Outline the pathophysiology of epilepsy.
- increased excitatory activity and decreased inhibitory activity
- loss of haemostatic control
- spread of neuronal hyperactivity
- Local loss of membrane potential homeostasis (bursting high rate of discharge) starts at focal point
- Small no. of neurones form generator site
- Neurone heavily depolarise
- Hyperactivity spreads via synaptic transmission to other neurones
What are the features of partial seizures?
Simple (conscious) or complex (impaired consciousness; often origin is in temporal/parietal lobes)
note: may become secondarily generalised
Loss of local excitatory/inhibitory homeostasis —> increased discharge in focal cortical area
S&S (depend on area affected):
- involuntary motor disturbance e.g. convulsions spreading from thumb —> hand —> arm —> face
- behavioural change
- impending focal spread accompanied by aura e.g. unusual smell/taste, déjà vu, visual/auditory hallucinations, automatism
What is automatism?
Patient performs well-organised movements or tasks whilst unaware of doing so
May be simple and repetitive e.g. hand clapping, lip smacking
May mimic normal conscious activities
What are the features of generalised seizures?
Generated centrally and spreads through both hemispheres causing loss of consciousness
Tonic-clonic (grand mal) seizures (~60%):
- tonic phase = fall to ground unconscious with spasming muscles (resp. muscle spasming may cause central cyanosis)
- clonic phase = convulsions (tongue may be bitten, urinary incontinence may occur)
- movements gradually cease and patient may rouse, be confused, complain of headache, or fall asleep
Absence (petit mal) seizures (~5%):
- brief spells of unconsciousness lasting for a few seconds during which posture and balance are maintained but eyes stare blankly
- eyelids may flutter and fingers and mouth may twitch
- usually occur in childhood, can subsequently develop into other types
- sometimes provoked by overbreathing or intermittent photic stimulation
What is status epilepticus? What is important to exclude?
Occurrence of repeated epileptic seizures without any recovery of consciousness between them OR single convulsion lasting over 30min (most seizures last ~5min)
EMERGENCY!
Exclude:
- hypoglycaemia
- hypoventilation
- high doses of anti-epileptics
Give some examples of the risks of severe uncontrolled epilepsy.
- physical injury relating to fall/crash
- hypoxia
- sudden unexpected death in epilepsy (SUDEP)
- brain dysfunction/damage
- cognitive impairment
- psychiatric disease
- ADRs to anti-epileptics
- stigma/loss of livelihood
Describe the aetiology of epilepsy.
PRIMARY (~65%-70%) = no identifiable cause
SECONDARY
- medical conditions affecting brain (~30%-35%)
- vascular disease
- tumours
note: in elderly, 60% of seizures have a secondary aetiology
PRECIPITANTS:
- sensory stimuli e.g. flashing lights/strobes, other periodic sensory stimuli
- brain disease/trauma e.g. brain injury, stroke, haemorrhage, drugs/alcohol, structural abnormality/lesion
- metabolic disturbances e.g. hypoglycaemia, hypocalcaemia, hyponatraemia
- infection e.g. febrile convulsions in infants
- therapeutics e.g. anti-epileptics + polypharmacy (pharmacokinetics affected)
What are the therapeutic targets of anti-epileptic drugs? What is their respective general mechanisms of action?
Voltage-gated Na+ channel blockers:
- e.g. carbamezepine, phenytoin, lamotrigine
- reduce probability of high abnormal spiking activity
- bind during depolarisation only (voltage-dependent) —> prolong inactivation state and return AP firing rate and membrane potential back to normal
Enhancing GABA action
- e.g. sodium valproate, benzodiazepines
- increase GABA action (inhibition of GABA inactivation, inhibition of GABA reuptake, increased rate of GABA synthesis)
- –> “excitatory brake” by increasing Cl- current into neurone —> increases threshold potential —> reduces likelihood of hyperactivity
Describe the pharmacokinetics, indications, and associated ADRs and drug-drug interactions of carbamezepine.
PHARMACOKINETICS:
- 75% protein-bound
- initial t1/2 = ~30hrs; repeated use t1/2 = ~15hrs (strong CYP450 inducer —> affects its own phase 1 metabolism)
- dose till effect and then adjust as half-life falls
INDICATIONS:
- tonic-clonic seizures
- partial seizures
ADRs:
- CNS = dizziness, drowsiness, ataxia, motor disturbance, numbness, tingling
- GI = N&V, BP variations (contraindicated in some AV conduction problems)
- rashes
- hyponatraemia
- neutropenia (bone marrow suppression)
DDIs (CYP450 inducer):
- combination of anti-epileptics will increase the concentration of the drug
- reduced warfarin efficacy
- reduced conc. of systemic corticosteroids
- reduced efficacy of OCP
- anti-depressants
Describe the pharmacokinetics, indications, and associated ADRs and drug-drug interactions of phenytoin.
PHARMACOKINETICS:
- 90% protein-bound
- CYP450 inducer
- non-linear PK at therapeutic concentrations; variable t1/2 (~6-24hrs)
- monitor [phenyotin]free in plasma/salivary levels
INDICATIONS:
- tonic-clonic seizures
- partial seizures
- status epilepticus
ADRs:
- CNS = dizziness, ataxia, headache, nystagmus, nervousness
- gingival hyperplasia (~20%)
- rashes (~2%-5%) = hypersensitivity, Stevens-Johnson syndrome
DDIs:
- competitive binding with sodium valproate, NSAIDs, aspirin —> increased [phenytoin]plasma
- reduced efficacy ofOCP
- cimetidine increases [phenytoin]plasma
Describe the pharmacokinetics, indications, and associated ADRs and drug-drug interactions of lamotrigine.
PHARMACOKINETICS:
- linear PK
- t1/2 = ~24hrs
- no CYP450 induction
INDICATIONS:
- tonic-clonic seizures
- absence seizures
- partial seizures
note: safe in pregnancy
ADRs:
- CNS = dizziness, ataxia, drowsiness, insomnia, aggression/agitation
- N&V
- diarrhoea
- dry mouth
- tremor
- back pain
- arthralgia
- diplopia
- nystagmus
- rashes
DDIs:
- sodium valproate competitively binds —> increased [lamotrigine]plasma
- OCP reduce [lamotrigine]plasma
Describe the pharmacokinetics, indications, and associated ADRs and drug-drug interactions of sodium valproate.
PHARMACOKINETICS:
- 90% plasma bound
- linear PK
- t1/2 = ~15hrs
- can monitor salivary levels
INDICATIONS:
- partial seizures
- tonic-clonic seizures
- absence seizures
ADRs:
- CNS = sedation, ataxia, tremors, weight gain
- hepatic = increase in transaminases, liver failure
DDIs:
- anti-epileptics
- anti-depressants inhibit action of sodium valproate
- anti-psychotics antagonise sodium valproate by lowering conductive threshold
- aspirin competitively binds in plasma —> increases [valproate]free
Describe the pharmacokinetics, indications, and associated ADRs and drug-drug interactions of benzodiazepines.
PHARMACOKINETICS:
- allosteric binding
- increase Cl- current
- highly plasma-bound
- linear PK
- t1/2 = ~15-45hrs
INDICATIONS:
- status epilepticus (lorazepam and diazepam)
- short-term treatment of absence seizures (clonazepam)
ADRs:
- sedation
- tolerance (+ dependence/withdrawal)
- confusion
- impaired coordination
- abrupt withdrawal triggers seizures
- resp. and CNS depression
DDIs:
- overdose (reversed by IV flumazenil - may precipitate seizure/arrhythmias)
What are some important ADRs of anti-epileptics in pregnancy? What are some methods of preventing these?
- contraception failure
- congenital malformations (~8%)
- neural tube defects (sodium valproate - ~8%)
- facial and digit hypoplasia (~8%)
- ?learning difficulties/mild neurological dysfunction
Use single agent at lowest possible dose
Give folate supplements to reduce risk of neural tube defects
Vitamin K supplements (10mg/day) in 3rd trimester (anti-epileptics associated with newborn vitamin K deficiency —> coagulopathy —–> cerebral haemorrhage)
What is the emergency management of status epilepticus?
ABCDE
- O2 supplementation
- identify/reverse cause
- terminate seizure
- measure glucose, U&Es, Ca2+, ABG, ?CT/MRI head (trauma, focal seizures)
Benzodiazepines e.g. IV lorazepam, rectal diazepam, or buccal midazolam —> repeat after 5min —> IV phenytoin —> ITU (paralysis and sedation)
+ midazolam, pentobarbital, propofol
Define epilepsy. What is the prevalence?
Episodic discharge of abnormal high frequency electrical activity in the brain, leading to recurrent seizures
More than one seizure required to diagnose
note: should be viewed a a symptom of an underlying disorder, not as a single disease entity
Prevalence = ~0.5%-1.0%
What advice regarding lifestyle and occupation should be given to epileptic patients?
Pregnancy = advise cessation of anti-epileptics
Contraception = advise about interactions of anti-epileptics with COCP
Driving = advise DVLA
Occupation = advise employers
Cycling, swimming, etc. = be accompanied in case of seizure
What treatment should be offered during pregnancy in epileptic patients? What problems occur in labour in epileptic patients?
Increase screening for foetal defects (increased incidence with anti-epileptics)
Folic acid supplementation (ideally before conception) to reduce risk of neural tube defects
Labour: greater risk posed to baby when the mother has untreated epilepsy than teratogenesis due to:
- reduced placental perfusion
- increased lactate
- hypoxia
(give newborn vitamin K to reduce risk of haemorrhage)
Eclampsia: give magnesium sulfate to prevent convulsions
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Neuroanatomy53
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Embryology13
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Glia & Neurotransmitters14
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Sensation & Ascending Tracts37
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Neurological Disorders65
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Movement & Descending Tracts50
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Pain26
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Embryology14
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Vision33
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Hearing18
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Strokes30
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Sleep & Consciousness24
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Epilepsy18
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Dementia & Memory18
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Neuro History Taking21
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Neuropathology28
