Recent Advances in the Diagnosis and Treatment of Epilepsy Salah Mesad, M.D.

Epilepsy & Seizures New onset seizures Established seizure disorder Questionable seizures Drug-resistant seizures Discontinuation anti-epileptic drugs (AEDs)

Epilepsy and Seizures Epilepsy: A seizure: a tendency toward recurrent seizures unprovoked by systemic or neurologic insults A seizure: the clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons

Seizures & Epilepsy Seizure: Single provoked or unprovoked episode Unprovoked seizure risk: 1/100 Epilepsy: Two or more unprovoked seizures 50 million people worldwide, 2 million in US Prevalence: 2.7-40/1000

Incidence (per 100,000 Person-Years) Epilepsy Incidence Male Female Total Incidence (per 100,000 Person-Years) Age (y)

Idiopathic/ cryptogenic Etiology of Seizures Idiopathic/ cryptogenic 65.5% Vascular 10.9% Congenital 8.0% Trauma 5.5% Neoplastic 4.1% Degenerative 3.5% Infection 2.5%

Classification of Seizures Seizures may be classified in a number of ways; by etiology, age of onset, pathological basis, and so on. The usual classification involves a combination of clinical and EEG features.

Classification of Seizures Partial Simple Complex Secondarily generalized Generalized Absence Atonic Clonic Tonic Tonic-clonic Myoclonic

Epidemiology of Seizures Generalized TC (23%) Complex Partial (36%) Simple Partial (14%) Unclassified (3%) Myoclonic (3%) Other Generalized (8%) Absence (6%)

Focal Seizures-Clinical

Diagnostic Approach History taking from the patient, family, caregivers and eyewitnesses Past treatments and diagnostic workups Family history Physical and neurological examination

Questions need to be answered Seizure or not? Focal onset? Evidence of CNS dysfunction? Identifiable precipitant? Seizure type? Syndrome? Studies? Start anti-epileptic drug (AED)?

Event/Seizure Types Absence Tonic-clonic Tonic Clonic Myoclonic Atonic Single Recurrent Nonepileptic Epileptic Syncope Migraine Psychogenic Toxic Cerebrovascular Metabolic Generalized Partial Absence Tonic-clonic Tonic Clonic Myoclonic Atonic Simple Complex Secondarily Generalized

Diagnostic Approach Initial tests Blood work EEG Head CT Brain MRI

EEG

EEG

Video-EEG Monitoring Continuous and simultaneous EEG and video monitoring Done mostly as an inpatient

Video-EEG Monitoring To confirm the diagnosis and to rule out other nonepileptic events Ultimately the goal is to try to record actual seizures to indentify and localize seizure onset(s) (esp. for drug resistant cases) AEDs might need to be reduced or stopped temporarily Sleep deprivation might be necessary Characterize epilepsy type Pre-surgical evaluation

Neuroimaging Routine screening CT MRI Surgical candidate PET SPECT MEG MRS fMRI

MRI

Mesial Temporal Sclerosis

Developmental Malformation

PET

SPECT

MEG

MRS

Non-Epileptic Events Physiological Psychological A patient can have both types of seizures Beware of pseudo-pseudo-seizures

Non-epileptic events Physiologic (other medical conditions) Referred to other medical specialist Psychological or pseudoseizures Referred to psychiatry and neuropsychologist who work with this type of stress-seizure Psychiatric medication, psychotherapy, education

Anti-epileptic drug treatment Bromides:1800’s Phenobarbital: 1912 Phenytoin: 1938 Primidone: 1954 Carbamazepine: 1974 Valproate: 1978 Ethosuximide (Zarontin) Benzodiazepines

Antiepileptic drugs Felbamate and Gabapentin: 1993 Lamotrigine: 1994 Topiramate: 1996 Tiagabine: 1997 Levetiracetam, Oxcarbazepine and Zonisamide: 2000 Pregabalin (Lyrica)

Anti-epileptic Drugs Lacosamide (Vimpat) Rufinamide (Banzel) Vigabatrin (Sabril)

Anti-epileptic Drugs Mechanisms of actions Side effects interactions

Mechanisms of Actions Enhancement GABAergic receptors Sodium channels blocking Decrease of glutamate release Decrease of GABA catabolism Decrease of GABA uptake Effects on Calcium cannels Carbonic anhydrase inhibition UNKNOWN

Epilepsy Treatment Establish the diagnosis Education Address psychosocial issues Lifestyle/non-medication treatments Medical treatments

Epilepsy medical treatment: principles Mono-therapy where possible Introduced slowly Education improves compliance If the first medication doesn’t work, substitute another If initial therapy is ineffective, refer for further assessment

Drugs for Generalized Epilepsy Depakote Lamictal Topamax Zonegran Keppra Rufinamide

Drugs for Partial Seizures Carbamazepine Oxcarbazepine Gabapentin Lamotrigine Leveitiracetam Phenytoin Valproate

Reason for drug failure Misdiagnosis such as Non-epileptic seizures, Cardiogenic, Migraine, etc. Incorrect drug for seizure type PGE v. Partial epilepsy Non-diagnosed brain lesion such as tumor Refractory epilepsy Inadequate dose and low levels Non-optimal scheduling timing of dose Excessive dose (e.g., sedation) Inappropriate combinations

Noncompliance & AED Failure Reasons for Noncompliance Forgetting individual doses (midday; bedtime) Lowering dose to reduce toxicity Fear of medication’s effects Denial of epilepsy Complicated dosing regimen Frequent seizures and postictal confusion Cost Memory and visual problems

Medical Intractability Seizures persists despite trial of several AEDs in various combinations at adequate and tolerated doses and levels over a period of time. Significantly and aversely affecting cognitive functions and quality of life.

The consequences of refractory epilepsy are numerous Seizure-related injuries Increased seizure severity Adverse effects with long-term AED use Depression and anxiety Cognitive and memory impairment Increased mortality and morbidity Impaired ability to obtain education, to work, drive, establish families, and develop and maintain social relations

Non-pharmacological Surgery Ketogenic Diet Experimental Drugs Focal resection hemispherectomy Callosotomy (palliative) Ketogenic Diet Experimental Drugs Brain Stimulation

Ketogenic Diet Low carb, high protein/fat Usually in children, for 2 years. Works best in children with generalized epilepsies (Lennox-Gastaut)

Ketogenic Diet Traditionally started gradually in the hospital after a 24-48 hour fast Families educated daily Ratio (fat: carbs and protein) 4:1 more strict 3:1 for infants, adolescents Calories 60-100% Fluids 85-100% Solid foods and/or formula Requires dietician support Strong family commitment

Pre-surgical Evaluation Video EEG monitoring to record several of patient’s typical seizures Neuroimaging Neuropsychological evaluation Additional tests depending on individual situation, such as neuro-ophthalmology

Pre-surgical Evaluation Neuropsychological Evaluation Pre-operative baseline Aid in localization Predicting risk of cognitive decline with surgery Psychological evaluation

Pre-surgical Evaluation Wada test (intracarotid amobarbital procedure; IAP) Language lateralization Memory lateralization prediction of postoperative decline

Epilepsy Surgery Intra-cranial EEG monitoring Depth electrodes Subdural electrodes Uni-or bilateral coverage

Types of Epilepsy Surgery Temporal Lobectomy Extratemporal Resections Hemispherectomy Corpus Callosotomy

Outcome after epilepsy surgery Anterior temporal lobectomy 70-80% seizure free Neocortical resection With lesion: 50-80% seizure free Without lesion: 30-50% seizure free Hemispherectomy Significant improvement Corpus Callosotomy Significant improvement for drop attacks

Complications of surgery Low rate of complications Infections Bleeding Anesthesia Function

Vagus Nerve Stimulator Computer attached to vagus in neck, delivers electricity to stop seizures. Reduces seizures 30-40%. NOT a cure. Well-tolerated and safe. Hoarseness during stimulation that improves.

Deep Brain Stimulation Trans-cranial Magnetic stimulation Intracranial stimulation Hippocampus Thalamus Cerebellum

Transcranial Magnetic Stimulation

Deep Brain Stimulation

Alternative Treatments Diets Supplements Herbs Cognitive-behavioral therapies Yoga Acupuncture