Journal Club

Management of
Seizures in
Palliative Care
 References
1. Krouwer, H., Pallagi, J., & Graves, N. (2000).
Management of Seisures in Brain Tumor Patients at
the end of Life. Journal of Palliative Medicine, 3(4),
465 – 473.
2. Caraceni, A., Martini, C., & Simonetti, F. (2010).
Neurological Problems in Advanced Cancer. In
Hanks, G., Cherny, N. I., Christakis, N. A., Fallon, M.,
Kaasa, S., & Portenoy, R. K (Eds.), Oxford Textbook of
Palliative Medicine (pp. 1035 – 1058). London :
Oxford University Press.
3. Bausewein, C., Borasio, G. D., & Voltz, R. (2010).
Primary Brain Tumours. pp. 1174 – 1177.
 References
4. Watson, M., Lucas, C., Hoy, A., & Wells, J.
(2009). Drug Interaction in Palliative Care.
Oxford Handbook of Palliative Care (61 – 96).
New York : Oxford University Press.
5. Neurological Problems in Advanced Cancer.
(pp 461 – 469)
 Definition of Seizure 2

“A seizure is a transient
occurrence of signs or
symptoms due to abnormal
excessive or synchronous
neuronal activity in the brain”
 Common causes of Seizure in
Palliative Care1,5 :
I. Brain Tumour
1. Primary Brain Tumors
Eg GBM
2. Metastatic Brain Tumors
• Common sites : lung, melanoma, breast
3. Mets to meninges
• Most commonly seen in Lymphoma,
leukemia
 Common Causes : 1,5

II. Biochemical disturbance

Eg severe hyponatraemia
III. Metabolic disturbance
Eg. hypoglycemia
IV. Drug toxicity
Eg. Amitriptyline
V. Previous CVA
VI. Long-standing epilepsy
VII. Infection
 Tumor can cause Seizure by :
• Compression
• Local destruction
• Irritation of brain tissue
• edema
• bleeding
 3 MainTypes of Seizures : 1

I. Simple partial seizure

• Consciousness not impaired; usually unilateral
hemispheric involvement associated with
- motor symptoms
- somatosensory symptoms
- autonomic symptoms, and
- psychic symptoms
 Types of Seizure : continue
II. Complex partial seizure
• Impairment of consciousness; frequently bilateral hemispheric
involvement:
- Beginning as simple partial seizure and progressing to impairment
of consciousness
- With no other features
- With features as in simple partial seizure
- With automatisms (aberration of behavior, e.g., lip
smacking, fidgeting with hands)
• With impairment of consciousness at onset
- With no other features
- With features as in simple partial seizure.
• Partial seizures become secondarily generalized
 Types of Seizure : continue
III. Generalized seizure (convulsive or non-
convulsive)
• Consciousness always impaired, frequently as first
manifestation. Motor manifestations are bilateral:
- Absence seizures
- Myoclonic seizures
- Clonic seizures
- Tonic seizures
- Tonic-clonic seizures
- Atonic seizures
 Management of Seizures
• Looking for reversible causes and treat as
appropriate
• Drug therapy for the seizures
• Family counseling
 Prophylactic Anticonvulsant
Treatment2
• In palliative medicine
usually should not be
undertaken if the patient
has never had a seizure
 Initiating Anticonvulsant 2, 5

• After one seizure in pat with terminal illness

Commonly used First-line Anticonvulsants
1.Phenytoin
• Broad spectrum
• Start 150 – 300mg daily.
• Usual maintenance dose 300 – 400mg daily
• Max 600mg/24h. Single or 2 divided doses
• Long and variable half life
 Initiating Anticonvulsant 2, 5

• Can take several days, even up to 3 – 4 weeks

for changes in dosage to take complete effect
• Bear this mind when measure plasma
phenytoin concentration for monitoring
• ↓ phenytoin level by corticosteroid (risk fit)
• Phenytoin can ↓ efficacy of corticosteroids
 Initiating Anticonvulsant 2, 5

• Phenytoin level ↑ by omeprazole, fluoxetine,

fluvoxamine, nifedipine, amiodarone,
fluconazole, metronidazole, (risk of toxicity)
• IV formulation, can be systematically loaded and
provide rapid control of seizures
• Advantage : relative lack of sedative effect
• Chronic use : ataxia, GI disturbance, gingival
hypertrophy, hirsutism, osteoporosis,
megaloblastic anaemia
 Initiating Anticonvulsant 2, 5

2. Sodium Valproate (epilim)

• broad spectrum first line anticonvulsant
• Starting Dosage : 200mg tds
• Increase 200mg/day at 3 days interval
• Usual maintenance dose : 1 – 2 g/day
• Max : 2.5g/24H
 Initiating Anticonvulsant 2, 5

• IV formulation available
• Suppository preparation not available in Sing
• Common side effects : tremors, sedation,
ataxia, GI symptoms, thrombocytopenia
 Initiating Anticonvulsant 2, 5

3. Carbamazepine
• Broad spectrum
• Starting Dosage : 100 to 200 once to BD
• Increment by 200mg every week
• Usual maintenance dosage 0.8 – 1.2g/24H in
2 divided doses
 Initiating Anticonvulsant 2, 5

• Max : 1.6 – 2g/24H

• Suppository not available in Singapore
• Level ↓ by corticosteroids
• ↓ efficacy of corticosteroids
• Acute intoxication can cause stupor, coma,
convulsions, and respiratory depression
 Initiating Anticonvulsant 2, 5

4.Levetiracetam (keppra)
• Broad spectrum
• Start with 250mg bd
• Increasing stepwise by 250mg bd to max
dose 1.5g bd
• Widely used in addition to phenytoin or
epilim
• May also be used alone
 Initiating Anticonvulsant 2, 5

• No interaction with other anticonvulsants or

other drugs have been reported
• Well tolerated
• Common side effects : somnolence, dizziness,
anorexia
 Initiating Anticonvulsant
• 4 x common broad spectrum first line
anticonvulsants – phenytoin, epilim,
carbamazepine and keppra
• How to choose one over the other1 ??
- Actually, none of the anticonvulsants has shown
superiority over the others for any seizure type
- Can substituting one for another
- if it is not effective at therapeutic levels
 Initiating Anticonvulsant
- causing significant side effects
- interaction with other drugs
• Combination
- Epillim + Keppra
- Phenytoin + carbamazepine
 Other Anticonvulsants 1, 2,5

1. Barbiturates
Phenobarbital
• Well proven for all types of seizure
• Have both sedative and anticonvulsant effect
• Rarely used as first line, too sedative
• Metabolized by cytochrome P450
• Slow plasma clearance (4 -5 days), can be
prolonged by liver diseases
 Other Anticonvulsants 1, 2,5

• Has a wide therapeutic index

• short-acting barbiturate
• It depresses the sensory cortex, reduces motor
activity, changes cerebellar function, and
produces drowsiness, sedation and hypnosis.
• Its anticonvulsant property is exhibited at high
doses.
• Available parenteral, oral
 Other Anticonvulsants 1, 2,5

2. Benzodiazepines
i. Midazolam
• Available parenteral, oral tab
• Oral solution for buccal admin not available
• Water soluable
• Very short half life
• Has no active metabolite
 Other Anticonvulsants 1, 2,5

• Onset of action : 3 mins, 5 mins, 15 mins, IV,

IM/SC, oral respectively
• Good SC/IM absorption
• More useful as a sedative than as an
anticonvulsant
• probably require 20 – 30mg/24 hour
minimum for anticonvulsant effect
 Other Anticonvulsants 1, 2,5

ii. Lorazepam
• Available parenteral and S/L formulation
• Dilute with equal vol of water or saline for
parenteral use
• Mainly used as a sedative
 Other Anticonvulsants 1, 2,5

iii. Diazepam
• Available oral, rectal, parenteral
• Useful by the rectal route for control of
acute seizure or status epilepticus
iv. Clonazepam
• Indicated for focal seizure
 Other Anticonvulsants 1, 2,5

• Can also be used as a temporary treatment to

control and prevent seizures not controlled by
on going therapy
• Compatible with many drugs used in CSCI
• Much less experience support use in this way
• Dose : 2 – 4mg/24H
 Other Anticonvulsants 1, 2,5

4. Others
i. Topiramate
• Indicated for partial and generalized seizure
• Initial dosage should be low, 25 mg
• Increased by 25 – 50mg/week
• Usual effective dose range from 200 – 400mg
• Usual side effects sedation, concentration
problem, unsteadiness, memory disturbance
 Other Anticonvulsants 1, 2,5

ii. Lamotrigine
• Approved for absence seizure
• Used as monotherapy for paritial and
secondary generalized seizure
• Metabolized by liver and has sig interaction
with all the classic anticonvulsants,
phenobarbitone, phenytoin, and
carbamazepine
 Other Anticonvulsants 1, 2,5

• Severe rashes related to rapid titration of the

drug dose observed
• Important to initiate therapy slowly, titrate
slowly with weekly increment of 25 or 50mg
up to 300 – 500mg/d
 Other Anticonvulsants 1, 2,5

iii. Gabapentin
• Effective monotherapy for partial seizure
with or without secondary generalization
• Its use facilitated by the lack of binding to
plasma protein, and lack of hepatic
metabolism
• Elimination is renal
• 1800 to 3600mg/d in 3 divided doses
 Corticosteroids
• Most, if not all patients with intracranial
tumors are on steroids to control tumor
associated edema
• Mechanism of action : blocks the outflow of
blood components from the capillary bed into
the brain tissue at the site of blood brain
barrier damage
• Dexamethasone is the corticosteriod of choice
 Corticosteroids
• It is found in higher concentration within CSF
compared with prednisolone because it is less
bound to plasma proteins
• It also has more potent anti-inflammatory
activity than prednisolone
• Well absorbed orally
 Corticosteroids
• High dose 16mg/day, clinical benefit may be
observed within first 24 hours
• duration of action : 36 – 54 hours
• If seizures occur despite anticonvulsant
therapy review corticosteroid dosage for
patients with intracranial tumors
• Seizures worsen brain oedema and oedema
can, in turn cause seizures
 Drug Interactions
• Many drugs used in palliative care are
metabolised by the cytochrome P450 isoenzymes
• Carbamazepine and phenytoin levels are
decreased by corticosteroids (risk of fit)
• Carbamazepine, phenytoin, and phenobarbital
can reduce the efficacy of corticosteroids
• Anticonvulsant effects of phenytoin may be
antagonized by tricyclic antidepressant, SSRIs
 Drug Interactions
• Phenytoin levels may be decreased or
increased by benzodiazepines
• Many potential drug interactions can occur
between drugs commonly used in palliative
care setting and anticonvulsants, therefore
sometimes it is important to them up
 Epilim (MIMS)
• Monitor (& adjust dosage when necessary)
when it is used w/ neuroleptics, MAOIs,
antidepressants, benzodiazepines, phenobarb,
primidone, phenytoin, carbamazepine,,
lamotrigine
• Cimetidine
• Antibiotics eg erythromycin, carbapenem
 Epilim (MIMS)
• Monitor prothrombin time when used w/
warfarin & other coumarin anticoagulants.
• Caution when used w/ newer antiepileptics
whose pharmacodynamics are not well-
established.
View more drug interactions with Epilim
 Patient unable to take oral
Medication5
• Due to dysphagia, vomitting, or in terminal stage
• No parenteral anticonvulsant needed if low risk
of seizure, and only a single dose is missed
• Because Half life of most anticonvulsant is quite
long >24 H
• Risk of seizure is high if the patient :
- Decreased or stopped steroids (intracranial
tumors)
 Patient unable to take oral
Medication5
- Has increasing headache, vomitting, or other
signs suggest ↑ICP (intracranial tumors)
- Exhibit myoclonus or other twitching
- Has a Hx of poor seizure control of recent
seizures
- Has previously needed more than a single
anticonvulsant to achieve control
 Patient unable to take oral
Medication5
• Because of the long half life of
anticonvulsant, parenteral
treatment can be started at
any time within 24 hours after
the last oral dose
 Choice of Non Oral
Anticonvulsant1, 2, 5
I. Parenteral
1. Phenobarbital
• Useful as replacement oral anticonvulsant
and in terminal agitation
• Can be given IV, CSCI, SC, IM
• Incompatible with most other drugs in a
syringe driver
• Can be given CSCI in separate syringe driver
 Choice of Non Oral
Anticonvulsant1, 2, 5
• Stat doses of SC and IM can sting
• Experience suggests effective dose
200mg/24H
• CSCI 200 – 1600mg / 24H
• Loading dose 100mg to 200mg slowly IV or SC
after diluting 1 in 10 with water for injection
• Onset : about 5 mins
• Duration IV : 4 – 10 hours
 Choice of Non Oral
Anticonvulsant1, 2, 5
2. Sodium Valproate
• patients already stabilized on oral valproate
may continue w/ the same dose
• Initiation of IV therapy
- Loading : 400-800 mg (up to 10 mg/kg) by
slow IV inj over 3-5 min
- followed by continuous or repeated infusion
up to max 2,500 mg daily
 Choice of Non Oral
Anticonvulsant1, 2, 5
3. Phenytoin Sodium
• Loading dose 15 to 20mg/kg IV slowly up to
50mg/min
• Maintenance dose : 4 – 7 mg/kg/d IV (qd –
tid)
 Choice of Non Oral
Anticonvulsant1, 2, 5
2. Rectal
• Advantage : can teach carer to admin
• Absorption occurs by passive diffusion
through the lipid membrane
• Absorption rate and extend is optimal if drug
is lipid soluble and nonionized
• Due to relatively small surface area and
various venous drainage pathway, rectal
 Choice of Non Oral
Anticonvulsant1, 2, 5
• Absorption is highly variable between subjects
and probably even in individuals from dose to
dose
• Absorption from solution is more rapid and
possible more complete than from
suspensions or suppositories
• Two categories are available and effective in
the setting of acute seizure and SE :
 Choice of Non Oral
Anticonvulsant1, 2, 5
i. Benzodizepines
• Diazepam is the drug of choice
• In gel form is rapidly absorbed, well
tolerated and highly effective
• Dose : 10 to 20mg (0.2mg/kg)
• Admin if a witnessed seizure > 5mins,
prevent the progression of a single seizure
into a cluster of seizures or SE
 Choice of Non Oral
Anticonvulsant1, 2, 5
ii. Carbamazepine
• Suppository has to be specially made by a
pharmacist
• Suspension available commercially (not in
Singapore)
• Same total oral daily dose given in small,
dilute, multiple doses (6-8/day) to reduce
the risk of early defecation
 Choice of Non Oral
Anticonvulsant1, 2, 5
iii. Valproate acid
• Suppositories found to be effective and well
tolerated for prolonged admin
• Has been given in a solution, using the syrup,
diluted with an equal vol in tap water, via a
small-diameter tube
• Emptying the rectum prior to admin helps
absorption
 Choice of Non Oral
Anticonvulsant1, 2, 5
• Pressing the buttocks together for 15 mins
after withdrawal of the tube helps to prevent
leakage of syrup
• Alternatively, the tube can be left in place,
clamped for 15 mins
• Dose : Same as oral dose
 Choice of Non Oral
Anticonvulsant1, 2, 5
3. Buccal
• Midazolam buccal 10mg/2ml – administered
by carer, if rectal route unacceptable
- Appears to be as effective or quicker-acting
than rectal diazepam 10mg
- An oral solution is available as a special order
(not available MIMS)
- Or the injectable preparation can be used
 Status Epilepticus 2, 4

• Defined as “SE is a seizure that lasts 30 mins

or more, or two or more seizures that occur
without complete recovery of consciousness
in between”
• Proposed Management :
 Midazolam
- 5 – 10 mg SC
- or slow IV (dilute 10mg with water to 10ml)
 Status Epilepticus 2, 4

- Repeat after 15 and 30 mins if not settled

• Or
 Lorazepam
- 4 – 6mg slow IV or subligually, may repeat once
after 20 mins
• Or
 Diazepam
- 10mg PR
 Status Epilepticus 2, 4

- or 2 – 10mg slow IV, may repeat once after

5mins
• If patient has not responded to repeat doses
of benzodiazepine or seizure recurs, consider :
 Phenobarbital
- 100mg IV or SC after diluting 1 in 10 with
water for injection
- repeat if necessary
 Status Epilepticus 2, 4

- Set up syringe driver 200 – 600mg/24H CSCI

- Once seizure controlled, review
anticonvulsant therapy
Management of Seizures at Home 5

• Most seizures are self limiting

• Prolonged seizures > 5 minutes
Measures :
• Diazepam 10mg PR – administered by carer or
nurse
or
• Midazolam 5 – 10mg SC/IM – by nurse
Management of Seizures at Home 5

• Or
• Midazolam buccal 10mg/2ml as mentioned
before
 Family Counselling
• Family members who have witnessed prior
seizures often have great fear about seizure
recurrence
• Need appropriate explanation and
reassurance
- Patient will not die from seizure
- Usually seizure will stop on its own
• Instruction what to do during and after seizure
 Family Counselling
• If patient fits > 5 mins give medicine
• Warn them that patient will be drowsy after
seizure