Epilepsy

1. Epilepsy Southern Neurology

2. Classification of seizures 1 • Partial – arises from an epileptic focus , that is, a localised region of the cerebral cortex in which the excessive discharge of neurons occurs. • Partial seizures may be simple (consciousness not impaired) – motor symptoms, somatosensory symptoms, autonomic or psychic symptoms; complex (with impairment of consciousness) – may or may not have reactive or stereotyped automatisms; or secondarily generalised.

3. Classification of seizures 2 • Generalised – simultaneous involvement of the whole cortex at the onset of the seizure. That is, bilaterally symmetric and without focal onset. • Subtypes include – absences and atypical absences; myoclonic seizures, clonic seizures; tonic seizures; and atonic seizures

4. Epilepsy syndromes 1 • Partial epilepsy syndromes include – idiopathic forms eg benign childhood epilepsy with centro-temporal spikes; childhood epilepsy with occipital paroxysms and primary reading epilepsy; symptomatic forms eg temporal, frontal, parietal and occipital lobe epilepsies; and cryptogenic. (Cryptogenic refers to idiopathic partial but cause obscure).

5. Epilepsy syndromes 2 • Generalised subtypes include – benign neonatal convulsions, childhood absence, juvenile absence, juvenile myoclonic, epilepsy with grand mal seizures on awakening; reflex seizures • Generalised epilepsies can also be cryptogenic or secondary (symptomatic) eg West syndrome and Lennox-Gastaut syndrome.

6. Epidemiology of epilepsy • Incidence of up to 100 per 100,000 population/year, while cumulative (life-time) incidence of a non-febrile seizure is 2-5%. • Prevalence of active epilepsy 4-10/1000. • More than 50% of patients will experience a recurrence after first seizure. • 60-70% of patients taking anti-epileptic medication will eventually become seizure free (approx. 40% adults will experience relapse after 2-years seizure freedom vs 20% of children).

7. Clinical example • A 6-year old girl has episodic staring spells of sudden onset which are typically characterized by a statue-like facial expression, cessation of ongoing activity, unresponsiveness, eye-blinking and lip-smacking; the spell stops abruptly and the child has no memory of the event. EEG shows 3 Hz spike-and-wave activity.

8. Clinical example (continued) • Clinical diagnosis – childhood absence epilepsy. • Epidemiology – incidence 6-8/100,00 children aged < 15 years; 10-12% of children with epilepsy ages 5-14 years; F>M (3:2); family history in 15-44%; 30-40% after age 7 years develop generalised tonic-clonic seizures; spontaneous remission in approximately 50% (no GTCS 75% vs GTCS 35% seizure free). • Treatment – ethosuximide age < 6 years; valproate age > 6 years or ethosuximide failure. Tegretol, tiagabine and vigabatrin may exacerbate absence seizures.

11. Partial seizures of frontal and temporal origin • >50% of partial seizures originate from the temporal lobe. • Auras (or simple partial seizures) occur in approximately 80% of patients with TLE. They may be useful in localisation but not necessarily reliable as ictal discharges may begin in a clinically silent area but manifest as auras after spreading to adjacent regions. • An aura typically lasts shorter duration than period of altered consciousness (or complex partial seizure) which may follow the aura.

12. Partial seizures (continued) • Auras can be psychic/cognitive phenomena (eg déjà vu jamais vu, dreamy state, fear, pleasure, altered sense of reality, mind-body dissociation or depersonalisation), speech phenomena (eg dysphasia, speech arrest), illusions and hallucinations (eg distortion of size-macropsia/micropsia, shape, colour, distance, olfactory and auditory hallucinations), and autonomic phenomena (eg nausea, irregular cardio-respiratory patterns, GI hypermotility, chest discomfort).

13. Partial seizures (continued) • Automatisms occur in 50-100% of temporal lobe seizures and may occur in the ictal or post-ictal phases. They typically appear during impaired consciousness. They may be stereotyped (eg lip smacking and chewing as seen with mesial temporal involvement or tonic/dystonic as seen with frontal lobe seizures) or reactive to environmental stimuli (eg fumbling with clothing, touching objects, looking around). • Post-ictal confusion, lethargy and/or aphasia may occur and often can last up to 30 minutes

16. EEG in epilepsy • An EEG cannot make or refute the diagnosis. • 35% of patients with epilepsy show interictal epileptiform activity in all routine waking EEGs, 15% do not show abnormalities even after multiple EEGs and 50% show epileptiform activity in some but not all recordings. • An EEG is of little help in predicting a subsequent relapse although in children, an active interictal EEG probably indicates an increased risk of recurrence.

17. First-line treatment options –which drugs? • Carbamazepine • Valproate • Phenytoin • All three are effective in the treatment of primary and secondarily generalised seizures. In patients with mixed seizure types eg myoclonic or absence, valproate is the drug of choice.

18. First-line treatment options- for how long? • Minimum 2 years; range 2-5 years seizure-freedom. • Studies have shown that about 70-80% of all patients with epilepsy will eventually become seizure-free and about half will successfully withdraw their medication.

19. What rate of dose increments 1 • The usual recommendation is to slowly adjust the drug dosage. For phenytoin and carbamazepine, plasma concentrations may help guide dose increments. • Typical doses for phenytoin –300-400 mg once daily, carbamazepine – 200-600 mg twice daily, valproate 500-1000 mg twice daily.

20. What rate of dose increments 2? • The commonest cause of failure of carbamazepine therapy is non-compliance as a result of unpleasant adverse effects (dizziness, drowsiness, nausea, vomiting). • It is reasonable to start slow (eg 100-200 mg twice daily) and increase by 100-200 mg/day every 4-7 days until a final desired dose (ranging from 600-1600 mg/day) is obtained. Final dose depends in part on type and severity of epilepsy

21. What constitutes optimal treatment outcome • Long-term seizure freedom is the ideal treatment outcome.25-30% of patients will continue to experience seizures despite optimal therapy. • The principles of treatment are to prefer monotherapy, and to titrate the dose of the primary drug chosen until seizure freedom is achieved in the absence of significant toxicity. • A major problem may be inadequate dosing due to side-effects.

22. Discontinuation of treatment • If seizure freedom has been achieved for 2-5 years, treatment discontinuation is an option. • Seizure recurrence in adulthood is highest for JME (80% recurrence) vs 40-50% for other subtypes. • 75% of relapses occur within first 12 months, and at least half of those relapses occur in the first three months. • No driving during tapering. Tapering should occur over 6-10 weeks for all drugs except barbiturates and benzodiazepines, which probably should be tapered over 10-16 weeks.

23. When is a decision made to change from a first-line agent ? • If the first drug fails, particular attention should be paid as to whether the diagnosis is correct, whether there are triggering factors (eg sleep deprivation, alcohol), and whether compliance is an issue. • Assuming these are satisfactory, the recommended approach is to commence another appropriate drug and gradually withdraw the initial agent. If the second agent also fails, then combination therapy is recommended. • If seizure control is achieved, consider gradual withdrawal of first agent.

24. What factors would determine choice of adjunct therapy? • Primary or generalised seizure disorder – newer agents proven effective are lamotrigine and topiramate. • Secondary or partial seizure disorder – newer agents proven effective are oxcarbazepine, lamotrigine, topiramate, gabapentin, tiagabine, vigabatrin, levetiracetam, pregabalin.

25. Characteristics making second-line agent the preferred option • Efficacy – seizures are reduced by 25-50% in 50% of patients for newer AEDs. Partial seizures are usually less effectively reduced in frequency than generalised tonic-clonic seizures. • Tolerability • Once or twice daily dosing • No drug interactions – no significant hepatic cytochrome P450 interactions, no adverse additive side-effects with concurrent medications • Pregnancy/breast-feeding

26. How have the newer AEDs influenced the management of epilepsy • Patients have more treatment options than previous. Studies would indicate that seizure control should be better. • Patients are more likely to be on two newer AEDS as combination rather than mix of old and new. • ? Patients are more likely to be offered triple therapy than previous.

27. Case history • 55 y.o. male. • Presents after first complex partial and/or secondarily generalised seizure. Patient drove into the back of another vehicle. Failed to stop an drove home. • Woke up in car outside his house and found police attending scene. Accident occurred 2 km from his house.

28. Case history (continued) • CT brain normal, EEG –left temporal focus, MRI left temporal atrophy. • Commenced tegretol 200 mg bd but ongoing seizures and not tolerated well. Changed to epilim 500 mg bd. Further CPS. Depressed as both unable and too afraid to drive again. Lamotrigine added – reports dizziness, drowsiness, diplopia. Still having CPS. Wants complete seizure freedom. • Changed to topiramate – no better. Changed to trileptal –some improvement. Referred for surgical consideration.

29. Carbamazepine (tegretol) • First synthesized in 1953 as part of a programme investigating analogues of chlorpromazine. • In an early study (Rodin et al 1974), carbamazepine or placebo was administered to 37 chronically hospitalized patients with intractable epilepsy and 44% of patients given carbamazepine became seizure-free, 55% had reduced ‘grand mal’ seizures and 83% had reduced ‘psychomotor’ attacks. • Comparison studies in the 1970 and 80s with phenytoin showed similar efficacy (up to 80% of patients with newly diagnosed epilepsy seizure free)

30. Carbamazepine (continued) • Skin rashes occur in approximately 5% of patients.. If an erythematous skin rash appears, treatment should probably be stopped. • GIT –nausea, vomiting, diarrhoea (esp children 9-14%). • Neurological effects – nausea, dizziness, vertigo, diplopia, headache, ataxia. Neuropsychological effects – impaired memory, cognition and visual information processing (?less if serum fluctuations are minimised). • Neutropenia – seen in 10-20% and usually transient. In 2%, it is more long-standing but may respond to dosage reduction. • Water intoxication – usually asymptomatic. SIADH is seen in –2% of patients.