Starting and continuing

treatment in epilepsyDr Sankalp Mohan

Resident ,Neurology

Epilepsy in India

• About 10 million people with epilepsy (prevalence of about 1%);

• One fifth of Global figures

• 70-80 % can lead normal lives

• Still 50-70% are receiving No treatment or inadequate treatment

DEFINING EPILEPSY

• Epilepsy is a chronic disorder characterized by recurrent unprovoked seizures

• An epileptic seizure refers to transient occurrence of signs and/or symptoms due to abnormally excessive or synchronous neuronal activity in the brain may be characterized by sensory, motor or autonomic phenomena with or without loss of consciousness.

• Seizures occurring in a setting of an acute illness or medical condition like high fever, hypoglycemia, etc. are classified as acute symptomatic seizures.

CLASSIFICATION

• ILAE classification of epilepsies

• 1. Localization-related epilepsies are characterized by seizures that have a focal or partial andgeneralized epilepsies are characterized by generalized onset of seizures.

• 2. Idiopathic epilepsies are those that are inherited or occur without identifiable pathologic cause. Symptomatic epilepsies are those associated with a

known or suspected brain disease or lesion. • 3. Epilepsy syndromes are age specific and may begin

during infancy, childhood or adolescence

DIAGNOSIS OF EPILEPSY

• Detailed History and examination

• Clues on Clinical Examination-

• Presence of an aura

• bilateral tonic clonic movements, sudden jerking, deviation of eyes and head, alteration or loss of consciousness, and may be associated with injuries, tongue bite or incontinence

• Postictally the patient may have confusion, drowsiness, headache or weakness.

ILAE CLASSIFICATION OF SIEZURE

SYNCOPE VS SIEZURE

SIEZURE AND PSEUDOSIEZURE

INVESTIGATIONS FOR FIRST SIEZURE

• Baseline blood counts, liver enzymes and renal functions, serum electrolytes ,-Metabolic screen

Serum Calcium

If diagnosis of siezure in doubt

- Serum Prolactin – within 10 -20 minutes of the event .sensitivity for GTC -60 %. CPS -46 %

- Can be false positive in syncope

- Serum Creatine kinase- elevated for hours

EEG

• An EEG should be performed only to support a diagnosis of epilepsy in children and young people

• Normal variants . False positive in syncope

• Within 24 hrs of siezure -

• Predicts recurrence

• Nature ,Type of Epilepsy, epilepsy syndrome

• sensitivity – variable ,specificity -99 %

3 Hz spike and wave – absence siezures

Generalised polyspike - JME 2 hz spike and wave –Lennox Gestaut syndrome

VIDEO EEG

• Long term Video EEG is time consuming

• Short term video EEG to distinguish from psychogenic

• Done for 24 hrs with documentation of 3 or more events

• Carried in centres with expertise

Neuroimaging Studies • Neuroimaging in epilepsy is useful in:

• • Focal seizures

• • Seizures suspected to be symptomatic in origin

• • Difficult to control seizures (MRI using special epilepsy protocol).

• Computed tomography scan should be the initial investigation in epilepsy patients in India

• Advanced epilepsy protocols and newer imaging modalities [functional magnetic resonance imaging (fMRI), single photon emission CT (SPECT), positron emission tomography (PET)

Invsestigations in suspected siezure

TREATMENT OF EPILEPSY

• Treatment should be initiated following the occurrence of two or more unprovoked seizures

• Risk of developing a second seizure following a single unprovoked seizure is about 35- 40%

• Therapy started only after diagnosis of epilepsy is confirmed.

• Treament after first siezure reduces recurrence by 50 %..15 % discontinue due to ADR

WHEN TO TREAT FIRST SIEZURE ?

AED treatment may occasionally be deferred

• Infrequent seizures with extremely long / several years interval

• Rolandic epilepsy in children

Principles of AED treatment

• Treatment should be started with a single conventional antiepileptic drug-monotherapy

• Start with a low dose and gradually increase the dose

• If ineffective or poorly tolerated, then monotherapy using another AED , first drug slowly tapered

• Combination therapy -considered when two attempts at monotherapy with AEDs have not resulted in seizure freedom.

CHOICE OF ANTIEPILEPTIC DRUG

• Preferable to use a conventional AED Phenytoin(PHT), Phenobarbitone (PB), Carbamazepine(CBZ), Oxcarbazepine (OXC)

• partial seizures -CBZ, OXC, PHT, VPA

• GTC S - VPA, PHT,PB, CBZ, OXC

• Absence seizures –VPA

• myoclonic jerks- VPA and benzodiazepines

Partial siezures

• Carbemzepine is more effective for complex partial siezures

Disadvantages – potent enzyme inducer,autoinduction –accelerates own metabloism

- Newer AED -

Topiramate and oxcarbezepine –FDA approved as monotherapy

oxcarbezepine – weaker enzyme induction, no autoinduction ,more likely to cause hyponatremia

GENERALISED SIEZURES

• Valproate is the AED of choice

• Phenytoin .CBZ and oxcarbazepine may be considered

• Newer AED – Topiramate is the only FDA approved for GTC s

Lamotrigine and leviteracetam for adjunctive therapy

SUBSTITUTION MONOTHERAPY

• Choice of substitution depends on reason for failure of orignal AED (ADR or lack of response)

• Usually a period of adjunctive therapy .

• Any AED can be considered .

ADJUNCTIVE THERAPY

DEPENDS ON

• Pharmacokinetic interactions –eg enzyme inducer with hepatically metabolized drug

• Newer drugs advantageous –less interactions

eg Gabapentin,Leviteractam,Pregabalin

• ADR – sodium channel blockers similar ADR

• Different mechanism of actions

• Synergistic effects – Valproate and Lamotrigine,

Newer drugs

- All newer drugs FDA approved for adjunctive therapy for partial siezures

- Lamotrigine,Topiramate and Leviteracteam –adjunctive for GTC s

- Leviteracetam FDA approved for adjunctive therapy in Myoclonic siezures .(lamotrigine,Topiramate and zonisamide may be considered)

- No FDA approved newer drugs for adjunctive therapy in absence siezures

NEWER ANTIEPILEPTICS

• People who have not benefited from treatment with the conventional AED

• contraindications to the first line drugs

• If The first line drugs interact with other drugs

Specific syndromes

• Benign Rolandic Epilepsy – Treament may not be necessary . Valproate or Carbamzepine

• Lennox Gestaut syndrome –difficult to control multiple siezure types . Valproate ,Clonazepam

- FDA approved.Lamotrigine ,topiramate used

- Juvenile Myoclonic Epilepsy – Myoclonic,90% -GTC s ,30% absence ..Valproate –DOC .Leviteracetam –Adjunctive therapy

COMMONLY USED DRUGS

Adverse reactions

• A.) Acute CNS ADR –- somonolence ,dizziness ,ataxia ,vertigo,cognitive

dysfunction .- depends on High initial dose ,rapid escaltion- phenytoin,CBZ (peak dose dependent)- cognitive dysfunction- Barbiturates ,BZD

,Topiramate- Hyponatremia ,water intoxication –OXC ,CBZ

B) Acute CVS – Arrythmias ,hypotension –CBZ,PHT

C) IDIOSYNCRATIC REACTIONS –

• -RASH – Highest with Phenytoin -10% ,CBZ-8.7%, LTG -6.2%

• -serious idiosyncratic reactions – SJS ,TEN

• Discontinuation of drug always recommended ,switch to BZD ,LEV – low rash potentialid

avoid switching if cross reacitvity

• HEPATOTOXICITY-

• - Acute hepatitis occurs usually within first 3 months

• Coexisting liver disease ,other enzyme inducing drugs

• Fulminant liver failure can occur

• ALT,AST poor predictors

• Felbamate ,Lamotrigine

• Hematotoxicity• -Macrocytic Anemia – PHT,CBZ,PHB ,VPA• Aplastic Anemia – CBZ .5-20 cases per million• Agranulocytosis – CBZ,PHT• Mild decrease in leucocyte count – CBZ• Mild decrease in platelet count –VPA .-Psychiatric- Vigabatrin ,Topiramate, Leviteracetam- Paradoxical Aggravation of Siezures-Typical

Absence ,Myoclnic aggravated by PHT,OXC,VGB- CBZ cause myoclonus ,Absence status

• Valproate induce pancreatitis – infrequent

• Poor corelation with amylase.Lipase more helpful

• Changes in Body weight-

Clinically significant weight gain – 62% seen with valproate

- BONE HEALTH- Higher risk of Fractures ,Osteoporosis .-PHT,CBZ Barbituartes .Enzyme inducing drugs

Teratogenicity

• Major or minor malformations

• Fetal anticonvulsant syndrome – many drugs share same effects

• Prenatal exposure is associated with 9% risk of major malformation (2-4 % in normal population)

• Number of AED used ,First trimester

• Valproate – maximum chance

• Risk lower for CBZ,lamotrigine

• Substitute VPA for lamotrigine

• Newer drugs not extensively studied

• Prenatal exposure to AED cognitive slowing in children

• Phenytoin associated with lymphoma./pseudolymphoma

Drug interactions

• (PHT, PB, CBZ and OXC ) induce hepatic enzymes and enhance the metabolism of lipid soluble drugs. Reduced efficacy of drugs like

oral contraceptives and oral anticoagulants.• VPA inhibits hepatic enzymes . slows down the

metabolism of concomitant AEDs causing toxicity

• Anti-tubercular drugs (like isoniazid and rifampicin are enzyme inducers and also hepatotoxic)

Frequency of follow-up

• maintain a seizure diary-prescribed medication is taken as advised and to detect any adverse effects of AED.

• The first follow-up -within 2-4 weeks of initiation of treatment

• Subsequent follow-ups at every 3-6 months,

Role of AED level monitoring

• Routine monitoring of AED blood levels is not recommended

Indications

• Non-compliance

• Suspected toxicity.

• Adjustment of AED dose while managing drug interactions

• Specific clinical conditions-status epilepticus, liver or renal disease and pregnancy

Failure of initial treatment

• Ascertain the accuracy of the diagnosis of epilepsy

• The appropriateness of the drug for the particular seizure type,

• the adequacy of dosage

• compliance of the individual

• should be encouraged to make a record seizure on a cell phone camera.

STATUS EPILEPTICUS

• CONVULSIVE status epilepticus –continous convulsive siezures lasting %min or more in which the patient doesn t return to baseline consiousness

• Non convulsive stutus Epilepticus –Change in Mental status for at least 30 minutes associated with ictal discharges on EEG

• Refractory status Epilepticus –Siezureactivity that continues after 1st and 2nd line drugs have failed

TREATMENT OF STATUS EPILEPTICUS

Treament of Refractory status

epilepticus

Withdrawal of AEDs

• seizure-free period of two to three years.• Avoided in certain epilepsy syndromes (e.g.,juvenile

myoclonic epilepsy) because of the higher risk of seizure relapse

• withdrawn gradually over several months (at least 3-6 months or longer).

• Withdraw one drug at a time in those patients who are on multiple AEDs

• The tapering may be performed at a slower rate for benzodiazepines (6 months or longer).

• If seizure recurs during withdrawal person may be advised to revert to their AED dose

Women with Epilepsy

• (WWE) who continue appropriate AEDs under proper supervision have more than 90% chance of having a normal pregnancy and children.

• All WWE should be advised to plan their pregnancies.

• cautioned that some AEDs may make OCPs ineffective

• All WWE in the reproductive age group should be started on folic acid (5 mg/day) at the time of starting AED

• The risk of major fetal malformations is approximately 5% more

• risk is further reduced when the mother is using monotherapy (a single AED)

• VPA at higher doses carries higher risk for neural tube defects

Siezures in pregnancy

• Seizures may remain unchanged in 50% WWE or improve (25%) or even worsen (25%) during pregnancy.

• Antiepileptic drugs should be continued in pregnancy.

• All pregnant WWE should be advised screening for fetal malformations by serum alpha fetoprotein at 16 weeks and by detailed ultrasound scanning by an experienced ultrasonologist at 18 weeks.

Recommendations

• All WWE should be given two doses of vitamin K 10 mg intramuscularly (IM) at 34 and 36 weeks of pregnancy, unless there is a contraindication for the same.

• All infants born to mothers taking AEDs should be given vitamin K 1 mg IM at birth.

• If preterm labor is threatened in women taking enzyme-inducing AEDs, 48 mg betamethasone (double the normal dose) should be given over 48 hours.

• Seizures during labor should be terminated as soon as possible using intravenous (IV) lorazepam (4 mg IV) or diazepam

• All WWE should be encouraged to breast-feed their babies

Epilepsy in Children and Neonates

• Subtle manifestations of seizures are common in neonates and infants and these must be looked for very carefully

• Febrile Seizures -• during fever between 6 months and 5 years of

age in the absence of intracranial infection

• Single FS occur in 3–5% children

West Syndrome and Infantile Spasms

• corticotropin or corticosteroids should be used as first-line treatment.

• benzodiazepines, VPA, vigabatrin and topiramate are used as second choice

EPILEPSY IN ADOLESCENTS

• Avoiding sleep deprivation,• alcohol and substance abuse,• driving,• potentially risky leisure activities like rock

climbing, horse riding, • prolonged television (TV) viewing, playing video

games and• dancing in dark rooms with flickering/flashing

lights (discotheques).

COMORBID CONDITIONS

• CARDIAC DISEASE – iv Phenytoin can cause arrythmias , Hypotension

• In patients with cardiac disease infusion rate <10 mg/min.

• Iv Valproate is safe, Leviteracetam may be safe• Chronic treatment –CBZ,OXC,PHT should be

avoided in AV conduction defects• Respiratory disease – iv benzodiazepines ,iv

Phenytoin can cause respiratory depression• Respiratory rate ,HR to be monitored• Valproate .Leviteractam safer

• LIVER DISEASE – Hepatic metabolism of drugs may be altered

• - Phenobarbitone ,benzodiazepines can precipitate Hepatic Encephalopathy

• Valproate C/I due to hepatotoxicity• Phenytoin highly protein bound

hypoalbuminemia – toxicity• Leviteracetam,oxcarbazepine,topiramate• Renal disease- Drugs eliminated by kidneys

require dose reduction .LEV,LTG,OXC,PB,TPM

EPILEPSY IN ELDERLY

• Generalized tonic-clonic seizures dominate for metabolic or toxic etiologies

• Every elderly patient with epilepsy should undergo, at least a CT scan, though MRI is preferable as symptomatic epilepsy is common in elderly

• nonconvulsive status epilepticus (NCSE)

• The choice of AEDs in elderly depends on many factors: changes in liver, kidney, gastrointestinal (GI) system

• Bioavailability of the drug in elderly is altered

MEDICALLY INTRACTABLE EPILEPSY

• Those in whom epilepsy is not controlled by two or more appropriate AEDs used in their optimal dosage

• Adults (16 years or above) who continue to have seizures even after 2 years of treatment.

• Pediatric epilepsy patients can be labeled as MIE much earlier (sometime even within weeks of onset of seizures), if they present with epileptic encephalopathy, infantile spasms, catastrophic onset of epilepsy, seizure frequency of more than one per month

• 30 -40 % SIEZURES persist despite multiple AED

• Rule out erroneous diagnosis, non compliance

• Partial/localization related epilepsy(30 -70 % cure ), MTS (20 -50 % cure), secondary genralised epilepsy ,Lennox gestaut syndrome

SURGERY IN EPILEPSY • GOOD SURGICAL CANDIDATE -

• Epileptogenic Area is Clearly Defined ,Amenable to Rescetion with minimal morbidity

• Presurgical Evaluation –

• High Resolution MRI- Thin Cuts Along Temporal Lobes – For detection of MTS

• Structural Lesion correspomding to Epileptogenic Zone

• Continuous video EEG- ictal and interictalrecord with discontinuation of drug

• 75 % cases Localisation with Scalp Recordings• Functional Neuroimaging-• Ictal or Interictal SPECT- Radioactive isotope –

Technitium 99 – siezure area has highest Perfusion

• FDG –PET – interictally done to indentify decreased metabolism

• Resective surgery includes

• lesionectomy (resection of the lesion and the surrounding epileptogenic area),

• amygdalohippocampectomy with or without temporal lobe resection

• Anterotemporal Lobectomy

• Nonresective surgery includes multiple subpial transections corpus colostomy and vagusnerve stimulation (VNS

VAGAL NERVE STIMULATION

• Those who are not surgical candidates

• Pacemaker device implanted subcutaneously in left infraclavicular region

• Efficacy is less in partial epilepsy ..10% of patients benefit

• Better response in lennox gestaut syndrome

Thank you

References

• Indian Epilepsy Association-

guidelines for the management of epilepsy in India (GEMIND). -2008

- International League against Epilepsy(ILAE) –Guidleines 2006

- NICE GUIDELINES

- Seminars in neurology –july 2008

- European journal of epilepsy -review