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Seizures lecture
- 2. Learning Objectives Define what we mean by seizures Understand the different types of seizures Understand the causes of seizures Know the emergency and longterm management of seizures Know the complications of seizures and their management Demonstrate achievement of learning objectives through clinical cases
- 3. Definitions - what does it all mean? Seizure spontaneous uncontrolled abnormal brain activity Status Epilepticus Seizure >20 - 30minutes OR Multiple seizures frequent enough to prevent recovery between episodes >2030mins Epilepsy tendency to have spontaneous uncontrolled abnormal brain activity, resulting in recurrent seizures
- 5. Pathophysiology GABA (gammaaminobutyric acid) is the main inhibitory neurotransmitter Glutamate is the major excitatory neurotransmitter
- 6. Pathophysiology Seizures are caused by abnormal synchronised discharge of many neurons Every individual has a seizure threshold the level of excitability at which neurons will discharge uncontrollably Triggers that push neuron excitation past the seizure threshold include: ‣ Sleep deprivation ‣ Drugs ‣ ‣ Flickering lights Infection / metabolic disturbance In patients with epilepsy the seizure threshold is lowered and the neurons are hyperexcitable
- 7. Cause Intracranial Underlying brain abnormality Extracranial Pyrexia • Raised intracranial pressure - cerebral tumour - cerebral odema → pregnant - eclampsia • Stroke Hypoxia • - Thrombo-embolic - Haemorrhagic Brain infections • Biochemical ↑↓Sodium, Glucose ↓ Calcium, Magnesium ↑ Urate Drugs - Prescribed / Recreational - Intoxication / Withdrawal
- 8. Types of seizures specific area in one cerebral hemisphere Seizures Partial no loss of conciousness Generalised conciousness impaired Simple both cerebral hemispheres Complex Absence Myoclonic Tonic-Clonic Tonic Atonic
- 9. Tonic Clonic Seizures Convulsive seizure with tonic phase (stiffening) and clonic movements (jerking) Before • Prodrome • Aura • Sudden onset • Triggers During •Tonic Phase: stiffening, loss of consciousness, falls, cries out • Clonic Phase: convulsion, jerking of arms and legs •Excessive salivation (drooling or foaming) •Biting of the tongue •Loss of bowel and/or bladder control •No breathing / random breaths •Eye rolling After • Post-ictal • Drowsy • Confused • Agitated
- 10. Febrile convulsions Presentation • most common seizure disorder in childhood • Peak age of onset 1418 months • Pyrexial • Tonic-clonic • <10 mins • Don’t predispose to epilepsy Management Risk Factors for Epilepsy • ABCDE • First fit <9months • Rule out underlying infection • Atypical seizure • Paediatric review if first fit • REASSURE parents! • FH epilepsy • Evidence of developmental delay • Abnormal neurology on examination
- 11. Emergency Management You are the F1 on call and you’re bleeped... “Please come quickly a patient is having a seizure and we don’t know what to do!” What is your initial management?
- 12. Emergency Management A B C D Airway Breathing Circulation Disability • Patent? • Give airway support if needed • RR • O2 sats • give O2 • HR • BP • Cap refill • IV access and bleed • Head injury? • Infection? • Bleeding? • Temperature? • BM?
- 13. Management of seizures Stepwise approach Start treating underlying cause Initial A,B, C, D Benzodiazepine Phenytoin Paralysis and Ventilation
- 14. Benzodiazepine - mechanism of action If seizure does not resolve after a few minutes give a benzodiazepine GAB A Enhances the inhibitory effect of GABA Reduces excessive neuronal firing Action Potential Action Potential
- 15. Benzodiazepines First line IV Access Lorazepam 0.1mg/kg IV (2-4mg bolus repeated after 15 mins) Diazepam 10-20mg rectally (repeated after 15 mins) Second line No Access Midazolam 10mg buccally (repeated after 15 mins) Side Effects • sedation • suppressed breathing • hypotension (worse with IV)
- 16. Management of seizures Stepwise approach Start treating underlying cause Initial A,B, C, D Benzodiazepine Phenytoin Paralysis and Ventilation
- 17. Phenytoin - mechanism of action If seizure does not resolve after benzodiazepine start a phenytoin infusion Infusion dose 20mg/kg over 20 minutes Blocks voltage-sensitive sodium channels Na+ Action Potential Inhibits excitatory neuronal transmission Action Potential
- 18. Phenytoin - Pharmacokinetics • Mainly hepatic break down • Zero order kinetics • Narrow therapeutic range • Risk of toxicity Continuous BP and ECG monitoring
- 19. Phenytoin - Side Effects At therapeutic levels •Gum hypertrophy •Nausea / vomiting •Headaches •Skin rashes •Hypotension •Arrhythmias (bradycardia) •Bone marrow suppression Megaloblastic anaemia •Teratogenicity At toxic levels •Ataxia •Nytagmus •Drowsiness •Dysphasia •Coma death •Arrhythmias (bradycardia) •Hypotension Monitor serum levels, FBC, LFTs If IV: BP and ECG (especially QT interval)
- 20. Management of seizures Stepwise approach Start treating underlying cause Initial A,B, C, D Benzodiazepine Phenytoin Paralysis and Ventilation If seizure not resolved following initial management patient may need paralysis and ventilation Should be done in ITU by an expert * Never spend long than 20 minutes with a patient with a seizure before calling an anaesthetist! *
- 21. Longterm Management - Drugs Seizures Partial Generalised 1st line carbamazepine / 2ndnd line sodium valproate 2 line sodium valproate Simple 1st line sodium 1st line sodium valproate/ / valproate 2nd line ethosuximide Complex 1st line sodium 1st line sodium valproate/ / valproate 2nd line levetiracetam Absence Myoclonic 1st line sodium 1 line sodium valproate / valproate / 2nd line lamotrigine 2nd line lamotrigine st Tonic-Clonic Tonic Atonic 1st st linesodium valproate 1 line sodium valproate
- 22. Summary of longterm drug therapy Type of Seizure PARTIA L Simple and Complex Absence GENERA L Myoclonic 1st line drug 2nd line drug Carbamazepine Sodium Valproate (Inhibits sodium channels reducing action potential propagation ) Sodium Valproate (Inhibits GABA transaminase so enhances inhibitory affect of GABA) Sodium Valproate TonicClonic Sodium Valproate Tonic Sodium Valproate Atonic Sodium Valproate Ethosuximide (Calcium channel inhibitor) Levetiracetam (Mechanism of action unknown) Lamotrigine (Inhibits sodium channels reducing action potential propagation)
- 23. Sodium Valproate - mechanism of action Inhibits GABA transaminase (inhibits GABA breakdown) GAB A Enhances the inhibitory effect of GABA Reduces excessive neuronal firing Action Potential Action Potential
- 24. Sodium Valproate - side effects At therapeutic levels In Pregnancy •Significantly increased risk of • Thinning and curling of hair • Hepatotoxicity (P450 inhibitor) • Weight gain • Thrombocytopaenia • Pancreatitis • Teratogenicity birth defects with Sodium Valproate •The relative risk is 2-5x higher than other antiepileptic drugs •Extreme caution in women of childbearing age
- 25. Cytochrome P450 Enzymes • P450 cytochromes are the major enzymes involved in drug metabolism • mainly act in the liver P450 inducers speed up the metabolism of drugs (decrease drug availability) P450 inhibitors lead to build up of unmetabolised drugs (increase drug availability) INDUCERS INHIBITORS Phenytoin / Carbamazapine Sodium Valproate
- 26. Longterm Management - Surgery Surgery may be considered when there is: •A mass lesion in the brain •Uncontrolled epilepsy
- 27. Living well with Epilepsy Lifestyle Driving • Safety Advice • First fit - cannot drive for 6 months • Ensure treatment compliance • Second or further fits - cannot drive • Have a predetermined plan for seizure emergencies and rescue treatment for 12 months • Medication change in the last 6 months - cannot drive for 6 months • ‘night-time’ only seizures - they can drive, if they have not had a ‘day time’ seizure for 3 years
- 28. Complications Brain Injury Physical Injury Todd’s Paresis Sudden Unexpected Death in Epilepsy
- 29. Clinical Case 1 • A 70kg 27 year old male presents with five minutes of generalised tonic-clonic seizures. • The immediate management would be: A. 4mg Lorazepam IV B. Maintain a clear airway C. Call an anaesthetist D. 20mg Diazepam rectally
- 30. Clinical Case 1 • Following an ABCD assessment, with attainment of IV access, he continues to fit. • The appropriate management would be: A. Lorazepam IV B. Phenytoin IV C. Midazolam buccally D. Diazepam rectally
- 31. Clinical Case 1 • 20 minutes after the administration of 4mg lorazepam he continues to fit. • The appropriate management would be: A. Lorazepam IV B. Phenytoin IV C. Move to ITU for paralysis and assisted ventilation D. hold him down to prevent injury
- 32. Clinical Case 1 • His seizure resolves with an IV Phenytoin infusion. Baseline investigations are unremarkable. He is discharged home for follow up in the ‘first fit’ clinic. • What advice should he be given about driving? A. He cannot drive for 6 months B. He cannot drive for 12 months C. He can continue to drive until he has been reviewed by a Neurologist in clinic D. He cannot drive again until he retakes his driving test
- 33. Clinical Case 2 An ambulance brings a 15 month old boy to ED following a seizure. His mother reports he suddenly started shaking his arms and legs and his eyes had a blank stare. This went on for what seemed like 5 minutes so she called 999. There is no vomiting, diarrhea or rash. He has no significant past medical history. O/E Temperature 39C, slight cough and mild nasal congestion. Alert and interactive. Normal neurological examination. The immediate management would be: • Maintain a clear airway • 10mg Diazepam rectally • 5mls Calpol • IV access and bloods
- 34. Clinical Case 2 He was reviewed by a Paediatrician who found no evidence of developmental delay or systemic infection. His temperature settled with Calpol. The likely diagnosis is: • Epilepsy • Febrile Convulsion A.Absence Seizure B.Brain tumour
- 35. Clinical Case 2 • Which of the following are Risk Factors for development of epilepsy in febrile convulsions: • (select as many as apply) A. Family history of a febrile convulsion B. Generalised seizure C. Recurrent febrile seizures D. Febrile seizure onset in first nine months E. Evidence of developmental delay
- 36. Clinical Case 3 •An 85 year old gentleman is brought in by his grandson with acute confusion and frank haematuria. •Past medical history: Hypertension, Hypercholesterolaemia, AF and Epilepsy •Drug History: Warfarin, Simvastatin, Sodium Valproate •Which one initial investigation will most aid your diagnosis? • Sodium Valproate level • INR • CT head • Cystoscopy
- 37. Clinical Case 3 • Which of the following anti-epileptic drugs are INDUCERS of P450 cytochromes? • (select as many apply) A. Phenytoin B. Carbamazepine C. Sodium Valproate D. Lamotrigine
- 38. Clinical Case 4 • A 37 year old man presented to the Emergency department following an epileptic seizure. He had suffered from epilepsy since childhood and takes sodium valproate and levertiracetam. Two hours following the seizure he complained that he was still unable to move his right arm. • The likely diagnosis is: A. Partial Seizure B. Todd’s Paresis C. TIA D. Stroke
- 39. Clinical Case 4 • Which of the following statements are correct about Todd’s Paresis? • (select as many as apply) A. There is paralysis of limbs lasting several hours after a seizure B. It is a type of lower motor neurone paralysis C. It has to be differentiated from acute stroke D. It usually resolves within 1-2 weeks E. It is associated with dysphasia
- 40. AMK practice • The most appropriate longterm drug for treatment of generalised tonic-clonic seizures is: A. Sodium valproate B. Lamotrigine C. Ethosuximide D. Carbemazepine E. Lorazepam
- 41. AMK practice The most appropriate longterm drug for treatment of complex partial seizures is: (Select as many as apply) • Phenytoin A. Sodium valproate B. Carbamazepine B. Ethosuximide C. Lamotrigine
- 42. AMK practice • A 30 year old lady is started on phenytoin for recurrent tonic-clonic seizures. Past medical history includes prednisolone for brittle asthma. Two weeks later she returns to clinic and complains that her asthma has worsened since she began the phenytoin therapy. • A likely reason for this new change is that phenytoin: • interferes with absorption of the prednisone • stabilizes cell membranes, preventing the prednisone from diffusing to the site of action • accelerates hepatic degradation of prednisone • induce renal excretory pathways, accelerating urinary excretion of the prednisone • Decreases hepatic degradation of prednisolone
- 43. AMK practice • Select 3 drugs with similar proposed mechanisms of action: A. Phenytoin B. Carbamazepine C. Lamotrigine D. Sodium valproate E. Ethosuximide
- 44. AMK practice • Which of the following statements about Phenytoin are true: • (select as many as apply) A. It follows first-order kinetics B. It follows zero-order kinetics C. It is mainly metabolised by the kidneys D. It has a narrow therapeutic window E. It can cause bone marrow suppression
- 45. AMK practice • Symptoms of Phenytoin toxicity include: • (select as many as apply) A. Gingival hyperplasia B. Nystagmus C. Ataxia D. Dysphasia E. Bone marrow suppression
- 46. Seizures Summary Seizures are caused by abnormal synchronised discharge of many neurons Anything that lowers the excitation threshold of neurons (makes them hyper excitable or reduces inhibition) can result in seizures Seizures are classified as Partial (affect a small area of one cerebral hemisphere) and Generalised (affecting both cerebral hemispheres) A seizure is an emergency ‘Status Epilepticus’ if it lasts >20 - 30minutes OR multiple seizures frequent enough to prevent recovery >20-30mins The stepwise management of seizures is ABCD assessment, Benzodiazepine, Phenytoin, Paralysis and assisted ventilation The first line drug for longterm management of generalised seizures is Sodium Valproate The first line drug for the longterm management of partial seizures is Carbamazepine Phenytoin displays zero-order kinetics and has potential for toxicity Sodium Valoprate is 2-5x more teratogenic than any other anti-epileptic agent
- 47. Questions Please send any questions that occur to you later to olivia.jagger@nhs.net
Editor's Notes
- SEIZURE spontaneous uncontrolled abnormal brain activity caused by abnormal and excessive excitation of neurons Status epilepticus is a medical emergency. It is defined as: Seizure >20 - 30minutes OR Multiple seizures frequently enough to prevent recovery between episodes lasting over 20-30mins It has a mortality of 5-10% secondary to brain cell swelling and herniation of the brain. Swelling occurs as a result of electrolyte imbalance that occurs when the body is no longer able to meet the massive energy demands of the rapid discharging neurons. EPILEPSY Epilepsy is the tendency to have spontaneous abnormal brain activity, resulting in seizures. Technically to have epilepsy you have to have had a minimum of 2 seizures. There is a mortality associated with epilepsy. Usually, the epilepsy causes some traumatic injury that results in death; e.g. crashing the car, fitting in the bath and drowning. This is rare! A more common cause of death in epilepsy is status epilepticus.
- Link to animation: http://outreach.mcb.harvard.edu/animations/synaptic.swf Messages are transmitted in the brain along neurons as an action potential The action potential is transmitted between neurons across a synapse The action potential causes calcium channels to open in the plasma membrane of the presynaptic cell. The calcium ions (Ca++) diffuse into the neuron and activate enzymes, which in turn, promote fusion of the neurotransmitter vesicles with the plasma membrane. This process releases neurotransmitter into the synaptic cleft. Neurotransmitter molecules diffuse across the cleft and stimulate the postsynaptic cell, causing Na+ channels to open and depolarization of the postsynaptic cell. The presynaptic neuron transmits messages to the postsynaptic neuron by secreting neurotransmitters across the synaptic cleft The neurotransmitters bind to membrane receptors on the postsynaptic neuron and result in the excitation or inhibition of this neuron. Excitatory neurotransmitters cause depolarization of the post synaptic membrane and generate an action potential in the post-synaptic neuron Inhibitory neurotransmitters bind to the receptors and cause hyperpolarisation of the post-synaptic membrane, making depolarisation and generation of an action potential less likely
- The main inhibitory neurotransmitter is GABA The main excitatory neurotransmitter is Glutamate
- In normal individuals, neurons are discharging all the time, resulting in normal neurological functions. In seizures there is an abnormal SYNCHRONISED discharge of many neurons – millions of neurons all fire at the same time and normal inhibitory mechanisms fail. Every individual has a seizure threshold – the level of excitability at which neurons discharge uncontrollably. Some chemicals can induce seizures in everyone In patients with epilepsy the seizure threshold is lowered, and the neurons are hyperexcitable. On this background of hyperexcitability, certain factor can excite the cells beyond the threshold for seizure. Triggers that push neuron excitation past the seizure threshold are: Sleep deprivation Alcohol (alcohol intake AND alcohol withdrawal) Drug misuse Physical/mental exhaustion Flickering lights –e.g. on TV/video games Infection / metabolic disturbance
- Any pathology that causes lowers the excitation threshold (either hyper excitability, or reduced inhibition) can result in seizures Can you think of any intracranial causes? Can you think of any extracranial causes?
- Built in hyperlinks to a youtube video demonstrating each type of seizure There are many different types of seizures. The type of seizure depends on which part and how much of the brain is affected by the electrical disturbance that produces seizures. Seizures are broadly divided into generalised seizures and partial seizures. In Partial Seizures the electrical disturbance affects a specific area on one side of the brain In Generalised seizures the electrical disturbance affects both cerebral hemispheres Partial seizures are divided into simple partial seizures (in which consciousness is retained) and complex partial seizures (in which consciousness is impaired or lost) SIMPLE partial seizures no loss of conciousness There can be any isolated motor/sensory sign Isolated limb jerking, transient weakness or loss of sensation COMPLEX partial seizures affect a larger part of the hemisphere than a simple partial seizure causing impairment of conciousness - stare blankly once conciousness is impaired the person may display automatisms such as lip smacking, chewing or swallowing drowsiness and confusion after the attack Partial seizures can spread from one hemisphere to the other side of the brain causing a tonic-clonic seizures, that is known as a secondarily generalized seizures In Generalised seizures the electrical disturbance affects both cerebral hemispheres ABSENCE seizures begin in childhood Patient stares blankly for 5-10 seconds Unresponsive but still conscious No warning, after event will immediately return to prior activity Many attacks can occur on the same day Can affect school performance Patients likely to develop tonic-clonic seizures later in life Myoclonic seizures are sudden, brief muscles contractions commonly occur at the same time on both sides of the body usually involve neck, shoulders, upper arms or legs Tonic-clonic seizures are the most common and best known type of generalised seizure They begin with a tonic phase which involves stiffening of the limbs, followed by the clonic phase which is characterised by jerking of the limbs. Atonic seizures produce a sudden loss of muscle tone they cause head drop or sudden collapse (also known as drop attacks) Because they are so abrupt and the people who experience them fall with force they can result in injuries to the head and face. Protective headgear is sometimes used Tonic seizures Increased tone in the extensor muscles
- unusual <6months and >5years 30% recurrent seizures check electrolytes and glucose and look for evidence of underlying infection dont predispose to epilepsy but some children with epilepsy may present with their first fit during a febrile illness
- What things would we do for each step of management? Bloods should be taken for blood gases (hypoxia and electrolytes), glucose, renal, liver, FBC, ca, mg, clotting, AED levels, toxicology Dont Forget Glucose
- The majority of seizures end naturally, after a few seconds or minutes and are not considered life-threatening. Begin your ABCD management and start to treat any underlying cause If seizure does not resolve after a few minutes give a benzodiazepine
- GABA is the main inhibitory neurotransmitter benzodiazepines enhance the effect of GABA to increase its inhibitory affect and reduce the excessive neuronal discharge
- Do you know any benzodiazepines you could give? First line: Lorazepam 0.1mg/kg (usually 4mg bolus repeated after 10-20 mins) (kids same dose to max 4mg) Diazepam 10-20mg rectally (15mins) (kids 500mcg/kg max 0.2mg) midazolam buccally 10mg (kids 500mcg/kg max .2mg) lorazepam firstline due to its relatively long (2–8 hr) duration of action when injected, and its rapid onset of action, which is thought to be due to its high affinity for GABA receptors and to its low lipid solubility, which causes it to remain in the vascular compartment. Diazepam – more rapid onset but doesn’t remain in vascular compartment has to be given again and again No real diff in between diazepam and midazolam – whats availables
- If seizure does not resolve after benzodiazepine start a phenytoin infusion Phenytoin takes a while to draw up so as you give the benzo you should be thinking about drawing up your phenytoin
- Phenytoin inhibits sodium channels and prevents the proliferation of action potentials Phenytoin selectively blocks the most active channels first and inhibits neurons that are firing at high frequency This is useful because in an epileptic attack, it stops the hyperexciteable cells, but normal cells will still function. The mechanism works because the drug is able to distinguish between a cell in its resting, open and blocked states, and will only bind to open channels. Infusion dose 15-18mg/kg at a rate of 50mg/minute (20mg/kg over 20 minutes) (kids is the same also consider Rectal paraldehyde)
- Narrow therapeutic range, with wide variability in the therapeutic dose between individuals When given in high doses, Phenytoin display zero-order elimination. Zero-order elimi-nation occurs when the body’s ability to eliminate a drug has reached its maximum capability (i.e., all transporters are being used). As the dose and drug concentration increase, the amount of drug elimi-nated per hour does not increase, and the fraction of drug removed declines. First order kinetics the drug has a constant half life and the rate of elimination of drug is proportional to the plasma concentration Zero order kinetics a constant amount of drug is eliminated per unit time - it is independent of plasma concentration means the amount of excretion depends on the amount of drug present (half life). Zero order kinetics means that the amount of excretion is independent of the amount of drug present.
- What monitoring should you do whilst patient is receiving a phenytoin infusion?
- only start drug therapy after a minimum fo 2 fits Sodium valproate first line for generalised and second line for partial Carbamazepine first line for partial
- Phenytoin, Carbamazepine, lamotrigine - are inhibitors of sodium channels, and as such, they prevent the proliferation of action potentials Sodium Valproate - Inhibits GABA transaminase so enhances inhibitory affect of GABA Ethosuximide (Calcium channel inhibitor) Levetiracetam (Mechanism of action unknown)
- Sodium valproate is useful, because it can treat a wide range of attacks. It also has low toxicity and is not sedative. SV has lots of mechanisms of action which are poorly understood We know that it inhibits GABA breakdown It also causes increase in GABA concentrations It is thought to enhance the action of GABA post-synaptically, and like carbamazepine and phenytoin, it is a sodium channel inhibitor.
- All anti-epileptic drugs increase the risk of birth defects (particularly spina bifida). It also has affects on the metabolism of other drugs through its affect on P450 cytochromes
- most drugs undergo deactivation by Cyt P450 (direct/facilitated excretion) and many substances are bioactivated by Cyt P450 Drugs with a low therapeutic index metabolised by P450 include WARFARIN
- There are various type of surgery, all involve removing part of the brain, with possible consequences on function
- Safety Advice not to climb ladders, operate heavy machinary, go swimming unattended The doctor is obliged to tell the patient to inform the DVLA – but the doctor does not have to directly inform the DVLA – UNLESS – after continued reminders to the patient, the patient continues to drive, the doctor then has a duty to break confidentiality to inform the DVLA.
- Brain injury – brain damage with recurrent seizures Physical Injury - Direct from fit - tongue biting, broken bones or Driving, operating heavy machinery Todd’s Paresis: Pathologically, the clinical features may represent neuronal exhaustion after the period of increased activity. The paralysis resolves spontaneously, usually within minutes or hours. SUDEP: The precise mechanism, or cause, of death is, as yet, not understood. By definition, the post mortem does not reveal a cause of death suggesting that the terminal event is due to disturbance of function, not structure. Most frequently, but not always, there is evidence for seizure activity prior to death and recent studies strongly support a close relationship between seizure episodes (especially generalized convulsions) and SUDEP.
- First fit <9months Atypical seizure FH epilepsy Evidence of developmental delay Abnormal neurology on examination
- P450 inducers speed up the metabolism of drugs (decrease drug availability) Phenytoin / Carbamazapine P450 inhibitors lead to build up of unmetabolised drugs (increase drug availability) Sodium Valproate
- P450 inducers speed up the metabolism of drugs (decrease drug availability) Phenytoin / Carbamazapine P450 inhibitors lead to build up of unmetabolised drugs (increase drug availability) Sodium Valproate
- Phenytoin, Carbamazepine, lamotrigine - are inhibitors of sodium channels, and as such, they prevent the proliferation of action potentials Sodium Valproate - Inhibits GABA transaminase so enhances inhibitory affect of GABA Ethosuximide (Calcium channel inhibitor) Levetiracetam (Mechanism of action unknown)