Diagnosis and Management in. Epilepsy : 9/29/16. Definition. Epilepsy in Asia and Thailand. Clinical manifestations. Epidemiology of Seizures and

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1 Diagnosis and Management in : Diagnosis and Management PASSWORD: epilepsy08 Dr. otin Chinvarun M.D. Ph.D. Comprehensive Program PMK hospital Definition Epidemiology of Seizures and Seizure: the clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons : a tendency toward recurrent seizures unprovoked by systemic or neurological insults Seizures Incidence: approximately 80/100,000 per year Lifetime prevalence: 9% (1/3 benign febrile convulsions) Incidence: approximately 45/100,000 per year Point prevalence: % in Asia and Thailand sufferers Clinical manifestations Clinical expression of seizures varies widely Worldwide 50 million Asia 30 million Thailand 700,000 cases Refractory Depending on type of seizure and the areas of the brain that are involved by epileptic activity Accurate identification specific types of seizures determines and dictates type of drug should receive Overall About 20 30% Asia Up to 10 million Thailand Up to 30,000 cases 1

2 New concept of classification : New classification Seizures Syndromes Etiologies Focal seizures Originate within networks limited to one hemisphere Focal seizures May be discretely localized or more widely distributed. Focal seizures (Blume et al Epilepsia 2001) Previous term: Simple partial No impairment of consciousness or awareness Motor or autonomic components eg. focal clonic Su b jective sen sory or p sych ic featu res -> Aura Previous term: Complex partial Altered cogn ition -> Dyscognitive Previous term: Secondarily generalized Evolving to bilateral, convulsive seizure With tonic, clonic or tonic and clonic components Focal seizures Generalized seizures Originate at some point within and rapidly engage Bilaterally distributed networks Can include cortical and subcortical structures but not necessarily the entire cortex 2

3 Tonic-clonic (in any combination) Absence Typical Atyp ical Absence with special features Myoclonic absence Eyelid myoclonia Myoclonic Myoclonic atonic Myoclonic tonic Generalized seizures Clonic Tonic Atonic Seizure types thought to occur within and result from rapid engagement of bilaterally distributed systems Generalized Seizures Myoclonic seizures consist of brief episodes of sudden motor contraction, can be focal, with one arm involved, or bilateral and massive, with involvement of both upper extremities and trunk. Consciousness preserved Atonic and tonic seizures, brief but extremely disabling motor events characterized by sudden increase or decrease in muscle tone, resulting falls and injuries with variable impairment of awareness Generalized Seizures s Unchanged! A diagnosis can be made as previously e.g. Lennox-Gastaut Childhood Absence A diagnosis is not the same as a classification Etiology Genetic Structural Metabolic Immune Unknown Use terms that mean what they say! Replace old fashioned terms: idiopathic, symptomatic, cryptogenic Genetic Concept: is the direct result of a known or inferred genetic defect Seizures are the core symptom of the disorder Evidence Appropriately designed family studies or replicated molecular genetic studies Genetic does not exclude the possibility of environmental factors contributing 3

4 Structural Concept: epilepsy is the result of a distinct other structural condition or disease e.g. tuberous sclerosis Evidence: Must have a substantially increased risk of developing epilepsy with the condition Metabolic Concept: epilepsy is the result of a metabolic condition or disease with widespread manifestations e.g. Aminoacidopathies Pyridoxine-dependent seizures Evidence: Must have a substantially increased risk of developing epilepsy with the metabolic condition Immune Concept: epilepsy is the result of autoimmune mediated central nervous system inflammation e.g. autoimmune encephalitides anti-nmda encephalitis limbic encephalitis Evidence: Must have a substantially increased risk of developing epilepsy with the immune condition Unknown Concept: The underlying cause is unknown Diagnostic specificity Electro-clinical s Epilepsies due to a known cause may not be localizing Structural e.g. Focal cortical dysplasia Metabolic e.g. GLUT1 deficiency Also applies to Genetic and Immune epilepsies Constellations or Associations Related concepts eg TLE with hippocampal sclerosis May carry surgical implications Unknown Diagnosis Basic diagnosis of seizures established by clinical history Although EEG, imaging, and laboratory studies commonly required to determine Type of epilepsy Site of origin of focal seizures Occurrence of nonepileptic seizures 4

5 Differential Diagnosis First question facing clinicians whether episodes under consideration are indeed seizures Disorders resembling seizures Common conditions resembling seizures include Syncope, transient Ischemic attacks Migraine Movement disorders Psychogenic nonepileptic seizures CLINICAL FEATURES THAT HELP DISTINGUISH GENERALIZED TONIC CLONIC SEIZURE FROM SNCOPE Differential Diagnosis Migraine and focal seizures not only resemble each other, but also coexist as comorbid conditions Features, favour diagnosis of seizures over migraine include Inconsistent occurrence of headache, a brief duration, and the occurrence of more severe seizures Differential Diagnosis Frontal lobe seizures arise predominantly during sleep and can dramatic motor expression Can be confused with nonepileptic psychogenic seizures, sleep disorders Video EEG monitoring may be necessary for diagnosis Panic attacks can experience events mimic focal seizures with autonomic and psychic features However, panic attacks usually longer duration, not progress to more severe seizures, can linked to specific circumstances Differential Diagnosis Psychogenic nonepileptic seizures are behaviors resemble seizures, often part of conversion reaction Precipitated by underlying psychological distress Psychogenic seizures can be difficult to diagnose because Can mimic almost any type of seizure Often coexist with epilepsy in same patient 5

6 Diagnostic Investigations Detailed history, EEG recordings, and MRI can lead to definitive diagnosis of epilepsy and its cause in up to 50% of patients In other patients, information insufficient or inconsistent, but physiologic and CNS abnormalities surrounding the actual event allow another 30% of patients Continuous video-eeg monitoring in inpatient epilepsy unit can increase diagnostic sensitivity Single Seizures Acute symptomatic seizures known consequence of an acute condition, and investigations should be directed possible cause of seizures When no known cause apparent, seizures considered to be unprovoked Evaluation includes CT or MRI, reveals possible cause 10% EEG demonstrate abnormalities with prognostic significance in 20 to 25% Blood tests reveal abnormalities 15%, but often nonspecific Lumbar puncture indicated if CNS infections suspected Electroencephalogram: EEG EEG keystone investigation in all patients with seizures and epilepsy Between seizures, EEG can assess overall brain function and type, location, and amount of epileptiform (spike) discharges. EEG crucial determining epilepsy and choosing appropriate AEDS In focal epilepsies, EEG often demonstrates focal slowing and spike discharges in area of abnormality Electroencephalogram: EEG EEG can establish definitive diagnosis of epilepsy if electrical changes consistent with seizure recorded during a clinical seizure However, EEG may fail to demonstrate electrical changes during typical clinical seizure if the seizure focus is Too small (at least 6 cm2 of cortical involvement needed to create EEG epileptiform change) Seizure focus in deep or in mesial or inferior surfaces of the brain Event in question may not be an epileptic seizure EEG always abnormal during generalized convulsive and absence Electroencephalogram: EEG Initial EEG normal up to 60% of people with known epilepsy However, epileptiform abnormalities occur > 80% with focal epilepsy if three or more interictal EEG studies are performed In generalized epilepsies, interictal epileptiform discharges more common and easier to capture Type of abnormality points to epileptic, i.e. EEG can show hypsarrhythmia in West s 3-Hz generalized spike wave in generalized epilepsies with absence seizures Electroencephalogram: EEG In some circumstances, such as evaluation of patients for epilepsy surgery and when the diagnosis of seizures is in question Continuous video EEG monitoring for prolonged periods has made it possible to capture these events Continuous EEG also used in comatose patients in intensive care unit setting when nonconvulsive seizure or status epilepticus suspected 6

7 Imaging Studies Brain MRI can demonstrate lesions in most patients whose epilepsy is associated with a structural cause Should be performed in essentially all patients with new-onset seizures Using of fluid-attenuated inversion recovery (FLAIR) sequences increases the sensitivity to detect abnormalities of cortical development as well as hippocampal sclerosis, point to need for chronic AEDS or possible surgical treatment Imaging Studies Functional imaging procedures such as positron emission tomography (PET) For analysis of metabolism Single-photon emission computed tomography (SPECT) for determination of blood flow Used to help localize areas of the brain to be targeted with epilepsy surgery Epileptic Syndromes Epileptic s include age-related s, which mostly begin or occur in infancy and childhood Diagnosis of epileptic s based on Types of seizures Setting in which seizures occur Patient s neurologic and cognitive status Age at onset Family history Results of diagnostic studies, including EEG and MRI Selection of specific drug and surgical treatment depends on types of seizures present Some Specific Seizure Syndromes Neonatal and Infantile Syndromes Benign neonatal convulsions occu r in previously heal thy newborns at day 5 as focal or generalized tonic seizures. Mutations potassium channel genes (KCNQ2, KCNQ3) EEG shows rhythmic slow- wave activity or spiking with seizures. Seizures refractory to treatment, recurrent over brief interval, and disappear within a month. About 90% of such infants subsequently have normal development, whereas 10% have subsequent seizures Some Specific Seizure Syndromes Neonatal and Infantile Syndromes Generalized epilepsy with febrile seizures plus consists of febrile seizures combination with other nonfebrile types of seizures, including myoclonic, absence, atonic, tonic-clonic, and focal seizures Mutations at least four different voltage-gated ion channel and GABA receptors genes have been identified. Dravet s (severe myoclonic epilepsy of infancy) Starts in 1 st year of life with myoclonic seizures plus other seizure types, including absence, atonic, and focal Seizures resistant to treatment and accompanied by cognitive decline Mutations in the SCN1A sodium channel identified Some Specific Seizure Syndromes Neonatal and Infantile Syndromes West s comprises Triad of epileptic spasms, developmental arrest, and an EEG pattern called hypsarrhythmia (high-amplitude slowing and superimposed multifocal spikes, polyspikes, and spike and slow-wave complexes) Appears before age of 12 months and ceases by 5 years of age Often replaced by other epilepsy s such as Len n ox -Gastaut. Tuberous sclerosis Hypoxia common causes, but cause may not be found. Associated abnormalities often include developmental delay, porencephaly, atrophic lesions, calcifications, and agenesis of the corpus callosum 7

8 Some Specific Seizure Syndromes Childhood Syndromes Childhood absence epilepsy Begins before age 12 years, onset peaks at age 5 to 7 years Strong genetic tendency More common in girls Characterized by very frequent daily absence seizures (up to hundreds per day), rarely with other types of generalized seizures Normal brain structure and function, self- limited in about 40% Seizures characteristic 3-Hz spike-and-wave EEG discharge, which appears in short bursts between seizures and in continuous runs during seizures Remission usually before 12 years, but generalized tonic-clonic seizures occasionally may develop in adolescence Some Specific Seizure Syndromes Childhood Syndromes Lennox-Gastaut Most severe childhood epilepsies Starts before age 8 years (peak 3 to 5 years) Characterized by triad of mental retardation, multiple types of generalized seizures (atypical absence, generalized tonic-clonic, tonic, atonic), focal seizures Highly resistant to treatment EEG: Lennox Gastaut Typical EEG pattern of slow spike and wave and bursts of fast rhythms at 10 to 12 Hz during sleep Often follows resolution of West s Some Specific Seizure Syndromes EEG study: centro-temporal spikes Childhood Syndromes Benign epilepsy with centrotemporal spikes (benign rolandic epilepsy) Starts 3-13 years of age Characterized by almost exclusively nocturnal focal motor or sensory seizures, have a facial or oral onset and often evolve to convulsive seizures Nearly 50% have a family history of epilepsy, but most patients have no known brain abnormality EEG shows spiking in the centrotemporal region In some cases may not require treatment 8

9 Some Specific Seizure Syndromes Adolescence and Adult Syndromes Juvenile myoclonic epilepsy Usually starts in second decade with generalized tonic-clonic and myoclonic seizures Mutations in GABA receptors, including GABRG1 Seizures typically occur in morning, immediately after awakening, especially linked to sleep deprivation, tend to appear in college students Patients may have absence seizures as well EEG typically shows fast (4 to 6 Hz) generalized spike and wave. Lifetime treatment generally needed Some Specific Seizure Syndromes Adolescence and Adult Syndromes Mesial temporal lobe epilepsy with hippocampal sclerosis Most common epilepsy to produce focal dyscognitive seizures in adults Characterized by recurrent focal limbic seizures, with and without impaired awareness, originate in mesial temporal and limbic structures Up to 70% have risk factor, such as lengthy and complicated seizures before the age of 4 years, frequently associated with fever or with encephalitis, meningitis, or trauma However, characteristic seizures generally begin some years later Most cases sporadic, some familial forms found Seizures with Less Specific Age Relationship Reflex seizures Triggered by specific simple (e.g., flashing lights) or elaborate (e.g., reading) stimuli Mechanisms diverse and may involve cortical and brain stem pathways, cortical dysregulation of extracellular calcium concentrations, and an imbalance between excitatory and inhibitory neurotransmitters Visual-sensitive seizures (triggered by light or visual patterns) most common type, commonly in females, incidence peaks around puberty Seizures with Less Specific Age Relationship Reflex seizures Represent 10% of all new cases of epilepsy Other triggers include specific thoughts, actions, reading, tactile stimuli, adopting certain positions, eating, listening to music, startle, and contact with hot water Can be myoclonic, convulsive, atonic, or focal, depending on the triggering stimulus Avoiding offending stimulus crucial to avoid seizures Conclusion Diagnosis of seizures established by clinical history Although EEG, imaging (MRI), and laboratory studies commonly required to determine Type of epilepsy Site of origin of focal seizures Optimum medical management in Adult and Children with difficult to treat epilepsy EEG crucial determining epilepsy and choosing appropriate AEDS Continuous video-eeg monitoring increase diagnostic sensitivity Dr. otin Chinvarun M.D. Ph.D. Comprehensive Program PMK hospital 9

10 Outline Choosing the right By seizure type Refractory/Difficult to treat AED options by seizure type : Generalized tonic-clonic seizure Seizure type First-line Adjunc tive Other that may be referral to tertiary c are (may Worsen seizures) 23 years old man 1 st seizure at the age 13 years old Sz proper GTCS Sz provoked by playing video-game, GTCS, gen tonic-clonic of both limbs, lasting several minutes Generalized tonic clonic Sodium valproate Clobazam Levetiracetam Sodium valproate (If there are ab sen ce o r myo cl o n i c seizures, or if JM E su sp ected ) Gabapentin Oxcarb azep in e EEG generalized epi D/C Treatment Trileptal mg Sz free for two years Phenytoin Pregabalin Ti agab i n e Vigabatrin EEG 2 Nov 2008 normal study, taper off the, no recurrence seizure AED options by seizure type Seizure type First-line Adjunc tive Other that may be referral to tertiary c are (may Worsen seizures) F 33 years old 1 st seizure at the age of 4 years old with intellectual disability Tonic or Atonic seizure Sodium valproate Rufinamide Gabapentin Pregabalin Tonic seizure with 2 GTCS Tonic sz with 2 GTCS tonic of both limbs, usually fell to the ground followed by 2 GTCS Frequency 8 Sz per years Tiagabine Vigabatrin MRI brain CD diffuse bilateral CH (FP lobes) 10

11 AED options by seizure type Previous med Depakine chro 500mg TPM 100mg 2-2 Seizure type First-line Adjunc tive Other that may be referral to tertiary c are (may Worsen seizures) Current med Deapkine chro 500mg TPM 100mg 2-2 VNS Sz frequency 1-2 per year Absence Ethosuximide Sodium valproate Rufinamide Gabapentin Pregabalin Tiagabine Vigabatrin : CAE Girl 8 years old 1 st seizure at the age 8 years old Sz proper Frequent having blank staring, with frequent eye blinking and eyes rolled up, lasting a few seconds, come into cluster Causing poor learning performance Before treatment Patient have absence per day Treatment Depakine chrono (500mg) 1.5 tab bid Treatment VPA level 98, seizure frequency per day Current med Depakine chrono 500 mg 1.5 tab bid LTG 25 mg 1-1 AED options by seizure type Seizure type First-line Adjunc tive Other that may be referral to tertiary c are (may Worsen seizures) M 35 years old 1 st Sz GTCS, since 17 yrs old seizure sine then became seizurefree, stopped AED at 20 yrs, (on PB gr I 1 hs) Myoclonic Levetiracetama Sodium valproate Levetiracetam Sodium valproate a Clobazama Clonazepam Piracetam Zonisamide Gabapentin Phenytoin Pregabalin Tiagabine Vigabatrin 6 month PTA had several episodes of myoclonoc jerk 1-3 daily EEG paroxysmal slow wave frontal lobe predominance Sleep deprived EEG paroxysmal high amplitude theta over both CH, provoked by HV 11

12 Diagnosis Juvenile myoclonic epilepsy Treatment Depakine chrono 0.5 tab bid Rivotril tab hs Ten years later, patient became seizure free and is on the same Previous Rx Depakine chr 500mg Rivotril 0.5 mg 1-1 Nootropil 400mg 1-0 Current Rx Depakine chr 500mg 1-1 Inderal 10 mg Rivotril 0.5 mg 1-1 Nootropil 400mg 1-1 Keppra 500mg 1-1 Treatment AED options by seizure type Focal Seizure type First-line Adjunc tive Other that may be Levetiracetam Sodium valproate Clobazam Gabapentin Levetiracetam Sodium valproate Lacosamide referral to tertiary c are Eslicarbazepine acetate Lacosamide Phenobarbital Phenytoin Pregabalin Tiagabine Vigabatrin Zonisamide (may Worsen seizures) F 53 years old 1 st seizure at the age of 53 years old Sz proper CPS, no aura, sudden loss of consciousness, no recollection, lasting for several minutes, no motor involvement EEG abnormal EEG study, definite focal epi D/C left frontotemporal lobe MRI brain: left hippocampal atrophy Treatment LTG 25 mg 1-1 Seizure-free But, developed Steven Johnson Current med Depakine chrono (500mg) 1 tab bid Became seizure-free since then F 47 years old 1 st seizure 30 years old Sz proper No aura, blank staring, tonic of both limbs, grunting, no tongue biting, lasting 10 minutes, nocturnal, recently had CPS only 2-3 minutes, initially had nocturnal CPS, recently had daytime CPS, talk nonsense, postictal feeling fatique, or sleepy MRI brain 2 July Nov 2002 large porencephalic cyst left post temporo-occipital lobes, with hippocampal atrophy Lt>Rt with slightly increase signal over the left hippocampus 12

13 Previous med Depakine chro 500mg PB gr I 1 hs Rivotril 0.5mg 0.5 tid Current med Depakine chro 500mg 2-2 Rivotril 0.5mg 0.5 tid Frisium 5 mg 1 prn B Keppra 500mg Neurontin TPM 25 mg 1-1 F 33 yrs old, Hx of 1st Sz 24 yrs old Sz semiology CPS with blank staring for a few minutes, oral automatisms 2 GTCS Sz frequency 1-3 per months EEG epileptiform discharges left fronto-temporal lobe MRI brain : unremarkable 171 Treatment Tegretol CR 1600 mg / day still having CPS 1-3 per month Added Depakine chrono 2000 mg per day Sz frequency 1-2 per month, weight gain Current med Tegretol CR Depakine chrono 500 mg Pregabalin 150 mg bid Remaining seizure free for 6 months now Master 15 years old 1 st Sz 12 years old Sz proper SPS: visual aura CPS 2 GTCS EEG focal epi right posterior quadrant Ictal SPECT: increased rcbf Rt. poster temporo-parietal anterior to porencephalic cyst 172 I AED options by epilepsy Med TPM Then TPM, Keppra TPM+Keppra+LTG First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Current Depakine chrono 500 mg 1-1 LTG 50 mg 1-1 Keppra 500 mg TPM 50 mg Childhood absence Juvenile absence epilepsy or other absence s Ethosuximide Sodium valproate Ethosuximide Sodium valproate Clobazam Clonazepam Levetiracetam Zonisamide Gabapentin Phenytoin Pregabalin Tiagabine Vigabatrin 13

14 AED options by epilepsy AED options by epilepsy First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Juvenile myoclonic epilepsy Levetiracetam Sodium valproate Levetiracetam Sodium valproate Clobazam Clonazepam Zonisamide Gabapentin Phenytoin Pregabalin Tiagabine Vigabatrin with generalized tonic clonic seizures only Sodium valproate Clobazama Levetiracetam Sodium valproate AED options by epilepsy Master 10 years old 1 st Sz 2.5 yrs old nonfebrile GTCS 2 nd Sz 7 years old, 3 rd seizure in Nov 2011 First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Sz proper No aura, sudden fall, generalized tonic-clonic seizure, no tongue biting, no incontinence, lasting 3-5 minutes Idiopathic Clobazam EEG study bi-occipital epileptiform discharges Rt > Lt. generalized epilepsy Sodium valproate Levetiracetam Sodium valproate Clonazepam Zonisamide Gabapentin Phenytoin Pregabalin Diagnosis: Generalized epilepsy? 1 or 2 Tiagabine Vigabatrin Treatment Depakine chrono 500 mg 0.5 tab bid : AED options by epilepsy M 20 years old 1 st seizure April 2010 Sleep deprived, had GTCS, lasting 3 minutes, Rx with Depakine chrono 500 mg 1 tab hs First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Had another seizure, waking up in the morning found out having tongue biting, abrasion wound over face MRI brain asymmetrical cerebellar EEG: generalized spike and wave complexes 3 Hz with photosensitive Infantile spasms ACTH Steroid (prednisolone) vigabatrin Current med Depakine chrono 500mg 1-1 Remaining seizure-free 14

15 AED options by epilepsy First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Master 9 years old 1 st seizure Nocturnal seizure, GTCS, facial distortion, gaggling, salivated, lasting 2-3 minutes Benign epileps y with centrotemporal spikes a Levetiracetam Clobazama Gabapentin Eslicarbazepine acetate Lacosamide Phenobarbital EEG Centro-temporal spikes (Horizontal dipole) Sodium valproate Levetiracetama Phenytoin Sodium valproate Pregabalin Tiagabine Vigabatrin Zonisamide Treatment LTG 25 mg 2 hs AED options by epilepsy AED options by epilepsy First-line Adjunc tive Other that may be (may worsen First-line Adjunc tive Other that may be (may worsen referral to tertiary seizures) referral to tertiary seizures) care care Panayiotopoulos Levetiracetam Clobazama Gabapentin Eslicarbazepine acetate Lacosamide Late-onset childhood occipital a Levetiracetama Clobazam Gabapentin Eslicarbazepine acetate Lacosamide Sodium valproate Levetiracetama Sodium valproate Phenobarbital Phenytoin Pregabalin Tiagabine Vigabatrin epilepsy (G as taut type) Sodium valproate Levetiracetam Sodium valproate Phenobarbital Phenytoin Pregabalin Tiagabine Vigabatrin Zonisamide Zonisamide AED options by epilepsy AED options by epilepsy First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) First-line Adjunc tive Other that may be referral to tertiary care (may worsen seizures) Dravet Sodium valproate Clobazam Stiripentol Gabapentin Phenytoin Pregabalin Tiagabine Vigabatrin Lennox Gastaut Sodium valproate Felbamate Rufinamide Lacosamide Parempanel Gabapentin Pregabalin Tiagabine Vigabatrin 15

16 AED options by epilepsy Previous med Depakine chrono 500mg Rivotril 0.5mg 1 tab tid Topamax 125mg bid Trileptal 300mg 0.5 tab bid Ketogenic diet Current med Depakine chro Rivotril 0.5 mg Topamax 125 mg bid Vagal nerve stimulation CPS 10 / day CPS 10 / year Landau Kleffner First-line Sodium valproate Prednisolone Adjunc tive Other that may be referral to tertiary care (may worsen seizures) IVIG Gabapentin Pregabalin Tiagabine Vigabatrin Girl 6 years and 9 months old Had slow response and poor memory since mid 2011 Progressive dysplasia 1 month had GTCS with generalized tonic-clonic of both limbs PH normal child before, normal birth full term, normal growth and development PE Hyperactive girl, short attention General examination was normal Neurological examination was unremarkable except language function When showed up the pen patient said it can be use for writing, but don t know the name When showed up the telephone she answered as using for talk No FH history of epilepsy Progression She underwent for MRI brain EEG BAER VEM Treatment Valproate (500 mg) 1 tab bid IVIG 5 days Prednisolone 16

17 Refractory epilepsy How to chose? Despite adequate treatment with and despite adequate adherence, still ~ 30 40% of patients will develop refractory epilepsy The choice of AED for patients who not responded to first AED, depends primarily on Seizure diagnosis Therefore, a first step, serious effort should be made to diagnose seizure type, localization, and In addition to efficacy profiles, considerations when choosing an AED include Gender Age Body weight Fertility Lifestyle Other medications Adverse effect Other concomitant diseases, and pharmacokinetic characteristics Treatment of Treatment of The goal of the treatment of refractory epilepsy (as with newonset epilepsy) is freedom from seizures with as few treatment adverse effects If the patient becomes seizure-free no ADRs, should consider not changing dose AED, even blood concentration below or slightly above therapeutic range However, seizures continue, then AED dose should be increased until patient is seizure-free or until adverse effects occur If seizure control not achieved, that should be slowly decreased and an alternative monotherapy instituted If 1 st drug has had some degree of efficacy, then adding 2 nd would be the most rational approach Treatment of If 2 nd AED causes patient to become seizure-free, then 1 st AED might be slowly withdrawn, but this must be up for discussion together with patient about risk/benefit Unsuccessful with the second drug, patient should be referred to tertiary epilepsy clinic for further evaluation and other treatment alternatives i.e. surgery, especially case with mesial temporal lobe focus Difficult to treat/refractory seizures Approximate one third of patients with epilepsy have seizures that are difficult to control Can be considered drug resistant Not to overlook the possibility of psychogenic nonepileptic seizures

18 International League Against Definition of Drug Resistant Failure of adequate trials of 2 tolerated, appropriately chosen and used schedules (whether as monotherapy or in combination) to achieve sustained seizure-freedom 1 st AEDS Seizure-free 47% Treatment outcome New onset Newly diagnosed epilepsy Uncontrolled seizures 53% 2 nd AEDS Seizure-free 13% Refractory 40% Rational Polytherapy Surgical asse ssme nt Kwan P. et. Al. Epilepsia 2010 Kwan P. et. Al. NEJM 2000 Chronology of antiepileptic drug introduction over the past 150 years Underlying type of epilepsy as a prognostic factor for recurrence 213 Question to consider when assessing patients with refractory seizures Assessing patient with Refractory seizures

19 Strategies for treating refractory Partialonset seizures Treatment selection for Refractory partial onset seizures How to prioritize treatment selection for Refractory partial onset seizures When 1st AED failed because lack of efficacy Wrong diagnosis Appropriate AED for seizure type Poor compliance? Provoked seizures? Adequate dosage? Does to clinical toxicity Physiological Syncope HV Migraine, vertigo TIA Psychological Behavioral events (NEPS) Psychotic episodes Panic attack Wrong diagnosis Substitution Gradual reduction and increase immediate switch Substitution consideration Evidence based informations Consider special populations Refer mechanisms of - different one

20 Substitution or add-on The average percentage seizure-free rates of alternative monotherapy and add-on therapy were similar The success rate did vary considerably between individual substitution studies and between individual add-on studies This suggest that it is important which substitution or add-on drug is chosen Substitution or add-on Combination therapy achieved 25% seizure freedom in those patients that failed on both drugs in monotherapy Patients who become seizure-free on a combination of may develop seizures again when the first AED is withdrawn (Deckers, 2002), suggest combination therapy may be more efficacious than monotherapy Two reasons may be given for this: Infra-additive toxicity of the combination which allows for higher drug loads to be prescribed during polytherapy, thus achieving better efficacy Pharmacodynamic synergism which may be accomplished by combining drugs complementary mechanisms of action Substitution or add-on In an observational study by Kwan and Brodie 26% of 42 patients treated with second-line combination therapy became seizure-free compared to 17% of 35 patients treated with alternative monotherapy (Kwan et al., 2001) Failure due to adverse effects 12 and 26%, respectively (no statistical significance) Substitution or add-on Shorvon (2000) suggested the following strategy when a patient does not become seizure-free On a first AED despite a maximal dose: alternative monotherapy should be introduced incrementally at suitable dose intervals and the first drug then withdrawn in decremental steps The second drug should titrated first to a low maintenance dose and then, if seizures persist, dosage increased to maximal If seizures continue, re-assessed diagnosis,? progressive lesion or? noncompliance 226 If continuing seizures, other first-line drugs should be tried in monotherapy 227 Substitution or add-on Add-on therapy also has disadvantages When add-on treatment proves to be efficacious, cannot exclude the possibility that the add-on drug have efficacious when given as alternative monotherapy Cannot discern effects of individual drugs on efficacy or toxicity in polytherapy Therefore, one does not know whether first-line drug can be withdrawn Pose problems with patients, they may not be willing to withdraw first drug and risk losing their seizure freedom Substitution or add-on Whether aims at substitution or at add-on therapy after a first drug has failed, usually titrate second drug to some level in presence of first drug To evaluate effectiveness of combination at this stage, in case of success, gradually withdraw first drug This would be preferred option especially when first drug did reduce seizure frequency to some degree If continuing seizures, other first-line drugs should be tried in monotherapy If continuing seizures, other first-line drugs should be tried in monotherapy

21 Substitution or add-on When combination not efficacious, replace the drug that least efficacious When alternative monotherapy not efficacious as the combination, first-line drug should be reintroduced Second-line Monotherapy for Partial onset seizures VPA: FDA approved LTG: well tolerate non sedating TPM: FDA approved-potent LEV, ZNS When alternative monotherapy is efficacious but associated with considerable adverse effects, low-dose polytherapy should be considered Co-morbidities and Special populations and Comorbidities Co-morbidities LTG, TPM, PGB: neuropathic pain VPA, TPM migraine LTG: bipolar depression For special population Pediatric: Barbiturate, BZD Women planning for pregnancy: Elderly Osteoporosis Mostly worsened by the enzyme inducers: phenytoin, phenobarbital, primidone. data equivocal. Equivocal data w ith valproate, unavailable f or other non- inducers. Take calcium /d; Vit D /d Depression Can be exacerbated by levetiracetam (and less so zonisamide) Can be helped by lamotrigine and possibly gabapentin, pregabalin (and vagus nerve stimulator) Migraine Consider topiramate, valproate Obesity Weight loss with topiramate and zonisamide Weight gain with valproate > gabapentin/pregabalin, carbamazepine Combination therapy Rational Polytherapy Although mechanisms of action of many not fully understood, this remains a logical basis for choosing combination therapy Evidence is emerging that certain combinations offer better efficacy than others When adding a new AED to existing therapy Should choose an AED with a different mechanism of action other than the drug or drugs already being Favorable pharmacodynamic interactions drug combination may provide more benefit than either drug alone Newer drugs, such seem to be particularly well tolerated as add-on therapy, due to lack of pharmacodynamic interactions However, still no evidence or study to equivocally demonstrate this principle 21

22 Emerging Rational Polytherapy Concepts Combination of low to moderate doses of is more effective than high-/maximum tolerable dose monotherapy Principle Combination of drugs for synergistic pharmacodynamic interactions Better efficacy and/or less toxicity Methods (i) Different mechanism of action - principle of pharmacotherapy in medicine (ii) No or less pharmacokinetic interactions - avoid enzyme inducing drugs (Cramer et al., 2002) (ii) Avoid drugs having similar AE-profiles Rational Polytherapy As for rational polytherapy and side effects Adding with same mechanism of action can cause exaggeration of side effects i.e. Adding sodium channel blocker LCM to another sodium channel blocker such as CBZ might achieve seizure control, but dizziness could be higher than on non sodium channel blocking agent + LCM Rational Polytherapy Many of have other mechanisms of action as well as one that is thought to be major mechanism Other activities may also contribute to antiepileptic function confuse purest concept of rational polytherapy i.e. LEV mainly affect the SV2a receptor on the synaptic vesicle, but has calcium-modulating properties and GABAeric properties CBZ a sodium channel blocker, has other mechanisms of action as well Rational Polytherapy Therefore, rational polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects However, rational polytherapy for improvement of efficacy based on known mechanism of action still not been convincingly demonstrated

23 A Mechanistic Assessment of Pharmacodynamic AED Interactions in Animal Models : Polytherapy No Class I/II evidence supporting its clinical value Clinical evidence (class III/IV) for specific mechanistic combinations Better efficacy by combination of Na-channel blocker (CBZ, LTG) + multiple actions (VPA, TPM) Sz free rate: 36% vs 7% (p=0.05; Kwan & Brodie, 2000) VPA/ESM in absence epilepsy (Rowan,1983) VPA/LTG: RR (64%),vs CBZ/LTG (41%), PHT/LTG (38%): Brodie et al.,1997 VPA/LTG: SF in 30% of pts failed to monotherapy of both drugs: Pisani et al., Experimental evidence of synergism (isobolographic analysis) LTG/TPM &LEV/TPM: most effective combination (Luzszcki et al.,2002,2006) 247 AED Synergism Idea of AED synergism further development of rational polytherapy The thought is that adding another AED to one with a different mechanism of action will enhance efficacy greater than the assumed efficacy addition of both 249 M 57 yrs old 1 st Seizure 5 yrs old had FC several times since then had nonfebrile seizure Sz proper Dyscognitive Sz, sometime have warning symptom before, blank staring with gestural automatism, lasting 1 minute, frequency Sz 3-4 per month Medication Previous : LTG, LEV (rash) VPA Presurgical evaluations Ictal epileptiform discharges Rt. mesial temporal lobe Rx Gamma knife 23

24 After Gamma knife Dysconitive Sz 2-3 per month Medication TPM, VPA, PGB, ZNS ( off), CBZ, Clonazepam Current med: TPM, VPA Added LCM since Jan 2014, however, patient just started LCM this month LCM 50 mg once daily one week and then 1 tab bid Girl 9 years old Hx of intellectual disability and epilepsy since childhood Sz semiology Nocturnal seizure with versive Sz: freq 1 per day Dyscognitive seizure: 1-2 per day 2 GTCS (1 / 1-2 month) EEG study: Regional slowing is noted over the right posterior quadrant. Frequent focal epileptiform discharges right temporo-occipital lobe Medication TPM, ZNS, LEV, Clonazepam Ketogenic diet Clobazam prn 2 Feb 2014, patient agitated, labile mood and aggressive (probably from Phenobarb), dyscognitive Sz still unchanged, had one GTCS Med: off PB, ZNS, LEV, TPM LCM 50 mg bid Previous medication GBP not worked Phenobarb: partially worked, but causing abnormal behavior, increased aggression 19 Jan 2014 Med: ZNS, LEV, TPM, Phenobarb, start LCM 50 mg daily 16 Feb 2014: No agitated, mood improved, No GTC, Dyscognitive seizure and nocturnal seizure reduced Girl 7 years old, Hx of epilepsy with intellectual disability 1 st Sz 3 month old Sz proper: Dyscognitive Sz, blank staring with non-verbal vocalization, Sz Freqency 5-15 per day Myoclonic jerk Tonic seizure: 3 seizure recently usually during having fever Delayed gr and development: unable to sit, speak, or crawling EEG study: occasionally focal epileptiform D/C left frontal lobe MRI brain unremarkable Med Previous med: Phenobarb- STS, VPA and Clonazepam: a poor response, LEV, CBZ Sz freq, Dyscognitive Sz per day LEV, CBZ, LCM LCM 12.5 mg slow titration up to 25 mg bid Dyscognitive Sz reduced 4 per day 24

25 Adverse drug reactions Acute side effects Idiosyncratic skin eruption: CBZ, OXC, LTG Psychiatric: LEV, TPM, ZNS Sedation: PB, BDZ Hepatotoxicity: FBM, VPA, CBZ, PHT, PB, LTG, GBP Long-term side effects Glaucoma: TPM Weight gain: VPA, PGB Renal stone: TPM, ZNS Hyponatremia: OXC, CBZ Dysmorphic figures: PHT Adverse drug reactions Adverse drug reactions FDA alert 12/2007 Risk of dangerous or even fatal skin reactions (SJS and TEN) are more common in those with HLA-B*1502 This allele is almost exclusively found in Asians In 10-15% of population in China, Thailand, Malaysia, Indonesia, the Phillipines, and Taiwan 2-4% in India <1% in Japan and Korea 59/60 Asian patients w/ SJS/TEN had this allele vs 4% of CBZ tolerant patients Estimated absolute risk for those with the allele: 5% Asians should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine These patients may also be at risk with other Use drugs not typically associated with rash with similar spectrum of ADR surgery Skin eruption: CBZ, OXC, LTG Weight gain: VPA, PGB, GBP, CBZ Weight loss: ZNS, TPM Nephrolithiasis: ZNS, TPM Cognitive dysfunction: PB, BZD, TPM (high dosage), ZNS, LEV Hyponatremia: OXC, CBZ Hepatotoxicity: FBM, VPA, CBZ, PHT, PB, LTG To remove the epileptogenic lesion aims to make the patients become seizure free or reducing the number of seizure Mesial temporal lobe epilepsy Neocortical temporal lobe epilepsy Extratemporal lobe epilepsy Hemispherectomy Corpus callosotomy Vagal nerve stimulation

26 Mesial Temporal Lobe Associated With Hippocampal Sclerosis Ictal EEG: Rt. fronto-temporal origin Patients with mesial TLE associated with hippocampal sclerosis are excellent surgical candidates Surgical approaches include Amygdalohippocampectomy Standard temporal lobe resections including en bloc resection of the temporal lobe or removal of larger neocortical areas Results of surgery uniformly good Impaired short-term memory and naming most noteworthy complication of dominant anterior temporal lobectomy, especially in patients Without hippocampal atrophy Those with normal memory Ictal EEG: Rt. fronto-temporal origin Ictal EEG: Lt. fronto-temporal origin Ictal EEG: Lt. fronto-temporal origin Temporal lobe epilepsy with bilateral MTS Refractory TLE with bilateral MTS Interictal EEG: Rt > Lt. Ictal EEG: Rt : Lt = 60:40 Interictal PET: lateralized right side Neuropychological test: memory more deficit on the right side The patient had Rt. antero-mesial temporal lobectomy and had only a few seizure without any further memory decline post-operatively 26

27 Nonlesional Focal surgery in Asia: A survey (2004) Localization of seizure focus and surgical therapy are challenging in patients with normal MRI Usually require chronic intracranial studies to define epileptogenic and functional areas Patients with nonlesional ETLE represent most challenging surgical group, owing to Extensive potential areas of seizure origin Complex ictal spread patterns Poorly defined epileptic networks Countries Hong Kong India Indonesia Japan Korea Mongolia Philippines Singapore Ta iwa n Thailand Vietnam Population (million) 6.8 1, N N surgery program Available Pediatric service N N N N No of case/yr Prevalence of pts requiring surgery 4,600 (270/yr) 68,000 (40,000/yr 14,000 (8,400/yr) 8,200 (4,800/yr) 3,200 (1,880/yr) 170 (100/yr) 5,500 (3,200/yr) 300 (170/yr) 1,500 (920/yr) 4,500 (2,180/yr) 5,400 (3,200/yr) Three hospitals had epilepsy surgery program: Chula hospital, PMK hospital and Bangkok hospital New coming centres: Ramathibodee, Prasart Neurological institute, Siriraj hospital Randomized Trials and Long-Term Outcome of Surgery Only one randomized trial has assessed efficacy of surgery compared with medical management After 1 year, patients with intractable TLE, seizure freedom achieved in 58% of surgical group and 8% of medical group Surgery also significantly improved quality of life Randomized Trials and Long-Term Outcome of Surgery Large retrospective, parallel longitudinal study found surgery resulted in Better seizure control than medical therapy 2-year remission rates in surgical group of 68% in patients with TLE and 50% in ETLE Engel J Engel J Randomized Trials and Long-Term Outcome of Surgery In meta-analysis of long term outcome 48% of patients who undergone temporal lobe resection seizure-free, 30-40% of patients who had undergone extratemporal resections After callosotomy, 35% of patients were free of disabling seizures Successful surgery leads to many improvements in social, psychological and overall quality of life Complication surgery can cause Functional impairments (e.g. memory, naming and visual field impairment) Other complications include infection, hemorrhage and stroke Occurring in <2% of patients) Surgery related death occurs in 0.1% of patients 27

28 In conclusion Radiosurgery for epilepsy in Thailand is still under utilized Patient with intractable seizure should be promptly refer to epilepsy surgery center for presurgical evaluation Surgical treatment is beneficial for appropriately selected patients surgery improve QOL and social and occupational function, reduced mortality, direct and indirect health care costs In 1995, Regis et al in Marseille performed selective amygdalo-hippocampal radiosurgery for MTS In 2000, 1 st case with TLE had Gamma knife at Bangkok hospital Radiosurgery for epilepsy Gamma knife in Temporal Lobe (since 2005) 8 cases had Gamma knife 3 casrs with benign tumor mesial temporal lobe Engel class Ia 2 cases with MTS, Engel class II and III 2 cases with hippocampal atrophy Engel class IV 1 case with dual pathology (CD and HS) Engel class Ia One case has eyes opsoclonus post radio-surgery Vagal nerve stimulation in epilepsy 6 cases were implanted at Bangkok hospital since 2005 Seizu re free none Seizu re redu ced > 5 0 % 4 Seizu re u n ch an ged - 2 At present, 22 cases had been treated with VNS, most benefit with seizure reduction but no one became seizure-free 5 cases had been implanted VNS at the Bangkok hospital 2 case had been done in PMK hospital in 2014 surgery in Refractory Status epilepticus Although rarely undertaken, surgery plausible option where electrographic SE remains focal, particularly if there is evidence causal structural lesion The same criteria can be extended to acute setting of refractory focal SE., however, consideration of postoperative deficits and prospect of long-term seizure freedom should be weighed against the risks associated with ongoing focal SE Identification of a structural lesion or functional region requires correlation of EEG with MRI and functional (usually PET or SPECT) imaging Reports of successful treatment of refractory focal SE by surgical removal of an underlying structural lesion, particularly in the pediatric Surgery generally lesionectomy, partial or complete lobectomy 28

29 Girl 4 year old Presenting with seizures, spastic quadriparesis, right facial palsy F 88 years old Presenting with dizziness, headache and ataxia Later on, had alteration of consciousness 64 29