First Seizures

· This addresses patients who, on first assessment, do not appear to have a clear precipitant for their seizure

· For general workup of all seizures see Seizures

Epidemiology and Prognosis

• NEJM study:

o Note that most patients (~75%) were started on medication after the first seizure

o Overall risk of a second seizure was 36% in this setting.

o Remote symptomatic seizure had a much higher risk of recurrence than idiopathic seizures (64% vs 87%)

• Other studies

o Show rate closer to 45-50% (populations with less initial medication prescription)

o FIRST trial – 42% in untreated (see below)

Classification

Seizure type

	Clinical	Clinical +EEG	Clinical+EEG+MRI
Classified	47%	77%	81%
Generalized	8%	23%	23%
Partial	39%	54%	58%
Unclassified	53%	23% (-30%)	19%

· Note that first EEG yield is higher in children than adults (39% vs 59%)

Investigations

• See classification (above) for overall success of investigations in classification.

EEG

Data from King et al. 1998:

· Initial EEG epileptiform in 43% of patients

· If non-diagnostic EEG and referred for sleep-deprive EEG – 35% epileptiform

· Total EEG/sleep-deprived EEG – 61% epileptiform

· Timing – early (<24hr) 51% epileptiform vs late (>24hr) 34% epileptiform

§ Suggests greater pick-up rate with early EEG, however other studies have not found such a similar difference.

Predicting recurrence:

· Very little data

· Focal abnormalities seem to have higher risk of recurrence than generalised

· Remote symptomatic seizures with abnormal EEG hold very high risk of recurrence.

Imaging

· Yield for epileptogenic lesion:

Total	14%
Patients presumed focal	17%
Patients presumed generalized	2%
Patients initially unclassified	18%

RMH MRI study 2013

• 764 patients who had MRI as part of first seizure clinic between 2000 and 2009

• Abnormal scan – 45%

• Potentially epileptogenic lesion identified – 23%

• Types of epileptogenic lesions

o Gliosis/encephalomalacia (48%) – mainly stroke, trauma or previous surgery

o Developmental abnormality (15%)

o Vascular anomaly (15%)

o Tumour (15%) – (57% of which were meningioma’s, 23% were glioma’s)

o Mesial temporal sclerosis (8%)

• Yield (i.e. epileptogenic lesion found) according to syndrome:

o Focal - 56%

o IGE – 8%

o Unclassified – 2%

• Reference: Hakami et al. 2013 Neurology 81: 920

Treatment

Should treatment be started after first seizure?

• FIRST trial

o Randomized within one week of first GTCS

o Immediate treatment – 24% relapse at 2yr

o Delayed treatment – 42% relapse at 2yr

- Delayed treatment patients were started on medication after relapse

o At end of 3 years similar numbers had achieved ‘seizure freedom’ with either strategy

- One year seizure freedom (87% vs 83%, immediate v delayed)

- Two year seizure freedom (60% vs 59%, immediate v delayed)

• MESS trial

o Patients for whom there was uncertainty about treatment

o Immediate treatment – 32% relapse at 2yrs

o Delayed treatment – 39% relapse at 2yrs

What medication?

Evidence for treatment options

Combined focal and generalised

• LaLiMo Trial (JNNP 2012)

o 400 patients randomised to LTG 200mg or LEV 2000mg

o ~50% focal, ~35% generalised, ~15% undefinable

o Assessed at 6 weeks and 26 weeks

o No significant difference in outcomes

o Trend towards slightly better seizure control with LEV

o Trend towards better tolerability and retention rate with LTG

Focal

• SANAD trials – Arm A – focal seizures

o Recruited patients for whom carbamazepine would have been deemed the best treatment and randomised to alternatives.

o Two major outcomes

- Time to treatment failure (i.e. stopping drug or adding other drugs)

- Achievement of 12months seizure freedom

o In general terms

- Carbamazepine had the best seizure control with Lamotrigine a close second.

- All the other medications had a better side effect profile – except for topiramate

- Lamotrigine had the lowest rate of overall treatment failure.

Generalised

• SANAD arm B – generalised seizures

o Patients whom were deemed most suitable for valproate were randomised to other medications

o Outcomes as for SANAD A above.

o In general terms:

- Lamotrigine has slightly better side effect profile (3-5% less failure) but much worse seizure control (15% less) than valproate

- Topiramate has significantly worse side effects (10% more failure) and slightly worse seizure control (~5%) than valproate.

SANAD at 4 years:

	Adverse effect failure %		Inadequate control %		Still on drug %
	Focal	Gen	Focal	Gen	Focal	Gen
CBZ	31		18		50
GAB	20		39		39
LTG	20	14	24	31	54	50
TPX	31	29	25	21	42	49
OXC	26		24		49
VPA		21		16		60

	Tonic-Clonic	Partial	Absence	Atypical*
First-line	Valproic acid Lamotrigine (child bearing women)	Carbamazepine Phenytoin Lamotrigine Valproic acid	Valproic acid Ethosuximide	Valproic acid
Alternatives	Phenytoin Carbamazepine Topiramate Zonisamide Felbamate Primidone Phenobarbital	Topiramate Levetriacetam Tiagabine Zonisamide Gabapentin Primidone Phenobarbital	Lamotrigine Clonazepam	Lamotrigine Topiramate Clonazepam Felbamate
Avoid	Ethosuximide Tigabine Vigabatrin		Phenytoin Carbamazepine Tigabine Vigabatrin