Dr Paul Timmings Neurologist and Senior Lecturer University of Auckland School of Medicine

9:20 - 9:45 Epilepsy, Fits and Faints - What's New?

Fits & Faints: Five New Things Dr Paul Timmings MBChB MD FRACP Neurologist, Hamilton

Fits & Faints: Five New Things • Jerking ≠ Seizure • TBI even mild, doubles seizure risk over 10 yrs • EEG; misused, helpful but poorly utilised • New AEDs not better than old

• Elderly are now the largest group with epilepsy

Its Not About the Jerking • LOC ? Cause is common • 2/3 is due to syncope

6% of ED attendances 3% of Medical admissions 15% under 18yrs have had “syncope” 25% of > 70yrs will have LOC ?cause in next 10yrs

• Common symptoms associated with syncope include • Limb jerking or twitching • Rolling eyes • Urinary incontinence • 90% of syncope cases have jerking • Jerking has been commonly assumed to indicate seizure

Syncope

Seizure

Syncope Vs Seizure • Some symptoms help discriminate • Prodrome, Pallor, Posture, Palpitation • The eye witness may unknowingly hold the answer: Ask in detail

• 2/3 of blackouts are syncope & ½ those are vasovagal • But • 9% of syncope cases had died by 18 months follow-up, including 26% of those found to have cardiac disease.

• Correct triage and management of cardiac cases will save lives Sarasin et al Am J Med 2001

Separate Syncope from Seizure: Symptom Scoring Questionnaire Symptom Scoring is 94% Accurate

Sheldon et al J Am Col Cardiol 2002

Correct identification of serious heart disease (SHD) is important

Collapse ?Cause Referral Decision Tree

Petkar et al. Post Grad Med J. 2006;630-641

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Collapse ?Cause Referral Decision Tree

Petkar et al. Post Grad Med J. 2006;630-641

Fits & Faints: Five New Things • Jerking ≠ Seizure

• TBI, even mild, doubles seizure risk over 10 yrs • EEG; misused, helpful but poorly utilised • New AEDs not better than old

• Elderly are now the largest group with epilepsy

Unprovoked Seizures after TBI: A population based case-control study

Mahler et al. Epilepsia;2015:1438-1444

Concussion is Serious Relative risk of unprovoked seizures is higher for >10yrs Type of injury

Time frame

RR

95% CI

Mild TBI

0-6 months 6mo-2yrs 2-10yrs >10yrs

8.1 2.6 1.5 2

3.1-21.7 1.0-6.4 0.9-2.4 1.4-2.9

Severe TBI

0-6 months 6mo-2yrs 2-10yrs >10yrs

48.9 10.9 7.1 2.2

10.9-218.9 4.6-25.8 3.5-14.6 0.6-8.0

Mahler et al. Epilepsia;2015:1438-1444

Fits & Faints: Five New Things • Jerking ≠ Seizure

• TBI, even mild, doubles seizure risk over 10 yrs • EEG; misused, helpful but poorly utilised • New AEDs not better than old • Elderly are now the largest group with epilepsy

EEG • A normal EEG cannot exclude Seizure/Epilepsy (due to technique dependent false negative rate)

• Sleep deprivation improves sensitivity to 75-85% • An abnormal EEG showing inter-ictal epileptogenic activity connotes a 60-75% probability of a second seizure by 2 yrs • A normal EEG (in a patient who had a seizure) connotes a 20-30% probability of a second seizure by 2 yrs

EEG • So, what use for EEG? • A test of function vs a view of structure • Useful in assessment of altered mental status – LOC ?Cause with suspicion of seizure – Single Seizure patients (gives prognostic data) – Epilepsy management – Non-convulsive status epilepticus (NCSE) – Metabolic & encephalopathic disease – Drug effects also often reflected in EEG

EEG • Get more from an EEG test, after you – Define your question – Use the test appropriately

• Understand the result and its limitations – Non-Specific means “NON-SPECIFIC” !! Don’t over interpret

Fits & Faints: Five New Things • Jerking ≠ Seizure

• TBI, even mild, doubles seizure risk over 10 yrs • EEG; misused, helpful but poorly utilised

• New AEDs not better than old • Elderly are now the largest group with epilepsy

AED Power Comparisons: Partial Onset Seizures

Chadwick et al. Ther Adv Neurol Dis: 2009;181-187

AED Power Comparisons: Generalised Onset Szs

Chadwick et al. Ther Adv Neurol Dis: 2009;181-187

Few Multi “Head to Head” Studies Inform • Levetiracetam not superior to Dr’s choice of CBZ-CR or VPA-ER (1688 pts. KOMET, 2013)

• LTG better tolerated than CBZ in focal onset szs & not inferior to CBZ, in Seizure suppression. (CBZ vs GBP vs LTG vs OXC vs TPM): (1721 pts. SANAD, 2007)

• VPA better than LTG or TOP in IGE or unclassified Seizures. (VPA vs LTG vs TPM): (1716 pts. SANAD, 2007) KOMET: Trinka et al. JNNP:2013;1138-1147 SANAD: Marson et al. Health Technol Acc. 2007;1-134

Fits & Faints: Five New Things • Jerking ≠ Seizure

• TBI, even mild, doubles seizure risk over 10 yrs • EEG; misused, helpful but poorly utilised • New AEDs not better than old

• Elderly are now the largest group with epilepsy

Elderly are the Largest Group with Epilepsy • Incidence & Prevalence of epilepsy in elderly is now the highest of any age group • Epilepsy in older people is their 3rd commonest condition • Exceeded only by stroke & dementia • Often undiagnosed Hauser 2007

Brodie 2005

Epilepsy in Elderly: Cerebrovascular Disease is Main Cause. Type of “Stroke” Affects Seizure Risk • By 5 yrs post event – 10% of ischaemic infarcts will have seizures – 25-30% of haemorrhages will have seizures

Burn 1997

Fits & Faints: Five New Things • Jerking during LOC ≠ Seizure

• TBI, even mild, doubles seizure risk for over 10 yrs • EEG; misused, helpful, but poorly utilised • New AEDs not better than old, but cost 10-20x more

• Elderly are now the largest group with epilepsy Dr Paul Timmings. MBChB MD FRACP Neurologist, Hamilton

Thank You

Paul Timmings Neurologist, Anglesea Clinic, Hamilton

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial. Marson AG1, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, Gamble C, Jacoby A, Shackley P, Smith DF, Tudur-Smith C, Vanoli A, Williamson PR. Abstract OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

KOMET: an unblinded, randomised, two parallel-group, stratified trial comparing the effectiveness of levetiracetam with controlled-release carbamazepine and extended-release sodium valproate as monotherapy in patients with newly diagnosed epilepsy. Trinka E1, Marson AG, Van Paesschen W, Kälviäinen R, Marovac J, Duncan B, Buyle S, Hallström Y, Hon P, Muscas GC, Newton M, Meencke HJ, Smith PE, Pohlmann-Eden B; KOMET Study Group. Author information 1Department of Neurology, Paracelsus Medical University, Christian Doppler Klinik, Salzburg, Austria. [email protected] Abstract OBJECTIVE: To compare the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients with newly diagnosed epilepsy. METHODS: This unblinded, randomised, 52-week superiority trial (NCT00175903) recruited patients (≥16 years of age) with ≥2 unprovoked seizures in the previous 2 years and ≥1 in the previous 6 months. The physician chose VPA or CBZ as preferred standard treatment; each patient was randomised to standard treatment or LEV. The primary outcome was time to treatment withdrawal (LEV vs standard antiepileptic drugs (AEDs)). Analyses also compared LEV with VPA-ER, and LEV with CBZ-CR. FINDINGS: 1688 patients (mean age 41 years; 44% female) were randomised to LEV (n=841) or standard AEDs (n=847). Time to treatment withdrawal was not significantly different between LEV and standard AEDs: HR (95% CI) 0.90 (0.74 to 1.08). Time to treatment withdrawal (HR (95% CI)) was 1.02 (0.74 to 1.41) for LEV/VPA-ER and 0.84 (0.66 to 1.07) for LEV/CBZ-CR. Time to first seizure (HR, 95% CI) was significantly longer for standard AEDs, 1.20 (1.03 to 1.39), being 1.19 (0.93 to 1.54) for LEV/VPA-ER and 1.20 (0.99 to 1.46) for LEV/CBZ-CR. Estimated 12-month seizure freedom rates from randomisation: 58.7% LEV versus 64.5% VPA-ER; 50.5% LEV versus 56.7% CBZ-CR. Similar proportions of patients within each stratum reported at least one adverse event: 66.1% LEV versus 62.0% VPA-ER; 73.4% LEV versus 72.5% CBZ-CR. CONCLUSIONS: LEV monotherapy was not superior to standard AEDs for the global outcome, namely time to treatment withdrawal, in patients with newly diagnosed focal or generalised seizures.

J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1138-47. doi: 10.1136/jnnp-2011-300376. Epub 2012 Aug 29

EEG – Who needs it? • LOC ?Cause with suspicion of seizure

• Single Sz patients (gives prognostic data) • Altered mental status ?Cause ?NCSE • Poor or worsening Ep control, - re ?new changes in EEG • Investigation of toxic / metabolic encephalopathies • Some coma & cerebral infections (eg Herpes, CJD, SSPE)

• Well controlled Epilepsy Patients: Re when to stop Rx

Fits & Faints: Five New Things • Its not about the jerking • Syncope & cardiac much more common • A few will have sinister underlying cardiac disease

• T‐LOC in the setting of definite SHD, or during (not after) exercise, • indicates likely malignant tachyarrhythmia.

• Minor concussion doubles epilepsy risk over 10 yrs • New AEDs are no more effective than old AEDs • They may be easier to use, but also cost 10-20x more

• Epilepsy in old people is a growth area and the largest proportion are in that age group • EEG is poorly underutilised • Recovery is possible in the long term