Associate Professor of neurology and consultant neurologist Epilepsy Dr. Suhail Al-Shammari Associate Professor of neurology and consultant neurologist

Epilepsy: Objectives To provide definition of epilepsy-ILAE Explain classification of epilepsy, semiology and differential diagnosis of epilepsy Describe epileptic syndromes Evaluation and diagnosis Treatment

Classification of Epilepsy The International League Against Epilepsy (ILAE) have classified epileptic seizures into groups using clinical data and electroencephalography (EEG) evidence They have also produced a classification of epilepsy syndromes 7 7 7 7 7 7 7 5 5 5 5 7

Practical definitions: Seizure Is a transient behavioral, somatosensory, motor, or visual symptom or sign and caused by abnormally excessive, synchronous neuronal activity in the brain Provoked : trauma, brain hemorrhage, metabolic dyscrasias or drug exposure Spontaneous Some patients may have recurrent provoked seizures without having epilepsy

Practical definitions: Epilepsy-ILAE-2014 A disease with either recurrent unprovoked seizures : 2 or more seizures occurring at least 24 hours apart A single seizure accompanied by evidence of heightened risk for future seizures exist Diagnosis of epilepsy syndrome Seizure type and epilepsy syndrome diagnosis: Description of seizure behavior EEG pattern Aided by neuroimaging, and genetics

Incidence and Prevalence Incidence: 50 - 120 per 100 000 per year Prevalence: 5 - 8 per 1000 3 - 5% of the population will experience at least one seizure in their lifetime Greatest risk at extremes of life Nearly 75% of first seizures are in those under the age of 20 2 2 2 2 2 2 2 2 2 2 2 2

Incidence of Seizures

First Time Seizure: Five-Step Approach Ictal semiology Is it really a seizure? Is it the first seizure? Determine whether treatment is needed What agents are appropriate?

Classification of Epilepsy: Causation Idiopathic epilepsy: is not associated with an identifiable cause often presumed genetic Cryptogenic: unknown, but with a likely causative pathology has not yet been identified Symptomatic epilepsy: The etiology is known and the brain is disordered or diseased before or between seizure episodes . e.g. a tumour, a stroke, traumatic brain injury, developmental abnormality, metabolic abnormality etc. 4 4 4 4 4 4 4 4 4 4 4 4

Epilepsy - ILAE Classification Generalised Seizures: Absence seizures e.g. petit mal Atypical absence Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures 6 6 6 6 6 6 6 7 7 7 7 6

Epilepsy - ILAE Classification Partial Seizures (seizures beginning focally) Simple - these may have motor features, sensory symptoms etc but consciousness is not impaired Complex - at some point consciousness is impaired and the seizure may become generalised 5 5 5 5 5 5 5 6 6 6 6 5

First Time Seizure: Five-Step Approach Ictal semiology Is it really a seizure? Is it the first seizure? Determine whether treatment is needed What agents are appropriate?

Ictal Semiology Generalized tonic-clonic seizures Most easily recognized Most frequently leads to emergency consultations Eye witness account often unreliable Usually lasts for about 1-3 minutes

Generalized tonic-clonic seizures (GTCS): Phases Partial seizure: Secondary generalization The patient may have a recollection of the aura No recollection of aura, GTCS of generalized onset or develop from complex partial seizure Onset of generalization: Heralded by a forced head movement to one side (versive) or by brief vocalization Pretonic clonic phase: Generalization begins with irregular, asymmetric clonic jerking of the extremities

Generalized tonic-clonic seizures (GTCS): Phases Tonic phase: Generalized and sustained contraction of all the muscles in the body Clonic phase: Slower muscle jerking, decreases in frequency before stopping Postictal state: The patient lies limp in deep sleep After several minutes awakens confused and may have headache and muscle pain

Temporal lobe Seizure - Generalization

Gelastic Seizure

Generalized Seizures: Absence Onset in childhood or adolescence Typical Absence: Last for few seconds with abrupt onset and termination Characterized by unresponsiveness, a fixed blank stare, eye fluttering and facial twitching Increased or decreases in postural tone Brief clonic jerks Automatism The patient may or may not be aware of the attack Resume pre-ictal activity as soon as seizure is over

Absence seizures

Generalized Seizures: Myoclonic Myoclonus: Sudden involuntary brief jerk of a muscle or a group of muscles Tends to occur in children, may also begin in adolescents or young adults in juvenile myoclonic epilepsy

Generalized Myoclonic Seizure

Generalized Tonic Seizure

Generalized Seizures: Atonic Sudden drop attacks: The patient suddenly loses tone and falls to the ground Associated with: Mental retardation Lennox-Gastaut syndrome

Partial Seizures Begins in focal area of the brain The most common seizure type in adults Produces vast array of manifestation: Motor Sensory Perceptual Behavioral

Simple Partial seizure (SPZ): Motor Arises from motor cortex Forced head deviation to one side Speech arrest or vocalization Stereotyped limb or facial movements Twitching or jerking or coordinated almost purposeful appearing movements Jacksonian marsh: Sequential spread of the seizure into the ipsilateralface, arm and leg occurs over seconds Todd’s paralysis: Muscle weakness persists for several minutes-hours

Simple Partial seizure: Sensory May affect any sensory modality Visual: Seeing spots, stars, bright light Auditory: ringing, buzzing, musical sounds Somesthetic: tingling, numbness, electrical sensation Olfactory: burning rubber. Other foul odors Gustatory: acidic. Bitter, sweet taste Vestibular: vertigo Epigastric: sensation of rising in abdomen, descending a rollercoaster, butterflies in the stomach Primary sensory cortex: unformed and primitive Higher level association/mesial temporal: detailed

Simple Partial seizure: Behavioral and Psychic Produces a wide variety of psychic or behavioral phenomena Déjà vu: the sensation of visual familiarity Déjà vu entendu: auditory familiarity Jamais vu/ Jamais entendu: sense of unfamiliarity Temporal lobe: a dreamlike, sense of watching themselves (autoscopy) Depersonalization, fear, pleasure, religious ecstasy and forced thinking

Complex Partial seizure (CPZ): Partial seizures characterized by impairment of consciousness Frequently arise from SPS and may progress to GTCS Often accompanied by automatic repetitive stereotyped behaviors: Temporal: simple Lip smacking, chewing, swallowing, grasping, fumbling Frontal: More complex: orbitofrontal Bicycling, pelvic thrusting

Frontal lobe seizure

Epileptic Syndromes

Lennox-Gastaut Syndrome Occurs in children Multiple seizure types: Generalized tonic clonic Atypical absence Atonic EEG: slow spike and wave discharges Impaired cognitive function Associated with CNS disease Poor prognosis

Juvenile Myoclonic Epilepsy - An example of an epilepsy syndrome 3 - 11% of all patients with epilepsy onset between 6 and 22 years characterised by myoclonic jerks, worst in the morning generalised tonic-clonic seizures, mainly in the morning 40% also have absence attacks 8 8 8 8 8 8 8 8 8 8 8 8

Differential Diagnosis of Epilepsy Syncope - postural, cardiac etc Non - epileptic or psychogenic attacks Migraine: history of headache, aura develop over minutes Transient ischemic attacks; risk factors, maximum, negative symptoms at onset Sleep disorders Metabolic disorders e.g. hypoglycaemia Narcolepsy 9 9 9 9 9 9 9 9 9 9 9 9

Syncope vs Seizures Syncope Seizure upright posture any posture pallor common gradual onset injury rare incontinence rare rapid recovery precipitants common Seizure any posture pallor uncommon sudden onset injury quite common incontinence common slow recovery precipitants rare 10 10 10 10 10 10 10 11 11 11 11 10

Diagnostically Relevant Factors Age Sex Social history Past medical history including head injury, birth trauma and febrile convulsions Past psychiatric history Alcohol and drug use Family history 31 31 31 10 10 10 10

Determining Seizure Etiology History From patient From witness Laboratory studies Neuroimaging Electroencephalography (EEG)

History from the Patient Frequency of attacks Circumstances and trigger factors Symptoms before, during and after attack Duration of attacks injury, tongue biting or incontinence 29 29 29 14 14 14 14

History from Witness Frequency of attacks Detailed description of observations before and during attacks - including level of responsiveness, motor phenomena, pulse, colour, breathing, vocalisation Detailed description of behaviour following attacks 30 30 30 15 15 15 15

Laboratory Testing Complete blood count Chemistry studies: Electrolytes, calcium. magnesium, phosphorus Renal and liver function tests Urinalysis Toxicology screen Therapeutic drug levels Lumbar puncture Fever or suspicion of meningitis or encephalitis Immunosuppression

EEG The EEG is not a diagnostic test for epilepsy It will be abnormal in only about 50% of those with clinically definite epilepsy It can be abnormal in those with no history of seizures It may help to define the type of epilepsy 13 13 13 13 13 13 13 16 16 16 16 13

Figure 1-1. Scalp-recorded EEG change during a habitual event showing the onset of a left temporal lobe seizure. This study was performed in the epilepsy monitoring unit with video-EEG recording. Bipolar montage.

Figure 1-2. EEG of a patient with focal seizures of right frontal lobe origin that reveals right superior frontal (F4) and midfrontal (Fz) spike discharges during sleep.

Figure 1-3. EEG during photic stimulation of a patient with a generalized seizure disorder showing a photoparoxysmal response. Ipsilateral ear reference montage.

Figure 1-4. EEG during a psychogenic nonepileptic seizure Figure 1-4. EEG during a psychogenic nonepileptic seizure. A, EEG during psychogenic nonepileptic seizure revealing a prominent artifact related to muscle activity and movement during the “convulsive” behavior. B- EEG immediately after the motor activity has ceased showing a normal awake background without epileptiform activity. The patient appeared unresponsive at this time. This study was performed in the epilepsy monitoring unit with video-EEG recording. Bipolar montage.

Neuroimaging in Epilepsy NOT essential in all cases e.g. juvenile myoclonic epilepsy, Useful to exclude underlying lesion e.g tumour in older individuals and those with clear-cut history of seizure of focal onset MRI is increasing used to assess patients for epilepsy surgery Slowly growing tumour Encephalitis Ischemic stroke 14 14 14 14 14 14 14 17 17 17 17 14

Bottom-of-Sulcus Dysplasia

Transmantle Sign in Cortical Dysplasia

Treatment

Drug Treatment of Epilepsy Select AED according to seizure type (s) and to a patient specific characteristics Use a single drug if possible (monotherapy) Use multiple drugs (polytherapy) if necessary When adding an AED start slow and go slow, titrate to maximum tolerated dose if necessary Consider changing timing of dosing to reduce toxicity Use pharmacokinetic principles to adjust doses Adjust dose for drug-drug interactions Beware interactions with other drugs including oral contraceptive pill

Recurrence after First Seizure

Data showing no difference in cumulative chance of seizure recurrence whether patients presented with a single seizure (n = 425) or multiple seizures (n = 72)

Risk of subsequent seizure over 10 years after acute symptomatic seizure during acute illness (eg, stroke, central nervous system infection, traumatic brain injury) compared with risk of subsequent seizure in patients with remote symptomatic unprovoked seizure (ie, previous stroke, central nervous system infection, traumatic brain injury)..

Patients at Increased Risk for Seizure Recurrence After First Seizure

Treatment Options -Generalized Onset Old AEDs Valproate Phenobarbital New AEDs Levetiracetam Perampanel Rufinamide Clobazam Lamotrigine Topiramate Zonisamide

Treatment Options - Partial Onset Old AEDs Phenytoin Carbamazepine Phenobarbital Valproate New AEDs Tiagabine Levetiracetam (Keppra) Lamotrigine ( Lamictal) Gabapentin(Neurontin) Topiramate (Topamax) Oxcarbazepine (Trileptal) Zonisamide ( Zonagran) Pregabalin ( Lyrica) Lacosamide ( vimpat) Retigabine Eslicarbazepine Perampanel Bivaracetam

Approach to Patients: Case 1 Patient profile Choice of Antiepileptic therapy 13 year-old- girl presented with her first-ever complex partial seizure. She is not on other medications and previously healthy Levetiracetam Lamotigine Carbamazepine-CR Oxcarbazepine

Approach to Patients: Case 2 Patient profile Choice of Antiepileptic therapy 13 year-old- boy presented with his first-ever generalized tonic-clonic seizure. He is not on other medications and previously healthy Levetiracetam Lamotigine Carbamazepine-CR Oxcarbazepine

Approach to Patients: Case 3 Choice of Antiepileptic therapy Patient profile 22 year-old woman presented with her first-ever partial seizure with secondary gneralization, She is otherwise healthy and no on other medications She is married Levetiracetam Lamotrigine Zonisamide Topiramate Valproate 10% birth defects Low IQ in newborn

Approach to Patients: Case 4 Choice of Antiepileptic therapy Patient profile A 70 year-old man presented with recurrent complex partial seizures despite being on maximum dose of levetiracetam. He has no co-morbid conditions Lamotrigine Lacosamide Carbamazepine-CR Eslicarbazepine

Side-effects of Therapy Sodium Valproate - Tremor, Weight Gain, Ataxia, Nausea, Drowsiness, Abnormal LFTs, Transient Hair Loss Carbamazepine - Ataxia, Drowsiness, Nystagmus, Blurred vision, Low serum sodium levels, skin rash. Lamotrigine –skin rash Topiramate – weight loss, word finding difficulties 18 18 18 18 21 21 21 21 18

Monitoring Drug Levels Serum levels should not be monitored without a clear clinical indication The main indications are: adjustment of Phenytoin dose assessment of compliance in patients with apparently refractory seizures assessment of possible toxic symptoms 20 20 20 20 22 22 22 22 20

Remission of Epilepsy Up to 80% of patients enter remission After two years free of seizures over 40% relapse if their drug is slowly withdrawn Over 20% relapse if they stay on the same medication Relapse is more likely if patients: are over 16 had seizures while on treatment have tonic-clonic or myoclonic seizures have an abnormal EEG 19 19 19 19 23 23 23 23 19

CASE 25 year old male student in lecture Suddenly notices a disgusting smell and has a memory of a familiar situation Stares into space for 60 seconds, friend notices him picking at his buttons and making some chewing movements Not responding to friends questions Recovers after the 60 s but feels tired and has a headache

Case What type of attack is it? What is the memory of a familiar situation called? Which brain region may be abnormal?

What is the pathology?

Mesial Temporal Lobe Epilepsy Syndrome Most common syndrome associated with complex partial seizures Symptomatic partial epilepsy Distinctive clinical, EEG and pathologic features MRI: Hippocampal sclerosis Refractory to medical therapy Responds well to epilepsy surgery

Surgical Treatment of Epilepsy Indications for consideration Intractable seizures Resectable structural abnormality on MRI Confirmation by EEG that seizures arise from this lesion IQ over 70 and no significant psychiatric problems Age under 50 21 21 21 21 24 24 24 24 21

Outcome of Surgery Study of 235 patients at UCLA 59% complete remission 19% rare recurrences 19% continued seizures at reduced frequency 2% unchanged 22 22 22 22 25 25 25 25 22

Status Epilepticus Prolonged or recurrent tonic-clonic seizures persisting for more than 30 minutes with no recovery period between seizures usually occurs in patients with no previous history of epilepsy (stroke, tumour, alcohol) Mortality : 5-10% 32 32

New Surgical & Stimulation Approaches •Laser ablation of amygdala/hippocampus for temporal lobe epilepsy & focal epileptogenic lesions •Gamma knife ablation of MTS: failed 12/06/16 •Robotic surgical assist device (ROSA) •Responsive neural stimulation for non-resectablefocal epilepsy (critical motor/language cortex or two foci)

Placement of electrodes in region where seizures originate •Real time detection of changes in EEG and delivery of local electrical current to abort or terminate seizure

Responsive Neurostimulation (RNS)