Epilepsy and other seizure disorders

Question 1

Choosing an antiepileptic drug depends on

Answer 1

several factors, and the seizure type should determine the choice of treatment.

• A single antiepileptic drug should be prescribed wherever possible
• Most antileptics can be given twice daily and the dose should be kept as low as possible to encourage adherence.
• If treatment with one drug fails it should be stopped and another drug should be tried alone. The first drug should slowly be withdrawn only when the new regimen has been established.
• Combination therapy with 2 or more drugs may be necessary, but this increases the risk of interactions and side effects.

Question 2

MHRA Advice: 3 risk-based categories of antiepileptic drugs: category 1

Answer 2

1. Category 1: Phenytoin, Carbamazepine, Phenobarbital + Primidone. Patient should be maintained on a specific manufacturer’s product (specific brand).

Question 3

Antiepileptic hypersensitivity syndrome

Answer 3

If after a few weeks the patient develops a rash, fever and lymphadenopathy this is indicative of antiepileptic hypersensitivity syndrome –> THE DRUG SHOULD BE STOPPED IMMEDIATELY.

Question 4

Withdrawal

Answer 4

• Avoid abrupt withdrawal because this can cause severe rebound seizures.
• The dose should be reduced gradually, and in the case of barbiturates withdrawal of the drug may take months.
• Even in patients who have been seizure-free for several years, there is a significant risk of seizure-recurrence on drug withdrawal.
• In patients receiving several anti-epileptic drugs, only one drug should be withdrawn at a time.

Question 5

Driving

Answer 5

 If a driver has a seizure (of any type) they must stop driving immediately and inform the DVLA.
 To continue driving, the patient must be seizure-free for atleast 1 year.
 Patients who have had a seizure while asleep cannot drive for 1 year from the date of each seizure unless:
- The seizures occur only ever while asleep or
- A pattern of PURELY ASLEEP SEIZURES can be demonstrated over the course of 3 years IF the patient has previously had seizures whilst awake (or awake and asleep).

Question 6

Pregnancy

Answer 6

• There is an increased risk of TERATOGENICITY associated with using antiepileptic drugs. The risk is highest for Valproate.
• It may be in the best interest of the fetus to withhold antiepileptics during the first trimester.
• Women of child-bearing potential who take anti-epileptic drugs should be given advice about the need for effective contraception to avoid unplanned pregnancy.
• If treatment with antiepileptic drugs must continue throughout pregnancy, then MONOTHERAPY is preferable at the lowest effective dose.

Question 7

To reduce the risk of neural tube defects

Answer 7

• To reduce the risk of neural tube defects (defects of the brain, spine or spinal cord), folate supplementation is advised before conception and throughout the first trimester.

Question 8

Breastfeeding

Answer 8

Women taking anti-epileptic monotherapy should be encouraged to breastfeed. All infants should be monitored for sedation, feeding difficulties, adequate weight gain and developmental milestones.

Question 9

Types of seizures

Answer 9

• Focal = localised to one hemisphere of the brain
• Tonic-clonic = Tonic (body is rigid), Clonic (uncontrolled jerking)
• Myoclonic = shock-like jerks of muscles,
• Absence = spells of STARING.

Question 10

first-line & 2nd line options for focal seizures

Answer 10

Carbamazepine and Lamotrigine;

2 line: Levetiracetam, oxcarbazepine, sodium valproate (consider treatment with phenytoin as adjunctive is poor control)

Question 11

first-line & 2nd line treatment for tonic-clonic

Answer 11

Sodium Valproate;

2nd line: Lamotrigine
3rd line: if both contra, carbamazepine, oxcarbazepine

Question 12

first-line & 2nd line options of absence seizures

Answer 12

Ethosuximide or Sodium Valproate.

2nd line: lamotrigine

Question 13

Dravet syndrome:

Answer 13

Sodium valproate or topiramate are first line

Question 14

Lennox-Gastaut syndrome:

Answer 14

Sodium valproate is first line

Question 15

Atonic and tonic seizures:

Answer 15

Usually seen in childhood, sodium valproate is first line

Question 16

Carbamazepine advice

Answer 16

 It is essential to initiate this drug at a low dose and build it up slowly.
 It may exacerbate tonic, atonic, myoclonic and absence seizures so should be avoided if these seizures are present.
 Patients should be told how to recognise signs of blood, liver and skin disorders: fever, rash, mouth ulcers, bleeding or bruising. In this case: the drug should be WITHDRAWN IMMEDIATELY.

Question 17

Gabapentin and Pregabalin

Answer 17

 Gabapentin and Pregabalin are used for the treatment of focal seizures. They are not recommended if tonic, atonic, absence or myoclonic seizures are present.

Question 18

 Gabapentin safety information:

Answer 18

the levels of propylene glycol, acesulfame K and saccharin sodium may exceed the recommended WHO daily intake limits if high doses of gabapentin oral solution (ROSEMONT BRAND) are given to adolescents or adults with a low body weight (39-50kg)

• risk of severe resp. depression

Question 19

Lamotrigine

Answer 19

• Lamotrigine can be used for focal, tonic-clonic, absence and as an adjunctive in atonic or tonic seizures.
• Myoclonic seizures may be exacerbated by Lamotrigine
• Valproate increases plasma-lamotrigine concentration whereas enzyme-inducing epileptics reduce it.

Question 20

Lamotrigine SE

Answer 20

Skin reactions … Severe skin reactions including SJ syndrome and toxic epidermal necrolysis have developed especially in children, most rashes occur within the first 8 weeks. Consider withdrawal if rash or signs of hypersensitivity syndrome develop. Factors associated with increased risk of serious skin reactions include concomitant use of valproate, initial lamotrigine high dosing and more rapid dose escalation. Look out for signs of bone marrow failure: anaemia, bruising or infection.

Question 21

Phenytoin

Answer 21

• Phenytoin is licensed for tonic-clonic and focal seizures but may exacerbate absence or myoclonic seizures.
• It has a NARROW THERAPEUTIC WINDOW and small dosage increases may produce LARGE increases in plasma concentration with acute toxic side-effects (Non-linear dose-plasma relationship).
- Similarly, a few missed doses or small change in drug absorption may result in a marked change in plasma-drug concentration. Thus, plasma-drug concentration should be monitored.

Question 22

Phenytoin SE

Answer 22

1. Rash: discontinue, if mild then re-introduce cautiously but discontinue immediately if recurrence
2. Bradycardia & hypotension: With IV: reduce rate of administration if bradycardia or hypotension occur
3. Overdose: symptoms of phenytoin toxicity include nystagmus, diplopia, slurred speech, ataxia, confusion and hyperglycaemia

• Blood or skin disorders: if fever, rash, mouth ulcers, bruising or bleeding seek medical attention urgent
• change in appearance (coarsening of hair)
• low vitamin D
• hepatotoxicity
• suicidal thoughts

Question 23

Topiramate SE

Answer 23

 This drug can be given alone or as an adjunctive treatment in generalised tonic-clonic or focal seizures.
 Side effects: Acute myopia (close objects look clear but distant objects are blurry) with secondary angle-closure glaucoma typically occurring within 1 month of starting treatment. If raised intraocular pressure occurs, seek ophthalmological advice + stop topiramate as rapidly as feasible.

Question 24

Sodium Valproate cautions

Answer 24

 It is the drug of choice for many types of seizures. Take with or just after food unless e/c tablet.
 Cautions: Liver dysfunction can occur when taking Valproate usually in the first 6 months, so liver function must be monitored. Raised liver enzymes during Valproate therapy are temporary but liver function must be monitored until return to normal – discontinue if abnormally long prothrombin time
- pancreatitis (abdominal pain, nausea, vomit)
 Withdraw if persistent vomiting and abdominal pain, anorexia, jaundice, oedema, malaise, drowsiness or loss of seizure control. Discontinue treatment is symptoms of pancreatitis develop (abdominal pain, nausea or vomiting). Advise patients how to recognise symptoms of blood or liver disorders.
 It should not be used in women and girls of child-bearing potential unless alternatives are ineffective/not tolerated due to its high teratogenic potential.
 Gives false-positive urine tests for ketones

Question 25

Benzodiazepines

Answer 25

 Clobazam can be prescribed as an adjunctive for tonic-clonic + focal seizures.
 Clonazepam can be prescribed for refractory absence and myoclonic seizures, but it has sedative s.e’s.
 Regardless, all benzodiazepines must be prescribed by or under experienced personnel.

Question 26

Vigabatrin SE & Cautions

Answer 26

 Used as an adjunctive for focal seizures (may worsen absence, myoclonic, tonic and atonic seizures)
 Side effects: Encephalopathic symptoms (marked sedation, stupor, confusion with non-specific slow wave ECG – reduce dose or withdraw.
 Cautions: Vigabatrin is associated with visual field defects. The onset of symptoms varies from 1 month to several years after staring. Product literature advises visual field testing before treatment and at 6-month intervals. Patients should be warned to report any new visual symptoms that develop.

Question 27

Fosphenytoin SE

Answer 27

 Pro-drug of phenytoin available as IV infusion only
 Side effects: Severe cardiovascular reactions including asystole, ventricular fibrillation + cardiac arrest. Hypotension, bradycardia and heart block have been reported. Thus, monitor heart rate, BP and respiratory function during infusion… observe patient for 30mins after and if hypotension occurs then reduce infusion rate or discontinue. Reduce dose of infusion rate in elderly and in renal or hepatic

Question 28

Status epilepticus (epileptic fits follow one after another without recovery of consciousness)

Answer 28

• Immediate measures to manage status epilepticus include positioning the patient to avoid injury, supporting respiration including provision of oxygen, maintaining blood pressure and the correction of any hypoglycaemia.
• Seizures lasting longer than 5 minutes should be treated with I.V. Lorazepam (repeated once after 10 minutes if seizures recur or fail to respond). Patients should be monitored for respiratory depression and hypotension.
• If after treatment with benzodiazepines, seizures recur or fail to respond 25 minutes after onset, phenytoin sodium, fosphenytoin sodium or phenobarbital sodium should be used (by I.V. injection).
• If these measures fail to control seizures 45 minutes after onset, anaesthesia with thiopental sodium, midazolam or a non-barbiturate anaesthetic should be used

Question 29

MHRA Advice: 3 risk-based categories of antiepileptic drugs: category 2

Answer 29

2. Category 2: Valproate, Lamotrigine, Clonazepam, Clobazam, Topiramate. The need for a specific manufacturer’s product (specific brand) is based on the clinical judgement of the HCP considering seizure frequency and treatment history.

Question 30

MHRA Advice: 3 risk-based categories of antiepileptic drugs: category 3

Answer 30

3. Category 3: Levetiracetam, Gabapentin, Pregabalin, Vigabatrin. Unnecessary to maintain on specific brand

Question 31

plasma conc. changes in pregnancy - which drugs?

Answer 31

Phenytoin, Carbamazepine, Lamotrogine

Question 32

monitor foetal growth

Answer 32

topiramate/levetiracetam

Question 33

breastfeeding monitor

Answer 33

drowsiness, weight gain, feeding difficulty, adverse effect, developmental milestones

Question 34

which drugs are present in high amounts in milk

Answer 34

zonisamide, ethosuximide, lamotrigine, primidone

Question 35

which drugs accumulate due to slower metabolism in baby

Answer 35

phenobarbital, lamotrigine

Question 36

which drugs are associated with antiepileptic hypersensitivity syndrome

Answer 36

rash, fever, lymphadenopathy, systemic involvement

• Phenytoin, Carbamazepine, Lamotrigine, phenobarbital, primidone

Question 37

which drugs are associated with skin rashes

Answer 37

Lamotrigine

Question 38

which drugs are associated with blood dyscrasias

Answer 38

Phenytoin, Carbamazepine, Lamotrigine, zonisamide, ethosuximide, valproate, topiramate

Question 39

which drugs are associated with eye problems

Answer 39

• vigabatrin (The onset of symptoms varies from 1 month to several years after starting. Visual problems usually
  persist despite discontinuation, and further deterioration cannot be excluded. Visual field testing before treatment and at 6-month intervals is advised. Any new visual symptoms that develop should be reported and reviewed urgently by an ophthalmologist. Gradual withdrawal of vigabatrin should be considered.)
• topiramate (acute myopia with secondary angle closure glaucoma, also choroidal effusions and anterior displacement of lens and iris)

Question 40

which drugs are associated with encephalopathic symptoms

Answer 40

vigabatrin (marked sedation, stupor, confusion)

Question 41

phenytoin interactions

Answer 41

• Increased plasma concentrations with amiodarone, chloramphenicol, cimetidine, diltiazem, fluconazole, fluoxetine,
miconazole, topiramate,
metronidazole, clarithromycin, (enzyme inhibitor) trimethoprim

• Reduced plasma concentrations with rifamycins,
st Johns Wort, (enzyme inducer) theophylline, itraconazole, ciclosporin

• Anticonvulsant effect antagonised: quinolones, tramadol, mefloquine, SSRI, antipsychotics, TCA
• Increased antifolate effect (increased risk of blood dyscrasias): MTX, trimethoprim
• phenytoin (enzyme inducer) reduces drug conc. of: warfarin, hormonal contraceptives/HRT, levothyroxine, liothyronine

Question 42

Carbamazepine interactions

Answer 42

• Increased plasma concentration with acetazolamide, cimetidine, clarithromycin, erythromycin, fluoxetine, miconazole (enzyme inhibitors)

• Decreased plasma concentration with phenytoin,
rifabutin, St. John’s Wort (enzyme inducer)

• Carbamazepine reduces plasma concentration of antipsychotics, corticosteroids, coumarins, eplerenone, warfarin, hormonal contraceptives/HRT, simvastatin
• Anticonvulsant effect antagonised: quinolones, , mefloquine, SSRI, antipsychotics, TCA
• risk of hyponatremia: aldosterone antagonists, SSRI, TCA, diuretics, NSAIDs
• risk of hepatotoxicity: tetracyclines, sulfasalazine, valproate, MTX, isoniazid, statins, fluconazole, alcohol.

Question 43

first-line & 2nd line treatment for myoclonic seizures

Answer 43

1st line: Sodium valproate (except in females)

2nd line: Levetiracetam or Topiramate

Question 44

Status Epileptics

Answer 44

O2, BP, hypoglycemia controlled.

0-5 min -> Benzodiazepine (lorazepam) IV and repeated once after 10mins.

10-30 min -> Phenytoin/fosphenytoin/phenobarbital (can be given by slow IV; IM or suppository too slow)

30-60 min -> General anaesthesia (Thiopental, midazolam)

NB: If alcohol induced give thiamine.
If pyridoxine deficiency induced give pyridoxine.

Question 45

valproate interactions

Answer 45

• valproate (enzyme inhibitor) increases plasma concentration of other antiepileptics
• Anticonvulsant effect antagonised: quinolones, , mefloquine, SSRI, antipsychotics, TCA
• risk of hyponatremia: aldosterone antagonists, SSRI, TCA, diuretics, NSAIDs
• risk of hepatotoxicity: tetracyclines, sulfasalazine, carbamazepine, MTX, isoniazid, statins, fluconazole, itraconazole

Question 46

medical seizure emergency in community:

Answer 46

convulsive seizures or febrile seizures >5 mins:

diazepam rectal or oromucosal midazolam

repeat once after 10-15 mins if necessary