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Recent advances epilepsy
1. Recent advances in treatment
of Epilepsy
Dr Salil P Shinde,
Resident,
Department of Pharmacology & Therapeutics
2. • Seizure: transient alteration of behavior due to the
disordered, synchronous and rhythmic firing of
populations of brain neurons
• Seizures: Non epileptic ; evoked
Epileptic; un provoked
• Epilepsy: Disorder of brain function characterized by
periodic and unpredictable occurrence of seizures
4. Epilepsy
• Second most common chronic neurological disorder
• Results from abnormal and sudden discharge of cerebral
neurons
• Produces changes in a person's movement, behavior or
consciousness
• Affects 1-2 % (40-50 million people) of the world‘s
population
• 75-80 % of patients respond to standard therapy
• In 20-25 % of patients seizures are uncontrollable
5. •
Causes
– Heredity
• Risk of getting epilepsy is 2.5 times
greater with a family history of
seizures
– Head trauma
• The more severe the injury, the
greater the risk of developing
epilepsy
– Brain tumour and stroke
– Poisoning
• Lead
• Alcohol
– Infections
– Maternal injury
• Infection or systemic illness
affecting the fetus' developing brain
during pregnancy.
6. Classification of Seizure Types
Self-limited seizure types
• Partial seizures
– Simple partial
• Focal with minimal spread of abnormal discharge
• Consciousness is maintained
– Complex partial
• Local onset, then spreads
• Usually starts with blank stare, followed by automatisms
(random motor activity).
• Person appears unaware of surroundings.
– Partial seizures secondarily generalized
• Begins focally
• Varies in the duration and intensity of tonic and aclonic
phases
• Lasts between 1-2minutes
7. •
Generalized seizures
– Generalized tonic–clonic (grand mal)
• Sudden cry, fall, rigidity, followed by muscle jerks, shallow
breathing or temporarily suspended breathing, bluish skin,
possible loss of bladder control (usually lasts a couple of
minutes).
– Absence (petit-mal)
• Blank stare (lasts few seconds)
– Atonic
• Sudden loss of postural tone (collapse and fall; 10 sec- 1
min)
8. – Clonic and Myoclonic
• Sudden brief, massive
muscle jerk that may
involve the whole body
or parts of the body
– Infantile spasms
• Quick, sudden
movements that start
between 3 months and
2 years of age.
9. Continuous seizure types
Status Epilepticus
More than 30 minutes of continuous seizure activity
OR
Two or more sequential seizures spanning this period
without full recovery of normal alertness in between
• Medical emergency required to prevent hypoxic cerebral
damage or metabolic complication
Focal status epilepticus
10. Precipitating stimuli for reflex seizures
o Visual stimuli
Flickering light -colour to be specified when possible
Patterns
Other visual stimuli
o Thinking
o Music
o Eating
o Somatosensory
o Proprioceptive
o Reading
o Hot water
o Startle
12. Evidence for the Pathophysiology
of Seizures
•
•
•
•
•
Increased EAA
Increased Excitatory Amino
Acid Transmission
Increased sensitivity to EAA
Progressive increase in
glutamate release during
kindling
Increased glutamate and
aspartate at start of seizure
Upregulation of NMDA
receptors in kindled rats
•
•
•
•
Decreased GABA
Decreased binding of GABA
and benzodiazepines
Decreased Cl- currents in
response to GABA
Decreased glutamate
decarboxylase activity
(synthesizes GABA)
Interfere with GABA causes
seizures
14. Scheme of Seizure Spread
small group of neurons. Contralateral
discharge
Both hemispheres are involved from
outset
evidence of anterior temporal lobe
focal abnormalities. Bilateral.
Thalamocortial relays are believed to
act on a hyperexcitable cortex
16. Therapy Has Improved Significantly !!
• “Give the sick person some blood from a pregnant
donkey to drink; or steep linen in it, dry it, pour alcohol
onto it and administer this”.
– Formey, Versuch einer medizinischen
Topographie von Berlin 1796, p. 193
17. Strategies in Treatment
– Inhibition of excitatory neurotrasmission
• Glutamate
– Enhancement of inhibitory neurotransmission
• GABA
– Blockage of voltage-gated positive current
• Na+
• Ca2+
– Increase outward positive current
• K+
•
Many anti-seizure drugs act via multiple mechanisms
18. Actions on Na+ Channels
A.
Resting State
B.
Arrival of Action Potential
causes depolarization and
channel opens allowing
sodium to flow in.
C. Refractory State, Inactivation
Sustain channel in
Phenytoin, Carbamazepine, this conformation
Lamotrigine, Topiramate
Valproic acid
Na+
Na+
Na+
23. Characteristics of AEDs
•
•
•
•
•
•
•
•
Most classical antiepileptic drugs exhibit similar
pharmacokinetic properties.
Good absorption (although most are sparingly soluble).
Low plasma protein binding (except for phenytoin, BDZs,
valproate, and tiagabine).
Conversion to active metabolites (carbamazepine,
primidone, fosphenytoin).
Cleared by the liver but with low extraction ratios.
Distributed in total body water.
Plasma clearance is slow.
At high concentrations phenytoin exhibits zero order
kinetics.
24. PHENOBARBITAL
Toxicity:
• Sedation.
• Cognitive
impairment.
• Behavioral changes.
• Induction of liver
enzymes.
• May worsen absence
and atonic seizures.
• Except for the bromides, it is the
oldest antiepileptic drug.
• Although considered one of the
safest drugs, it has sedative effects.
• Many consider them the drugs of
choice for seizures only in infants.
• Acid-base balance important.
• Useful for partial, generalized tonicclonic seizures, and febrile seizures
• Prolongs opening of Cl- channels.
• Blocks excitatory GLU (AMPA)
responses. Blocks Ca2+ currents
(L,N).
• Inhibits high frequency, repetitive
firing of neurons only at high
concentrations.
25. PHENYTOIN
• Oldest nonsedative antiepileptic
drug.
• Fosphenytoin, a more soluble
Toxicity:
prodrug is used for parenteral
•Ataxia and nystagmus.
use.
•Cognitive impairment.
• “Fetal hydantoin syndrome”.
•Hirsutism
• It alters Na+, Ca2+ and K+
•Gingival hyperplasia.
conductances.
•Coarsening of facial features.
•Dose-dependent zero order • Inhibits high frequency repetitive
firing.
kinetics.
•Exacerbates absence seizures. • Alters membrane potentials.
•At high concentrations it
• Alters a.a. concentration.
causes a type of decerebrate
• Alters NTs (NE, ACh, GABA)
rigidity.
26. PRIMIDONE
Toxicity:
•Same as phenobarbital
•Sedation occurs early.
•Gastrointestinal
complaints.
• Metabolized to phenobarbital and
phenylethylmalonamide (PEMA), both
active metabolites.
• Effective against partial and
generalized tonic-clonic seizures.
• Absorbed completely, low binding to
plasma proteins.
• Should be started slowly to avoid
sedation and GI problems.
• Its mechanism of action may be closer
to phenytoin than the barbiturates.
27. ETHOSUXIMIDE
•
•
•
•
•
Drug of choice for absence seizures.
High efficacy and safety.
Toxicity:
VD = TBW.
•Gastric distress,
Not plasma protein or fat binding
including, pain, nausea
Mechanism of action involves
and vomiting
reducing low-threshold Ca2+ channel
current (T-type channel) in thalamus.
•Lethargy and fatigue
At high concentrations:
•Headache
• Inhibits Na+/K+ ATPase.
•Hiccups
• Depresses cerebral metabolic rate.
•Euphoria
• Inhibits GABA aminotransferase.
•Skin rashes
•Lupus erythematosus (?)
• Phensuximide = less
effective
• Methsuximide = more
toxic
28. CARBAMAZEPINE
• Tricyclic, antidepressant (bipolar)
• 3-D conformation similar to
Toxicity:
phenytoin.
•Autoinduction of
• Mechanism of action, similar to
metabolism.
phenytoin. Inhibits high frequency
•Nausea and visual
repetitive firing.
disturbances.
•Granulocyte supression. • Decreases synaptic activity
presynaptically.
•Aplastic anemia.
• Binds to adenosine receptors (?).
•Exacerbates absence
• Inh. uptake and release of NE, but
seizures.
not GABA.
• Potentiates postsynaptic effects of
GABA.
• Metabolite is active.
29. CLONAZEPAM
Toxicity:
• Sedation is prominent.
• Ataxia.
• Behavior disorders.
• A benzodiazepine.
• Long acting drug with efficacy for
absence seizures.
• One of the most potent
antiepileptic agents known.
• Also effective in some cases of
myoclonic seizures.
• Has been tried in infantile
spasms.
• Doses should start small.
• Increases the frequency of Clchannel opening.
30. VALPROATE
• Fully ionized at body pH, thus active
Toxicity:
form is valproate ion.
•Elevated liver enzymes • One of a series of carboxylic acids with
including own.
antiepileptic activity. Its amides and
•Nausea and vomiting.
esters are also active.
•Abdominal pain and
• Mechanism of action, similar to
phenytoin.
heartburn.
•Tremor, hair loss,
∀ ⇑ levels of GABA in brain.
•Weight gain.
• Facilitates
Glutamic
acid
•Idiosyncratic
decarboxylase (GAD).
hepatotoxicity.
• Inhibits the GABA-transporter in
•Negative interactions with neurons and glia (GAT).
other antiepileptics.
∀ ⇓ [aspartate]Brain?
•Teratogen: spina bifida
• May increase membrane potassium
conductance.
31. What is the Role
of the New AEDs??
• Different mechanism of action
– treatment of refractory seizures
• Rational polytherapy
• Different (less ?) adverse effects
• Less drug interactions
• Potential advantages in the use of Women with epilepsy
32. FELBAMATE
Toxicity:
•Aplastic anemia
•Severe hepatitis
• Effective against partial seizures but
has severe side effects.
• Because of its severe side effects, it
has been relegated to a third-line
drug used only for refractory cases.
34. LAMOTRIGINE
Toxicity:
•Dizziness
•Headache
•Diplopia
•Nausea
•Somnolence
•Life threatening
rash “StevensJohnson”
• Add-on therapy with valproic acid .
• Almost completely absorbed
• T1/2 = 24 hrs
• Low plasma protein binding
• Effective in myoclonic and generalized
seizures in childhood and absence
attacks.
• Involves blockade of repetitive firing
involving Na channels, like phenytoin.
• Also effective in myoclonic and
generalized seizures in childhood and
absence attacks.
35. TOPIRAMATE
Toxicity:
• Somnolence
• Fatigue
• Dizziness
• Cognitive slowing
• Paresthesias
• Nervousness
• Confusion
• Weak carbonic
anhydrase
inhibitor
• Urolithiasis
• Rapidly absorbed, bioav. is > 80%,
has no active metabolites, excreted
in urine.T1/2 = 20-30 hrs
• Blocks repetitive firing of cultured
neurons, thus its mechanism may
involve blocking of voltagedependent sodium channels
• Potentiates inhibitory effects of
GABA (acting at a site different from
BDZs and BARBs).
• Depresses excitatory action of
kainate on AMPA receptors.
• Teratogenic in animal models.
36. TIAGABINE
Toxicity:
•Abdominal pain and
•
nausea (must be taken •
w/food)
•Dizziness
•
•Nervousness
•
•Tremor
•Difficulty concentrating
•Depression
•
•Asthenia
•
•Emotional liability
•Psychosis
•Skin rash
Derivative of nipecotic acid.
100% bioavailable, highly protein
bound.
T1/2 = 5 -8 hrs
Effective against partial seizures in
pts at least 12 years old.
Approved as adjunctive therapy.
GABA uptake inhibitor γ aminibutyric
acid transporter (GAT) by neurons
and glial cells.
37. LEVETIRACETAM
Toxicity:
•Somnolence.
•Dizziness.
•Asthenia.
• SV2A, a synaptic vesicle protein, has
recently been identified as the likely
target for levetiracetam.
• SV2A is an abundant protein component
of synaptic vesicles that is structurally
similar to 12-transmembrane domain
transporters, although a transporter
activity for SV2A has not yet been
identified.
• It seems reasonable that the SV2A
ligands could protect against seizures
through effects on synaptic release
mechanisms.
• Does not induce liver enzymes.
• not bound to plasma proteins.
• Useful as adjunct in refractory epilepsy.
38. OXCARBAZEPINE
Toxicity:
•Hyponatremia
•Less
hypersensitivity
and induction of
hepatic
enzymes than
with
carbamazepine
•
•
•
•
•
Closely related to carbamazepine.
With improved toxicity profile.
Less potent than carbamazepine.
Active metabolite.
Use in partial and generalized
seizures as adjunct therapy.
• May aggravate myoclonic and
absence seizures.
• Mechanism of action, similar to
carbamazepine It alters Na+
conductance and inhibits high
frequency repetitive firing.
39. ZONISAMIDE
Toxicity:
•Drowsiness
•Cognitive
impairment
•Anorexia
•Nausea
•High incidence of
renal stones (mild
anhydrase inh.).
•Metabolized by
CYP3A4
• Marketed in Japan. Sulfonamide
derivative. Good bioavailability, low
pb.
• T1/2 = 1 - 3 days
• Effective against partial and
generalized tonic-clonic seizures.
• Approved by FDA as adjunctive
therapy in adults.
• Mechanism of action involves
voltage and use-dependent
inactivation of sodium channels.
• Inhibition of Ca2+ T-channels.
• Binds GABA receptors
• Facilitates 5-HT and DA
neurotransmission
40. VIGABATRIN (γ-vinyl-GABA)
Toxicity:
•Drowsiness
•Dizziness
•Weight gain
•Agitation
•Confusion
•Psychosis
• Absorption is rapid, bioavailability is
~ 60%, T 1/2 6-8 hrs, eliminated by the
kidneys.
• Use for partial seizures and West’s
syndrome.
• Contraindicated if preexisting mental
illness is present.
• Irreversible inhibitor of GABAaminotransferase (enzyme
responsible for metabolism of
GABA) => Increases inhibitory
effects of GABA.
• S(+) enantiomer is active.
41. INTERACTIONS BETWEEN ANTISEIZURE
DRUGS
With other antiepileptic Drugs:
- Carbamazepine with
phenytoin
Increased metabolism of carbamazepine
phenobarbital
Increased metabolism of epoxide.
- Phenytoin with
primidone
- Valproic acid with
clonazepam
phenobarbital
phenytoin
Increased conversion to phenobarbital.
May precipitate nonconvulsive status
epilepticus
Decrease metabolism, increase toxicity.
Displacement from binding, increase toxicity.
42. ANTISEIZURE DRUG INTERACTIONS
With other drugs:
antibiotics
anticoagulants
phenytoin, phenobarb, carb.
phenytoin and phenobarb
cimetidine
isoniazid
oral contraceptives
salicylates
theophyline
displaces pheny, v.a. and BDZs
toxicity of phenytoin
antiepileptics metabolism.
displaces phenytoin and v.a.
carb and phenytoin may
effect.
45. Levetiracetam Analogs
• Seleteracetam and brivaracetam - Both have 10-fold greater
affinity for SV2A than does levetiracetam, brivaracetam may
also have modest sodium-channel blocking activity.
• Overall, seletracetam seems to have a similar pharmacological
profile to levetiracetam, but is more potent.
• In contrast, brivaracetam has a broader spectrum of activity
• However, it has a lower protective index than levetiracetam.
46. Valproate-Like Agents
• Analogs of valpromide that resist metabolic hydrolysis to
their corresponding acids - valnoctamide (2-ethyl-3methylpentanamide) and diisopropyl acetamide (PID)
• exhibit greater anticonvulsant potency than valproate
and their corresponding acids.
• Valnoctamide has been marketed as an anxiolytic and
sedative (as Axiquel and Nirvanil) in the U.S., Italy, the
Netherlands and Switzerland.
• Whether it is useful in epilepsy remains to be
determined.
47. Valproate-Like Agents
• valrocemide (valproyl glycinamide) - does not cause
embryotoxicity in rats and rabbits.
• cyclic analogs possess two quaternary carbons in the βposition to the carbonyl and cannot be biotransformed into
metabolites with a terminal double bond, which is
presumed to be the souce of hepatotoxicity - MTMCD (Nmethyl-tetramethylcyclopropanecarboxamide) and
2,2,3,3-tetramethylcyclopropanecarbonylurea (TMCU)
• Dried roots of valerina species – isovaleramide, very safe
in phase I trials
48. Carbamates:
• Flurofelbamate and RWJ-333369
• Felbamate - formation of an aldehyde - that reacts with
proteins. Substitution of a fluorine atom for a hydrogen
prevents the formation of this reactive aldehyde.
• Fluorofelbamate may inhibit NMDA receptors and might
also affect sodium channels.
• RWJ-333369 is currently in Phase II clinical development
for the treatment of partial epilepsy and migraine
headache.
49. Carbamazepine Analogs
•
Licarbazepine and (S)-Licarbazepine Acetate
•
Oxcarbazepine - metabolites (R)- and (S)-licarbazepine, which appear
in plasma and urine in a 4:1 ratio. As metabolite ? Advantage.
•
(S)-licarbazepine acetate (BIA 2-093) is also in Phase III clinical trials.
BIA 2-093 only forms (S)-licarbazepine,. In addition, BIA 2-093, as is
the case for other sodium channel blocking AEDs inhibits sodium
channel-dependent release of neurotransmitters with similar potency to
carbamazepine and oxcarbazepine.
•
Although BIA 2-093 is chemically distinct from licarbazepine and could
potentially have distinct pharmacodynamic properties related to its
novel structure, there is little evidence that it is substantially different
mechanistically.
50. Benzodiazepine-like Agents
• Benzodiazepine-like agents that act as partial agonists at
the benzodiazepine recognition site - RWJ-51204 is of
particular interest as it has highly potent anticonvulsant
activity and a favorable protective index.
• None of the partial benzodiazepine agonists, however,
has been proven to lack tolerance in clinical trials.
51. Stiripentol
•
Increase γ-aminobutyric acid (GABA) levels in brain tissue
•
involves at least two independent neurochemical mechanisms:
inhibition of synaptosomal uptake of GABA and inhibition of GABA
transaminase
•
The drug is currently undergoing phase III clinical trials – good results
in refractory partial epilepsy.
•
Characterized by nonlinear pharmacokinetics and inhibition of liver
microsomal enzymes.
52. New Scaffolds and Mechanisms
Functionalized Amino Acids
• lacosamide (formerly
harkoseride), SPM 927.
• Lacosamide may act as an
antagonist of NMDA
receptors through an
interaction with the strychnine
insensitive glycine site.
• Phase II clinical studies have
been promising and Phase III
trials are in progress.
53. AMPA Receptor Antagonists
• Glutamine – Agonist AMPA
• The first selective AMPA receptor antagonists to be identified were
quinoxalinedione derivatives, such as NBQX
• However, they tend to produce motor impairment at doses similar to
those that are protective against seizures.
• The early quinoxalinediones had poor solubility and so that they
precipitated in the kidney, leading to crystaluria and nephrotoxicity.
• Newer agents include the water soluble quinoxalinedione-analog
zonampanel; YM872, and ZK200775.
• Unfortunately, the results were not encouraging, largely because of
sedative side effects and a negative impact on the level of
54. Neuroactive Steroids
• Endogenous steroid hormones when reduced at the 5- and
3-positions of the steroid A-ring, form metabolites that lack
classical hormonal activity but instead are high affinity,
positive allosteric modulators of GABA-A receptors.
• Ganaxolone, the 3β-methyl analog of the endogenous
steroid allopregnanolone has been most extensively
evaluated, and early clinical trials have been completed.
• Open label clinical studies have provided indications of
efficacy in infantile spasms and complex partial seizures.
• may be useful in catamenial epilepsy – useful in pregnancy.
55. Rufinamide
•
Compound that bears some structural similarity with lamotrigine .
•
Has been reported to prolong the inactivation of sodium channels and
to limit the frequency of action potential firing in cultured and acutely
isolated neurons
•
Several late stage clinical trials of rufinamide have been completed in
patients with partial seizures, primary generalized tonic-clonic seizures
and the Lennox-Gastaut syndrome.
•
Some of these studies reached statistically significant endpoints and
applications with regulatory agencies to market the drug have been
filed.
56. Retigabine
•
Retigabine - the desazaanalog of flupirtine (a nonopiate analgesic
approved in Europe for general nocioceptive pain).
•
Retigabine has undergone clinical testing in several Phase II clinical
trials, largely in patients with partial seizures with or without secondary
generalization who were refractory to available therapies.
•
The drug is a “potassium channel opener” - is specific for M-type
potassium current.
•
The critical action of the drug is to increase potassium current near
resting potential, which reduces excitability and presumably is
responsible, at least in part, for the anticonvulsant effect of retigabine.
There are
Retigabine acts on all neuronal KCNQ subunits, but not on KCNQ1
which is expressed in cardiac muscle
•
57. Anti – Epileptogens?
• Single and repeated administrations of LEV in adult SERs
produce unusual long-lasting anti-seizure effects (>4
weeks), which are not considered to be merely due to LEV
accumulation in the brain.
• Receptor tyrosine kinase - TrkB
– the plasticity of epileptogenesis is eliminated in TrkB(-/-)
mice.
– Its requirement for epileptogenesis in kindling implicates
TrkB and downstream signaling pathways as attractive
molecular targets for drugs for preventing epilepsy.
59. Vagus Nerve Stimulator (VNS)
• Is an FDA approved device
• Provides chronic intermittent
electrical stimulation of the
vagus nerve
• Exact mechanism is
unknown
60. VNS candidates
• Patients with refractory epilepsy
– Partial or generalized
– Lennox-Gastaut Syndrome
– Poor surgical candidates
• Contraindicated in:
– Patients with left or bilateral vagotomy
61. Deep Brain Stimulation
• Based on stimulating widespread inhibitory pathways
– Thalamus
• Anterior Thalamic Nucleus
• Centromedian Nucleus of the Thalamus
– Cerebellum
•
•
Pros
– Minimal invasive
– Safe, Well tolerated
Cons
– Malfunction
– Unknown long term
benefits/complications
62. Melatonin
• Regulates sleep
• Anti-seizure properties
• Blocks effects of Glutamate, enhances Gaba actions
• Potentiates the effect of carbamazepine and
phenobarbital
• Given orally 30 minutes to one hour before bedtime,
dose ranges from 3-10 mg
64. Individuals with epilepsy and their families and/or carers
should be given, and have access to sources of, information
about (where appropriate):
•
•
•
•
•
•
•
•
•
•
•
•
epilepsy in general
diagnosis and treatment options
medication and side effects
seizure type(s), triggers and seizure control
management and self-care
risk management
first aid, safety and injury prevention at home and at school or
work
psychological issues
social security benefits and social services
insurance issues
education and healthcare at school
employment and independent living for adults
65. Individuals with epilepsy and their families and/or carers should
be given, and have access to sources of, information about
(where appropriate):
• importance of disclosing epilepsy at work, if relevant (if further
information or clarification is needed, voluntary organisations
should be contacted).
• road safety and driving
• prognosis
• sudden death in epilepsy (SUDEP)
• status epilepticus
• life style, leisure and social issues (including recreational drugs,
• alcohol, sexual activity and sleep deprivation)
• family planning and pregnancy
• voluntary organisations, such as support groups and charitable
organisations, and how to contact them
66. Investigations
• The EEG should not be used in isolation to make a
diagnosis of epilepsy.
• MRI should be the imaging investigation of choice in
individuals with epilepsy
• In an acute situation, CT may be used to determine
whether a seizure has been caused by an acute
neurological lesion or illness.
67. Diagnosis
Questions used that, if positive, support a diagnosis of epileptic
seizure:
• At times do you wake up with a cut tongue after your spells?
• At times do you have a sense of déjà vu or jamais vu before your spells?
• At times is emotional stress associated with losing consciousness?
• Has anyone noticed your head turning during a spell?
• Has anyone ever noted that you are unresponsive, have unusual
posturing or have jerking limbs during your spells or have no memory of
your spells afterwards?
• Has anyone noticed that you are confused after a spell?
68. Diagnosis
Questions used that, if positive, support a diagnosis of
syncope:
• Have you ever had light-headed spells?
• At times do you sweat before your spells?
• Is prolonged sitting or standing associated with your spells?
69. Treatment recommendations
•
Only start one drug at a time and only make one change at a time.
•
Prior base-line biochemistry and full blood count
•
Started in a dose no higher than recommended by the manufacturer.
•
Start at a low dose and work up slowly.
•
Dosing will be determined by adverse effects and continuation of
seizures with the aim being to have seizure freedom and no adverse
effects.
•
The rate of changes and the end dose will be determined by the
individual’s response to therapy. The balance of seizure control and
adverse effects should be discussed with the individual.
70. Treatment recommendations
•
Formulation or brand.
•
Individuals and carers should be given clear instructions to seek
medical attention urgently for symptoms including rash, bruising, or
drowsiness with vomiting especially in the first weeks of treatment.
•
If an AED has failed because of adverse effects or continued
seizures, start a second drug (which may be an alternative first-line or
secondline drug), build up to an adequate or maximum tolerated dose
and then taper the first drug slowly. If the combination is successful,
some individuals may prefer to remain on the combination.
•
If the second drug is unhelpful, taper off either drug depending on the
side effects and how well the drug is tolerated, maintaining the
alternative drug, before starting a third drug.
71. Treatment
Seizure
type
First-line
drugs
Second-line
drugs
Other drugs
Drugs to be
Generalised
tonic–clonic
Carbamazepine
Clobazam
Acetazolamide
avoided
Tiagabine
Lamotrigine
Levetiracetam
Clonazepam
Vigabatrin
Sodium
valproate
Oxcarbazepine
Phenobarbital
Phenytoin
Clobazam
Lamotrigine
Clonazepam
Carbamazepin
e
Sodium
valproate
Absence
Topiramate
Ethosuximide
Topiramate
Gabapentin
Primidone
Oxcarbazepine
Tiagabine
Myoclonic
Sodium
valproate
Clobazam
Clonazepam
Vigabatrin
Carbamazepin
e
(Topiramate)
Lamotrigine
Gabapentin
Levetiracetam
Oxcarbazepine
Piracetam
Tiagabine
72. Treatment
Seizure type
Atonic
Second-line
drugs
Other drugs
Drugs to be
Lamotrigine
Clobazam
Acetazolamide
Sodium
valproate
Tonic
First-line
drugs
Clonazepam
Phenobarbital
avoided
Carbamazepin
e
Levetiracetam
Phenytoin
Oxcarbazepine
Topiramate
Clobazam
Primidone
Acetazolamide
Clonazepam
Phenobarbital
Carbamazepin
e
Levetiracetam
Primidone
Oxcarbazepine
Lamotrigine
Sodium
valproate
Acetazolamide
Gabapentin
Clonazepam
Levetiracetam
Phenobarbitala
Focal
with/without
Carbamazepin
e
secondary
Lamotrigine
generalisation
Oxcarbazepine Phenytoina
Sodium
Tiagabine
valproate
Topiramate
Phenytoina
Topiramate
Clobazam
Primidonea,
74. AEDs – pregnancy outcome
•
exposure to AED in utero
– 2-3 x inc in background rate
(1-2%)
• cardiac
• cleft lip/palate
• neural tube
– polytherapy increases risk
– retrospective small studies –
‘older’AEDs
75. Reducing risk in pregnancy – best practice
Pre-pregnancy assessment
• diagnosis
• AED monotherapy,
– lowest effective dose
• folic acid
SIGN (2003) NICE (2004)
76. Reducing risk in pregnancy – best practice
care during pregnancy & delivery
•
•
•
•
•
•
high risk
shared care between the obstetrician & specialist
high resolution ultrasound scan at 18-20 weeks
hospital delivery with appropriate facilities
no need for routine monitoring of AED levels
should be given 1mg of vit K parenterally at delivery
(enzyme-inducing AEDs)
• breastfeeding should be encouraged
SIGN (2003) NICE (2004)
78. Conclusion
• Many new AEDs, better tolerated and fewer drug
interactions than the older AEDs
• Most patients can find an AED that is effective and
causes minimal or no side effects
• Herbal meds : untested
– Studies finally in progress on this and other alternative
treatment modalities (Melatonin)
• More advances coming every year (ER preparations)…
79. Cool stuff for the (near) future
• New Drugs
– Prevention of Epilepsy
• New Diets (ketogenic)
• Brain Stimulation
• Direct brain drug delivery
• Gamma Knife
• Stem Cells
Notes de l'éditeur
Pros: With improvements in technology, Minimally invasive, safe operations
Cons: possible malfunction, breakdown, need to replace generator, lack of knowledge of the long term benefits and delayed complications such as infection and skin eroision over the device.
Sleep deprivation, dehydration, and stress are facts of life for most mothers and are common triggers for seizures. Parents need to consider the risks to the baby from maternal seizures, particularly during carrying and bathing, and appropriate adjustments in lifestyle should be made. The epilepsy specialist nurse and patient’s associations can give life-saving advice and support here (e.g. Epilepsy Action)
Epilepsy is common in women in the childbearing years and there were 13 maternal deaths reported in the Confidential Enquiry into Maternal Deaths 2000-2002 associated with suboptimal care
Women with epilepsy on enzyme-inducing drugs need higher doses of hormonal contraception and also higher doses of emergency, post-coital contraception
Preconceptual drug adjustments, establishing monotherapy if possible, good seizure control, high dose (5 mg) folic acid, and vitamin K make a big difference and improve outcomes
Fetal anomaly scanning at 18–20 weeks and fetal echocardiography can detect most significant fetal abnormalities
Most women with epilepsy will have normal pregnancy outcomes with good care from an interested obstetrician in close liaison with their epileptologist and specialist nurse
The demands of parenting need to be considered and various patient support organisations can give advice.