pancreas, gut, muscle and fat tissue.
what is the Suprachiasmatic nucleus (SCN)
The SCN is the small area above the optic chiasm in the anteroventral region of the hypothalamus. It is the master body clock and regulates other circadian rhythms; it is a circadian pacemaker. The master clock in the SCN is composed bilaterally paired nuclei which contain 8,000–10,000 clock cells packed closely together. The SCN receives light information via the retino-hypothalamic tract (RHT).
what is meant by the entrained SCN and what doe it do?
The entrained SCN coordinates the timing of slave oscillators in other areas of the brain (e.g. cortex) and peripheral organs (heart, liver), regulating brain homeostasis, peripheral metabolism (glucose homeostasis), vascular & peripheral regulation, and peripheral inflammation. The SCN also regulates amyloid plaque breakdown/ removal.
what is the role of melatonin
Entrainment is mediated by melatonin, a naturally occurring hormone which induces sleep. It is released in response to low levels of light.
how does melatonin induce sleep
Light is detected by the photoreceptors of the retina, including the rods and cones as well as photosensitive retinal ganglion cells (pRGCs), expressing the photopigment melanopsin. A signal is output to the SCN via the retino-hypothalamic tract (RHT), where it entrains an intracellular clock mechanism consisting of positive (BMAL1 and CLOCK) and negative (PER1/2 and CRY1/2) elements. The SCN projects excitatory information to the paraventricular nucleus (PVN). Long axons send nerve pulse to the preganglianic sympathetic neurons in the spinal cord. This modulates the activity of the superior cervical ganglia, projecting to the pineal gland and regulating melatonin secretion. The CLOCK genes operate on a negative feedback system; the under-lying principle of circadian clocks is successive gene activation in the form of a cycle: the initial activation of a gene is regulated by the last one in the sequence, making up an auto-regulatory feedback loop for which one cycle takes about 24-hours.
what is meant by wakefulness
The neurotransmitters involved in maintaining wakefulness include acetylcholine, norepinephrine, serotonin, and histamine
The brain is kept ‘awake’ by the activity of the Ascending Reticular Formation. The ascending reticular formation projects to the thalamus and cerebral cortex. It exerts some control over which sensory signals reach the cerebrum and come to our conscious attention. For example, if a loud sound is heard during sleep, the signal is received as an auditory impulse. Reticular formation radiates to the cerebral cortex, resulting in waking. Lesions to this brain area leads to constant sleep.
how are arousal signals stimulated
Cholinergic (ACh) cell groups in the upper pons – pedunculopontine (PPT) and laterodorsal tegmental nuclei (LDT) – and project through the thalamus and facilitate thalamocortical transmission of arousal signals.
what is involved in the second pathway of arousal signals
A second pathway involves the hypothalamus and cortical centres. It facilitates processing of thalamocortical inputs from midbrain centres.
The following areas of the brain, and neurotransmitters are involved:
• Locus coeruleus, LC / noradrenergic
• Raphe / serotonergic
• Tuberomammillary nucleus, TMN / histaminergic
• Ventral periaqueductal grey matter, vPAG / dopaminergic
• Basal forebrain BF / GABA and ACh
• Lateral hypothalamus, LH / orexin – aka hypocretin – and melanin concentrating hormone
During sleep, the ventrolateral preoptic (VLPO) nucleus of the hypothalamus sends descending GABAergic inhibitory signals to the midbrain’s arousal centres, turning them off.
list the steps during the sleep cycle
A complete cycle of sleep is 90-110 minutes and is divided into 5 stages.
•Stage 1 - Light sleep. Muscle activity slows with occasional twitching
•Stage 2 - Breathing and HR slows. Slight decrease in body temperature. ~50% of sleep is stage two
•Stage 3 - Deep sleep begins. Brain generates slow delta waves
Stage 4 - Very deep sleep. Rhythmic breathing with limited muscle activity. Delta waves are produced.
Stage 5 - Rapid eye movement (REM). Brainwaves speed up and dreaming occurs. There is an increase in HR and breathing is rapid and shallow. ~20% of sleep is REM sleep. The first sleep cycles have relatively short periods of REM and long periods of deep sleep but later in the night, REM periods lengthen, and deep sleep time decreases.
what does EEG measure
Electroencephalography (EEG) is the measurement of electrical activity produced by the brain (cerebral cortex). It can be recorded from electrodes placed on the scalp.
what does gamma waves measure during the sleep cycle
Gamma waves (40-100 Hz) are involved in higher processing tasks as well as cognitive functioning.
what does the alpha waves measure during the sleep cycle
Alpha waves (9-14 Hz) bridge the gap between our conscious thinking and subconscious mind, promoting deep relaxation.
what does the theta waves measure during the sleep cycle
Theta waves (4-8 Hz) are involved in daydreaming and stage 1 sleep.
what does the delta waves measure during the sleep cycle
Delta waves (0-4 Hz) are the slowest recorded brain waves in human beings.
They are associated with the deepest levels of relaxation and restorative, healing sleep. They have also been found to be involved in unconscious bodily functions such as regulating heart beat and digestion; blood pressure, respiratory rate and basal metabolism is reduced by 10-30%. Less delta waves are produced as humans age.
Delta waves are produced in stages 3 and 4 (slow-wave sleep). During slow-wave sleep, the same neurons that are active during the day become re-active. Slow-wave sleep is implicated in memory consolidation. Long-term potentiation occurs in the synapses that are activated and are strengthened. In the elderly, stage 3-4 sleep is less commonly experienced, and there is increased cycling between stages and waking.
describe how neuromodulators modulate neurone transmitters
Neuromodulates modulate neurotransmitters. When a neuron is active, it generates ATP.
ATP signalling can regulate both excitatory and inhibitory neurotransmission. ATP surges during the initial hours of sleep, displaying a significant positive correlation with the intensity of slow-wave activity in non-rapid eye movement (NREM) sleep.
Intracellularly, ATP is metabolized to ADP then to AMP, then to adenosine.
what does the adenosinergic regaulation predominately mediate?
The adenosinergic regulation of sleep is predominantly mediated either via A1 inhibitory receptors (A1Rs). This activates purinergic receptors on glial cells, causing the release of low-levels of cytokines, such as TNF- and IL-ß1, and glutamate. They activate their own receptors, and can activate the transcription factor, NF-kB. This causes increased expression (insertion) of inhibitory A1 receptors on the post-synaptic neuron, altering the sensitivity of neurons. Thus, adenosine regulates either the amount of sleep or sleep homeostasis in multiple ways depending on the brain area and receptor subtype.
how are sleep regulatory substances involved in the synaptic scaling
Sleep-regulatory substances are involved in synaptic scaling, which increases or decreases the efficiency of synaptic efficiency. Events or skills are remembered if they are novel or emotional, mediated by the brain itself. If the brain decides the event is not important, the synapse is depressed; if the brain decides something is worth remembering, synapses stay active (potentiated) or depressed.
what is narcolepsy
Narcolepsy is a rare sleep disorder (0.02-0.06) characterised by excessive daytime sleepiness. It is possibly an autoimmune disorder caused by hypocretin deficiency.
how does wake promoting drugs work
Amphetamines, methylphenidate and modafinil all act on the dopamine (DA)-reuptake transporter in the vPAG. They directly prevent the reuptake of dopamine and noradrenaline. Increased synaptic dopamine activates the cerebral cortex to maintain wakefulness. WPDs also indirectly increase serotonin, glutamate, histamine and orexin levels & decrease the levels of GABA, through the hypothalamus & cortical pathway in the midbrain (see above).
Caffeine is an adenosine receptor antagonist, blocking the A1a receptor therefore reducing the inhibitory effects of adenosine.
what is meant by insomnia
Insomnia is a difficulty in initiating or maintaining sleep. In adolescence, insomnia is commonly a result of circadian rhythms maladjustment. It may be transient (e.g. jet lag), short-term (e.g. stress) or chronic (e.g. psychiatric illness). Insomnia has many causes: physical (pain); physiological (shift work, noise, caffeine); psychological (stress), psychiatric (depression) and iatrogenic (ß-blockers).
what are some of the side effects associated with insomnia
Too little sleep increases likelihood of developing a cold, worsen symptoms of inflammatory bowel disease/ acid reflux and deplete sex drive. Sleep deprivation is linked to visual disturbances, such as tunnel vision; the longer one is awake, the more likely they are to experience hallucinations. In addition, poor sleep can affect memory and learning, headaches and irritability.
Insomnia is linked to psychiatric disorders, such as anxiety and mood disorders.
Patients should be educated to have realistic sleep expectations and should be advised to find and treat the underlying cause of insomnia. This includes considering alcohol, drug and caffeine use. However, pharmacological interventions can be made.
what are hypnotics
Hypnotics induce sleep by modulating the effects of GABA at the GABAa receptor, causing sedation.
describe the MoA of benzodiazepines
Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or causing the patient extreme distress.
Acting on GABAa chloride channels (on the gamma subunit), they induce Cl- conduction, inhibiting the AP. This enhances the action of the inhibitory neurotransmitter, GABA, causing sedation. BDZ induce and increase the duration of sleep.
Benzodiazepine-derivatives are not traditional BDZ but have BDZ activity.
name 2 Benzodiazepines (BDZ) and their dose strength
Diazepam 5–15 mg ON
Temazepam 10–20 mg ON
what are the side effects associated with Benzodiazepines (BDZ)
BDZ depress REM and slow-wave sleep, so quality of sleep and memory formation is negatively affected. As a result, continuous use can cause amnesia, ataxia (movement disorders) and impaired memory/ cognition. In the elderly, hypnotic use is attributed to an increased risk of falls and confused state. Hypnotics should be used for a maximum of two weeks, so REM deprivation does not occur.
Paradoxical effects occur in < 1% of patients. It causes increased excitement, excessive talking, restlessness, agitation and aggression. If these occur, flumazenil, a competitive benzodiazepine antagonist at GABAa, can be given.
There are various factors which may predispose one to these effects, including:
Very young/ very old – varying pharmacokinetics
Alcoholism – effect on GABA
Psychiatric disorders
Genetic polymorphism affects response
what are the counselling points for someone who is on BDZ?
Patients should be advised not to drive, because the sedative effects of BDZs can impair concentration. As of 2015, “driving, attempting to drive, or being in charge of a vehicle, with certain specified controlled drugs in excess of specified limits” is an offence. One can be prosecuted unless the drugs was prescribed and there is no effect of impairment on driving.
Patients should be warned of the risks of dependence; it can occur within a 7-10 days and. If suspected, the patient should begin gradual withdrawal. Withdrawal symptoms include confusion, psychosis, convulsions or tremors.
Withdrawal syndrome occurs more rapidly for short acting DBZ; withdrawal may occur up to three weeks after abrupt withdrawal in longer-acting agents.
- Transfer patient stepwise, one dose at a time over about a week, to an equivalent daily dose of diazepam preferably taken at night.
- Reduce diazepam dose, usually by 1–2 mg every 2– 4 weeks. If uncomfortable withdrawal symptoms occur, maintain this dose until symptoms lessen.
- Reduce diazepam dose further, if necessary, in smaller steps of 500 micrograms. Then stop completely.
- For long-term patients, the period needed for complete withdrawal may vary from several months to a year or more.
name a Non-benzodiazepine hypnotics – Z-drugs drugs and describe how do they work
Zolpidem tartrate and zopiclone are non-benzodiazepine hypnotics (sometimes referred to as Z-drugs), but they act at the benzodiazepine receptor. They are not licensed for long-term use; dependence has been reported in a small number of patients. Both zolpidem tartrate and zopiclone have a short duration of action.
name a anti-cholinergic agent and describe how do they work
Diphenhydramine is an anti-histamine with anti-muscarinic activity (antagonist at H and M receptors). It crosses the blood-brain-barrier that blocking the arousing influence of central histamine causing drowsiness and promoting sleep. It may have effects on 5-HT1 receptor
CNS-acting dopamine antagonists (SGA antipsychotics) have a sedative action due to histamine receptor occupancy.
describe how barbiturates work
The intermediate-acting barbiturates should only be used in the treatment of severe intractable insomnia, in patients already taking barbiturates. They should be avoided in the elderly.
what are melatonin receptor agonists
A potential new treatment (still in clinical trials) involves enhancing the activity of melatonin.
explain why alcohol is a poor hypnotic
Alcohol depresses neuronal activity – it is an agonist at GABAa receptors and a antagonist at NMDA receptors (for electrical signals to pass, the NMDA receptor must be open and to remain open, glutamate and glycine must bind to the NMDA receptor – antagonist action prevents NMDA activation). Alcohol is a poor hypnotic because the diuretic action interferes with sleep during the latter part of the night. Alcohol also disturbs sleep patterns, and so can worsen sleep disorders. Using alcohol with hypnotics may cause respiratory depression due to CNS toxicity.
define epilepsy
Epilepsy is a neurological condition characterised by uncoordinated electrical activity of the brain. Recurrent epileptic seizures are unprovoked by any immediately identifiable cause.
Epilepsy affects ~65m worldwide, and there is a 5% lifetime risk of seizures.
what are the risks of developing epilepsy
The risk of developing epilepsy increases in age; this is due to stroke and neurodegeneration.
what is meant by an epileptic seizure
An epileptic seizure is abnormal electroactivity. Convulsions associated with epilepsy result from the repeated triggering of a neuronal circuit. The convulsions tend to last 1-2 minutes, and the seizure is followed by a postictal state (recovery, which may last minutes to hours).
list some of the causes of epilepsy
- Hypo/hyperglycaeimia
- Hypo/hypernatraemia
- Hypocalcaemia
- Hypomagneseamia
- Uraemia
- Drugs (phenothiazines, benzodiazepine withdrawal, antibiotics, antidepressants, EtOH, tramadol, antiepileptics, ciclosporin, cocaine, lithium, inteferons, barbiturates)
- Meningitis
- Encephalitis
- Head trauma
- Space Occupying Lesion
- Stroke / TIA
- Genetics (polygenetic)
- Epileptogenisis
what are the presentations of epilepsy
Syncope, where insufficient blood to the brain caused the patient to faint
Hyperventilation
Migraine
Panic attack
Pseudo seizure (non-epileptic attack), which is where a patient presents with a convulsion in the absence of abnormal electroactivity; it is thought to be a psychological issue
Transient global amnesia
Transient ischaemic attack
what is the prognosis of epilepsy
Remission is defined as achieving a 5-year seizure-free and 5-year medication-free period. Any subsequent seizure for any reason was considered a relapse. Complete remission at last contact was defined based on the date of last seizure and date seizure medications were completely stopped. Prognosis is highly dependent on the number of seizures experienced during the first 6 months of epilepsy; the higher the number of seizures, the less likely are the chances of remission.
Half of patients remit with 1 anti-epileptic drug (AED), 1/3 of the remainder remit with 2nd AED and ~ 10% of remainder remit with 3rd AED.
what are the two categorises of epilepsy
There are two broad categories of epilepsy: Generalised (global) and Partial (focal).
what is meant by generalised epilepsy
Generalised epilepsy affects the whole brain. The following types of epilepsy fall under this category:
•Absences (petit mal)
•Tonic-clonic (grand mal)
•Myoclonic (Juvenile myoclonic epilepsy)
•Tonic
•Akinetic – all muscle tone is lost, resulting in falls thus risk of head injury
what is meant by partial epilepsy
Partial epilepsy affects a local area of the brain. The following types of epilepsy fall under this category:
•Simple – consciousness is maintained, so the patient is aware of the seizure
•Complex – impaired awareness
•Secondary generalised (aka Focal to bilateral tonic-clonic seizures) – starts local, then becomes generalised
what age group is absence seizures most common and what is the cause of it
This type of seizure is most common in children aged 4-8. It is caused by a developmental abnormality.
what are the characteristics of an absence seizure
A typical absence seizure is characterised by a sudden loss of awareness, but the patient remains conscious. The seizure is sometimes associated with automatisms – repetitive, purposeless movements of the fingers, hands or mouth, such as some lip-smacking. There may also be eyelid flickering or fluttering.
how long does absence seizure last for?
Absence seizure usually lasts between 5 and 15 seconds and usually stops as suddenly as it starts; absences that last longer than 15 or 20 seconds or that have a lot of automatisms are called ‘atypical’ absences.
Absence seizures tend to happen more commonly when the child is bored, sitting quietly or when they are tired or unwell. They happen less often when the child is busy or focused on an activity that they enjoy.
how do you go about diagnosing absence seizures
The only diagnostic test for absence seizures is the EEG; a patient with absence epilepsy has similar electrical pattern of activity to a healthy patient during non-REM sleep. Atypical absence seizures are characterized by slow spike-and-wave paroxysms, classically 3 Hz.
what 3 things are considered to be the underlying mechanism of absence seizures
The thalamic relay neurons, reticular thalamic nucleus, and neocortical pyramidal cells form a circuit that sustains oscillatory burst firing and is regarded as the underlying mechanism of absence seizures.
how does the T- type calcium channels play a key role in the circuit that causes absence seizures
T-type calcium channels – CaV3 –play a key role in this circuit, as the pacemaker. It provides an inward, positive current into the neurone that brings the membrane up to a threshold of action potential firing.
describe how the T- type calcium channels plays a key role in the mechanism of absence seizures?
CaV3 are activated on at low voltages (similar to the resting membrane potential, -40mV). At low voltages, the activation gate can sense changes in voltage.
When the threshold for VgCa2+ is reached, channels open and there is an influx of Ca2+, resulting in depolarisation of the membrane.
This depolarisation causes the threshold for VgNa+ channels to be met; channels open and there is an influx of Na+, resulting in further depolarisation. VgNa+ channels are only open for a short time before closing.
At depolarised potentials, the threshold for opening VgK+ is met; channels open and there is an efflux of K+, causing hyperpolarisation of the membrane.
how does the concentration of calcium ions build up in the mechanism of absence seizure
With repeated APs, intracellular calcium concentration builds-up. Calcium can be cytotoxic leading to neuronal death, so cells have several mechanisms for removal. CaV3 has an inactivation gate which is sensitive to voltage and calcium concentration.
When calcium channels rise, calcium-dependent inactivation occurs; Ca2+ channels close, and no longer contributes to pacemaker neuronal firing. Gates will not reopen until the cell becomes hyperpolarised
. Calcium-activated potassium channels (KCN) are also present in the membrane. This conducts potassium from the inside to the outside, taking the cell to very hyperpolarised potentials, resetting CaV3 (voltage-sensitive).
name the 2 modes in which the thalamic neurone can fire
tonic and burst mode.
how does the thalamic neurone work in absence seizures
- When the thalamic neurone is firing in tonic-mode, information can be transmitted to the cortex, and one is conscious. The thalamic relay neuron receives inputs from other neurons via neurotransmitters, causing depolarisation of the cell & the threshold for VgNa+ is reached – without the need for a pacemaker. Because the membrane is depolarised, there is no Ca2+ entry to the cell. Therefore, there is no calcium-activated potassium channel activation and firing is constant.
- When the thalamic neurone is firing in burst-mode, information cannot be transmitted to the cortex, and one is unconscious. Burst firing is seen when the CaV3 channels are activated from a hyperpolarized state (KCN), allowing for low-threshold depolarization of neurons which creates bursts of action potentials through voltage-gated sodium channels.
how is the transition from tonic to burst firing implicated in absence seizures
The transition from tonic firing to burst firing is implicated in absence seizures. In absence epileptic patients, the thalamic neurones may prefer to fire in the burst-mode due to genetic variation of the Ca2+ channel, where the calcium or voltage sensitivity is disturbed.
The brain has ~ 100 billion neurons. Neurotransmitters include acetylcholine, dopamine, serotonin, glutamate and GABA.
Glutamate is the most abundant excitatory transmitter
what is TRet and TRel
TRet = thalamic reticular neuron TRel = thalamic relay
how is GABA involved in absence seizures
GABA is the most abundant neurotransmitter and is inhibitory. The abundance of GABA means that the brain is in a highly suppressed state. There are two types of GABA receptor:
GABAa is ligand-gated receptor which conducts Cl- from outside-in (influx). The influx of negative ions hyperpolarises neurons, inhibiting neuronal firing.
GABAb is G-coupled protein receptor. It is inhibitory, reducing cAMP and activating K+ channels causing a movement inside-out. The efflux of positive ions hyperpolarises neurons, inhibiting neuronal firing.
