Showing Page:
1/45
MANAGEMENT OF
SEIZURES
1. Definition of terms
- Seizure
- Fit
- Convulsion
- Epilepsy
2. EPIDEMIOLOGY
5-10% of the general
population has had a seizure
during their lifetime.
Incidence of epilepsy is 0.3
Showing Page:
2/45
0.5 % worldwide and the
prevalence 5-10 per 1000
3. CLASSIFICATION
According ILAE 1981
(i) partial seizures
a) simple partial motor
sensory, autonomic
psychic signs
b) complex partial
c) partial seizures
secondarily generalised
(ii) generalized seizures
Showing Page:
3/45
a) grand mall (tonic
b) clonic) 10% of all
c) absence (petit mal)
15-20 % of childhood
epilepsies
d) tonic
e) atonic
f) myoclonic
(iii) unclassified
- neonatal seizures
- infantile spasms
3 points to note about
seizures:
- spread
- induction
Showing Page:
4/45
- status epileptics
EPILEPSY SYNDROMES
a) Juvenile myoclonic
epilepsy
They may also have tonic
clonic seizures. 1/3 have petit
mal also .It comes in early
adolescence.
b) Lennox Gestaut syndrome
Occurs in children,
characterized by multiple
Showing Page:
5/45
seizures - tonic clonic, atonic,
atypical absence.
- EEG shows slow < 3 Hz
spike and wave discharge
and other abnormalities .
- Impaired cognitive
function in most cases
- Associated with CNS
disease or dysfunction
c) Mesial temporal lobe
epilepsy syndrome (MTLE)
Has typical clinical, EEG
and pathologic features. It is
the most common syndrome
associated with complex
Showing Page:
6/45
partial seizures. There’s
hippocampal sclerosis, it is
resistant to drugs and is
usually cured by surgery.
d)West’s syndrome – A
clinical triad of infantile
spasms, arrest of
psychomotor development
and hypsarrhythmia on EEG.
Causes can be prenatal,
perinatal or post natal. Upto
40% no cause. Onset usually
before 1 year, peaks at 3-7
months. Prognosis very poor
for those with infantile
Showing Page:
7/45
spasms. Drug of first choice
is vigabatrin. Others are
valproate, clonazepam and
zonisamide. ACTH and
corticosteroids are used when
others fail. Focal lesions
respond to surgery.
e) LandauKleffner
syndrome. Presents as an
acquired aphasia with
seizures. Several seizure
types occur including GTC,
partial and myoclonic.
Characteristically manifest
word deafness despite normal
Showing Page:
8/45
hearing. EEG shows spike
activity over temporo-central
regions. Occurs at 3-9 years.
Responds to standard drugs.
Language recovery variable.
4. AETIOLOGY
Two types of epilepsy
-Idiopathic
-Secondary
Showing Page:
9/45
CAUSES IN
NEONATES
- prenatal
hypoxia/ischemia
- intracranial
hemorrhage/trauma
- acute CNS infection
- metabolic disturbances -
decreased ca, mg, glucose
pyridoxine
- drugs withdrawal
- developmental diseases
- genetic abnormalities
IN INFANTS/CHILDREN (1/12 12
YRS)
Showing Page:
10/45
- febrile seizures
- genetic diseases
- CNS Infections
- Trauma
- Developmental diseases
- Idiopathic
IN ADOLESCENTS (12-18YRS)
- Trauma
- Genetic diseases
- Infection
- Brain Tumors
- Illicit drug use
- Idiopathic
YOUNG ADULTS (18-35 YRS)
- Trauma
Showing Page:
11/45
- Alcohol withdrawal
- Illicit drugs use
- Brain Tumors
- Idiopathic
OLDER ADULTS
- Cerebrovascular accidents
- Brain Tumors
- Alcohol withdrawal
- Metabolic diseases anemia,
liver failure, electrolyte
abnormalities, hypoglycemia
- Alzheimers disease, other
degenerative diseases
- Idiopathic.
DRUGS + OTHER SUBSTANCES
CAUSING SEIZURES
Showing Page:
12/45
- Antibiotics β-lactams, quinolones,
INH, acyclovir, gancyclovir
- Anesthetics /analgesics
meperidine, tramadol, Local
anaesthetics
- Immunomodulatory drugs -
Cyclosporin, tacrolimus, interferons
- Psychotropcis - Antidepressants,
antipsychotics, lithium
- Theophylline
- Radiocontrast agents
- Sedative/hyphotics withdrawal -
Alcohol, benzodiazepines,
barbiturates
- Drugs of abuse
- Amphetamine, cocaine,
phencyclidine, methylphenidate
- Flumazenil
Showing Page:
13/45
DRUG MECHANISMS
1. Inhibition of sodium Channels -
Phenytoin, carbamazepine
topiramate, zonisamide, felbamate
2. Inhibition of voltage gated calcium
Channels phenytoin,
ethosuximide, valproate,
trimethadione
3. Decrease of glutamate release
lamotrigin, topiramate act on
AMPA receptors, felbamate act
on NMDA receptors
4. Potentiation of GABA receptor
function - benzodiazepines,
barbiturates, topiramate , they
increase chloride
Showing Page:
14/45
5. Increase in availability of GABA -
valproate, gabapentine inhibits
GABA transaminase, tiagabine
inhibits GABA reuptake.
DRUGS
CHEMICAL CLASSIFICATION
1. Hydantoins Phenytoin,
methotoin, ethotoin, phenacemide
2. Imminostilbenes carbamazepine,
oxcarbazepine
3. Barbiturates - phenobarbital,
primidone, mephobarbital
4. Benzodiazepines - diazepam,
clonazepam, clorazepate
dipottasium, nitrazepam,
clobazam, lorazepam,
Showing Page:
15/45
5. Carboxylic acids(fatty acids)-
valproic acid, Sodium valproate
6. Succinamides ethosuximide,
phensuximide, methsuximide
7. Oxazolidinediones --
trimethadione, dimethadione,
paramethadione
8. Steroids - ACTH, Prednisone
9. Amino acids 5-0H tryptophan
10. Miscellaneous vigabatrin,
- lamotrigin
-Topiramate
- Levetiracetam
- felbamate
-Acetazolamide
-Zonisamide
- gabapentin
- pheneturide
- pregabalin
- progabide
Showing Page:
16/45
- sulthiame
- tiagabine
- barbexaclone
- beclamide
TREATMENT OF EPILEPSY
1. Carbamazepine (Tegrettol,
zheptol)- 400-1600mg/d, in 2-3
divided doses
First line or adjunctive therapy
in partial and generalized seizures
(except petit mal and myoclonus),
Lennox Gestaut syndrome,
childhood epilepsy syndromes.
Therapeutic levels 20-50 μmol/l
2. Clobazepam - 10-30mg/d, in 1-2
divided doses,
Showing Page:
17/45
- Adjunctive therapy for partial
and generalized seizures.
- Also for intermittent therapy,
on/off prophylactic therapy, non
convulsive status epilepticus,
- Excellent second line for some
resistant epilepsy.
3. Clonazepam(rivotril) - initially
0.25mg, maintainance 0.5- 4mg
per day in 1-2 doses, or 0.1- 0.2
mg /kg in adults, children 0.01
0.02 mg/kg//d.
Therapeutic levels, 5-70ng/ml
Adjunctive therapy in partial
and generalised seizures, including
absence and myoclonus, Lennox
Gestaut syndrome, status epilepticus.
Showing Page:
18/45
4. Lamotrigine (lamictal) - initially
12.5-25mg/d, maintenance 100-
200mg/d.
Monotherapy or comedication
with valproate, Comedication with
enzyme inducers 200 400mg/d
Adjunctive or mono therapy in
partial and generalized epilepsy,
Lennox Gestaut syndrome.
5. Phenytoin(dilantin) - initially
300mg, maintainance 100-300mg/d in
adults, children 5mg/kg,
maintainance 3-8mg /kg. Adjustment
guided by serum levels. Therapeutic
levels 40-80μmol/l (10-20μg/ml)
Given orally or I.V in 1-2 doses.
First line or adjunctive therapy for
partial and generalized seizures,
excluding absence and myoclonus,
Showing Page:
19/45
Lennox Gestaut syndrome (LGS),
childhood epilepsy syndromes.
Use limited by adverse effects.
6. Valproate (depakene, depakote,
epilim) initially 400 - 600mg/d in
adults in 2-3 divided doses,
maintenance 500-2500mg/d in adults.
20mg/kg/d in children < 20kg,
40mg/kg/d in children >20/kg
Therapentic levels - 300-600
μmol/l
Drug of choice in primarily
generalised epilepsy and useful in
many others myoclonus,
absence, partial.
7. Felbamate (felbatol) - initially
1200mg/d in adults, in 3-4 divided
doses, maintenance 1200-
Showing Page:
20/45
3600mg/d. Children - initially
15mg/kg/d, maintenance 45-80
mg/kg/d.
Adjunctive therapy in refractory
partial and secondarily generalized
seizures, Lennox Gestaut
syndrome, highly effective in severe
resistant epilepsy but use limited
by rare but severe hepatic and
hematological toxicity.
Therapeutic levels 200-
460μmol/l.
8. Gabapentin (neurontin) - 300-
1800mg/d
Adjunctive therapy for refractory
partial and secondarily generalised
seizures. Well tolerated.
Showing Page:
21/45
9. Levetiracetam (keppra) 1000-
3000mg/d
Adjuctive therapy in partial ±
secondarily generalised seizures
10. Oxcarbazepine (trileptal) -
initially 600mg/d in 2 divided doses.
Maintenance 900 2400 mg/d.
Structure similar to carbamazepine
but better tolerated with fewer
adverse effect.
Adjunct or monotherapy in partial
and secondarily generalised seizures.
11. Primidone (mysolin) - initially
125mg/d in 1-2 divided doses
Maintenance 500-1500 mg/d.
Children < 2yrs 250 - 500mg, 2-5
yrs 500-700mg, 6 - 9 yrs 750-
1000mg.
Showing Page:
22/45
Adjunctive therapy in partial and
secondarily generalised seizures,
absence, myoclonus, L.G.S. Active
metabolite is phenobarbital.
12. Tiagabine (gabatril) - initially
15mg/d in 2-3 divided doses
Maintenance 30 45 mg/d ( and in
combination with enzyme inducers)
15-30 mg/d combined with
nonenzyme inducers.
Adjunct therapy for partial and
secondarily generalized seizures,
especially refractory cases.
13. Vigabatrin - initially 1000mg /d
in 2 divided doses, maintenance 1000-
3000mg/d, children 40mg/kg /d
Adjunct therapy in partial and
secondarily generalised seizures. Use
Showing Page:
23/45
limited by neuropsychiatric side
effects and visual field constriction.
14. Topiramate (topamax)
Initially 25-50 mg/d in 2 doses,
Maintenance 200-600mg/d.
Adjuct therapy in partial and
secondarily generalised seizures, LGS
and grand mal seizures.
15. Ethosuximide (zarontin)
initially 250mg in 2-3 divided doses,
children 10-15 mg/kg,
Maintenance 750 2000mg in
adults, 20-40mg/kg /d in
children.
Therapeutic levels 300-700μmol/l
Showing Page:
24/45
16. Piracetam- initially 7.2 g/d in 2-
3 divided doses, maintenance upto
24g/d.
For some patients with refractory
myoclonus
17. 5-OH Tryptophan
For intention myoclonus
18. Steroids - ACTH 25-40 units/d,
upto 240 units/d
prednisone - 15- 60 mg/d
prednisolone 2 mg/kg /d
dexamethasone 0.3 mg/kg/d
For refractory infantile spasms
and myoclonus
19. Trimethadone 900-2400 mg /d
in adults,
children 30mg /kg/d
Showing Page:
25/45
Therapeutic level >700μg/ml
Not used because of severe adverse
effects on bone marrow, kidney
and liver. It used to be the drug
choice for petit mal.
20. Lorazepam - 2-3 mg b.d I.V in
normal saline infusion.
For status epilepticus.
21. Clorazepate dipottasium
45mg/d in 2-3 divided doses,
- initially 7.5 22.5 mg
For myoclonus.
22. Nitrazepam
For infantile spasms and
myoclonic seizures.
Less potent than clonazepam.
Showing Page:
26/45
23. Acetazolamide 250 -
500mg/d. or 10/kg, max 1000mg
Effective as adjunct therapy in
catamenial epilepsy, started 7-10days
prior to onset of menses and until
bleeding stops.
24. Phenobarbital ( gardenol, luminal)
30 180mg/d in 1-2 divided doses
in adults, 3 - 8mg /d in children, 3 4
mg/d in neonates PO.
IM or IV 50 200mg repeated PRN,
maximum 600mg, in status
epilepticus
Adjunct or first line therapy in partial
or generalized seizures + absence +
myoclonus, status epilepticus, Lennox
Gestaut syndrome, childhood epilepsy
Showing Page:
27/45
syndromes, febrile seizures, neonatal
seizures.
Therapeutic levels 40 170 μmol/l
PRINCIPLES OF
MANAGEMENT OF EPILEPSY
1. Early diagnosis and treatment of
seizure disorders with a single
appropriate agent offers the best
prospect of achieving prolonged
seizure free periods with the
lowest risk of toxicity.
2. An attempt should be made to
ascertain the cause, as it may be
correctable. This is most likely in
the very young and those with the
first episode in adulthood.
Showing Page:
28/45
3. The goal of therapy is to keep
patient seizure free without
interfering with normal function.
Drug adjustments are best assisted
by drug plasma levels.
4. Treatment should be initiated with
a single drug. Adjust doses
upwards for control until maximal
doses are reached or until
toxicities are intolerable.
Large doses are started only if
there is urgency in controlling the
seizure.
5. First substitute another drug if
maximum doses have not achieved
control before using combinations.
In substituting, gradually reduce
dose of the first drug as you
gradually increase the dose of the
second.
Showing Page:
29/45
Consider AEDS acting on new
targets.
Combinations should be as rational as
possible.
6. Once control achieved with
polytherapy, attempt to come back
to monotherapy. Any drug should
be withdrawn only gradually
7. After seizure free period of 3yrs,
you can start withdrawing the
drugs. 70% children, 60% adults
will have seizures controlled and
can do without drugs after this
period.
Showing Page:
30/45
SIMPLE, COMPLEX PARTIAL
AND SECONDARILY
GENERALISED TONIC CLONIC
SEIZURES.
(a) Carbamazepine and phenytoin are
the most effective single drug
therapy of partial and generalized
tonic clonic epilepsies. The choice
depends on toxicity considerations.
Long term use of Phenytoin causes
untoward cosmetic effects e.g
hirsutism, coarsening of facial
features, gingival hypertrophy, so it
is often avoided in young patients.
Carbamazepine can cause
leukopenia, aplastic anemia or
hepatotoxicity and is therefore not
appropriate for patients predisposed
to these conditions.
Showing Page:
31/45
(b) Valproic acid is broad spectrum
and is preferred for patients with
mixed seizures especially the epilepsy
syndromes. It is an effective
alternative for partial seizures
especially with secondarily
generalised seizures. It rarely causes
reversible bone marrow suppressions
and hepatotoxicity which may be
fatal. Avoid in those with bone
marrow or liver disease. Risk of the
fatal liver failure is higher in those <
2yrs age, those on multiple drugs
and those with inborn errors of
metabolism.
It is used in infants and young
children only if benefit outweighs
risk. It more commonly causes
tremors and weight gain.
Showing Page:
32/45
(c) Lamotrigin, gabapentin,
topiramate, tiagabine and
Phenobarbital and primidone are
additional drugs used for partial
seizures with or without secondary
generalization. Lamotrigine is as
effective as the standard drugs and is
used as monotherapy. It may cause
rash in children especially. It is
introduced gradually from small doses
when added to valproate. It inhibits its
metabolism. Gabapentin has no
significant drug interactions making it
a useful add on therapy. Phenobarbital
and primidone cause sedation in
adults, hyperactivity in children and
other subtle cognitive changes.
Primidone causes more toxicity
including nausea, dizziness, ataxia,
Showing Page:
33/45
somnolence and decreased libido.
Their use should be limited to
situations in which there is no suitable
alternative.
(d) Oxcarbazepine is as effective as
carbamazepine with less adverse
effects. Benzodiazepines are used for
limited periods as tolerance to them
develops.
(e) Clobazepam, tiagabine,
vigabatrin, piracetum, felbamate,
topiramate, levetiracetam are
currently reserve drugs, for resistant
cases.
Felbamate rarely causes severe
hepatic and hematological toxicity.
Showing Page:
34/45
ABSENCE SEIZURES
The drug of first choice is
ethosuximide. Valproate is equally
effective. It is of second choice.
Clonazepam is useful especially in
those with myoclonic component.
Ethosuximide rarely causes bone
marrow suppression.
MYOCLONIC SEIZURES
Valproate is the drug of first choice.
Clonazepam is equally effective and
its effect can be dramatic.
Nitrazepam is also effective.
Showing Page:
35/45
FEBRILE CONVULSIONS
2-3% of cases become epileptic in
later years. Factors associated with
risk of epilepsy are:
- neurological disease
- developemental delay
- family history of epilepsy
- complicated febrile seizure i.e >
15min, one sided, several in a day
Phenobarbital prophylaxis has been
used before but now only rectal
diazepam during fever is
recommended.
SEIZURES IN INFANTS AND
YOUNG CHILDREN.
Showing Page:
36/45
Infantile myoclonic spasms with
hypsarrhythmias are refractory to the
usual anti-seizure agents. ACTH and
adrenal corticosteroids are the drugs
of choice. Valproate and clonazepam
may be effective. Valproate is
effective for akinetic myoclonic and
atonic seizures in young children.
STATUS EPILEPTICUS
It is a medical emergency. Mortality
is 3-35%. Signs become subtle after
30-45 min continuous fits, therefore
monitor with EEG.
.
1. Benzodiazepines are the drugs of
first choice for initial treatment.
Showing Page:
37/45
(a) Diazepam 0.2mg/kg. 10-20mg
bolus iv stat then 40mg in 500mls
5% dextrose to run slowly over 6
hours. If it recurs you can give
another bolus. At the same time
start a longer acting drug like
phenytoin IV or orally.
(b) Lorazepam 0.1mg/kg at
2mg/min
2. Phenytoin i.v 15-20 mg/kg at
50mg/min. Additional doses of 5-
10mg/kg can be given if fits
continue.
3. Phenobarbital 20mg/kg i.v at 50-
75mg/min. Additional doses of 5-
10mg/kg can be given if fits
continue.
4. Anaesthetic agents - thiopentone
sodium, midazolam, or propofol
Showing Page:
38/45
for G.A with assisted respiration if
fits still persist.
Should be in I.C.U with EEG
monitor. Attend to acute cardio
respiratory problems.
TREATMENT OF REFRACTORY
EPILEPSY
About 1/3 patients of epilepsy are
resistant to a single drug and require
multiple drug therapy. The most
likely are :
- Focal epilepsy related to a structural
lesion
- Multiple seizures patients
- Those with developmental delay
In most cases, the initial combination
therapy, combine the first line drugs
Showing Page:
39/45
i.e carbamazepine, phenytoin,
valproate, lamotrigine.
If these are unsuccessful then addition
of a newer drug like topiramate,
gabapentin is indicated.
In resistant absence seizures,
valproate can be added to
ethosuximide. Potential drug
interactions should be recognized.
If there is no improvement with two
drugs, a third can be added to the first
two.
It there is improvement, the least
effective of the first two should be
gradually withdrawn.
SURGERY
For those resistant to combination
therapy, surgery can be extremely
Showing Page:
40/45
effective in substantially reducing
seizure frequency and even may give
complete seizure control.
The most common surgical procedure
for those TLE is temporal lobectomy
Other procedures are:
- Hippocampal and amygdala limited
removal
- Focal neocortical resection
- Lessionectormy
- Multiple subpial transection
- Hemispherectomy
- Multilobar resection
- Corpus callostomy
VAGUS NERVE STIMULATION
This for patients with refractory
epilepsy who are not candidates for
surgery
Showing Page:
41/45
A bipolar electrode is placed on the
cervical portion of the left vagus
nerve and connected to a small
subcutaneous generator put in the
infraclavicular region. It delivers
intermittent impulses to the vagus
nerve. Side effects are mild and
transient.
NON INVASIVE DEEP BRAIN
STIMULATION
Using current and two electrodes on
the scalp.
EPILESY IN PREGNANCY
Rates of still births and infant
mortality are higher for epileptic
mothers. Drug administration in first
trimester especially increases
Showing Page:
42/45
incidence of birth defects.
Combination therapy cause increased
incidence of birth defects. Increase is
up to 7% compared to 2-3 % in
normals.
Nevertheless most women with
epilepsy will have uncomplicated
gestation delivery normally. Seizure
frequency remains the same in 50%,
increases in 30% and decrease in
20% .
Phenytoin, valproate, carbamazepine
cause a syndrome of facial
dysmorphism, cleft lip cleft palate,
cardiac defects, digital hypoplasia and
nail hypoplasia.
Valproate and carbamazepine are
associated with 1-2% incidence of
neural tube defects, spina bifida.
Showing Page:
43/45
Carbamazepine will in addition cause
developmental delay.
A combination of carbamazepine,
valproate and either phenytoin or
phenobarbital causes the greatest
incidence of congenital
malformations.
To minimize drug effects:
1. Use a single drug at the lowest
dose possible to control
generalised tonic/clonic fits
2. Divide doses into 2 per day to
minimize plasma drug level peaks
3. Trimethadione and valproate
should be avoided in pregnancy.
4. Patients should take folate 1-4 mg
o.d
5. Enzyme inducing drugs like
phenytoin, phenobarbital,
primidone cause deficiency of vit.
Showing Page:
44/45
K depended clothing factors in
50% newborns. Give vit.k 1mg at
birth.
6. Monitoring drugs plasma levels
useful to reduce toxicity.
CONTRACEPTION
Many drugs e.g carbamazepine,
phenytoin, Phenobarbital, topiramate,
can significantly antagonize effects of
oral contraceptives.
Either use other methods or modify
drugs dosage.
BREASTFEEDING
Most anticonvulsants are excreted in
milk. Ratio of milk to plasma
concentrations are:
Showing Page:
45/45
- Ethosuximide 80%
- Phenobarbital 40-60%
- Carbamazepine 40%
- Phenytoin 15%
- Valproate 5%
Nevertheless drugs are freely given in
lactation, only changed if drug effects
on infant such as lethargy, poor
feeding occurs.

Unformatted Attachment Preview

MANAGEMENT OF SEIZURES 1. Definition of terms - Seizure - Fit - Convulsion - Epilepsy 2. EPIDEMIOLOGY 5-10% of the general population has had a seizure during their lifetime. Incidence of epilepsy is 0.3 –0.5 % worldwide and the prevalence 5-10 per 1000 3. CLASSIFICATION According ILAE 1981 (i) partial seizures a) simple partial – motor sensory, autonomic psychic signs b) complex partial c) partial seizures secondarily generalised (ii) generalized seizures a) grand mall (tonic b) clonic) – 10% of all c) absence (petit mal) – 15-20 % of childhood epilepsies d) tonic e) atonic f) myoclonic (iii) unclassified - neonatal seizures - infantile spasms 3 points to note about seizures: - spread - induction - status epileptics EPILEPSY SYNDROMES a) Juvenile myoclonic epilepsy They may also have tonic clonic seizures. 1/3 have petit mal also .It comes in early adolescence. b) Lennox Gestaut syndrome Occurs in children, characterized by multiple seizures - tonic clonic, atonic, atypical absence. - EEG shows slow < 3 Hz spike and wave discharge and other abnormalities . - Impaired cognitive function in most cases - Associated with CNS disease or dysfunction c) Mesial temporal lobe epilepsy syndrome (MTLE) Has typical clinical, EEG and pathologic features. It is the most common syndrome associated with complex partial seizures. There’s hippocampal sclerosis, it is resistant to drugs and is usually cured by surgery. d)West’s syndrome – A clinical triad of infantile spasms, arrest of psychomotor development and hypsarrhythmia on EEG. Causes can be prenatal, perinatal or post natal. Upto 40% no cause. Onset usually before 1 year, peaks at 3-7 months. Prognosis very poor for those with infantile spasms. Drug of first choice is vigabatrin. Others are valproate, clonazepam and zonisamide. ACTH and corticosteroids are used when others fail. Focal lesions respond to surgery. e) Landau–Kleffner syndrome. Presents as an acquired aphasia with seizures. Several seizure types occur including GTC, partial and myoclonic. Characteristically manifest word deafness despite normal hearing. EEG shows spike activity over temporo-central regions. Occurs at 3-9 years. Responds to standard drugs. Language recovery variable. 4. AETIOLOGY Two types of epilepsy -Idiopathic -Secondary CAUSES IN NEONATES - prenatal hypoxia/ischemia - intracranial hemorrhage/trauma - acute CNS infection - metabolic disturbances decreased ca, mg, glucose pyridoxine - drugs withdrawal - developmental diseases - genetic abnormalities IN INFANTS/CHILDREN (1/12 – 12 YRS) - febrile seizures genetic diseases CNS Infections Trauma Developmental diseases Idiopathic IN ADOLESCENTS (12-18YRS) - Trauma Genetic diseases Infection Brain Tumors Illicit drug use Idiopathic YOUNG ADULTS (18-35 YRS) - Trauma - Alcohol withdrawal Illicit drugs use Brain Tumors Idiopathic OLDER ADULTS - Cerebrovascular accidents Brain Tumors Alcohol withdrawal Metabolic diseases – anemia, liver failure, electrolyte abnormalities, hypoglycemia - Alzheimers disease, other degenerative diseases - Idiopathic. DRUGS + OTHER SUBSTANCES CAUSING SEIZURES - Antibiotics – β-lactams, quinolones, INH, acyclovir, gancyclovir - Anesthetics /analgesics – meperidine, tramadol, Local anaesthetics - Immunomodulatory drugs Cyclosporin, tacrolimus, interferons - Psychotropcis - Antidepressants, antipsychotics, lithium - Theophylline - Radiocontrast agents - Sedative/hyphotics withdrawal Alcohol, benzodiazepines, barbiturates - Drugs of abuse - Amphetamine, cocaine, phencyclidine, methylphenidate - Flumazenil DRUG MECHANISMS 1. Inhibition of sodium Channels Phenytoin, carbamazepine topiramate, zonisamide, felbamate 2. Inhibition of voltage gated calcium Channels – phenytoin, ethosuximide, valproate, trimethadione 3. Decrease of glutamate release – lamotrigin, topiramate – act on AMPA receptors, felbamate – act on NMDA receptors 4. Potentiation of GABA receptor function - benzodiazepines, barbiturates, topiramate , they increase chloride 5. Increase in availability of GABA valproate, gabapentine inhibits GABA transaminase, tiagabine inhibits GABA reuptake. DRUGS CHEMICAL CLASSIFICATION 1. Hydantoins – Phenytoin, methotoin, ethotoin, phenacemide 2. Imminostilbenes – carbamazepine, oxcarbazepine 3. Barbiturates - phenobarbital, primidone, mephobarbital 4. Benzodiazepines - diazepam, clonazepam, clorazepate dipottasium, nitrazepam, clobazam, lorazepam, 5. Carboxylic acids(fatty acids)valproic acid, Sodium valproate 6. Succinamides –ethosuximide, phensuximide, methsuximide 7. Oxazolidinediones -trimethadione, dimethadione, paramethadione 8. Steroids - ACTH, Prednisone 9. Amino acids – 5-0H tryptophan 10. Miscellaneous – vigabatrin, - lamotrigin -Topiramate - Levetiracetam - felbamate -Acetazolamide -Zonisamide - gabapentin - pheneturide - pregabalin - progabide - sulthiame - tiagabine - barbexaclone - beclamide TREATMENT OF EPILEPSY 1. Carbamazepine (Tegrettol, zheptol)- 400-1600mg/d, in 2-3 divided doses First line or adjunctive therapy in partial and generalized seizures (except petit mal and myoclonus), Lennox Gestaut syndrome, childhood epilepsy syndromes. Therapeutic levels 20-50 μmol/l 2. Clobazepam - 10-30mg/d, in 1-2 divided doses, - Adjunctive therapy for partial and generalized seizures. - Also for intermittent therapy, on/off prophylactic therapy, non convulsive status epilepticus, - Excellent second line for some resistant epilepsy. 3. Clonazepam(rivotril) - initially 0.25mg, maintainance 0.5- 4mg per day in 1-2 doses, or 0.1- 0.2 mg /kg in adults, children 0.01 – 0.02 mg/kg//d. Therapeutic levels, 5-70ng/ml Adjunctive therapy in partial and generalised seizures, including absence and myoclonus, Lennox Gestaut syndrome, status epilepticus. 4. Lamotrigine (lamictal) - initially 12.5-25mg/d, maintenance 100200mg/d. Monotherapy or comedication with valproate, Comedication with enzyme inducers 200 – 400mg/d Adjunctive or mono therapy in partial and generalized epilepsy, Lennox Gestaut syndrome. 5. Phenytoin(dilantin) - initially 300mg, maintainance 100-300mg/d in adults, children 5mg/kg, maintainance 3-8mg /kg. Adjustment guided by serum levels. Therapeutic levels – 40-80μmol/l (10-20μg/ml) Given orally or I.V in 1-2 doses. First line or adjunctive therapy for partial and generalized seizures, excluding absence and myoclonus, Lennox Gestaut syndrome (LGS), childhood epilepsy syndromes. Use limited by adverse effects. 6. Valproate (depakene, depakote, epilim) – initially 400 - 600mg/d in adults in 2-3 divided doses, maintenance 500-2500mg/d in adults. 20mg/kg/d in children < 20kg, 40mg/kg/d in children >20/kg Therapentic levels - 300-600 μmol/l Drug of choice in primarily generalised epilepsy and useful in many others – myoclonus, absence, partial. 7. Felbamate (felbatol) - initially 1200mg/d in adults, in 3-4 divided doses, maintenance 1200- 3600mg/d. Children - initially 15mg/kg/d, maintenance 45-80 mg/kg/d. Adjunctive therapy in refractory partial and secondarily generalized seizures, Lennox Gestaut syndrome, highly effective in severe resistant epilepsy but use limited by rare but severe hepatic and hematological toxicity. Therapeutic levels 200460μmol/l. 8. Gabapentin (neurontin) - 3001800mg/d Adjunctive therapy for refractory partial and secondarily generalised seizures. Well tolerated. 9. Levetiracetam (keppra) – 10003000mg/d Adjuctive therapy in partial ± secondarily generalised seizures 10. Oxcarbazepine (trileptal) initially 600mg/d in 2 divided doses. Maintenance 900 – 2400 mg/d. Structure similar to carbamazepine but better tolerated with fewer adverse effect. Adjunct or monotherapy in partial and secondarily generalised seizures. 11. Primidone (mysolin) - initially 125mg/d in 1-2 divided doses Maintenance 500-1500 mg/d. Children < 2yrs – 250 - 500mg, 2-5 yrs 500-700mg, 6 - 9 yrs 7501000mg. Adjunctive therapy in partial and secondarily generalised seizures, absence, myoclonus, L.G.S. Active metabolite is phenobarbital. 12. Tiagabine (gabatril) - initially 15mg/d in 2-3 divided doses Maintenance 30 – 45 mg/d ( and in combination with enzyme inducers) 15-30 mg/d combined with nonenzyme inducers. Adjunct therapy for partial and secondarily generalized seizures, especially refractory cases. 13. Vigabatrin - initially 1000mg /d in 2 divided doses, maintenance 10003000mg/d, children 40mg/kg /d Adjunct therapy in partial and secondarily generalised seizures. Use limited by neuropsychiatric side effects and visual field constriction. 14. Topiramate (topamax) – Initially 25-50 mg/d in 2 doses, Maintenance 200-600mg/d. Adjuct therapy in partial and secondarily generalised seizures, LGS and grand mal seizures. 15. Ethosuximide (zarontin) – initially 250mg in 2-3 divided doses, children 10-15 mg/kg, Maintenance – 750 – 2000mg in adults, 20-40mg/kg /d in children. Therapeutic levels 300-700μmol/l 16. Piracetam- initially 7.2 g/d in 23 divided doses, maintenance upto 24g/d. For some patients with refractory myoclonus 17. 5-OH Tryptophan For intention myoclonus 18. Steroids - ACTH 25-40 units/d, upto 240 units/d prednisone - 15- 60 mg/d prednisolone 2 mg/kg /d dexamethasone 0.3 mg/kg/d For refractory infantile spasms and myoclonus 19. Trimethadone – 900-2400 mg /d in adults, children 30mg /kg/d Therapeutic level >700μg/ml Not used because of severe adverse effects on bone marrow, kidney and liver. It used to be the drug choice for petit mal. 20. Lorazepam - 2-3 mg b.d I.V in normal saline infusion. For status epilepticus. 21. Clorazepate dipottasium – 45mg/d in 2-3 divided doses, - initially 7.5 – 22.5 mg For myoclonus. 22. Nitrazepam For infantile spasms and myoclonic seizures. Less potent than clonazepam. 23. Acetazolamide – 250 500mg/d. or 10/kg, max 1000mg Effective as adjunct therapy in catamenial epilepsy, started 7-10days prior to onset of menses and until bleeding stops. 24. Phenobarbital ( gardenol, luminal) – 30 – 180mg/d in 1-2 divided doses in adults, 3 - 8mg /d in children, 3 – 4 mg/d in neonates PO. IM or IV 50 – 200mg repeated PRN, maximum 600mg, in status epilepticus Adjunct or first line therapy in partial or generalized seizures + absence + myoclonus, status epilepticus, Lennox Gestaut syndrome, childhood epilepsy syndromes, febrile seizures, neonatal seizures. Therapeutic levels 40 – 170 μmol/l PRINCIPLES OF MANAGEMENT OF EPILEPSY 1. Early diagnosis and treatment of seizure disorders with a single appropriate agent offers the best prospect of achieving prolonged seizure free periods with the lowest risk of toxicity. 2. An attempt should be made to ascertain the cause, as it may be correctable. This is most likely in the very young and those with the first episode in adulthood. 3. The goal of therapy is to keep patient seizure free without interfering with normal function. Drug adjustments are best assisted by drug plasma levels. 4. Treatment should be initiated with a single drug. Adjust doses upwards for control until maximal doses are reached or until toxicities are intolerable. Large doses are started only if there is urgency in controlling the seizure. 5. First substitute another drug if maximum doses have not achieved control before using combinations. In substituting, gradually reduce dose of the first drug as you gradually increase the dose of the second. Consider AEDS acting on new targets. Combinations should be as rational as possible. 6. Once control achieved with polytherapy, attempt to come back to monotherapy. Any drug should be withdrawn only gradually 7. After seizure free period of 3yrs, you can start withdrawing the drugs. 70% children, 60% adults will have seizures controlled and can do without drugs after this period. SIMPLE, COMPLEX PARTIAL AND SECONDARILY GENERALISED TONIC CLONIC SEIZURES. (a) Carbamazepine and phenytoin are the most effective single drug therapy of partial and generalized tonic clonic epilepsies. The choice depends on toxicity considerations. Long term use of Phenytoin causes untoward cosmetic effects e.g hirsutism, coarsening of facial features, gingival hypertrophy, so it is often avoided in young patients. Carbamazepine can cause leukopenia, aplastic anemia or hepatotoxicity and is therefore not appropriate for patients predisposed to these conditions. (b) Valproic acid is broad spectrum and is preferred for patients with mixed seizures especially the epilepsy syndromes. It is an effective alternative for partial seizures especially with secondarily generalised seizures. It rarely causes reversible bone marrow suppressions and hepatotoxicity which may be fatal. Avoid in those with bone marrow or liver disease. Risk of the fatal liver failure is higher in those < 2yrs age, those on multiple drugs and those with inborn errors of metabolism. It is used in infants and young children only if benefit outweighs risk. It more commonly causes tremors and weight gain. (c) Lamotrigin, gabapentin, topiramate, tiagabine and Phenobarbital and primidone are additional drugs used for partial seizures with or without secondary generalization. Lamotrigine is as effective as the standard drugs and is used as monotherapy. It may cause rash in children especially. It is introduced gradually from small doses when added to valproate. It inhibits its metabolism. Gabapentin has no significant drug interactions making it a useful add on therapy. Phenobarbital and primidone cause sedation in adults, hyperactivity in children and other subtle cognitive changes. Primidone causes more toxicity including nausea, dizziness, ataxia, somnolence and decreased libido. Their use should be limited to situations in which there is no suitable alternative. (d) Oxcarbazepine is as effective as carbamazepine with less adverse effects. Benzodiazepines are used for limited periods as tolerance to them develops. (e) Clobazepam, tiagabine, vigabatrin, piracetum, felbamate, topiramate, levetiracetam are currently reserve drugs, for resistant cases. Felbamate rarely causes severe hepatic and hematological toxicity. ABSENCE SEIZURES The drug of first choice is ethosuximide. Valproate is equally effective. It is of second choice. Clonazepam is useful especially in those with myoclonic component. Ethosuximide rarely causes bone marrow suppression. MYOCLONIC SEIZURES Valproate is the drug of first choice. Clonazepam is equally effective and its effect can be dramatic. Nitrazepam is also effective. FEBRILE CONVULSIONS 2-3% of cases become epileptic in later years. Factors associated with risk of epilepsy are: - neurological disease - developemental delay - family history of epilepsy - complicated febrile seizure i.e > 15min, one sided, several in a day Phenobarbital prophylaxis has been used before but now only rectal diazepam during fever is recommended. SEIZURES IN INFANTS AND YOUNG CHILDREN. Infantile myoclonic spasms with hypsarrhythmias are refractory to the usual anti-seizure agents. ACTH and adrenal corticosteroids are the drugs of choice. Valproate and clonazepam may be effective. Valproate is effective for akinetic myoclonic and atonic seizures in young children. STATUS EPILEPTICUS It is a medical emergency. Mortality is 3-35%. Signs become subtle after 30-45 min continuous fits, therefore monitor with EEG. . 1. Benzodiazepines are the drugs of first choice for initial treatment. (a) Diazepam 0.2mg/kg. 10-20mg bolus iv stat then 40mg in 500mls 5% dextrose to run slowly over 6 hours. If it recurs you can give another bolus. At the same time start a longer acting drug like phenytoin IV or orally. (b) Lorazepam 0.1mg/kg at 2mg/min 2. Phenytoin i.v 15-20 mg/kg at 50mg/min. Additional doses of 510mg/kg can be given if fits continue. 3. Phenobarbital 20mg/kg i.v at 5075mg/min. Additional doses of 510mg/kg can be given if fits continue. 4. Anaesthetic agents - thiopentone sodium, midazolam, or propofol for G.A with assisted respiration if fits still persist. Should be in I.C.U with EEG monitor. Attend to acute cardio respiratory problems. TREATMENT OF REFRACTORY EPILEPSY About 1/3 patients of epilepsy are resistant to a single drug and require multiple drug therapy. The most likely are : - Focal epilepsy related to a structural lesion - Multiple seizures patients - Those with developmental delay In most cases, the initial combination therapy, combine the first line drugs i.e carbamazepine, phenytoin, valproate, lamotrigine. If these are unsuccessful then addition of a newer drug like topiramate, gabapentin is indicated. In resistant absence seizures, valproate can be added to ethosuximide. Potential drug in