Managing Patients with Seizure Disorders while Waiting for the Neurology Consult

Managing Patients with Seizure Disorders while Waiting for the Neurology Consult Paolo Federico MD, PhD, FRCPC Associate Professor Departments of Clinical Neurosciences and Diagnostic Imaging 14 Jul 2016 Family MD Resident Academic Half Day

Disclosures UCB speaker fees, advisory board member Sunovion advisory board member 2

Learning Objectives Describe the management of the newly diagnosed patient with a seizure disorder Review how to manage when the epileptic patient is not in good control Select the appropriate medication Describe the role of older medications Identify important drug-drug interactions 3

Outline Background First seizure New epilepsy diagnosis Refractory seizures 4

New Definition of Epilepsy Epilepsy is a disease of the brain defined by any of the following conditions 1. At least two unprovoked (or reflex) seizures occurring >24 h apart 2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years 3. Diagnosis of an epilepsy syndrome Fisher et al. (2014) Epilepsia 55:475-482.

Background 1-2 % of the population has active epilepsy 300,000 Canadians have epilepsy About 50 million worldwide affected 3 % will have epilepsy at some time in their life 10 % lifetime chance of having at least 1 seizure (any cause) 6

Etiology Most common known cause in: 1. Older adults (> 45 yrs) 2. Children (< 15 yrs) 3. Young adults (15-24 yrs) 7

New Classification of seizures (2010) - - OLD Partial Simple partial seizure Complex partial seizure Secondarily generalized tonic-clonic seizure NEW Focal Focal non-dyscognitive seizure Focal seizure with dyscognitive features Focal seizure evolving to bilateral convulsions

EEG - interictal discharges Focal Generalized FP1-F3 F3-C3 C3-P3 P3-O1 FP2-F4 F4-C4 C4-P4 P4-O2 Interictal discharge 1 sec 9

Outline Background First seizure New epilepsy diagnosis Refractory seizures 10

Case 1 You are in clinic and are asked to see a 55 year old male who recently had his first witnessed generalized tonic-clonic seizure. What pertinent details do you wish to know on history? 11

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Case 1 Patient had first unprovoked seizure. No precipitating factors. No epilepsy risk factors. What would you do? What advice would you give? 13

Management of first seizure After first unprovoked seizure CBCd, lytes, BUN, glucose, Ca2+, Mg2+, PO4-, ECG CT head Routine EEG Restrict Class 5 license & other risky activities for 3 months Restrict commercial driving for 1 year No AED treatment necessary (with rare exceptions) Lifestyle discipline Avoidance of sleep deprivation, alcohol and other intoxicants. Bathing, driving, work issues 14

Outline Background First seizure New epilepsy diagnosis Refractory seizures 15

Case 1 continued. Blood work, CT head, and routine EEG were unremarkable and patient had driving restriction for 3 months. ************************************* 1 year later, patient sees you after having several brief blank spells during which he is seen to smack his lips. Patient states he has been having brief spells of smelling/tasting blood for the past 3 months. What do you think is going on? 16

New Classification of seizures (2010) - - OLD Partial Simple partial seizure Complex partial seizure Secondarily generalized tonic-clonic seizure NEW Focal Focal non-dyscognitive seizure Focal seizure with dyscognitive features Focal seizure evolving to bilateral convulsions

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Mesial Temporal Lobe Epilepsy +/- aura: Rising epigastric sensation, nausea, butterflies, fear, emptiness, déjà vu, olfactory or gustatory hallucinations +/- autonomic symptoms: Flushing, pupillary dilation, pallor, cyanosis, etc. +/- automatisms: Purposeless, involuntary motor activity that occurs during a state of impaired consciousness either in the course of or after an epileptic seizure Initial behavioral arrest or brief motionless stare may precede or accompany Oro-alimentary automatisms = lip smacking, chewing, swallowing Limb automatisms = picking, fumbling. Usually ipsilateral to seizure onset zone, by can be contralateral +/- dystonia: is contralateral to seizure onset zone

Case 1 What investigations would you like to order? How would you manage the patient? Any restrictions? 20

Initial Management of Epilepsy After second unprovoked seizure MRI brain (seizure protocol) Sleep-deprived EEG (if routine EEG non-diagnostic) Restrict private driving for 6-12 months and start anticonvulsant treatment Daily folic acid supplementation for young females (> 1 mg) After first seizure + suspected focal onset by history/examination Same as for after second seizure, but restrict driving for 6 months 21

Management of Epilepsy Education and counselling Avoidance of sleep deprivation, alcohol and other intoxicants. Bathing, driving, work issues Situation Private Drivers Professional Drivers 1 st unprovoked sz & pt neurologically normal After epilepsy diagnosis 1 st sz in pt neurologically AbN or new acquired problem (e.g., old or new stroke) Seizures in sleep or immediately upon awakening Simple partial seizures only CMA Driving Guidelines CMA Driving Guidelines 3 months 12 months 6 months (12 months if >1 seizure/year in past 2 years) 5 years seizure free 6 months 5 years seizure free Same as above but if ongoing seizure and all in sleep or upon wakening x 1 year can drive 1 yr (and neurologist approval; no impairment in consciousness; no head/eye deviation) No driving commercial vehicles for at least 5 years 3 years (& all other conditions as for private drivers) Initial medication withdrawal 3 months 6 months Sz recurrence after med withdrawal 3 months 6 months Alcohol withdrawal induced seizures Drive if: (1) remain alcohol and seizure free x 6 months; (2) complete a recognized rehabilitation program for substance dependence; (3) compliant with treatment 22

Case 1 Repeat sleep-deprived EEG shows right temporal epileptiform discharges. MRI shows right mesial temporal sclerosis. 23

MRI - Hippocampal Sclerosis Right Left 24

MRI - Hippocampal Sclerosis Right Left 25

Courtesy of Dr. J. Joseph 26

Initiating treatment Explain to patient: Treatment is not curative First drug might not be successful Wait several average seizure intervals before deciding on efficacy Main goal is no seizure - no side effects but need to consider: Need for COMPLETE seizure control Susceptibility to side effects Ease of use Cost What type of seizures/epilepsy does the patient have? Maintain seizure diary to monitor treatment benefit 27

Initiating treatment Start low and go slow, unless rapid titration is required If rapid titration required, consider phenytoin, carbamazepine, valproic acid, levetiracetam Watch for allergic side effects (esp. rash) Some side effects may be short-lived Monotherapy is preferred 28

Basic Treatment Strategies Focal Phenytoin, carbamazepine Clobazam Lamotrigine, levetiracetam, topiramate (if not in a hurry to treat) Generalized Valproic acid Lamotrigine Ethosuximide (absence seizures only; will not treat generalized tonic clonic seizures) Others: phenytoin, levetiracetam, topiramate Uncertain (?focal vs generalized) Phenytoin, valproic acid, lamotrigine, topiramate, levetiracetam, clobazam Note: consider avoiding valproic acid and phenytoin in young women (fetal malformations) 29

Drug Starting Dose* Typical initial maintenance dose Carbamazepine (Tegretol CR) Clobazam (Frisium) Lamotrigine (Lamictal) Levetiracetam (Keppra) Phenytoin (Dilantin) Topiramate (Topamax) Commonly used medications 200 mg qhs 400 mg bid 15 days 5 mg qhs 10 mg qhs 1 week 25 mg qhs* 100 mg bid 7 weeks 250 mg qhs 500 mg big 4 weeks Typical titration period 300 mg qhs 300 mg qhs Can give oral loading dose (approx 250-500 mg bid x 2 doses) as outpatient 25 mg qhs 100 mg bid 7 weeks Valproate (Epival) 250 mg qhs 500 mg bid 15 days * Suggest starting an anticonvulsant medication at night to minimize the perception of side effects. The only exception is lamotrigine which can be associated with insomnia à recommend taking it at supper instead of bedtime 30

Monitoring Consider pretreatment CBC, BUN, Cr, liver enzymes and at 3 months (esp. for carbamazepine, valproic acid, phenytoin) Therapeutic range for anticonvulsants are only guidelines Treat the patient not the drug level Consider other pharmacokinetic factors: Auto-induction of carbamazepine after 4-6 weeks Zero order kinetics of phenytoin Constant fraction of drug eliminated per unit time Constant amount of drug eliminated per unit time 31

Drug Interactions Antiseizure Meds 32

Outline Background First seizure New epilepsy diagnosis Refractory seizures 33

Case 1 Despite trying carbamazepine 400 mg bid, patient continues to have focal dyscognitive seizures. What should you do? 34

Failure of first AED Ensure compliance and following lifestyle counseling Rule out drug interactions, poor absorption, etc. Check AED levels Increase dose, if possible Beware of zero order kinetics of phenytoin! If the above steps have been followed Add a second AED +/- down titration of first AED after therapeutic dose of second AED is achieved (if possible) Driving restrictions must be maintained 35

Medication side effects Ensure dose is not too high Check levels, if applicable Treat the patient, not the drug level! Ensure no drug-drug interactions are occurring If the above steps have been followed Down titrate AED either completely or to previously tolerated dose (if this dose provided adequate coverage) Restrict driving and dangerous activities for 3 months If the first AED needs to be discontinued, start a second AED once side effect has cleared (if it does) 36

Case 1 The patient was following all treatment recommendations and the carbamazepine level was in the high therapeutic range. Clobazam was added. Despite trying carbamazepine 400 mg bid (with therapeutic levels) and clobazam 20 mg qhs for 3 months, the patient continues to have focal dyscognitive seizures. What should you do? 37

Drug Resistant Epilepsy Drug resistant epilepsy: failure of adequate trials of TWO tolerated and appropriately chosen and used AEDs (as monotherapies or in combination) to achieve seizure freedom Medication resistant (36%) Probability of Seizure Freedom with Antiepileptic Drug Use Seizure free with 1st drug (47%) Seizure free with 3rd drug (3%) Seizure free 2nd drug (14%) Kwan and Brodie (2000) NEJM 342:314-319.

Basic Epilepsy Surgery Investigations Video-EEG monitoring MRI Need special sequences 5 mm (no spacing) coronal slices through temporal lobe 3D whole brain volume acquisition (3D SPGR) SPECT Hypoperfusion (interictal) or hyperperfusion (ictal) at focus PET Hypo- (interictal) at focus Neuropsychology testing Psychology/Psychiatry consultation Standard protocol Epilepsy protocol 39

Basic Treatment Strategies Focal Phenytoin/carbamazepine (400 mg bid) Clobazam (20 mg qhs) Lamotrigine/levetiracetam/topiramate (if not in a hurry to treat) Generalized Valproic acid Lamotrigine Ethosuximide (absence seizures only; will not treat generalized tonic clonic seizures) Others: phenytoin, levetiracetam, topiramate Uncertain (?focal vs generalized) Phenytoin, valproic acid, lamotrigine, levetiracetam, clobazam, topiramate, Note: consider avoiding valproic acid and phenytoin in young women (fetal malformations) 40

Old AEDs OLD Carbamazepine (Tegretol) Clobazam (Frisium) Phenobarbital Phenytoin (Dilantin) Valproate (Epival) NEW Gabapentin (Neurontin) Lamotrigine (Lamictal) Levetiracetam (Keppra) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Topiramate (Topamax) VERY NEW Lacosamide (Vimpat) Perampanel (Fycompa) Rufinamide (Banzel) Eslicarbazepine (Aptiom) 41

Role of old AEDs Carbamazepine (Tegretol) Focal epilepsy Less well tolerated in the elderly Clobazam (Frisium) Focal or generalized epilepsy Good add-on medication Drug shortages have occurred recently Phenobarbital Focal or generalized epilepsy Less commonly used due to long half life and very long down titration period Phenytoin (Dilantin) Focal or generalized epilepsy Good for rapid up-titration, if necessary Higher risk of fetal malformations Valproate (Epival) Focal or generalized epilepsy Good for rapid up-titration, if necessary Highest risk of fetal malformations of all AEDs 42

Summary: Management Strategies First seizure Blood work, EKG, EEG, CT head Restrict driving for 3 months Second seizure (or epilepsy diagnosis) Sleep-deprived EEG, MR brain Start AED and folate (if appropriate) Restrict driving for 6-12 months Seizures not responding to first AED Add second AED, if first AED is at maximum tolerated dose +/- down titration of first AED Refractory seizures Refer to neurology/epilepsy clinic In the meantime, add a third AED +/- down titration of one of the first two AEDs 43

Summary: Other Drug levels Treat the patient, not the drug level Beware of zero order kinetics of phenytoin Drug-drug interactions Beware of AEDs that can induce liver clearance (e.g., carbamazepine, phenytoin, phenobarbital, oxcarbazepine) Old AEDs Are effective and inexpensive options Particularly useful in patients without a drug plan and limited financial resources 44

Questions? Thank you pfederic@ucalgary.ca 45