SEIZURES AND EPILEPSY. David Spencer MD. School of Pharmacy 2008

Transcription

1 SEIZURES AND EPILEPSY David Spencer MD School of Pharmacy 2008

2 Outline Definitions and epidemiology Etiology/pathology Pathophysiology: o ogy: Brief overview of molecular and cellular basis of epileptogenesis Evaluation of the patient with seizures Seizure types Epilepsy syndromes Treatment principles

3 Definitions Seizure: paroxysmal episode of neurological dysfunction caused by excessive electrical discharge of CNS neurons Epilepsy: syndrome of recurrent Epilepsy: syndrome of recurrent unprovoked seizures

4 Incidence 10% will have a seizure in their lifetime 1% will have epilepsy 2,000,000-3,000,000 in USA

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7 Incidence of Epilepsy by Etiology: The Elderly Ramsay et al Neurology Mar 9;62(5 Suppl 2):S24-9

8 Acquired vs. Genetic Etiologies Acquired Head trauma CNS infections Stroke Tumors Vascular malformations Neurodegenerative diseases Genetic 200 single gene defects (1% of epilepsy) Polygenic (Complex genetic factors contribute to ~40% of epilepsy)

9 Pathophysiology: Genetic Causes of Epilepsy Gene defects affecting neuronal excitability Ion channel defects Genes encoding development Neuronal migrational disorders Genes encoding cerebral energy metabolism Mitochondrial disorders Genetic Neurodegenerative disorders Progressive myoclonic epilepsies p

10 Mechanisms of Epileptogenesis Hyperexcitability Intrinsic membrane properties of neurons Changes in neural networks

11 Mechanisms of Epileptogenesis Hyperexcitability Intrinsic membrane properties of neurons Changes in ion channels Number of channels Gti Gating properties Voltage dependency Extrinsic Factors Concentration of ions Clearing of ions, neurotransmitters from extracellular space

12 Na+ Channel Channelopathies Generalized epilepsy with febrile seizures + K+ Channel Benign Familial Neonatal Convulsions Ca++ Channel Absence epilepsy

13 Mechanisms of Epileptogenesis Ratio of inhibitory to excitatory synapses Decrease in inhibitory transmission (GABA) Increase in excitatory transmission (Glutamate) Complex interactions Changes in connectivity (plasticity) Hyperexcitability

14 Excitatory and Inhibitory Transmitter Receptors Glutamate Ionotropic Metabotropic GABA GABA A Fast synaptic inhibition i Opens Cl- channel Hyperpolarizes cell GABA B G-protein coupled Opens K+ or Closes Ca2+ channels Prolonged hyperpolarization

15 GABA receptor GABA site Barbiturate site Benzodiazepine site Steroid site Picrotoxin site Diagram of the GABA A receptor From Olsen and Sapp, 1995

16 Acute vs. Chronic Epileptogenesis Acute process initiating a seizure [Na+], [K+], [Ca++], GABA, Glutamate Chronic process converting normal brain into epileptic brain Changes in gene expression Changes in receptors, transporters, ion channels Plasticity

17 Animal Models of Epilepsy Increased Excitation Kainic Acid (parenteral or intracerebral) Stimulates Glutamate receptors Causes prolonged seizures/status epilepticus Leads to hippocampal damage Model of human temporal lobe epilepsy

18 Animal Models of Epilepsy Decreased Inhibition Pentylenetetrazol (PTZ) GABA antagonist Model of absence epilepsy

19 Animal Models of Epilepsy Kindling Electrical Stimulation Repeated subthreshold focal electrical (or chemical) stimulation of hippocampus or amygdala Initial applications produce afterdischarges Increasing severity of clinical i lseizures Spontaneous seizures Maximal Electroshock (MES) Model of Generalized Tonic-Clonic seizures

20 Animal Models of Epilepsy Application of other topical agents Penicillin Aluminum Models of cortical dysplasia

21 Animal Models of Epilepsy Limitations for Drug Development Simple acute seizure models show response of a healthy (not chronically epileptic) p brain to AEDs Efficacy may be model or species specific No good models for several seizure types Rli Reliance on few models dl produces me too drugs

22 Evaluation of the Patient with Seizures

23 Does the Patient Have Epilepsy? Syncope TIA Migraine Sleep disorder Psychogenic event

24 Description of the Typical Attack Is there a warning (aura)? What is the evolutionary pattern What is the patient like after a typical attack?

25 Assess Historical Risk Factors Birth and developmental history History of febrile seizures Acquired brain insults (CNS infection, head injury, stroke) Family history of seizures

26 The Influence of Provocative Factors Sleep deprivation Menses Physical/emotional stress Intercurrent illness Alcohol/drugs Specific Triggers

27 The Physical and Psychological Examinations

28 The Laboratory Examination Serum and urine studies Electroencephalogram Ictal Interictal Neuroimaging

29 The Laboratory Examination Serum and urine studies Electroencephalogram Ictal Interictal Neuroimaging

30 Serum and Urine Studies Serum Chemistries Na+ Ca2+ Glucose Toxicology Screen Antiepileptic p drug levels CBC Serum Prolactin

31 The Laboratory Examination Serum and urine studies Electroencephalogram Ictal Interictal Neuroimaging

32 Focal Epileptiform Discharge

33 EEG: Simple Partial Seizure Right temporal seizure

34 EEG: Simple Partial Seizure Continuation of same seizure Right temporal seizures with maximal phase reversal in the right sphenoidal electrodes

35 Generalized Epileptiform Discharge: Absence Seizure

36 The Laboratory Examination Serum and urine studies Electroencephalogram Ictal Interictal Neuroimaging

37 Arteriovenous Malformation

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40 Cortical Dysplasia (perisylvian)

41 Heterotopic Gray Matter

42 CT vs. MRI % Abnormal CT MRI McLach. Latock Schorner Jabbri Heinz

43 Specialized Neuroimaging Studies PET SPECT Magnetic Resonance Spectroscopy

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45 Subtraction Ictal-Interictal SPECT

46 Classification of Seizures Partial Seizures Generalized Seizures

47 Types of Seizures: Partial Simple Partial Complex Partial Generalized

48 Simple Partial Seizures (Aura) Motor Clonic, Versive, Dystonic Sensory Somatosensory, Visual, Auditory, Olfactory, Gustatory Autonomic Epigastric rising, Sweating, Flushing, Piloerection, Pupillary Dilatation Psychic Fear, Déjà vu, Jamais vu

49 Types of Seizures: Partial Simple Partial Complex Partial Generalized

50 AUTOMATISMS Stereotyped elemental behaviors Usually occur during impaired consciousness in complex partial seizures

51 Automatisms in 79 patients during complex partial seizures Automatism # of pts. Chewing, swallowing, pursing lips 74 Looking around, smiling, grimmacing, crying 43 Attempting to sit up 39 Examining or fumbling with objects 28 Tonic adversive head turning 11 Bilateral arm movements 11 Bilateral leg movements 11 Fighting restraint 7 Verbalization 6 Standing up 6 Walking or running away 6 Source: Delgado-Escueta et al 1987

52 Types of Seizures: Partial Simple Partial Complex Partial Generalized

53 Post-ictal Changes Transient Follows complex partial or generalized tonic-clonic seizures. Confusion, Combativeness Todd s paralysis transient, post- ictal, focal neurological ldeficit i

54 Seizure Types: Generalized Absence Generalized Tonic-Clonic Myoclonic Tonic Atonic

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56 Seizure Types Epilepsy Syndromes

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58 Seizure Type vs. Epileptic p Syndrome A group of signs and symptoms that occur together and characterize a particular abnormality A seizure type is determined by the patient s behavior and EEG pattern during the ictal event. An epileptic syndrome is defined by: Seizure type(s) History EEG (ictal and interictal) Imaging Etiology-Genetics

59 Epilepsy Syndrome Focal (Localization-Related) Generalized Idiopathic (Genetic) Symptomatic or Cryptogenic (Lesional)

60 Epilepsy Syndrome: Example Symptomatic Localization-related Epilepsy Onset in early teens Focal onset seizures Focal right temporal EEG sharp waves MRI shows right hippocampal sclerosis Prognosis X Usually refractory to medications Epilepsy surgery is curative in up to 80-90%

61 Epilepsy Syndrome Focal Generalized (Localization-related) ltd) Idiopathic (Genetic) Symptomatic (Cryptogenic) Mesial Temporal Sclerosis

62 Epilepsy Syndrome: Example Idiopathic Generalized Epilepsy Onset at puberty X Mix of generalized seizures Generalized spike/wave on EEG Normal intellect and neurological exam Normal MRI Treatment tand dprognosis Responds well to monotherapy (VPA or LTG) Unlikely to spontaneously remit

63 Epilepsy Syndrome Focal (Localization-related) Generalized Idiopathic (Genetic) Juvenile Myoclonic Epilepsy Symptomatic (Cryptogenic)

64 Juvenile Myoclonic Epilepsy Onset in teenage years Myoclonic seizures (AM) (A.M.) Generalized tonic-clonic seizures Absence in 10-30% Normal intellect Family history in ~ 50% Excellent response to valproate (Depakote) An idiopathic generalized epilepsy syndrome

65 Epilepsy Syndrome: Example Symptomatic Generalized Epilepsy Onset on childhood Mix of generalized seizures Impaired intellect X Abnormal MRI (multifocal or diffuse abnormality) Generalized slow spike-wave on EEG Prognosis Poor: usually refractory to many medications Non-medical options may be considered

66 Epilepsy Syndrome Focal (Localization-related) ltd) Generalized Idiopathic (Genetic) Symptomatic (Cryptogenic) Lennox-Gastaut Syndrome

67 Treatment Avoid seizure triggers Sleep deprivation Alcohol Medication withdrawal Medications Surgery

68 Unmasking Photosensitivity

69 Treatment for First Seizure? Individualize Decision! Estimate risk of recurrence Overall, 16-62% will recur within 5 years 30% recurrence rate with normal evaluation Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increases relapse risk Individual determination Driving? Working? Consequences of 2 nd seizure? Reference: First Seizure Trial Group. Randomized Clinical Trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic- clonic seizure. Neurology 1993; 43 (3, part1): Reference: Camfield P, Camfield C, Dooley J, Smith E, Garner B. A randomized study of carbamazepine versus no medication after a first unprovoked seizure in childhood. Neurology 1989; 39:

70 37%

71 TREATMENT GOAL Complete seizure control No side effects

72 Antiepileptic Drug Choice Adverse effects Individual circumstances Effectiveness for epilepsy syndrome Pharmacokinetics Cost Drug Interactions

73 What If Seizures Don t Respond to Medications? Incorrect diagnosis Noncompliance Incorrect medication choice Inadequate medication levels Mdi Medically refractory seizures

74 Case 17 year old boy with history of headaches diagnosed with pseudotumor cerebri Headaches resolved No seizure risk factors Developed frequent seizures with unusual description i

75 Non-Epileptic Seizures (NES) Seizures Epileptic Non-epileptic 10% - Physiologic Syncope Movement Disorders Hypoglycemia Parasomnias... Psychogenic Conversion Somatization Dissociative Factitious %

76 Pseudoepilepsy Pseudoseizures Non-epileptic events Hysterical seizures Psychogenic seizures

77 Physiologic Non-Epileptic Events

78 Psychogenic Non-Epileptic Events

79 Non-epileptic seizures Video-telemetry monitoring is the gold standard for diagnosis Proves the diagnosis Patients may not accept the diagnosis without clear-cut laboratory documentation

80 Frontal Lobe Seizures vs. Non-epileptic Seizures Feature Frontal Lobe Non-Epileptic Arises from sleep ++ - Brief duration ++ - Hypermotor activity Postictal confusion +/- +/- Clustering pattern + + Associated itdij Injuries + + Stereotyped ++ - Affective Change - ++ EEG Change +/- -

81 Types of Epilepsy Surgery Epilepsy Surgery Focal Resection Corpus Callosotomy Vagus Nerve Stimulation

82 Medically Refractory Seizures PET SPECT Epilepsy p Surgery? MRI Wada Test Video EEG

83 Surgically Remediable Epilepsy Syndromes Mesial Temporal Sclerosis 80-90% seizure-free Other Symptomatic Partial Epilepsies With discrete lesion (70%?) Without discrete lesion Hemispheric i Disorders in Children

84 Refractory Epilepsy 26-year-old with complex partial seizures and secondarily GTC seizures for 8 years History of prolonged febrile convulsion Poor response to 3 monotherapy and 2 combination trials of antiepileptic meds MRI: right mesial temporal sclerosis

85 Refractory Epilepsy Incorrect diagnosis No Noncompliance No Inadequate medication levels No Incorrect medication choice No Medically refractory seizures Yes Syndrome: Mesial Temporal Sclerosis Seizure free with further med trials = 5% Seizure free with epilepsy surgery = 80-90% Appropriate for Surgical Evaluation

86 Mesial Temporal Sclerosis

87 Mesial Temporal Sclerosis

88 Anterior Temporal Lobectomy

89 Selective Amygdalohippocampectomy

90 Selective Amygdalohippocampectomy

91 Anterior Temporal Lobectomy

92 Ketogenic Diet Main experience with children, especially with multiple seizure types Anti-seizure effect of ketosis (beta hydroxybutyrate) Low carbohydrate, low protein, high fat after fasting to initiate ketosis Long-term adverse effects unknown

93 Vagal Nerve Stimulation Approved for the treatment of refractory partial seizures in patients over 12 years old Palliative Patients may reduce, but not discontinue AEDs > 40,000 patients to date

94 Vagal Nerve Stimulator

95 Vagal Nerve Stimulation Partial Seizures 37% have > 50% reduction at one year Atonic Seizures 50% have > 50% reduction at one year Idiopathic Generalized Epilepsies 59% have > 50% reduction at one year

96 The Future?

97 Summary Definitions and epidemiology Etiology/pathology Pathophysiology: Evaluation of the patient with seizures Seizure types Epilepsy syndromes Treatment principles