Epilepsy update- September 2016

Kasia Sieradzan

Consultant Neurologist

Epidemiology of epilepsy

Epilepsy is the most common serious neurological condition within the general population

Incidence 50/ 100,000/ year

Prevalence 5-10/ 1000 persons

(excluding febrile convulsions, single seizures, inactive cases)

- Lifetime prevalence 5%

(chance of having a seizure at some point in life)

65 million people world wide diagnosed with epilepsy

There are as many people with active epilepsy as there are people with insulin- dependant diabetes

Causes of Epilepsy Head injury CNS infections Stroke Hippocampal sclerosis Cortical dysplasias/ neuronal migration disorders Brain tumours Anoxic brain injury Autoimmune Drugs and alcohol Genetic or presumed genetic Epilepsy Syndromes; Juvenile myoclonic epilepsy (JME), Dravet syndrome, Juvenile absence epilepsy, Rasmussen syndrome, Angelman syndrome, Lennox- Gastaut syndrome etc……

No cause found in about 50% of patients .

Definitions

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive synchronous neuronal activity in the brain.

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological, and social consequences.

Basic concepts and definitions – evolving picture

Work towards improved classification of epilepsies

Work towards improved classification of seizures

Attempts to incorporate new concepts of aetiology and pathogenesis

Difficult shift away from old classification

Current International League Against Epilepsy definition – 2014

Classification of Seizures –prior to 2010

Changing classification of seizures – ILAE proposal 2016

“ The pyramid of care”

1st seizure clinic - diagnosis &support

AED treatment - good control

Special patient groups

Refractory epilepsy

Epilepsy surgery

Comprehensive Epilepsy Service

• Epileptology • Neurophysiology • Neuropsychology • Neuropsychiatry • Neurosurgery • Epilepsy Nurses • Ketogenic diet • Full diagnostic

facilities • Research

• Transitional care • Women & Epilepsy • Epilepsy in Older Age • Epilepsy in Learning

Disability • Liaison with GPs and

community based-services

The essential service of the epilepsy specialist nurse

Medicines management

Education and training

Adviceand information

Specialised clinics

AssessmentCounselling And support

Liaison

Point of contact

Risk management

VNS, preoperative clinic, telephone clinics, Antenatal, Oncology

Empowerment

Increased awareness,

Ensuring adherence, reviewing and making changes in treatment, managing side effects

Current seizures, social and

Psychological situation, general

health and wellbeing

Improvement of quality of life

Continuity of care, liaison with, Epilepsy team,

paediatric service, GP’s allied health

professionals, LD service, charities, social services

etc

For Patients and other health

professionals, etc.

Fewer accidents, management of

prolonged seizures in community care,

reduction of admissions

Epilepsy Treatments

• AEDs

• SURGERY – Brain Surgery, VNS or DBS

AED Introduction in UK: 1865–2016 First Generation

Bromide = 1865 Phenobarbital = 1912 Phenytoin = 1938 Primidone = Ethosuximide = 1955 Acetazolamide = 1988

Second Generation Carbamazepine = 1965 Sodium Valproate = 1973 Clonazepam = 1974 Clobazam = 1979

Third Generation Vigabatrin = 1989 Lamotrigine = 1991 Oxcarbazepine = 2000 Gabapentin = 1993 Topiramate = 1995 Tiagabine = Levetiracetam = 2000 Pregabalin = 2004 Stiripentol = Rufinamide = Zonisamide = Lacosamide = 2011 Piracetam = Eslicarbazipine = Retigabine = Perampanel = 2011 Brivaracetam =2016

Choosing an AED Primary criterion

Efficacy in particular seizure type Mechanism of action(s) may be an important criterion in the drug select process(s) may be an important criterion in

the drug selection process

Secondary criteria Ease of prescribing

Dose linearity – dosing straightforward

Time to steady state – allows rapid drug changes

Minimal interaction potential – co-medication not an

important consideration

Patient compliance

Elimination half-life of 12-24 hour – allows bid/od dosing

All dependent on AED Pharmacokinetics

Choice of 1st line AEDs

Focal epilepsies– Lamotrigine Levetiracetam Carbamazepine Lacosamide Eslicarbazepine Perampanel Pregabalin

Generalised epilepsy – Sodium Valproate (not in women of reproductive age)

Lamotrigine Levetiracetam Carbamazepine Perampanel Topiramate Zonisamide Ethosuximide (typical absence)

Shared care – traffic light system

• New AEDs introduced in the last 5 years

• Shared care protocols on SGNS

Brivaracetam – 2016

Lacosamide, Eslicarbazepine, Perampanel, Rufinamide, Tiagabine, Pregabaline

Carbamazepine; Levetiracetam, Lamotrigine; Topiramate; Valproate, Phenytoin, Clobazam, Clonazepam

SUDEP

Sudden Unexplained Death in Epilepsy “Sudden, unexpected, witnessed or unwitnessed, non traumatic and non

drowning death in patients with epilepsy, with or without evidence of a seizure,

and excluding documented status epilepticus, in which post mortem

examination does not reveal a toxicological or anatomic cause for death”

(Nashef 1997)

Probably accounts for approx 500 deaths a year in the UK

May account for 17% of all deaths of people with epilepsy

SUDEP – risk factors

• Early onset

• Male

• 20 – 40yrs old

• Tonic-clonic seizures

• Nocturnal

• Living alone

• Poor records

• Poor seizure control

• Non-compliance

• Polytherapy (more than one drug)

• Abrupt/frequent changes in AEDs

• Alcohol

Epilepsy in Women

Pregnancy

Epilepsy-related risks to the pregnancy outcome

• Effects of maternal seizures

• Effects of antiepileptic drugs

Core objectives: Prevent t-c seizures Reduce risk of foetal exposure

to AEDs major congenital

malformations neurocognitive &

behavioural toxicity

Epilepsy and Pregnancy registries – MCM in monotherapy

MCM rates after monotherapy exposure for new AEDs

Dose -dependence of teratogenicity – EURAP data

MCM rate at 1 y following monotherapy exposure Tomson and Battino, Lancet

Neuorlogy 2012,

Dose dependence – UK Epilepsy &Pregnancy Register data 2014

Levetiracetam

Seizure control vs risk of MCM

Hernandez-Diaz Neurology 2012;78:1692-99

Neurocognitive Effects of

Antiepileptic Drugs (NEAD) Study

Neurocognitve outcome by AED

and type of maternal epilepsy

Meador et al. NEJM 2009; 360: 1597-1605

Neurocognitive outcomes by AED

and dose

Meador et al. NEJM 2009; 360: 1597-1605

Neurocognitive outcome in different monotherapy groups vs maternal intelligence

Meador et al. NEJM 2009; 360: 1597-1605

Behavioural toxicity of valproate

Absolute risk of autism spectrum disorder 4.4% (2.6-7.5%) after VPA exposure

JAMA 2013;309:1696

Physiological changes in AED concentrations during pregnancy

From Tomson, Pregnancy and Breastfeeding, EEC, Stockholm 2014

Lamotrigine – management in pregnancy

• Document individual pre-pregnancy plasma level • Monitor Ltg level monthly in pregnancy

– Problem with delayed reporting

• Increase dose empirically if seizures worsen and level not available

• Increase dose if level falls to 60-65% of pre-pregnancy value • Follow the experience of previous pregnancies • Anticipate post-partum Ltg toxicity – reduce dose (e.g. on days 3, 7, 10 to pre-conception dose + 50 mg extra to

compensate for sleep deprivation) Pennell et al. Neurology 2007; 70: 2130-36

Folic acid in pregnancy

Breast feeding and AEDs

• Levels in breast milk lower than maternal plasma levels except for levetiracetam, but v. low plasma levels in neonate

• V. small amonts of carbamazepine or valproate excreted in breast milk

• No significant problems with lamotrigine but some infants have 18-30% of maternal plasma level

• Potential for accumulation in some neonates due to immature liver (glucuronidation) and kidney function

• Adverse effects on the neonate generally not reported

Breast feeding & nurocognitive development

Summary – management

– Effective liaison between GPs and specialist neurology and obstetric services

– Patient education from the stage of transition from the paediatric to adult service

– Consider elective transition to monotherapy

– Optimal AED therapy before conception

– Avoid valproate if alternatives exist

• make the patient aware of teratogenic risks

– Monitor Ltg plasma levels (? Other AEDs eg Lev)

– Support breast feeding

Epilepsy surgery

Resective surgery for patients with refractory epilepsy arising from a defined area of the brain that can be safely resected Criteria – medically refractory focal epilepsy -disabling, recurrent seizures - failed treatment for > 2 y on > 2 first line AEDs. Suitable patients: Hippocampal sclerosis in TLE patients Cortical dysplasias Benign tumours Small AVMs Postraumatic gliotic scarring Some non-lesional (“MRI-negative”) patients

Examples of “surgical” lesions causing epilepsy

Hippocampal

sclerosis

Low grade glioma

Focal cortical

dysplasia

EPILEPSY SURGERY ASSESSMENT:

•CONCORDANCE

Stage I clinical assessment epilepsy hx and seizure semiology

Stage II 3T MRI ?lesion

Neuropsychology localization

functional risks

Vidoetelemetry record seizures / seizure onset zone

Neuropsychiatry co-morbidities

risk post-op

consent in LD

Neurosurgery risk of surgery

suitability for invasive studies

consent

Stage III Ictal SPECT, FDG PET

fMRI, MEG, (Wada)

Stage IV Intracranial EEG

Stage V Surgery

The Epilepsy Surgery Team Multidisciplinary team work

Robotic Stereo EEG (SEEG)

Depth electrode implantation 3D reconstruction – fusion of pre-operative MRI and post-operative CT – parietal epilepsy

Unsuitable for epilepsy surgery

Multifocal epilepsy

Primary generalized epilepsy

Seizure focus in eloquent cortical areas = high risk of postoperative deficits

May be suitable for vagus nerve stimulation (VNS) or disconnection procedures

Summary

• Vast topic clinically and scientifically

• Source of major disadvantage and stigma for patients

• Simple and complex epilepsy

• 70-80% achieve lasting remission and can be managed in primary care with re-referral/ specialist input as required

• Special needs of certain groups of patients

• Awareness of SUDEP

• Awareness of non-medical treatment options – too few patients referred for specialist assessment for surgery

• Cost effectiveness of treatment / utilisation of resources

Thank you

Questions ?