Refractory epilepsy

1. Refractory epilepsy management stategies Dr Parag Moon Senior Resident Dept of Neurology GMC Kota

2. 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

3. 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 )

4. Predictive Factors of Refractoriness Epileptic syndrome O nly 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 .

5. 2. Localization of the epileptogenic zone The temporal lobe ,striate cortex, namely the fourth layer . 3.Response to AEDs - Absence of seizure freedom when 2 past AEDs proved inefficient 4.Younger Age of onset 5.Seizure frequency at epilepsy onset

6. 6. Electroencephalography - Q uantity of interictal spikes is predictive of severity in temporal lobe epilepsy Oligospikers -less than 1 spike per hour less severe epilepsy A ssociation between multifocal spikes and intractability

7. Frequency of refractory epilepsy varies from 10 to 37.5%

8. Diagnosis of Refractory Epilepsy Exclude 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

9. Treatment of Refractory Epilepsy Non pharmacologic C lassic ketogenic diet -high fat content and low carbohydrate Content The medium chain triglyceride ( MCT ) diet Modified Atkins diet ( MAD ) L ow glycemic index treatment ( LGIT ).

10. 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

11. 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.

12. 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,

13. 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

14. 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)

15. Surgical management Candidates for Epilepsy Surgery Ideally have a single epileptogenic focus in a non-eloquent cortical region Intractable epilepsy Present for a substantial duration (usually years) Refractory to medical therapy Substantially impairing quality of life Benefit of surgery should outweigh the risks

16. Evaluation of Candidates for Epilepsy Surgery Localization of seizures by interictal EEG Localization by brain imaging- MRI; PET scanning Localization by video-EEG monitoring of seizures ( may combine with ictal SPECT ) Localization by neuropsychological testing Other methods- Depth electrodes,Cortical grids or strips,Nuclear magnetic resonance scans,Magnetoencephalography

17. Types of Resective Epilepsy Surgery Temporal lobectomy Extratemporal resections ( lobar: frontal , occipital) Corpus Callosotomy Hemispherectomy Multiple subpial transections

18. 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

19. Vagus Nerve Stimulation (VNS) Approved by FDA in July 1997 Patients 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

20. Proposed Mechanisms of Action for VNS Desynchronization of EEG Suppression of spikes Block ictal rhythmic build-up in a seizure Release of GABA and Glycine Effects on limbic and brainstem systems Increased thalamic blood flow

21. 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 time Seizure severity decreased Improved level of alertness (medication may be decreased ) Few adverse effects-Hoarseness, sleep apnoea,infection (rare) Batteries require replacement every ~ 10 yrs

22. 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

23. Complications - Infection, hemorrhage and stimulation-induced seizures Impaired memory and higher levels of depression

24. 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

25. 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

26. Thanks

27. 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