Which new antiepileptic drug for which patient?

1
The Medical and Surgical Treatment of Epilepsy
Professor Ley Sander Department of Clinical and
Experimental Epilepsy UCL Institute of
Neurology National Hospital for Neurology
Neurosurgery Queen Square, London WC1N 3BG
2
The Treatment of Epilepsy

• The incidence and prevalence
• Aetiologies and risk factors
• Aims of treatment
• Clinical settings
• Principles of treatment
• Medical treatment
• Surgical treatment
• Guidelines
• Conclusions

3
Incidence and Prevalence

• Incidence of new cases of epilepsy
• 50/100,000/year
• Incidence of single seizures
• 20 - 30/100,000/year
• Prevalence of active epilepsy
• 5 - 10/1,000 (50 because on AEDs)
• Severe epilepsy 1 - 2/1,000
• Cumulative Incidence (lifetime prevalence)
• 2 - 5

4
Incidence and Prevalence in the UK

• 30 000 new cases a year
• 300 000 - 400 000 cases
• 72 000 - 80 000 cases of severe epilepsy

5
Incidence and Prevalence in the UK

• GP
• 1 - 2 new cases of epilepsy/year
• 10 - 12 cases of active epilepsy
• Neurologist
• 150 cases of epilepsy/single seizures/year
• 1,200 cases of active epilepsy

6
Epilepsy Aetiologies and Risk Factors

• Risk factors varies with age and geographic
  location
• Congenital, developmental and genetic conditions
  in childhood, adolescence and young adults
• Head trauma, infection and tumours at any age
  although tumours more likely over age 40
• Cerebrovascular disease common in elderly
• Endemic infections are associated with epilepsy
  in certain areas
• malaria, neurocysticercosis, paragonomiasis,
• no adequate large scale study of attributable
  risk yet

7
Antiepileptic Treatment

• AEDs are mainstay treatment
• Non-pharmacological options feasible in only few
  selected cases
• Surgery
• Curative
• Palliative
• Ketogenic diet (children)
• Behaviour modification
• Avoidance therapy in cases with clear
  precipitants

8
Aims of Antiepileptic Treatment

• Complete seizure freedom
• 50 seizure reduction of little benefit
• No adverse effects
• long term treatment - long term effects ?
• cognitive effects debilitating
• teratogenicity
• Non-obtrusive treatment
• once or twice daily
• No PK or PD interactions
• Maintenance of a normal lifestyle
• Reduction in morbidity and mortality

9
AED Treatment Clinical Settings

• Prophylactic Treatment
• Newly Diagnosed Epilepsy
• Single seizure
• Recurrent seizures
• Chronic Epilepsy

10
Prophylactic use of AEDs

• Often advocated after
• Head injury
• Craniotomy
• There are considerable compliance problems
• There is no evidence of a protective effect of
  this policy
• No place for this!
• Better wait for the event to happen

11
Is it Epilepsy ?

• Newly diagnosed or suspected cases at Primary
  Care level
• gt 50 not epilepsy
• commonest differential diagnosis syncope
• Chronic cases
• 15 - 20 not epilepsy
• mostly psychological in nature
• Careful diagnostic assessment a must in all cases

12
The Single Seizure

• A controversial area!
• Single unprovoked attack usually not treated
  practice to defer treatment until 2 or more
  seizures, although patients at high risk may be
  treated after a first attack
• Incidence of epilepsy much greater than of single
  seizures
• Community-based studies show that overall risk of
  a second seizure greater than previously accepted
  
• selection bias
• Patients
• Seizure type
• time to entry bias

13
The Single Seizure

• AED treatment following a single seizure reduce
  risk of recurrence in the short term although
  long term prognosis not changed
• This may eventually lead to changes in the way
  single seizures are managed
• treatment after first seizure
• - for six months, for a year?
• tailored treatment and not symptomatic
• Meanwhile, involve patient and or guardians in
  the decision

14
Recurrent Seizures

• Treatment recommended after two or more seizures
• Exceptions
• - Long interval between seizures
• - Clear identifiable precipitant factor
• - Patient against treatment
• - Unlikely compliance

15
Precipitating Factors

• Fever
• Drugs
• Alcohol
• Photo-Sensitivity
• Sleep Deprivation
• Reflex Mechanisms
• Acute Metabolic Stress
• Emotional Stress/Major Life Events

16
Starting an AED

• Starting AED treatment is a major event and
  should not be undertaken without careful
  evaluation of all relevant factors
• Therapy is a long term prospect
• All implications must be fully explained to the
  individual and or guardian
• Paramount that the patient or guardians are kept
  informed about the treatment process and the
  rationale behind it

17
Starting Treatment

• Treatment should always be started with a single
  drug at a small dose
• All common side-effects must be discussed
• teratogenicity and contraception if applicable
• Importance of compliance should be stressed
• Careful titration is a must
• - start low, go slow

18
Choice of AEDs treatment

• Choice of AED influenced by
• Type of seizure and or epileptic syndrome
• Individual circumstances of patient
• Side effect profile of drug
• Personal preferences
• No clear cut evidence based medicine is
  available!
• Clinical practice is based more on dogmatic
  teaching than on scientific knowledge
• Empirical rather than rational

19
Principles of AED treatment

• Diagnosis clearly established
• Appropriate first line drug for syndrome and
  patient
• One drug at a time as a rule
• If first drug ineffective add another first line
  drug and then withdraw first drug
• Combination therapy only when single drug
  ineffective

20
What Is Chronic Epilepsy ?

• Active 2 years after onset
• Failed 2 first line AEDs
• Great number of seizure in early history

21
Chronic Epilepsy 1

• Review history of epilepsy
• - Obtain and review old notes if possible
• - Interview patient and witness
• - Classify seizures
• Review diagnosis
• - Non-epileptic events
• - Identifiable aetiology
• - High resolution MRI scanning
• Question Compliance
• Check serum AED levels
• Review past and present AED treatment for
  efficacy and side-effects

22
Chronic Epilepsy 2

• Select the AED that is most likely to be
  efficacious and with the least side-effects
• Adjust the dose of the selected drug to the
  optimum
• Attempt to reduce and taper other AEDs
• If seizures continue despite a maximally
  tolerated dose of a first-line drug
• - Check compliance
• tablet count, serum levels, counselling
• Commence another first-line AED if there is one
  that has not been used to its optimum

23
Chronic Epilepsy 3

• If seizures continue try a combination of two
  AEDs
• If combination unhelpful, AED which appears
  most effective and with fewer side-effects should
  be continued and the other AED replaced
• If this drug is effective, withdrawal of the
  initial agent should be considered if not, it
  should be replaced by another AED
• Consider the possibility of surgical treatment
• Consider using an experimental AED

24
Inappropriate use of AEDs

• Inappropriate treatment of people who do not have
  epilepsy
• Inappropriate drug treatment of patients who do
  have epilepsy
• JME easily treated with some AEDs but poorly
  controlled with others
• Partial epilepsies often misdiagnosed as
  generalised epilepsy
• Incorrect dosages or inappropriate use of
  polytherapy
• Overzealous adherance to therapeutic AED drug
  levels

25
AED drug levels monitoring

• Measurement of AED levels
• drug toxicity occurs and needs to be documented
• suspected non-compliance
• suspected drug interactions
• during pregnancy (free levels)
• during systemic illness
• phenytoin therapy
• Not a guide to dosing!

26
Who Should be Evaluated for Surgery

• Partial seizures simple, complex, sec gen.
• Stereotyped onset
• No non-epileptic attacks
• No contraindication for Neurosurgery
• Active epilepsy for gt2-3 yr, despite 3 AEDs
• Inadequate seizure control gt 1-2 c p s /month
• Acceptance of best risk / benefit ratio

27
Best risk vs benefit ratio of temporal lobe
epilepsy surgery

• Medical Surgical
• Chance of seizure control
• 10 70
• Risk
• Morbidity from seizures 1/100 long-lasting
  impairment
• Psychosocial handicap hemiparesis,
  aphasia
• 1/100 Annual mortality 1/20 quandrantanopia
  prevents driving

28
Range of Epilepsy Surgery

• 70 Anterior temporal lobe resection
• 20 Extra-temporal cortical resection
• Lesionectomy
• 10 Palliative Procedures
• Hemispherectomy
• Corpus callosotomy
• Subpial transection
• Vagal Nerve Stimulation

29
Components of Presurgical Evaluation

• Convergence of data
• One epileptogenic dysfunctional area
• Rest of brain normal
• Clinical
• Neuro-Imaging
• EEG
• Neuropsychology
• Neuropsychiatry
• Psychosocial

30
Psychosocial

• Realistic expectations?
• Improvement in life from seizure control?
• Intelligence, memory will not improve
• Not more attractive, employable
• Need to continue AEDs after
• Social support
• Family, friends, community, finances

31
Neuro-imaging

• Fundamental
• MRI predicts nature and extent of pathology
• Unusual to resect area with normal imaging
• Poor results if imaging normal

32
Pathology and Outcome

• TLE Anterior Temporal Lobe resection
• Focal pathology 70 seizure free, 25 gt90
  reduced
• DNT, cavernomagtHSgtAVMgttraumagtMCD
• 20 seizure free if no focal pathology
• Extra Temporal Lobe
• Focal pathology 60 seizure free, 20 gt90
  reduced
• DNT, cavernoma, gliomagtAVMgttrauma
• MCD 20-30 seizure free, if focal
• lt20 seizure free if no focal pathology

33
Treatment Guidelines for Epilepsy

• NICE www.nice.org.uk National Institute for
  Clinical Excellence (England and Wales)
• SIGN www.sign.ac.uk Scottish Intercollegiate
  Guidelines Network (Scotland)
• AAN www.aan.com American Academy of Neurology
  (USA)

34
Primary Care Guidelines for Epilepsy

• Referral of ALL who experience a suspected
  seizure
• Seen within 14 days by specialist
• Risk and safety precautions documented
• Care Plan in place
• At least a yearly review
• Early re-referral if
• Treatment failure
• Seizures not controlled
• Diagnostic uncertainty
• Considering pregnancy
• Considering drug withdrawal

35
Managing People With Epilepsy

• Holistic issues
• Interest and continuity of care
• Clear plan
• Information provision
• SUDEP
• Easy access
• - Practical Issues
• Cooking, Bathing, Driving, Contraception,
  Conception
• - Reasonable Expectations
• Prognosis, Independent Living, Employment

36
AED Treatment Conclusions

• Correct diagnosis and classification paramount to
  treatment
• AEDs are mainstay treatment
• Treatment empirical rather than rational!
• gt 70 of patients become seizure free
• Potential complications toxicity
• Low threshold for s/effects

37
AED Treatment Conclusions

• Potential for misuse of AEDs not to be dismissed
• New AEDs may be better tolerated, but more
  effective?
• Chronic side effect profile of new AEDs not fully
  known
• Surgical treatment very successful but only
  possible in a few selected cases
• Consider stopping AED if seizure free for years
• New treatment still needed!