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1

What is epilepsy?

Epilepsy actively affects about 1 in 200 people and is a tendency towards recurrent “seizures’.

A seizure is a convulsion or transient abnormal event from episodic discharge of high frequency impulses in the brain, or a part of it. Various types of seizures occur, their symptoms characterised by the location and extent of the discharges.

It is important to understand that having a single seizure is not sufficient to make a diagnosis of epilepsy. It is the tendency towards recurrent seizures that defines the condition. Many acute medical emergencies may present as tonic clonic seizures in response to traumatic, metabolic or infective processes. In these cases, there may be no underlying susceptibility to seizures.

Therefore the diagnosis of epilepsy can only be made if more than one attack occurs.

    Diagnosis requires evidence of recurrent seizures unprovoked by other identifiable causes

    Reckless labelling of patients as “epileptic” has huge social, financial and medical implications and should not be made lightly. 

2

What are possible treatment options for epilepsy?

For 75% of those with epilepsy, drug treatment can completely control symptoms but side effects and interactions are common especially with older drugs. However, 10% of patients still have frequent fits during treatment.

    Anti-epileptic drugs have common ADRs, some serious.

    DDIs: some positive combined with other AEDs, often significant negative pharmacokinetic interactions

Epilepsies should be viewed as a symptom of underlying neurological disorder and not a single disease entity.

    Common condition. Prevalence estimates about 0.5-1.0% (`450,000 in UK) with some form of epilepsy.

    Chronic epilepsy – 500 sudden deaths / year in UK

    Therapeutics currently effective for about 75%

    Vagal Nerve Stimulation: in some cases, where patients are refractory to AEDs, is effective.

3

What could epilepsy be caused by?

Epilepsy can be caused due to

    Increased excitatory activity, decreased inhibitory activity and/or loss of homeostatic control => spread of neuronal hyperactivity

4

What are the two main types of seizures?

During a seizure, large groups of neurones are activated repetitively, unrestrictedly and hyper-synchronously, with inhibitory neurones failing. A partial (focal) seizure is confined to one area of the cortex, yet can spread to cause a secondary generalisation. Generalised seizures can also occur as a focal seizure, thus can also be a primary generalised major convulsion. The two main types are described but there is a whole spectrum.

5

Describe partial seizures

Partial seizures: here the discharges begin in a localised area of the brain. Thus the symptoms reflect the area affected, but might include abnormal sensations or thoughts, a change in behaviour or an involuntary motor action.

    Loss of local excitatory/inhibitory homeostasis

    Increased discharges in focal cortical area

    Types include:

  • Simple (conscious)
  • Complex partial seizures (impaired consciousness) (neuronal hyperactivity spreads)
  • Secondary generalised seizures (neuronal hyperactivity has spread through the corpus callosum to the other hemisphere).

    Symptoms reflect area affected e.g. involuntary motor disturbance, behavioural change, impending focal spread accompanied by ‘Aura’ (strange inner feeling) e.g. unusual smell or taste (smell of burning rubber), déjà vu/jamais vu (don’t recognise something you’ve seen many times).

    Partial seizures may become secondarily generalised.

    Other partial seizure types include Jacksonian (focal motor seizures) or Temporal Lobe (develops as feelings of déjà vu/ jamais vu)

6

Describe generalised seizures

Generalised seizures: the whole brain is affected, including the reticular system, and there is immediate loss of consciousness (generated centrally spread through both hemispheres with loss of consciousness). Neuronal hyperactivity spreads very quickly. These are further divided into the tonic-clonic  (Grand mal) seizure (60%) and the absence (petit mal) seizure (5%). Many other types/subtypes recognised.

    Tonic-clonic: following vague, warning signs, the tonic phase commences, as the body becomes rigid and the patient commonly falls to the floor (as all the muscles contract), tongue is bitten and incontinence of both urine and faeces occur, The clonic phase will then begin with a generalised convulsion, frothing at the mouth and rhythmic jerking of muscles. Normally self-limiting and followed by drowsiness, confusion or a coma for several hours.

    Typical absences – generalised epilepsy that occurs in childhood, where the patient will stare, eyelids may twitch and a few muscle jerks occur. After an attack, normal activity is resumed yet children with typical absence attacks are more likely to develop generalised grand mal seizures as adults.

    Other types include tonic, clonic, myoclonic, atonic.

7

What is meant by Status Epilepticus?

Status Epilepticus: prolonged seizure of any type

    The most common and dramatic is convulsive status epilepticus, although non-convulsive status epilepticus also occurs. It is defined as either a single convulsion lasting >30 minutes or convulsions occurring back to back with no recovery between them (no recovery interval).

    However, any convulsion lasting longer than 5 minutes or two convulsions without full recovery of consciousness in between should receive emergency treatment.

    Uncontrolled convulsions – untreated status epilepticus - can lead to hypoxia and irreversible brain damage or death (Sudden Unexpected Death in Epilepsy)

    Diagnosis should be self-apparent but a careful consideration of underlying cause must be made. Additionally, if the seizures seem odd or atypical, one must consider the possibility of pseudoseizures, which are non-epileptic in nature. 

8

Describe how Status Epilepticus is a medical emergency

    Status Epilepticus is a Medical Emergency

Adult mortality ~20%

Risk increases with length of SE

50% of cases occur without a previous history of epilepsy

Serial epilepsy may lead to SE

Priorities are ABC (airway, breathing and circulation)

Exclude hypoglycaemia

Hypoventilation may result with high AED doses

ITU for paralysis and ventilation if failing

9

How would you treat Status Epilepticus?

    Priorities include airway protection, the delivery of supplemental oxygen, identification of the cause and its reversal, and the termination of the seizure as quickly as possible.

    Investigations should include a bedside glucose, lab U&Es and calcium, blood gases and further tests (perhaps later) to ascertain underlying cause (e.g. CT/MRI head – especially in trauma or focal fits).

    Treatment of the seizures is vital. First line treatment includes benzodiazepines (e.g. IV lorazepam) and then IV phenytoin. Phenytoin is not widely used for long term control but because of its zero order kinetics, a therapeutic level can be reached quickly. It is however, toxic, and has a narrow therapeutic index. If these measures are failing, or if the patient’s airway is compromised, ITU referral, sedation and paralysis and intubation will be required.

Lorazepam (0.1 mg/kg) preferred – longer pharmacodynamic half life than diazepam (0.2 mg/kg). IV route (rectal if difficult IV access)

Phenytoin:

  • Zero order kinetics (15-20 mg/kg)
  • Rapidly reaches therapeutic levels IV
  • Cardiac monitoring – arrhythmias + hypotension

Other drugs: midazolam, pentobarbital, propofol (targets GABA, used in anaesthesia)

10

What are the dangers of severe (uncontrolled) epilepsy?

    Physical injury relating to fall/crash

    Hypoxia   

    SUDEP

    Varying degrees of brain dysfunction/damage

    Cognitive impairment

    Serious psychiatric disease

    Significant adverse reactions to medication

    Stigma / Loss of livelihood (person cannot function fully in livelihood)

Epilepsy and driving

  •     All patients should be advised appropriately and to inform the DVLA.
  •     Check DVLA for specific guidance

11

What's important in an epilepsy history?

    A detailed history of the attacks is essential. This should include witness statements from family and ambulance crew etc. This is of the utmost importance in determining the nature of the attack, differentiating it from non-epileptic attacks and to decide on the likelihood of underlying structural brain disease.

    The history should include assessment of precipitants, a description of the warning phase (if any), the unconscious phase and the period of recovery. 

12

What is meant by the primary and secondary causes of epilepsy?

Seizures may result as a consequence of a medical condition affecting the brain (secondary – about 1/3 – 30-35%) or as an inherent tendency of an individual towards seizures (primary – about 2/3 – 65-70%). It is always important to consider secondary causes of convulsions when assessing patients presenting with fits.

Aetiology of epilepsy

    Primary: idiopathic (no identifiable cause),  most likely channelopathies (mutations where there is leakage of currents => drifting towards depolarisation)?

    Secondary: medical conditions affecting brain, vascular disease, tumours

13

Describe some of the major recognized precipitants in epilepsy

A seizure may have no antecedent (especially in primary epilepsy) but many conditions are associated with either a fit in a person who does not have epilepsy, or the lowering of the fit threshold in those that do.

Relevant conditions to consider when appropriate include

    Sensory stimuli e.g. flashing lights/strobes or other periodic sensory stimuli (provoked seizures)

    Brain Disease/Trauma:

  • Head injury (traumatic or “chemical”) – perinatal trauma, decreased skull fracture, intracranial haematoma or cerebral contusion can cause sufficient damage to result in epilepsy
  • Pyrexia causing seizures is common in children yet reoccurrence is rare
  • Drugs and alcohol including drug withdrawal
  • Structural abnormality/lesion – brain tumours will cause a partial focal or secondary generalised seizure
  • CVA/subarachnoid haemorrhage etc

    Metabolic disturbances: Hypoglycaemia (including diabetics), hypocalcaemia (calcium is important in regulating excitability of neurons), hyponatraemia

    Infections (especially CNS but elsewhere too), particularly in children – febrile convulsions in infants, cerebral abscesses or neurosyphilis

    Therapeutics: Poor compliance with anti-epileptic drug therapy; some drugs can lower fit threshold, AEDs + polypharmacy can lead to reduced plasma levels of the AED (PKs lower levels)

14

What are the therapeutic targets in management of epilepsy?

Therapeutic Targets: the mechanisms of action of the AEDs are described by the known pharmacology associated with the following targets

    Enhancement of GABA(A) Action (benzodiazepines, phenobarbitones but ironically not gabapentin) – enhancing GABA mediated inhibition

    Inhibition of voltage gated sodium channel function (phenytoin, valproate, carbamazepine, lamotrigine)

    Inhibition of calcium channel function (ethosuximide, gabapentin)

    Inhibition of glutamate release or function

15

What are the common drugs used?

    The majority of patients seen in everyday clinical experience are generally on those commonly prescribed drugs. However, increasing use of the newer drugs (lamotrigine, gabapentin etc) is occurring. Additionally, few patients are started on barbiturates or even phenytoin these days but some people who have been on them for a long time may still be on them.

Major Drug Classes:

  1. Carbamazepine
  2. Valproate Sodium
  3. Benzodiazepines
  4. Phenytoin
  5. Lamotrigine (increasingly first line nowadays)

The following drugs are used more rarely and generally only by neurology specialists

6. Gabapentin

7. Barbiturates (few started on this now, but some on it for decades)

8. Vigabatrin

9. Clonazepam

16

Carbamazepine is a Voltage Gated Sodium Channel Blocker. How do they work?

    Mechanism of action: VGSC blockers reduce probability of high abnormal spiking activity

  • Local loss of membrane potential homeostasis starts at focal point
  • Relatively small number of neurones form generator site
  • Neurones heavily depolarise (vicious positive feedback loop)
  • Hyperactivity spreads via synaptic transmission to other neurones => loss of homeostasis – bursting high discharge (spontaneous).

The VGSC blocker gets access to binding site on the internal face of the sodium channel only during depolarisation – hence VOLTAGE-DEPENDENT. The VGSC prolongs inactivation state – firing rate returns back to normal. Once neurone membrane potential returns back to normal, VGSC blocker detaches from binding site.

They work by acting preferentially on the neurones causing the high frequency discharge that occurs in an epileptic fit, whilst not interfering with the low-frequency firing neurones in their normal state.

Depolarisation of a neurone increases the proportion of the sodium channels in the inactivated state, and VGSC blockers bind preferentially to channels in this state, preventing them from returning to a resting state where they would continue to depolarise the neurone – keep the sodium channels in the inactivated state for a longer amount of time. They thus reduce the number of functional channels available to generate action potentials

NB: remember sodium channels have 3 states: open, closed and inactivated

17

Describe the pharmacology of Carbamazepine including ADRs and DDIs

Carbamazepine prolongs VGSC inactivation state

Pharmacokinetics: well absorbed, 75% protein bound – shows linear pharmacokinetics, initial half life = 30 hours but STRONG INDUCER OF CYP 450 (specifically CYP A4). This affects its own Phase I metabolism. Repeated use half life gradually decreases to 15 hours thus close monitoring is required.

ADRs: wide ranging Type As:

  • CNS – dizziness, drowsy, ataxia, motor disturbance, numbness, tingling
  • GI: upset, vomiting
  • CVS: can cause variation in BP
  • Contraindicated with AV conduction problems
  • Others: rashes, hyponatraemia
  • Rarely – severe bone marrow depression => neutropenia

DDIs: because CYP450 inducer can affect many other drugs

  • Decreased phenytoin concentration + PK binding => leading to increased Carbamazepine plasma concentration thus increasing risk of side effects.
  • Decreased warfarin concentration
  • Decreased systemic corticosteroids levels
  • Decreased oral contraceptives levels (reduced effectiveness of OCP)
  • Antidepressants – SSRIs, MAOIs, TCAs and TCA interfere with action of carbamazepine. 

18

Describe drug monitoring and what seizures you would treat with Carbamazepine

Drug Monitoring: dosing to effect and adjust dosing as half life decreases. CHECK BNF with any other drugs given

Epilepsy types treated with Carbamezepine

  • Generalised Tonic Clonic
  • Partial – all
  • Not absence seizures

19

Phenytoin is another VGSC. Describe its pharmacology including ADRs and DDIs

Phenytoin prolongs VGSC inactivation state

Pharmacokinetics: well-absorbed but 90% bound in plasma so competitive binding can increase levels of other drugs. It is also a CYP 450 inducer (CYP 3A4 – not CYP2C9 & CYP2C19 which metabolise phenytoin – so doesn’t self-induce its own metabolism). But as it is a CYP 3A4 inducer, it induces the rate of metabolism of other drugs including Carbamazepine.

Sub-therapeutic concentrations shows linear PK but shows NON-LINEAR PK at therapeutic concentrations – very variable half life = 6-24 hours. Depends and varies from individual to individual so very close titration of the drug is required to gain effective control – limits its use.

NB: Graph shows variation in the daily dose to get to the therapeutic range. Paracetamol is also a drug that shows non-linear PKs.

ADRs : very wide ranging Type As

  • CNS: dizziness, ataxia, headache, nystagmus, nervousness
  • Gingival hyperplasia (20%)
  • Rashes – hypersensitivity
  • + Stevens Johnson (2-5%) – life threatening toxic epidermal necrolysis in which cell death causes the epidermis to separate from the dermis.

DDIs:

  • Competitive binding e.g. with Valproate (AED)/NSAIDs/salicylate, increases plasma levels of phenytoin – exacerbates Non-Linear PKs
  • Very wide range of interactions including decreases oral contraceptives. Cimetidine increases the concentration of phenytoin. Need to check BNF for any other drugs given in combination.

20

Describe drug monitoring and what seizures you would use to treat Phenytoin with

Drug Monitoring:

  • Close monitoring of free concentration plasma
  • Can use salivary levels as indicator of concentrations in free plasma (so blood test not required)

Epilepsy types treated with Phenytoin

  • Generalised Tonic-Clonic
  • Partial – all
  • Not Absence seizures

21

Lamotrigine is a VGSC. Describe its pharmacology including ADRs, DDIs and uses

Pharmacology: Lamotrigine (LTG) prolongs VGSC inactivation state

  • - Possibly also a Calcium channel blocker? May also decrease glutamate release?

Pharmacokinetics: not metabolised by CYP

  • Well absorbed – linear PK (once daily dosage drug)
  • Half life = 24 hours (phase II)
  • No CYP450 induction => fewer DDIs

ADRs: less marked

  • CNS: dizziness, ataxia, somnolence (drowsiness, sleepiness)
  • Nausea
  • Some mild (10%) and serious (0.5%) skin rashes

DDIs

  • Adjunct therapy with other AEDs
  • Oral contraceptives reduce Lamotrigine plasma level
  • Valproate increases lamotrigine in plasma (competitive binding)

Epilepsy types treated with Lamotrigine

  • Partial seizures
  • Generalised  - tonic-clonic and Absence (where specific pathways and neurotransmitters are involved – theory that LTG acts on these whereas the other VGSC blockers have no effect) seizures and other subtypes
  • LTG increasingly first line AED for epilepsy
  • Not first line paediatric use as ADRs increase
  • Appears safer in pregnancy?

22

Apart from blocking sodium channels, what's the other main therapeutic target?

Enhancing GABA Mediated Inhibition

    Major role in post-synaptic inhibition – 40% synapses in brain are GABA-ergic

    Increased GABA is natural anticonvulsant or excitatory ‘brake’ – thought to help dampen down activity

23

Describe Direct GABA agonists

Distinct Pharmacological Targets I: binding with GABA(A) receptor (direct GABA agonists)

  •     Benzodiazepine Site: enhance GABA action
  •     Barbiturate Site: enhance GABA action

    General Mechanism

  • Binding on their own – nothing happens. But when GABA happens, both enhance GABA effect. Can work synergistically together.
  • Increased chloride current into neurone – increases threshold for action potential generation (facilitates the GABA-mediated opening of chloride ion channels).
  • Reduces likelihood of epileptic neuronal hyper-activity
  • Makes membrane potential more negative
  •     Valporate acts as a GABA-agonist.

24

Describe the 2nd therapeutic target  - GABA metabolism

GABA Metabolism

  •     Inhibition of GABA inactivation => increased GABA concentration
  •     Inhibition of GABA re-uptake => increased GABA
  •     Increased rate of GABA synthesis => increased GABA
  •     Targeting these sites enhance action of GABA

25

Describe the pharmacology, pk and ADRs of Valporate

   Pharmacology

  • Evidence in vitro for mixed sites of action – pleiotropic
  • Weak inhibition of GABA inactivation enzymes => increased GABA
  • Weak stimulus of GABA synthesising enzymes => increased GABA
  • VGSC blocker + weak Ca2+ channel blocker => decreased Discharge

   Pharmacokinetics

  • Absorbed 100% - then 90% plasma bound
  • Linear pharmacokinetics
  • Half life = 15 hours

   ADRs

  • Generally less severe than with other AEDs
  • CNS sedation, ataxia, tremor
  • Weight gain
  • Hepatic function – increased transaminases in 40% patients
  • Rarely – hepatic failure (but monitoring is required)

26

Describe the DDIs, drug monitoring and types of seizures you would treat with Valporate

   DDIs

  • Not mainline - Adjunct therapy with other AEDs
  • Care needed with adjunct therapy. Both Valproate and adjunct PKs affected. Always check BNF.
  • Antidepressants: SSRIs, MAOIs, TCAs and TCA inhibit action of Valproate
  • Antipsychotics: antagonise Valproate by lowering convulsive threshold
  • Aspirin: competitive binding in plasma Valproate (increased Valporate)

    Drug Monitoring:

  • Close monitoring of free concentration plasma
  • Can use salivary levels as indicators of free plasma
  • Plasma valproate not closely associated with efficacy
  • Monitor for blood, metabolic and hepatic disorder

    Epilepsy types treated with Valproate

  • Partial seizures
  • Generalised: tonic-clonic + absence seizures (probably because of its pleiotropic effects)

27

Describe the pharmacology and PK of benzodiazepines

Pharmacology   

  • Benzodiazepines (BZDs) act at distinct receptor site on GABA Chloride channel
  • Binding of GABA or BZD enhance each other’s binding – act as positive allosteric effectors
  • Increases Chloride current into neurone – increases threshold for action potential generation

   Pharmacokinetics

  • Well absorbed 90-100% - highly plasma bound 85-100%
  • Linear pharmacokinetics
  • Half-life varies between 15-45 hours (highly variable – so close monitoring is required)

28

Describe the ADRs and DDIs of Benzodiazepines. What seizures would you treat them?

   ADRs

  • Sedation
  • Toleration with chronic use
  • Confusion impaired co-ordination
  • Aggression
  • Dependence/withdrawal with chronic use
  • Abrupt withdrawal can act as a seizure trigger
  • Respiratory and CNS depression

   DDIs

  • Some adjunctive use – perhaps for fine control
  • Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia

    Epilepsy types treated with BZDs

  • Side effects limit first line use
  • IV Lorazepam/rectal Diazepam & buccal Midazolam – Status Epilepticus
  • Clonazepam – Absence seizure short term use

29

Describe the basic rules of prescibing AEDs

Basic Prescribing Rules: Epilepsy is a highly specialised field, and expert advice should generally be sought for all but the most basic of management issues. However, certain principles should be borne in mind when managing drug therapy in a person with epilepsy

    The choice of drug should be based on the individual patient and their syndrome, and the side-effect profile of the drug.

    Treatment should be started at a low dose and increased only gradually to maximize effect and limit side effects. This will aid the patient’s adherence to therapy.

    With the exception of phenytoin, drug levels are generally not useful except to prove that the drug is being taken.

    IF a first line drug is ineffective despite adequate compliance, it should be replaced by a second drug. Monotherapy should always be the aim unless this has obviously failed

    Patients started on anti-epileptic drugs must remain under review (e.g. monthly follow-up).

    Significant variation in AED plasma levels – monitor and titrate to therapeutic effect

    ITU sedation is a treatment

    Side effects with AEDs are very common. Adjunctive drug use and polypharmacy with epilepsy is common. Always consult BNF in detail when managing patients on AEDs.

30

Describe the very basic rule of thumb for prescribing AEDs

Valproate sodium as first line therapy for primary generalised seizures

Carbamazepine for partial seizures (or generalised seizures)

Lamotrigine can be used in either circumstances and is probably the drug of choice for women of childbearing age.

Benzodiazepines and phenytoin are first line therapies for acute life threatening status epilepticus. Phenytoin has non-linear kinetics and so can reach therapeutic (and toxic) levels rapidly.