New Trends in Epilepsy

Management

Dr. V. Natarajan

Consultant Neurologist

Chennai

AVAILABLE OPTIONS

• Pharmacological

• Neurosurgical

• Stimulation techniques

• Ketogenic diet

NEWER AEDs: 2nd generation

• Levetiracetam• Oxcarbazepine• Lamotrigine• Topiramate• Gabapentin• Zonisamide• Vigabatrin• Felbamate• Pregabalin• Tiagabine

Problems of Newer AEDs

• Similar effectiveness to established AEDs in the treatment of partial seizures

• All AEDs have adverse effects

• Not appropriate for all seizure types

• Possible teratogenicity

• Limited data available for efficacy and safety

• Most used as adjunctive therapy

AEs with New AEDs

• Lamotrigine - not indicated for use in patients below the age of 16 years.▫ Rash is reported in 0.3% of adults and in 0.8% of

children

• Topiramate▫ Cases of secondary angle closure glaucoma

reported in pediatric and adult populations. If left untreated permanent vision loss, may occur.

• Levetiracetam▫ Cognitive and behavioral adverse events

• All newer AED have CNS side effects

Benefits of Extended-release AEDs

• Benefits of extended-release formulations include:

▫ Fewer fluctuations in blood levels and hence improved seizure control and tolerability

▫ Less frequent dosing

▫ Improved compliance

Managing Patients on ER Formulations

• Extended-release formulations of AEDs improve tolerability and enhance compliance

• Flexibility in dosing AEDs simplifies regimens for patients

• Initiation is simple• Switching from traditional formulations to

extended-release formulations can be done overnight

• A slightly higher total daily dose of the extended-release formulation is usually necessary in order to maintain serum AED levels

AEDs in the Pipeline

IN PHASE III TRIAL

• Valrocemide

• Biveracetam

• Milacemide

• Losigamone

• Ganaxalone

• Rufinamide

IN PHASE II TRIAL

• Seletracetam

• Isovaleramide

• Caraberstat

• Flurofelbamate

IMMUNO THERAPY

• Immunotherapy includes treatment with ACTH , CS, IVIG.

• Definite place in the therapy of a number of paediatric epilepsy syndromes – particularly epileptic encephalopathies

• Best response in Infantile Spasms

• EFNS Guidelines concluded that IVIG is effective in childhood refractory epilepsy

DIRECTIONS IN TREATMENT OF

MEDICALLY REFRACTORY EPILEPSY

• Non Pharmacologic treatment of Epilepsy▫ Resective Brain Surgery▫ Ketogenic Diet▫ Stimulators

Deep Brain Stimulation Vagus nerve Stimulation Trans Cranial Magnetic Stimulaion

• Future Trends▫ Genetic Based treatment of epilepsy

KETOGENIC DIET

• Based on starvation

• Diet high in fat and low in CHO;maintains Ketosis and Acidosis longer

• Re-emergence in recent years especially in children

Ketogenic Diet

• Main experience with children, especially with multiple seizure types

• Likely anti-seizure effect of ketosis (beta hydroxybutyrate), but other mechanisms also may be responsible for beneficial effects

• Low carbohydrate, adequate protein, high fat

• 50% with a <50% seizure reduction

• 30% with <90% reduction

• Side effects include kidney stones, weight loss, acidosis, dyslipidemia

Alternative Diets

• Modified Atkins diet

• 10 g/day carbohydrates to start, fats encouraged

• No protein, calorie, fluid restriction

• Low-glycemic index treatment

• 40-60 g/day low-glycemic carbohydrates

• Portions generally controlled

• Single report from Massachusetts General

Surgical Treatment

• Potentially curative

▫ Resection of epileptogenic region (“focus”) avoiding significant new neurologic deficit

• Palliative

▫ Partial resection of epileptogenic region

▫ Disconnection procedure to prevent seizure spread

Callosotomy

Multiple subpial transections

TREATMENT OPTIONS

• Focal seizures - Resective surgery

• Resection is an option only when EPILEPTOGENIC ZONE can be identified

• EZ - The brain volume necessary and sufficient to initiate seizures and the removal of which is necessary for abolition of seizures

• Target – identification of this tissue

EZ IDENTIFICATION

• Predominantly noninvasive, localizing tests

• No single test can directly and unequivocally define the EZ

• Combination and integration of several individual tests required to formulate a hypothesis on the location and extent of the EZ

• The tests also need to assess the possible overlap of the ELOQUENT cortex

IMAGING MODALITIES

• MRI – most sensitive and specific structural neuroimaging procedure for persons with partial or localisation related epilepsy – brain tumour, AVM, malformations of cortical development, MTS

• The methodology used is important in determining the diagnostic yield

• MRI volumetry

IMAGING MODALITIES

• SPECT – Inter Ictal has a low sensitivity in showing regions of hyperperfusion concordant with epileptogenic brain tissue

• Ictal SPECT is useful to identify a region of focal hyperperfusion in TLE

• FDG – PET is very useful in revealing a focal area of hypometabolism in TLE

• Newer PET tracers may identify epileptogeniccortex in extra temporal epilepsy or TS

IMAGING MODALITIES

MAGNETO ENCEPHALOGRAPHY [MEG]

• Non invasive neuro imaging tool – helps localisation of inter ictal discharges and identify brain regions concerned with specific activity

• Attempts to localise onset of epileptic activity and plan resection of the epileptogenic focus without compromising functional abilities

IMAGING MODALITIES

• f MRI – can lateralise and to some extent localise language function reliably and other functions with evolving protocols

• Replacing WADA test

• EEG – f MRI simultaneously records EEG along with MRI and indicates the haemodynamiccorrelates of spontaneous brain activity in particular interictal discharges to provide a clue to the location of irritative and seizure onset zones

STIMULATION TECHNIQUES

• VNS – Only licensed method

• DBS – Cerebellum, CN, Thalamus, Hippocampus

• TMS

VNS

• Drug resistant focal epilepsy and secondary generalized

• Well tolerated, improvement over 18-24 months

• At least one AED needed

VNS DEVICE

• Battery powered electrical pulse generator

• Stimulating electrodes wrapped around the trunk of L VN

• Programmed to stimulate at varying frequencies

Vagus Nerve Stimulator

• Intermittent programmed electrical stimulation of left vagus nerve

• Option of magnet activated stimulation

• Adverse effects local, related to stimulus (hoarseness, throat discomfort, dyspnea)

• Mechanism unknown

• Clinical trials show that 35% of patients have a 50% reduction in seizure frequency and 20% experience a 75% reduction after 18 months of therapy.

• May improve mood and allow AED reduction

• FDA approved for refractory partial onset seizures and refractory depression

Vagus Nerve Stimulator

Responsive Neurostimulator System

• The RNS is a flat device about the size of a half-dollar. It is implanted just under the scalp and connected to insulated wires with small electrodes at the end. These leads are implanted in the patient's brain or on the brain surface near where seizures are believed to start. When a seizure is detected by the RNS, a brief, mild electrical shock is delivered to suppress it.

NeuroPace Responsive Stimulator

• TRANSCRANIAL MAGNETIC STIMULATION• Extracranial form of neurostimulation• Transmits magnetic fields via a coil over the

scalp• Influences both excitatory and inhibitory

functions of the cerebral cortex• TRIGEMINAL NERVE STIMULATION [TNS]• Involves transcutaneous stimulation of the infra

orbital and supra orbital branches of the Trigeminal nerve

• DEEP BRAIN STIMULATION [DBS]

• The precise mechanism of action and the ideal candidates are unidentified yet

• Thalamus , Sub Thalamic Nucleus and the IctalOnset Zone itself

• CM thalamic and AN thalamic DBS and Hippocampal stimulation done

• Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy [SANTE] conducted in multiple centres and was promising

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