Julia B. Toub, MD Providence Brain & Spine Institute November 12-13, 2015

Transcription

1 Julia B. Toub, MD Providence Brain & Spine Institute November 12-13, 2015

2 I HAVE NO FINANCIAL RELATIONSHIPS TO DISCLOSE.

3 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.

4 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.

5 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

6 Onset age 4-8 years Clinical: Brief staring spells Daydreaming, Eye-flutter +/- GTC Classic EEG 3-HZ spike-wave Juvenile absence epilepsy is similar but with onset age 9-13 years and longer/less frequent absences.

7 Common. ~25% of genetically-based generalized epilepsy and ~10% of all epilepsies +/- seizures in childhood Onset usually during teenage years; infrequently in 20s and 30s. Hereditary component; genetically heterogeneous and often no family history Clinical GTC, myoclonic, absences, especially in AM Klutzy, frequently dropping things Triggers: sleep-deprivation, EtOH, psychological stressors Photosensitivity Requires lifelong therapy Typical EEG: Generalized spike/poly-spike wave

8 Generalized epilepsy with febrile seizures plus (GEFS+) Familial epilepsy syndrome GTCs during illness (usually febrile illness) Autosomal dominant; heterogeneous inheritance pattern with incomplete penetrance SCN1A mutation (sodium channel neuronal type 1 alpha subunit) most common but some other genes may also be implicated. Some patients stop having seizures in mid-childhood but others persist to have GTCs later in life along with other seizure subtypes.

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

10 May originate from any single focus or multiple foci. Temporal lobe epilepsy The most common focal epilepsy Mesial temporal > lateral temporal. Structural-metabolic: Associated with the neurocutaneous syndromes: TS, NF1, NF2, Sturge Weber (overlap with genetic subclass) Secondary to prior neurological insults (stroke, tumor) Malformations of cortical development/cortical dysplasias Vascular malformations Benign childhood occiptal epilepsies: Benign rolandic epilepsy, Panayiotopoulos syndrome.

11 Frontal: Primary motor area: Jacksonian march, often escalating to GTC. Supplementary motor area (SMA): Hypermotor, asymmetric tonic, brief, may lack postictal period. Lateral Temporal: Auditory/visual hallucinations, vestibular symptoms, language impairment (dominant) Mesial Temporal: Epigastric/olfactory/gustatory aura, prodromal fear, orolingual automatisms, dysautonomia. Memory compaints Parietal: Somatosensory symptoms, visual illusions/hallucinations, distortions of body image. Occipital: Forced eye deviation, visual hallucinations, visual perseverations (palinopsia).

12 Medically refractory seizures with mental retardation; multiple etiologies. Onset early, usually age <5 years but case reports as late as age % are idiopathic (genetic vs. unknown). 70% associated with prior insult or epileptic encephalopathy: Encephalitis and/or meningitis Tuberous sclerosis Brain malformations (e.g., cortical dysplasias) Birth injury Hypoxic-ischemic injury Frontal lobe lesions Trauma 9-39% of cases are preceded by West Syndrome: Infantile spasms Classic hypsarrhythmia EEG Mental retardation

13 Three categories proposed by ILAE in 1989 and revised in Genetic (previously idiopathic): Presumed genetic basis, usually onset in childhood but some in early adulthood. 2. Structural-metabolic (previously symptomatic): Related to tumor, TBI, cortical dysplasia, infection, etc. 3. Unknown (previously cryptogenic)

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16 HYPER-SYNCHRONIZATION OF CORTICAL NEURONS Increased excitatory post synaptic potentials (EPSPs) Glutamate* Aspartate Decreased inhibitory post synaptic potentials (IPSPs) GABA Changes in voltage gated ion channels depolarization Excessive inward Na +, Ca 2+ currents Inadequate inward Cl -, outward K + currents Mutations 1. Voltage-gated Na-channels: GEFS+ (SCN1A, SCN1B, SCN2A1) 2. Voltage-gated Cl-channels: JAE, JME (ClCN)2A 3. Voltage-gated K-channels: TLE (KCND2) Alteration of local ion concentrations

17 emedicine.com

18 Isolated unprovoked generalized tonic-clonic seizure lasting < 3 minutes without localizing features: History CMP CBC Tox screen If no head trauma, no imaging necessary Driving restriction Reassurance EEG Pregnancy test Recurrent GTC, prolonged GTC or new onset seizure with focality, complete the above and: CT to r/o acute injury; if available, MRI. Initiation of AED therapy In any case in which history or EEG demonstrate focality, MRI is indicated.

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

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21 Quotes-To-Describe-Your-Mother-In-Law-3.jpg

22 Borrowed from Joseph I. Sirven, AAN Fall Conference Epilepsy Uldate (10/2015)

23 AED Mechanisms Of Action Mechanisms: 1. Blockage of inward Na+ currents: CBZ, LTG, OXC, PHT, TPM, VPA, ZNS 2. Enhancement of GABAmediated Cl- currents: clonazepam, tiagabine. 3. Blockage of T-type calcium channels: ETX 4. Blockage of glutamatemediated currents Many AEDs have overlapping MOAs. Some without well-defined MOAs (i.e. LEV).

24 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. Mechanism of action.

25 BROAD SPECTRUM OLDER Clonazepam Valproic Acid/Divalproex * NEWER Lamotrigine * Levetiracetam * Topiramate * Zonisamide NARROW SPECTRUM Carbamazepine Ethosuximide Phenobarbital Phenytoin Primidone Clobazam Eslicarbazepine Ezogabine Felbamate Gabapentin Lacosamide Oxcarbazepine * Perampanel Pregabalin Rufinamide Tiagabine Vigabatrin * Available in once-daily extended release formulation

26 Newer AEDs have fewer side-effects. Choose broad spectrum coverage if unsure of seizure subtype: 3. Valproic acid (better for generalized seizures) 4. Topiramate 5. Zonisamide (approved only as an adjunct in treatment of partial seizures, though it does have broad-spectrum efficacy). Focal epilepsy agents (CBZ, OXC, ESL, GBP, PRG) may worsen generalized epilepsies. Generalized seizures only: Levetiracetam, lamotrigine, valproic acid, sometimes topiramate. Focal onset: Levetiracetam, lamotrigine, oxcarbazepine, lacosamide, carbamazepine.

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

28 Stevens Johnson Syndrome with lamotrigine 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, hair loss, GI upset, hematologic, hepatic/pancreatic dysfunction, osteoporosis Patients on warfarin: Avoid VPA, PHT, PHB, CBZ, and primidone if possible.

29 TPM: Cognitive slowing, kidney stones, weight loss, rare acute angle closure glaucoma. LEV: Irritability, mood changes, 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 Newer AEDs- Clobazam, lacosamide, rufinamide, eslicarbazepine, perampanel. XR formulations are expensive, require prior authorization. All AEDs carry small increased risk of suicide. Perampanel: Increased homicidal ideation.

30 PHT: Gingival hyperplasia, osteoporosis, hepatic dysfunction, hirsutism, weight gain, dermatitis, neuropathy, cerebellar atrophy. At high doses, beware of dramatic changes in serum levels with small change in dose. Phenytoin metabolism is dose dependent. Low drug concentrations: Elimination follows first-order kinetics Fixed percentage of drug metabolized during a per unit time High drug concentrations: Zero-order kinetics Fixed quantity of drug metabolized per unit time Due to saturation of metabolic pathways. c/p1/ch20/ch2003.html

31 Women of childbearing age Potential for teratogenicity of ALL AEDs. Newer AEDs better than older AEDs. Consider urine pregnancy test prior to initiation. 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

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33 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

34 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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36 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. Proposed mechanisms: Apnea/Hypoventilation (central or obstructive) hypoxia Dysautonomia Ictal changes in brain perfusion resulting in increased intracranial pressure Highest risk in patients with: Poor seizure control Intractability Multiple AEDs (unclear if AEDs are the cause or multiple AEDs are a marker of intractability) Sudden Unexplained Death In Epilepsy. Shorvon. The Lancet, Volume 378, issue 9808 (December ), p

37 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.

38 21 y.o. Caucasian female with history of MVA and concussion. ROS: Headaches, poor concentration, anxiety, depression, anhedonia, unexplained weight loss confusion. Only epilepsy risk factor is MVA. SH: 5 cigarettes per day, medical marijuana, schooled through grade 10, unemployed, partnered with 2 children under age 2. FH: NC Prior w/u: 3 EEGs and MRI all normal.

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40 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).

41 Psychiatric comorbidities are more common in epileptic patients than in the general population- 50% of epilepsy patients. Depression is VERY common. Physical: Seizures, subclinical hyper-synchronous neural discharges and some antiepileptic drugs may cause acute states of depressive mood on a purely neurobiological basis. Psychosocial: Socioeconomic hardship, impact on employment, disruption in family life, etc. Failure to address and treat psychiatric symptoms results in poor seizure control.

42 53 y.o. AA male with predominantly nocturnal convulsions preceded by a lapse in awareness and a joker grin. Prodromal irritability, per wife. Continued seizures with trials of PHT and LEV monotherapy (some non-adherence). PMH: OSA, remote head trauma with LOC, GERD, asthma, HTN SH: Engineer, married. FH: NC

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44 EMU data and semiology consistent with left temporal lobe epilepsy. Seizure free on LEV XR 750/1500; OXC 300/300 since 10/2014.

45 Prolonged stay in a weightless environment, sequela (X52.XXXS)

46 ~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.

47 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

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

49 Surgical Resection Neuromodulation Neuroablation Epilepsy Diet

50 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

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

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

53 Both generalized and focal epilepsies. Pacemaker-sized generator implanted during minor day-surgery. Generator connects to a tiny electrode in the neck via thin wire. Electrode envelops the vagus nerve in the neck and is programmed to deliver pulses to the vagus nerve in regular intervals. Mechanism poorly understood.

54 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. Magnet

55 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 within a small window taken out of the skull. - Electrodes are placed near the seizure focus. - Efficacy Similar to VNS. - No head-to-head trials between VNS and RNS. How? - Detects early changes in brain activity and deliver stimulation to prevent propagation of a seizure. - Programmed noninvasively by physician.

56 1. Deep Brain Stimulation Relatively new and experimental in the US (approved in Europe) Subcortical stimulation paradigms involving the anterior and centromedian thalamic nuclei, the subthalamic nucleus, the caudate, and the cerebellum 2. Cortical Stimulation: Primarily targeting the hippocampi. Very much experimental. 3. Transcranial Magnetic Stimulation: Little data. Few case reports suggest some benefit.

57 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).

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

59 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. Poor seizure control can result in permanent neurological sequelae and increases the risk for sudden death. 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.

60 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.

61 Bizarre personal appearance (R46.1)

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63 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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