Refractory epilepsy management stategies

Dr Parag Moon Senior Resident

Dept of NeurologyGMC Kota

Definition In investigational studies, criteria of

refractoriness include: (1) absence of response to 2 AEDs tolerated at

reasonable doses; (2) minimum frequency of seizures (e.g. 1

seizure per month) to be considered refractory or the duration of minimum remission (e.g. 6– 12 months) to be qualified as nonrefractory,

(3) duration of 1 year to 1 decade of noncontrolled epilepsy

Flexible scale of refractoriness potential (no seizure freedom with AEDs

taken less than 1 year and predictive factors for refractoriness)

probable (no seizure freedom more than 1 year with at least 2 AEDs)

definitely refractory(catastrophic epilepsy or no freedom of seizure for more than 1 year after 5 years of treatment with at least 3 AEDs)

Predictive Factors of Refractoriness1. Epileptic syndromeOnly 13% with idiopathic generalized epilepsy,

and no case with idiopathic partial epilepsy, were refractory.

Typical refractory generalized epilepsy of pediatric ages are the Ohtahara syndrome, early myoclonic encephalopathy (neonatal period), West syndrome, Dravet syndrome (infancy) and Lennox-Gastaut syndrome (early childhood) .

In focal epilepsy, hippocampal sclerosis, cortical dysplasia and hemorrhage are associated with refractoriness .

2. Localization of the epileptogenic zoneThe temporal lobe ,striate cortex, namely the

fourth layer .3.Response to AEDs-Absence of seizure

freedom when 2 past AEDs proved inefficient4.Younger Age of onset5.Seizure frequency at epilepsy onset

6. Electroencephalography -Quantity of interictal spikes is predictive of severity in temporal lobe epilepsy

Oligospikers-less than 1 spike per hour less severe epilepsy

Association between multifocal spikes and intractability

Frequency of refractory epilepsy varies from 10 to 37.5%

Diagnosis of Refractory EpilepsyExclude false refractoriness related to

nonepileptic seizures, inadequate AEDs, noncompliance and seizure-precipitating factors

Defined as inadequate control of seizures despite at least 2 potentially effective AEDs (mono- or polytherapy) taken in tolerable doses

Treatment of Refractory EpilepsyNon pharmacologicClassic ketogenic diet -high fat content and

low carbohydrate ContentThe medium chain triglyceride (MCT) diet Modified Atkins diet (MAD)Low glycemic index treatment (LGIT).

Classic ketogenic diet is a high fat and low carbohydrate diet that uses long chain fatty acids (LCFAs) as its main source of fat.

Patient must consume 3–4 grams of fat for every 1 gram of carbohydrate plus protein

In MCT more carbohydrates and proteins can be consumed for every gram of fat and is more ketogenic

No limit on the amount of protein consumed or the total number of calories per day in MAD

Typical MAD uses a ratio of 1 gram of fat for every gram of carbohydrate plus protein, is less restrictive than the other two high fat diets.

LGIT restricts carbohydrate intake to food items with a glycemic index of less than 50 at 40–60 grams per day, in order to prevent large fluctuations in blood glucose concentrations, which are thought to exacerbate seizures.

15.6%–15.8% of patients on the diet can achieve seizure freedom whilst 33.0%–55.8% of the patients can have a >50% reduction in number of seizures

West syndrome (infantile spasms)-ketogenic diet is used as a first line agent.

Also recommended for patients suffering from glucose transporter defects and pyruvate dehydrogenase deficiency,

Effects of a ketogenic diet can be seen within a few days and is cost effective

Side effects of dietary treatments are constipation, acidosis, temporary hypercholesterolemia, kidney stones and hunger, Growth restriction

Contraindicated in pyruvate decarboxylase deficiency, primary carnitine deficiency, fatty acid oxidation abnormalities, the porphyrias and some mitochondrial disorders

Herbal medicine Cannabinoids have the largest body of

evidence supporting their use as anticonvulsant.

Approved in canada and licensed in 14 states of America

Other -kava (Piper methysticum) and mistletoe (Viscum sp)

Surgical management Candidates for Epilepsy SurgeryIdeally have a single epileptogenic focus in a

non-eloquent cortical regionIntractable epilepsyPresent for a substantial duration (usually

years)Refractory to medical therapySubstantially impairing quality of lifeBenefit of surgery should outweigh the risks

Evaluation of Candidates for Epilepsy Surgery

Localization of seizures by interictal EEGLocalization by brain imaging-MRI; PET

scanningLocalization by video-EEG monitoring of

seizures ( may combine with ictal SPECT)Localization by neuropsychological testingOther methods-Depth electrodes,Cortical

grids or strips,Nuclear magnetic resonance scans,Magnetoencephalography

Types of Resective Epilepsy Surgery

Temporal lobectomyExtratemporal resections (lobar: frontal,

occipital)Corpus CallosotomyHemispherectomyMultiple subpial transections

68% of the patient who received temporal lobectomies experienced seizure remission for 2 years.

Side effects – period of disability, infection, transient endocrine abnormalities, transient dysphoria, depression,occasionally mania

Permanent neurological and neuropsychological complications

Possibility to create new lesions which may become epileptogenic

Vagus Nerve Stimulation (VNS)

Approved by FDA in July 1997Patients with intractable epilepsy ≥ 12 yo

• Intermittent electrical stimulation is delivered to the left vagus nerve, which has ascending fibers with widespread connections to the limbic, autonomic and reticular brain regions

Proposed Mechanisms of Action for VNS

Desynchronization of EEGSuppression of spikesBlock ictal rhythmic build-up in a seizureRelease of GABA and GlycineEffects on limbic and brainstem systemsIncreased thalamic blood flow

Benefits of Vagus Nerve Stimulation

Median seizure reduction of 24.5%–28.0% in the group receiving high level VNS compared to just 6.1%–15.0% in patients receiving low level VNS

Effect increases over timeSeizure severity decreasedImproved level of alertness (medication may be

decreased)Few adverse effects-Hoarseness, sleep

apnoea,infection (rare)Batteries require replacement every ~ 10 yrs

Deep brain stimulation DBS involves electrical stimulation of specific

subcortical nuclei, which have widespread neural connections.

Anterior nucleus of the thalamus is often the target of DBS.

Centromedian nucleus is also a potential location for DBS

Complications -Infection, hemorrhage and stimulation-induced seizures

Impaired memory and higher levels of depression

Responsive neurostimulation (RNS)

Does not deliver electrical stimulation throughout the day.

RNS device is composed of a combined recorder and stimulator device

Detects clinically relevant epileptiform discharges and delivers an appropriate electrical stimuli in response

Reduction in seizure frequency of 37.9% in the treatment arm compared to 17.3% in the control group

Other modalities available-repetitive transcranial magnetic stimulation (rTMS).

Based on principles of electromagnetic induction, where small intracranial electric currents are generated by a strong fluctuating extracranial magnetic field.

Risk of precipitating seizures

Thanks

References Pharmacotherapeutic and Non-Pharmacological Options

for Refractory and Difficult-to-Treat Seizures ;James W. Mitchell et al ; Journal of Central Nervous System Disease 2012:4 ;105–115

Refractory Epilepsy: A Clinically Oriented Review;Pedro Beleza; Eur Neurol 2009;62:65–71

Schuele SU, Luders HO: Intractable epilepsy: management and therapeutic alternatives. Lancet Neurol 2008; 7: 514–524

Treatment of refractory epilepsy: Barbara Oslon: Adv Stud Med 2005:5:470-473