Julia B. Toub, MD Providence Brain & Spine Institute November 17-18, 2016

Transcription

1 Julia B. Toub, MD Providence Brain & Spine Institute November 17-18, 2016

2 I have no financial relationships to disclose.

3 1. To provide an overview of the diagnosis and management of patients with epilepsy, including new onset seizure. 2. To review available pharmacologic and nonpharmacologic therapies for patients with epilepsy. 3. To introduce providers to the range of epilepsy services available in the Providence Portland health system.

4 1. Seizure: the clinical manifestation of an abnormal and excessive synchronization of a population of cortical neurons. 2. Practical definition of epilepsy (2014) 2 unprovoked seizures separated by at least 24 hours. 1 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 Epilepsy Syndrome 3. Epileptogenesis: The process by which normal brain undergoes changes that generate seizure.

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6 Worldwide prevalence ~ 50,000,000 underestimated due to: Limited access to healthcare Social/cultural stigma ~3,000,000 Americans As common as breast cancer with a similar mortality. 10% of the population will have a seizure at some point in their lives; 1-3% will be diagnosed with epilepsy. 4 th most common neurological disease after migraine, stroke, and Alzheimer s disease

7 Seizures classified on the basis of: 1. Localization (focal vs. generalized vs. unknown onset) 2. Seizure subtype (semiology with distinction between retained/altered awareness) 3. Epilepsy etiology Genetic (previously idiopathic): Presumed genetic basis, usually onset in childhood but some in early adulthood. Structural-metabolic (previously symptomatic): Related to tumor, TBI, cortical dysplasia, infection, etc. Unknown (previously cryptogenic) 4. Epilepsy Syndrome (if applicable) Examples: Lennox Gastaut Syndrome, JME, Childhood absence epilepsy

8 Seizures arising from the whole brain all at one time Seizure subtypes a. Absence b. Tonic-Clonic c. Tonic d. Clonic e. Myoclonic f. Atonic/Astatic Generalized Epilepsy Syndromes a. Childhood absence epilepsy (CAE) b. Juvenile absence epilepsy (JAE) c. Juvenile myoclonic epilepsy (JME) d. Generalized epilepsy with febrile seizures plus (GEFS+) e. Benign myoclonic epilepsy in infancy f. Epilepsy with myoclonic absences

9 Seizures arise from part of the brain. Focal seizure subtypes a. Without dyscognitive features: No alteration in level of consciousness. *** Previously simple partial b. With dyscognitive features: Accompanied by altered consciousness. *** Previously complex partial c. Secondarily generalized Focal epilepsy syndromes a. Most focal epilepsies are not associated with any classified epilepsy syndrome b. Benign Rolandic epilepsy c. Childhood Epilepsy with Occipital Paroxysms d. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

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13 Isolated unprovoked generalized tonic-clonic seizure lasting < 3 minutes: History CMP CBC Tox screen If no head trauma, no imaging necessary Driving restriction Reassurance Pregnancy test Provoked seizure: Remove offending agent

14 Diagnosis: Establishing a diagnosis (epileptic vs. nonepileptic events) Characterization of epilepsy (generalized vs. focal) Identification of epilepsy syndrome Identify triggers (photosensitivity, sleep deprivation) Management: Assessing risk of recurrence after single unprovoked seizure Guiding selection of appropriate anticonvulsant Localizing seizure focus Surgical planning Assessing mental status change Evaluating for nonconvulsive status epilepticus Monitoring/guiding treatment in status epilepticus Risk stratification for seizure recurrence prior to taper off anticonvulsants Prognostication in the ICU setting

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16 Psychiatric: clozapine Analgesic: (common), SSRIs/TCAs (rare), (common), Antibiotics: PCN, Cephalosporins, Imipenem, Amphotericin B Pulmonary: Aminophylline Immunologic: Cyclosporin

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18 Borrowed from Rudzinski, et. al, Journal of Investigative Medicine June 2016

19 Confirm a diagnosis of epilepsy (+/-) Determine seizure subtype (history, EEG, imaging) How quickly does medication needs to be introduced? Consider comorbid conditions, social circumstances, finances, etc. Cost Mechanism of action

20 BROAD SPECTRUM NARROW SPECTRUM OLDER Valproic Acid/Divalproex * Carbamazepine (focal) Ethosuximide (absence) Phenobarbital (focal>generalized) Phenytoin (focal>generalized) Primidone (focal) NEWER Lamotrigine * Levetiracetam * Topiramate * Zonisamide Perampanel Brivaracetam (focal) Clobazam (Lennox Gastaut) Eslicarbazepine (focal) Ezogabine (focal) Felbamate (focal; severe refractory) Gabapentin (focal) Lacosamide (focal) Oxcarbazepine * (focal) Pregabalin (focal) Rufinamide (Lennox Gastaut) Tiagabine (focal) Vigabatrin (focal, infantile spasms) * Available in once-daily extended release formulation

21 Newer AEDs have fewer side-effects. Choose broad spectrum coverage if unsure of seizure subtype: 1. Levetiracetam 2. Lamotrigine 3. Valproic acid 4. Topiramate 5. Zonisamide (approved only as an adjunct in treatment of partial seizures, though it does have broad-spectrum efficacy). Focal epilepsy agents can exacerbate generalized epilepsies CBZ, OXC, ESL, GBP, PRG

22 Comorbid mood disorder? Consider LTG, VPA, OXC (focal epilepsy only) Avoid LEV, BRV, PER Neuropathic pain? GBP, PRG, CBZ, OXC Migraine? TPM, VPA, GBP, PRG Hepatic dysfunction? LEV Poor compliance or wearing off? Consider XR formulations

23 Stevens Johnson Syndrome with lamotrigine Rare Most often associated with rapid initiation Increased risk with co-administration of VPA PHT, CBZ, PHB, PRM, and VPA hasten bone loss. Assess for vitamin D deficiency Supplement vitamin D at least 2,000 IU per day DEXA VPA: weight gain, tremor, hirsutism, GI upset, hematologic, hepatic/pancreatic dysfunction, osteoporosis Patients on warfarin: Avoid VPA, PHT, PHB, CBZ, and primidone if possible

24 TPM: Cognitive slowing, kidney stones, weight loss, rare acute angle closure glaucoma LEV: Dizziness, fatigue, insomnia, irritability, mood changes/depression, rare overt psychosis. Renally cleared; needs re-dosing after dialysis Patients of Asian decent with HLA-B*1502 have increased risk of Stevens Johnson Syndrome with CBZ, OXC, ESL CBZ, OXC, ESL: hyponatremia Felbatol: Aplastic anemia

25 XR formulations and brand-only medications are more expensive All AEDs carry small increased risk of suicide Esp. LEV, BRV, and PER Perampanel: Homicidal ideation Marijuana: No FDA indication

26 Chronic adverse effects: Gingival hyperplasia, osteoporosis, hepatic dysfunction, hirsutism, weight gain, dermatitis, neuropathy, cerebellar atrophy Multiple drug-drug interactions At high doses, beware of dramatic changes in serum levels with small change in dose Phenytoin metabolism is dose dependent. c/p1/ch20/ch2003.html

27 Women of childbearing age Potential for teratogenicity of ALL AEDs Newer AEDs better than older AEDs Folic acid in ALL women of childbearing potential LTG and LEV levels drop in pregnancy Other AEDs: Possible reduction in contraceptive efficacy; secondary contraception should be used. Women of all ages LTG: Estrogen-containing OCPs increases LTG clearance and may decrease levels by as much as 50%. VPA: Hirsutism, weight gain

28 SUDEP has been defined as the sudden, unexpected, witnessed or unwitnessed, non-traumatic, and nondrowning death in patients with epilepsy, with or without evidence for a seizure, with exclusion of documented status epilepticus, and when post-mortem examination does not reveal a structural or toxicological cause for death (Nashef, 1997) fold risk of sudden death in epileptic patients relative to the general population. Annual risk 0.1% per year in all patients with epilepsy Risk increases to ~0.6% per year in patients with poor seizure control. Sudden Unexplained Death In Epilepsy. Shorvon. The Lancet, Volume 378, issue 9808 (December ), p

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30 No uniform definition for status epilepticus exists. Recent data recommends aggressive treatment following 5 minutes of convulsion. Rationale for early treatment: Permanent neurological damage occurs following 30 minutes of seizure activity. Seizures beget seizures : Persistent seizures produce physiologic changes that potentiate further seizure activity. Synapses increase through axonal sprouting Apoptosis of inhibitory neurons Loss of excitatory input to inhibitory neurons Local changes in ion channels and conductivity

31 Seizures persisting > 5 minutes becoming progressively intractable to AEDs. Beware of subclinical seizure and non-convulsive status epilepticus. Continuous EEG monitoring Adverse consequences include hypoxia, hypotension, cardiac arrhythmia, acidosis, aspiration pneumonia, rhabdomyolysis, hyperthermia, and death.

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38 Elective (usually) admission for diagnostic purposes, seizure classification, and/or pre-surgical evaluation Should be considered in patients with continued seizures despite therapeutic levels of AEDs Continuous video EEG monitoring Added stresses to provoke events in question: Reduced/discontinuation of medications Sleep deprivation Hyperventilation Photic stimulation Exposure to agents known to provokes seizures in individual patients Important to capture ALL of the patient s events-some patients may have epileptic and nonepileptic events.

39 PNES, PNEE, spells, fits, pseudoseizures, convulsions +/- prior psychiatric diagnoses Common co-morbidities: Anxiety Depression Bipolar disorder Hx/o multiple life stressors, psychosocial trauma, etc. Other diagnoses with strong somatic components: IBS, complex regional pain syndrome, reflex sympathetic dystrophy, fibromyalgia. Conversion/somatization disorder. No AEDs indicated unless accompanied by true epileptic seizures (e.g. lamotrigine for bipolar disorder). Reassurance, referral to psychiatry/mental health specialists (cognitive behavioral therapy).

40 Psychiatric comorbidities are more common in epileptic patients than in the general population- 50% of epilepsy patients. Depression/bipolar Anxiety Psychosis Somatization: 30% of patients have psychogenic spells which are non-neurological in origin. Uncontrolled psychiatric symptoms = uncontrolled seizures. Mental health resources are scarce Insurance Lack of comfort with treatment of psychogenic spells

41 Neuroanatomical/neurochemical Psychosocial Medication? Genetics

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43 ~1/3 epileptic patients. International League Against Epilepsy (ILAE): When a person has failed to become (and stay) seizure free with adequate trials of two seizure medications. Antiepileptic medications (AEDs) must be appropriate for seizure subtype and utilized in dosages sufficient to treat seizures.

44 Evaluate reasons for poor seizure control: Is the diagnosis correct? Are the prescribed medications appropriate? Are medications being taken as directed? Are there other factors that may be contributing to seizure control? Excessive stress Poor sleep Effects of other health conditions Missed medication doses Alcohol, illicit substances Drug-drug interactions Concurrent use of medications that lower the seizure threshold

45 All patients with medically refractory seizure disorder should be referred to an Epilepsy Center.

46 Surgical Resection Neuromodulation Neuroablation Epilepsy Diet

47 Who? Focal seizure disorder Failure of 2 or more seizure medications Favorable candidates: All seizures look similar /arise from one focus Temporal lobe epilepsy Underlying lesion (cortical dysplasia, tumor) No involvement of eloquent areas Electrophysiologic and imaging data are concordant

48 T1 Low-grade glioma FLAIR Cortical Dysplasia Mesial Temporal Sclerosis

49 Vagal Nerve Stimulation Responsive Neurostimulation External Trigeminal Nerve Stimulation Deep Brain Stimulation

50 Both generalized and focal epilepsies. Pacemaker-sized generator implanted. Generator delivers pulses to the vagus nerve at regular intervals via thin lead. Mechanism poorly understood. Patient modulates through magnet swipe. Noninvasive programming in the office. Efficacy similar to addition of another medication. Side effects: Cough, voice change, tickling at the back of the throat, changes in heart rate rarely vocal cord paralysis. Battery life up to ~10 years. MRI limitations.

51 Who?: >18 years old with medically refractory focal epilepsies who are not candidates for surgical resection. Seizure foci (up to 2) must be clearly identified. What? - Device is implanted in skull. - Electrodes are placed at seizure focus. How? - Detects early changes in brain activity and deliver stimulation to prevent propagation of a seizure. - Programmed noninvasively by physician.

52 MRI-guided thermal laser ablation New indication for epilepsy Uses laser contained within cooling sheath to target focal lesions while preserving surrounding tissue. MRI-guided, less invasive (small hole in skull) Applications: - Focus not easily accessed with more conventional surgery. - Multiple foci (tubers, cortical dysplasias).

53 Ketogenic Diet Modified Atkins Diet Low Glycemic Index Diet All diets must be monitored by a dietitian/nutritionist and your doctor

54 Epilepsy is common. All that shakes is not seizure. All seizures do not shake. 2/3 of patients with epilepsy are well-controlled with antiepileptic medications. Medications should be carefully selected based on seizure subtype and medical/psychiatric comorbidities. Use of the EMU to differentiate between epileptic and nonepileptic events is imperative to providing patients with appropriate treatment. Non-epileptic events do not preclude the coexistence of epileptic seizures.

55 Poor seizure control can result in permanent neurological sequelae and increases the risk for sudden death. Medically refractory epilepsy = failure of 2 or more AEDs. All medically refractory patients should be referred to an epilepsy center as soon as intractability is evident. Optimization of seizure control has a tremendous impact on patients quality of life.

56 1. NAEC accredited epilepsy clinic 3 board-certified epileptologists, an epilepsy NP, epilepsy RN First seizure clinic Appointments at PSV and PPMC Tele-epilepsy (Seaside, Hood River) 2. 4-bed Epilepsy Monitoring Unit (PPMC) 3. Comprehensive EEG services Outpatient and inpatient routine and continuous EEG monitoring 24/7 EEG coverage Tele-EEG Ambulatory EEG 4. Neuroradiology: 3T MRI PET fmri angiography 5. Surgical options Vagal nerve stimulator Invasive pre-surgical evaluations * Surgical resections * 6. Nutritional counseling/epilepsy diet 7. Clinical trial enrollment opportunities 8. Neuropsychological assessment * * Collaboration with other centers/practitioners

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58 Berg, etal. New concepts in classification of the epilepsies: Entering the 21st century inepilepsia, 52(6): , Bodde, NMG et.al. Psychogenic Non-Epileptic Seizures-Diagnostic Issues: A Critical Review in Clinical Neurology and Neurosurgery 111(2009) 1-9. Fattore, Cinzia; Perucca, Emilio. Novel Medications for Epilepsy. Drugs 2011: 71 (16) Fischer, et al. A practical Definition of Epilepsy in Epilepsia, 55(4): , Knake, Susanne et.al. Status Epilepticus: A Critical Review in Epilepsy and Behavior 15 (2009) Kohrman, Michael H. What Is Epilepsy? Clinical Perspectives in the Diagnosis and Treatment in J Clin Neurophysiol 2007;24: Noachtar, S et. al. Epilepsy surgery: a critical review. Epilepsy Behavior May;15(1): Epub 2009 Feb 21. Pitkanen, et. al. Mechanisms of epileptogenesis and potential treatment targets. The Lancet Neurology, Vol. 10, February Rabinstein, Alejandro. Management of Status Epilepticus in Adults in Neurol Clin 28(2010) Rosetti, A and Lowenstein, D. Management of refractory status epilepticus in adults: still more questions than answers in Lancet Neurology 2011; 10: Schmidt, Dieter. Drug Treatment of Epilepsy: Options and Limitations in Epilepsy and Behavior 15 (2009) Shorvon. Sudden Unexplained Death In Epilepsy.The Lancet, Volume 378, issue 9808 (December ), p

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