Epilepsy 2

Question 1

What is epilepsy?

Answer 1

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

Question 2

What percentage of children experience one or more seizures (mostly benign febrile convulsions)?

Answer 2

2-5%

Question 3

What is the prevelance of ‘active’ epilepsy?

Answer 3

• about 0.5 - 1% of the adult population have ‘active’ epilepsy.
• the prevalence is slightly higher in men than in women.

Question 4

What is the incidence of epilepsy?

Answer 4

about 0.1% of the total population

The incidence of epilepsy is high in children and also in the elderly.

Question 5

The symptoms/presentation of the epilepsy will depend on what factors?

Answer 5

• The CNS region(s) in which the electrical seizure occurs.
• Whether the seizure is localized or general.
• If localized initially, whether the seizure then spreads to other regions of the CNS.

Question 6

When is a seizure referred to as partial, primarily generalized and secondarily generalized?

Answer 6

A seizure is said to be PARTIAL (localized, focal) if the seizure is restricted to a limited region

PRIMARILY GENERALIZED if most of the CNS is involved but no focus can be distinguished

SECONDARILY GENERALIZED if most of the CNS is involved eventually but the excitation has spread from an initial focus

Question 7

What determines whether a partial seizure is described as simple or complex?

Answer 7

A partial seizure is said to be SIMPLE if the subject remains conscious and aware

COMPLEX if consciousness is impaired.

Question 8

What is an ‘aura’?

Answer 8

Siezures are frequently preceded by an ‘aura’: a feeling or experience that warns the subject of an impending seizure.

Question 9

What is an absence seizure (old name: petit mal)?

Answer 9

• A primarily generalized seizure that is common in children
• Characterised by sudden loss of awareness lasting up to about 30 sec.

Question 10

What is a Tonic-clonic seizure (old name: grand mal)?

Answer 10

A generalized seizure lasting 2 - 5 minutes

• characterized by sudden stiffening (‘tonic’) of muscles, a fall, followed by jerking (‘clonic’) movements.

Question 11

What is a simple partial seizure?

Answer 11

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

Question 12

What is Temporal lobe epilepsy?

Answer 12

• 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 a complex partial seizure where the seizure spreads throughout the temporal lobe impairing consciousness and may be secondarily generalized to provoke a tonic-clonic seizure. This is the commonest form of epilepsy

Question 13

What is status epilepticus?

Answer 13

When a seizure does not spontaneously stop but continues or repeats for a period of 30 min or more the condition is termed status epilepticus and is life-threatening.

Question 14

What are epilepsy syndromes?

Answer 14

Epilepsies, especially childhood epilepsies, can sometimes, further classified as ‘syndromes’ which are collections of signs and symptoms that more closely identify the particular conditions. Better definition helps to achieve the optimum therapeutic approach definition helps to achieve the optimum therapeutic approach.

Factors that are considered on defining a syndrome include the type and pattern of seizures their frequency the location of seizures, their frequency, the location of the focus, physical and mental symptoms, the age of onset and gender of the patient and prognosis.

There are at least 40 identified epilepsy syndromes.

Question 15

What are the causes of epilepsy?

Answer 15

• most cases not known (idiopathic) or cannot be proven (cryptogenic).

About 30% of cases are symptomatic i.e. the seizures occur following:

• head injury (often after a delay)
• stroke
• infection
• tumour growth
• drug abuse.
• 2-3 fold increase in the chances of developing epilepsy if you have a close relative who suffers from the disease but clear genetic links have been difficult to trace suggesting multiple genes or environmental factors are involved.
• ‘Benign febrile epilepsy’ is linked to mutations in KCNQ2 and KCNQ3: genes that encode voltage gated potassium KCNQ3: genes that encode voltage-gated potassium channels.
• Familial generalized epilepsy with febrile seizures plus is linked to mutations in SCN1B, a gene that encodes an accessory subunit of the voltage-gated sodium channel.

Drug-induced: many drugs have pro-convulsant effects.

Question 16

What animal models are used in epilepsy research?

Answer 16

1. Kainic acid (KA) injection.
   - Local (e.g. intrahippocampal) or systemic injections of KA can induce seizures in animals and lead to chronic epileptic behaviour.
2. Kindling.
   - Repeated low intensity electrical stimulation (usually in the amydgala or hippocampus) of some brain regions leads after a delay, to development of chronic epileptic behaviour. The frequency of the kindling stimulus is critical.

Studies using these (and many other: pentylenetetrazol injection; electroshock) models suggest that the focal synchronous excitation that occurs to initiate a seizure involves (a) increased synaptic transmission and (b) decreased surround inhibition.

Question 17

What is the cellular event that initiates a focal seizure?

Answer 17

paroxysmal depolarizing shift (PDS).

Question 18

Upon what do the rise and curtailment of depolarisation in the PDS depend?

Answer 18

The rise (depolarizing phase) of the cellular PDS depends on:         - activation of ionotropic glu receptors (AMPA and NMDA)
- opening of voltage gated Ca2+ channels.

Curtailment of the PDS and repolarization depends on:

• opening of voltage-gated K+ channels
• activation of ionotropic GABA receptors

Question 19

What causes a paroxysmal depolarising shift (PDS)?

Answer 19

The mechanism by which the PDS is initiated is not known but the ability of the PDS to spread to neighboring cells to generate a synchronous focus implies a failure of inhibitory feedback through local interneurons focus implies a failure of inhibitory feedback through local interneurons. (Poor surround inhibition)

Epilepsy is often described as being due to an “imbalance” between glutamate mediated excitation and GABA mediated inhibition which has led to attempts to develop drugs that inhibit glutamate or enhance GABA as potential therapeutic agents.

Question 20

What are the differences in nervous transmission when surround inhibition is present or not present?

Answer 20

No surround inhibition:
- diverging synaptic connections of neurones in a ‘relay’ nucleus can lead to spreading as well as blending of information flowing out

Surround inhibition present:
‘surround inhibition’ mediated by interneurons through feedback pathways has the effect of limiting spread of the ‘input’ signalling i.e. it has a focusing effect.

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.

Question 21

What drugs which enhance the activity of GABAergic systems do we use or tonic-clonic, partial, temporal lobe seizures – may provoke absences?

Answer 21

Benzodiazepines (e.g. diazepam, clonazepam)

• enhance the activity of GABA.
• bind to a regulatory site on the GABA receptor
• increase the affinity of the receptor for GABA.

Barbiturates (phenobarbitone)
- prolong the time that GABA-activated Cl channels stay open when the GABA receptor is occupied.

Vigabatrin
- inhibits GABA transaminase (decreases metabolism of GABA).

Tiagabin
- inhibits GABA uptake (increases the concentration of GABA in the extracellular space)

Benzodiazepines are given intravenously to treat status epiliepticus but are usually too sedative for prophylactic use in other epilepsies although oral BDZs are used sometimes in patients who do not respond well to other treatments.

Question 22

What drugs which involve Use-dependent block of voltage-gated sodium channels do we use or tonic-clonic, partial, temporal lobe seizures – may provoke absences?

Answer 22

Carbamazepine, phenytoin, lacosamide:

These drugs will reduce the likelihood of action potentials firing g p g at high frequencies but have relatively little effect at low frequencies. (Increase refractory period?)

Their binding (and hence blocking action) to the voltage-gated sodium channels is state-dependent.

(Use-dependent blockers of sodium channels bind to and stabilize the inactivated state of the channel which increases the refractoriness of the cell and limits the maximum frequency at which the cell can fire. Some drugs may also have affinity for the open state of the channel and combine an open-channel blocking action with prolongation of inactivation.)

Question 23

Which drug is used to treat absense seizures only?

Answer 23

Ethosuximide:

• Mechanism uncertain.
• Thought to work by blocking T-type voltage-gated Ca2+ channels in thalamic neurons.
• These channels are important for the generation of rhythmic activity in the neurones.
• Not useful for tonic-clonic seizures

Question 24

Which drugs are useful for both tonic-clonic and absence seizures?

Answer 24

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.

Question 25

How do Gabapentin and pregabalin work?

Answer 25

Mechanism is uncertain but the molecular target is known to be the alpha2delta-subunit of voltage-gated Ca2+ channels so they probably work by compromising neurotransmitter release.

Question 26

How does Retigabine (Ezogabine in USA) work?

Answer 26

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.

Question 27

How does Perampanel (approved in EU not USA @2012, felbamate) work?

Answer 27

Thought to act as antagonists of AMPA receptors (ionotropic glutamate receptors).

Question 28

How do Levetiracetam, topiramate and zonisamide work?

Answer 28

Mechanism(s) uncertain - levetiracetam binds to a synaptic | vesicle protein called SV2A so it may affect neurotransmission.

Question 29

How do you know what drug to give in epilepsy?

Answer 29

The usefulness of individual agents for different epileptic conditions is varied and based on clinical experience - general rules are difficult to define or apply. Many drugs are useful given alone (monotherapy e.g. carbamazepine, phenobarbitone, ethosuximide, sodium valproate, topiramate) whilst 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 tonic-clonic seizures. Sodium valproate and lamotrigine are potentially useful for both classes of seizure. Monitoring dose and the potential for drug interactions is very important

Question 30

What role might kerogen if diet play in epilepsy treatment?

Answer 30

It is 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 therap is not sufficiently effective.

Question 31

What is the role of vagus nerve stimulation (VNS) in the treatment of epilepsy and how is it though to work?

Answer 31

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. - thought to be by NA release through brain from locus sorelius

Question 32

What role can surgery play in the treatment of epilepsy?

Answer 32

Removal of tissue that harbours a recurrent focus or to limit spread of excitation. (Only if all else fails - may even cut corpus callosum to localise the focus.)

Question 33

List the inhalational general anaesthetics that you know

Answer 33

``` Volatile liquids: • sevoflurane • isoflurane • desflurane • halothane • ether (obsolete) • chloroform (obsolete) ``` Gases: • nitrous oxide (Entonox with 50% O2) • xenon (expensive uncommon) gases

Question 34

List the injectable general anaesthetics that you know

Answer 34

* propofol * etomidate * thiopental sodium (rarely used) * ketamine (rarely used -paediatric)

Question 35

How would and ideal general anaesthetic act and what would its properties be?

Answer 35

An ‘ideal' general anaesthetic drug will cause: • Analgesia • Suppression of nocifensive reflexes and stress responses • Immobility • Amnesia ``` and will have: • A rapid onset of action • A rapid recovery • Minimal after effects • Minimal drug interactions • Minimal side-effects ``` (No single drug satisfies these ‘ideal' criteria adequately so usually a combination of drugs is used to achieve a state y g of general anaesthesia that is suitable for surgery.)

Question 36

Administration of a general anaesthetic provokes a series of biological responses known as ‘stages' of anaesthesia. What are these stages?

Answer 36

Stage 1: Analgesia. Stage 2: Disinhibited responses (delirium) Stage 3: Surgical anaesthesia, this stage is divided into 4 ‘planes'. Stage 4: - overdose - medullary depression - respiratory and circulatory failure

Question 37

What does an EEG look like in general anaesthesia?

Answer 37

Drug-induced general anaesthetic states resemble non-REM sleep states - Mean frequency gradually decreases - increasing depth of anesthesia. - Mean EEG amplitude increases initially and then decreases

Question 38

What brain areas do general anaesthetics particularly affect?

Answer 38

General anaesthetics affect some brain regions more than others – especially cortical regions and thalamus inhibition of activity in the cerebral cortex especially in regions of: - parietal cortex - occipital cortex

Question 39

What causes the cortical inhibition in general anaesthesia?

Answer 39

Cortical inhibition: - partly a direct effect - also secondary to inhibition (hyperpolarization) of thalamic neurones. - Turning off of a thalamic ‘switch' mechanism isolates the cortex from sensory input. Activity originating in ‘arousal' nuclei e.g. from the reticular activating system in the brainstem that would normally excite thalamic relay neurones is also suppressed

Question 40

What did Meyer and Overton note ca 1900?

Answer 40

Meyer and Overton, ca 1900, 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. But this idea cannot explain why some anaesthetics have stereospecific actions or why there is a ‘cut-off' with respect to molecular size – anaesthetic potency falls off after a critical molecular size.

Question 41

What is MAC?

Answer 41

MAC is a measure of potency of volatile and gaseous anaesthetics and is the minimum end-tidal alveolar concentration necessary to prevent a reaction in 50% of patients subjected to a surgical incision.

Question 42

What is Oil gas partition coefficient?

Answer 42

a measure of how soluble the anaesthetic is in oil/fat.

Question 43

What did Franks and Leib (1984) find?

Answer 43

Franks and Leib (1984) showed that the ability to block the activity of the enzyme firefly luciferase in an aquaeous environment q correlated with anaesthetic potency in animals. Also, the blocking effect, like the anaesthetic effect was stereospecific which was a better match to data that the Meyer and Overton idea This has led to the more modern ‘protein hypothesis' that anaesthetics bind to a lipophilic ‘pocket' in membrane – most probably ion channels

Question 44

How are GABA receptors involved in general anaesthesia?

Answer 44

Most therapeutically useful general anaesthetics: - enhance the activity of GABA at GABA ionotropic receptors - can directly activate the Cl- channel of the receptor at high concentrations.

Question 45

What effect can the introduction of specific point mutations into GABA subunits have on general anaesthesia?

Answer 45

The introduction of specific point mutations into GABA subunits can reduce the efficacy of most general anaesthetics. The subunit composition of the GABA receptor can affect the selectivity of individual agents. This is an especially important mechanism for causing loss of consciousness and deactivating the thalamic ‘switch ‘to isolate the cortex from sensory input.

Question 46

How is activation/opening of Two Pore domain K+ channels involved in general anaesthesia?

Answer 46

Some general anaesthetics open K + channels that stabilize the membrane potential. Two pore domain K + (2PK) channels are a large family of K + channels that stabilize the membrane potential at negative values thereby inhibiting depolarization. Acronyms for the family members include TASK and, TREK. 2PK channels are normally opened or closed by a variety of stimuli e.g. more acid pH inhibits TASK channels. The effect is anticipated to have a general inhibitory effect in neurones Effects of 2PK channels may also account for some effects of general anaesthetics on other systems e.g. cardiovascular system

Question 47

What role does Antagonism / block of NMDA receptor activity have in general anaesthesia?

Answer 47

Some general anaesthetics decrease the activity of NMDA receptors (ionotropic glutamate receptors). NMDA receptors are one of the main types of ionotropic 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)(eg. Ketamine) The mechanism is uncertain but there is evidence that anaesthetics work at the 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 necessary for normal function of the NMDA receptor) This is an especially important mechanism for the analgesic effect by blocking nociceptive sensory input at the level of the spinal cord.

Question 48

Which general anaesthetics work via increaaed GABA, decreased NDMA transmission and increased 2PK activity?

Answer 48

halothane desflurane Isoflurane sevoflurane

Question 49

Which general anaesthetics act by increasing 2PK channel activity and decreasing NMDA activity?

Answer 49

NO Xenon

Question 50

Which general anaesthetics act by increasing 2PK channel activity?

Answer 50

Ketamine

Question 51

Which general anaesthetics work via increaaed GABA, decreased NDMA transmission?

Answer 51

thiopental propofol etomidate

Question 52

How do IV general anaesthetics take effect in just seconds?

Answer 52

• To traverse the ‘blood-brain barrier' drugs must be lipophilic. - Intravenous anaesthetics are highly lipophilic - readily and rapidly absorbed by brain tissue causing rapid (i.e. in seconds) induction of anaesthesia.

Question 53

Reversal of the anaesthetic effects of a ‘bolus' injection occur by what mechanism?

Answer 53

- by redistribution to other tissues and metabolism.

Question 54

Why can propofol be used for longer operations than other IV general anaesthetics?

Answer 54

Most intravenous anaesthetics collect in muscle and fat and are unsuitable for long procedures (since saturating concentrations take a long time to eliminate). Propofol is an exception that can be used for total intravenous anaesthesia e.g. in day case surgery if given by intravenous infusion.

Question 55

What is different about the pharmocokinetics of inhalation all general anaesthetics as compared to IV?

Answer 55

• Inhalational anaesthetics have a second pharmacokinetic barrier to negotiate – alveolar absorption via a blood-gas interface. - This dictates the rate of onset of anaesthesia which is much slower for inhaled agents than for intravenous agents. - Paradoxically, drugs that have a low solubility in blood have the fastest induction rates and drugs that are very soluble in blood have slower induction rate

Question 56

Why are inhalational anaesthetics so useful, how are they administered and how Is reversal achieved?

Answer 56

- mainstay of surgical procedures and can be used in combination with other drugs to maintain surgical anaesthesia for very long periods. - Administered (sometimes as a mixture of anaesthetics) together with humidified O2 - Reversal is by excretion (exhalation) and metabolism.

Question 57

What does equilibration of the gas/vapour with the blood depend on?

Answer 57

- concentration of gas in the lungs - respiration rate - solubility in blood

Question 58

Why are inhalational general anaesthetics with a low blood soluablility faster to act?

Answer 58

• Low solubility drugs (N2O) saturate the low capacity of the blood quickly, breath by breath, which is then given up to the tissues readily to achieve an optimum concentration in the CNS.

Question 59

Why are inhalational general anaesthetics with a high blood soluablility slower to act?

Answer 59

• High solubility drugs (halothane) take longer, breath by breath, to saturate the relatively large blood capacity and are given up to the tissues less readily so induction takes longer

Question 60

Name four inhalational general anaesthetics in decreasing order of soluablility

Answer 60

N2O Cyclopropane Halothane ether

Question 61

Describe a typical use of drugs before, during and after an operation

Answer 61

Before: • Before surgery a narcotic analgesic (e.g.an opioid such as fentanyl) and an anxiolytic/sedative/amnesic (e.g. midazolam) may be administered. A muscarinic antagonist (e.g. hyoscine) may be used to reduce secretions. During the procedure • An intravenous induction agent (typically propofol) Is used for rapid induction of anaesthesia * A maintenance agent (e.g. sevoflurane with nitrous oxide) * A muscle relaxant* may be given to decrease unwanted movements including those due to reflexes (typically atracurium – respiratory assistance required). During recovery • An analgesic to reduce post operative pain (morphine) * An anti-emetic * An anticholinesterase (e.g neostigmine to reverse muscle relaxant) * Note: another drug called dantrolene is a muscle relaxant that works in a different way from the neuromuscular blocking agents and is used in anaesthesia to treat malignant hyperthermia which can occur occasionally as a complication of the use of volatile anaesthetics

Question 62

Define channelopathies and explain why they are relevant to epilepsy

Answer 62

* Channel - ion channel, including voltage-gated, ligand-gated etc. gated, ligand gated etc. * Pathy- dysfunction - genetic - autoantibodies (eg. Myasthenia gravis) - toxins - channels can act as lethal agents. A proportion of epilepsy may be due to mutations in ion channels.

Question 63

What are the causes of mutation?

Answer 63

* Radiation (UV, X-rays, microwaves?) * Infections (viruses) * Chemicals & toxins (tobacco tar) * Germline (error in replication of DNA) * Somatic (error in development) * Scientists (experimental tool)

Question 64

3 types of mutation?

Answer 64

Point mutation (Mis-sense) Nonsense mutation Frameshift mutation

Question 65

4 types of genetic disease?

Answer 65

* Autosomal Dominant - disease expressed in heterozygote * Autosomal Recessive - disease expressed in homozygote, heterozygote is a carrier * Dominant negative - mutant protein disrupts the function of normal protein * Haploinsuffiency - both genes required for full function

Question 66

4 examples of hyperexcitability of the nervous system?

Answer 66

- Hyperekplexia (Spinal cord) (receptor operated channels) - Erythromelalgia (peripheral sensory nerve) - (Voltage Gated Ion Channels) - GEF (CNS) - BFNC (CNS)

Question 67

What are the signs and symptoms of Hyperekplexia (Startle disease or Stiff Baby Syndrome)

Answer 67

Over active startle response •muscle spasm in response to unexpected stimuli • become rigid & fall over Exaggerated reflexes Hypertonia • increased muscle tone as infant (hypertonia)

Question 68

What are the genetics of hyperekplexia?

Answer 68

* Autosomal dominant * Genetic linkage chromosome 5q32 * same place as the gene for the glycine receptor * point mutation R271Q in GLRA1 Arginine at 271 to Glutamine or R271Q GLRA1 - glycine receptor alpha subunit 1 gene

Question 69

What is it that causes hyperekplexia?

Answer 69

Reduced glycinergic inhibition in the spinal cord

Question 70

What do you know about Familial Erythromelalgia (Weir Mitchell's disease)?

Answer 70

An idiopathic paroxysmal vasodilation of peripheral vasculature marked by sudden onset of burning pain in the hands and feet, diminution of temperature sense, and occasional glossalgia and feeding difficulty. The fingers and toes usually become red with thickened terminal phalanges and nail beds, and superficial veins are grossly engorged. Although sensitivity to temperature changes are diminished, cold acts as a pain depressor and heat as a stimulator. Most pronounced in the toes. Occurs equally in both sexes. Onset usually over middle age

Question 71

Main symptoms of Familial Erythromelalgia (Weir Mitchell's disease)?

Answer 71

• Burning pain in extremities in response to warm stimuli or moderate exercise

Question 72

Describe the genetics of Familial Erythromelalgia (Weir Mitchell's disease)

Answer 72

• Autosomal dominant chro2 • Linkage 2q31-32 • Gene SCN9A • • Point mutation • F1449V (phenylalanine at 1449 to valine) SCN9A sodium channel alpha subunit gene NaV1.7

Question 73

See page 14 of channelopafhies lecture for the mechanism of disease for familial erthethromelalgia

Answer 73

-

Question 74

What is Generalised Epilepsy with Febrile Seizures (GEFS)?

Answer 74

• convulsions * fever * 3% children under 6 • proportion go on to get generalised epilepsy in later life

Question 75

What are the genetics of Generalised Epilepsy with Febrile Seizures (GEFS)?

Answer 75

* Autosomal dominant * Linkage chromosome 19q13.1 * Same place as SCN1B • Same place as SCN1B * point mutation C121W SCN1B - sodium channel beta 1 subunit gene C121W - cysteine at 121 mutated to tryptophan Prevents formation of disulphide bridge in Beta subunit

Question 76

What is the role of the Beta subunits in voltage gated sodium channels?

Answer 76

Beta subunits are not pore forming or voltage sensing but can coassemble with the large alpha subunit. Beta subunits can alter inactivation kinetics of the alpha.

Question 77

What can the channelopathy of Generalised Epilepsy with Febrile Seizures (GEFS) (abnormally excitable sodium channel) explain? What can't it explain?

Answer 77

What the channelopathy can explain •Slower inactivation •Persistent inward sodium current •More depolarised membrane potential and hyperexcitability •Temperature dependence (Egri et al, 2012) What the channelopathy cannot explain •Why in most cases the symptoms resolve

Question 78

What do you know about Benign Familial Neonatal Convulsions (BFNC)?

Answer 78

* 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 (Similar risk as serious head injury)

Question 79

Genetics of BFNC?

Answer 79

• Linkage 20q13.3 • Same place as KCNQ2 * Frameshift mutation * 300 amino acid deletion * Non-functional potassium channel * Haploinsufficiency * Hyperexcitability

Question 80

What are the problems with gene therapy?

Answer 80

• Conceptually simple - replace defective gene with normal one. - But: • how do you get the gene into a cell * how do you get into the correct cell * how do you insert a gene into the genome without disrupting other genes * how do you ensure the gene is under the normal cellular controls (oncogene) * Some success in animal models, little clinical success so far.