Epilepsy eisenschenk by adss8UF

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									                          Clinical Epilepsy




                          www.neurology.ufl.edu/Epilepsy
                                                           1
Stephan Eisenschenk, MD
Department of Neurology
                                     Seizures vs Epilepsy
                                      Seizures                          Epilepsy
                          Definition: the clinical            Definition: a tendency toward recurrent
                             manifestation of an abnormal       seizures unprovoked by systemic or
                             and excessive excitation of a      neurologic insults
                             population of cortical neurons
                                                              Incidence: approximately 45/100,000 per
                          Incidence: approximately              year Approximately 181,000 people will
                              80/100,000 per year               experience seizures or develop epilepsy
                                                                each year
                          Lifetime prevalence: 9%
                              (1/3 benign febrile             Point prevalence: 0.5-1% (2.5 million)
                              convulsions)                         14 years or younger          13%
                                                                   15 to 64 years               63%
                                                                   65 years and older           24%

                                                              Cumulative risk of epilepsy through 74
                                                                years old: 1.3% - 3.1%
                                                                                                2
Stephan Eisenschenk, MD
Department of Neurology
                                       Partial (focal) Seizures
                          •   Simple Partial Seizure
                               –   no loss of awareness

                          •   Complex Partial Seizure
                               –   Impaired consciousness/ level of
                                   awareness (staring)
                               –   Clinical manifestations vary with origin
                                   & degree of spread
                               –   Presence and nature of aura
                                     • Temporal lobe: smell, epigastric
                                       sensation, deja vu
                               –   Automatisms (manual, oral)
                               –   Other motor activity
                                     • Frontal: bicycling and fencing
                                       posture
                               –   Duration (typically 30 seconds to 3
                                   minutes)
                               –   Amnesia for event


                          •   Partial Seizure with Secondary                  3
Stephan Eisenschenk, MD
Department of Neurology
                              Generalization
                          Localization of Partial Seizure Focus


                                      20%


                                     70%          10%



                                                            4
Stephan Eisenschenk, MD
Department of Neurology
                          Temporal Lobe Complex Partial Seizure




                                                                                   5
Stephan Eisenschenk, MD
Department of Neurology          Rhythmic 5-7 Hz theta from the mesial temporal lobe
                              Primarily Generalized Seizures
                          •   Absence
                               –   Typical (3 Hz spike and wave)
                               –   Atypical (2.5 to 4.5 Hz spike and wave, polyspike)
                               –   Brief staring (<30sec); automatisms rare; not post-ictal confusion

                          •   Myoclonic
                               –   Brief, shock-like muscle contractions
                                   - Head
                                   - Upper extremities
                               –   Usually bilaterally symmetrical
                               –   Consciousness preserved
                               –   Precipitated by awakening or falling asleep
                               –   May progress into clonic or tonic-clonic seizure
                               –   May be associated with a progressive neurolgic deterioration

                               – Juvenile Myoclonic Epilepsy (JME)
                                     •   Polyspike wave
                                     •   Onset late adolescence
                                     •   Chromosome 6p

                               – Progressive Myoclonic Epilepsies

                          •   Atonic/ Tonic/ Tonic-Clonic
                                                                                                        6
Stephan Eisenschenk, MD
Department of Neurology
                          Absence Seizure




                           3 Hz spike and wave   7
Stephan Eisenschenk, MD
Department of Neurology
                                         Seizure vs Epilepsy
                                                       Seizures


                              Nonepileptic                                     Epilepsy
                                                                          (recurrent seizures)
                          Cardiovascular
                          Drug related
                          Syncope
                          Metabolic (glucose, Na, Ca, Mg)          Idiopathic             Symptomatic
                          Toxic (drugs, poisons)                    (primary)             (secondary)
                          Poison
                          Infectious
                          Febrile convulsions
                          Pseudoseizure
                          Alcohol/drug withdrawal
                          Substance abuse
                          Psychiatric disorders
                          Sleep disorders (parasomnias, cataplexy)                                8
Stephan Eisenschenk, MD
Department of Neurology
                              Psychogenic Nonepileptic Seizures

                          •   Represent genuine psychiatric disease
                          •   10-45% of refractory epilepsy at
                              tertiary referral centers
                          •   Females > males
                          •   Psychiatric mechanism:
                              dissociation, conversion, unconscious
                              (unlike malingering)
                          •   Association with physical, sexual
                              abuse
                          •   Epileptic and nonepileptic seizures
                              may co-exist
                          •   Video-EEG monitoring often helps
                              clarify the diagnosis
                          •   Once recognized, approximately 50%
                              respond well to specific psychiatric
                              treatment
                                                                      9
Stephan Eisenschenk, MD
Department of Neurology
                          Epidemiology of Seizures and Epilepsy
                                                            Epilepsy: Incidence Rates by Seizure Type
                                                  90                                    Head Trauma
                                                                                                      Vascular
                                                                                                                                            Hemorrhage
                                                                                                        1% Neoplastic                                    Head Trauma
                                                                                            5%                                                 2%
                                                  80                       Congenital
                                                                              4%
                                                                                                                4%               Unknown
                                                                                                                                   24%
                                                                                                                                                             7%
                          Incidence per 100,000


                                                                                                             Degenerative                                             Other*
                                                                                                                 1%
                                                                                                                                                                       19%
                                                  70                                                      Infectious
                                                                                                             0%


                                                  60                                                                             Cerebral                          Atherosclerosis
                                                                  Idiopathic
                                                                                                                                  Infarct                              15%

                                                  50                 85%                                                           33%




                                                  40                                                                                                                                                 Partial
                                                                                                                                                                                                     Generalized tonic-clonic
                                                  30                                                                                                                                                 Primary Generalized
                                                  20
                                                  10
                                                   0
                                                        0          10                   20              30                  40         50                60            70            80
                                                                                                                        Age
                                                   Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF. In: The Treatment of Epilepsy: Principles and Practice. 2nd
                                                   ed. Baltimore, Md: Williams & Wilkins; 1997:165-172.
                                                   Hauser et al, 1992                                                                                                                                                   10
Stephan Eisenschenk, MD                            Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-S29                                               *                                                      .
                                                                                                                                                             Includes known etiologies such as arteriovenous malformation and venous angioma.
Department of Neurology
                                   Seizure Precipitants
                          Low (less often high) blood glucose
                          Low sodium
                          Low calcium
                          Low magnesium
                          Stimulant or other proconvulsant toxicity (i.e., cocaine)
                          Sedative (i.e., valium or alcohol) withdrawal
                          Severe sleep deprivation


                                                                                  11
Stephan Eisenschenk, MD
Department of Neurology
                                  EEG Abnormalities
                          •Background abnormalities
                             -Significant asymmetries and/or degree of slowing
                                 inappropriate for clinical state
                          •Transient abnormalities associated with seizures
                                 -Spikes (< 70 m sec)
                                 -Sharp waves (~70 – 200 msec)
                                 -Spike-wave complexes
                          •May be focal, lateralized or generalized

                                                                              12
Stephan Eisenschenk, MD
Department of Neurology
                          EEG Abnormalities




                                              13
Stephan Eisenschenk, MD
Department of Neurology
                          Medical Treatment of First Seizure(s)
                           •Whether to treat first seizure is controversial
                              •16-62% will recur within 5 years
                              •Relapse rate for second seizure is reduced by AEDs,
                                  BUT long term prognosis of whether the patient will
                                  have refractory epilepsy is not
                              •Increased risk of relapse
                                  Abnormal imaging
                                  Abnormal EEG
                                  Family history of epilepsy
                           •Currently, most patients are not treated for the first seizure
                                                                                      14
Stephan Eisenschenk, MD
Department of Neurology
                                  unless there is an increased risk for relapse
                                            First Tonic-clonic Seizure
                                       Treatment Does NOT Improve Prognosis of Epilepsy
                                 Cumulative time-dependent probability of initiating a period of seizure remission
                                 according to whether an AED was given after the first tonic-clonic seizure

                                            1 year seizure-free                    2 years seizure-free
                          100%                                          100%                              Treated
                           90%                                           90%                              Untreated
                           80%                              Treated      80%
                           70%                              Untreated    70%
                           60%                                           60%
                           50%                                           50%
                           40%                                           40%
                           30%                                           30%
                           20%                                           20%
                           10%                                           10%
                            0%                                            0%
                                 0      1       2       3         4            0     1      2       3         4

                                            YEARS                                        YEARS



                                                                                                                  15
Stephan Eisenschenk, MD
Department of Neurology
                           Choosing Antiepileptic Drugs
                          • Seizure type/ Epilepsy syndrome
                          • Comorbid conditions
                          • Adverse side effects or events
                          • Interactions/other medical conditions
                          • Pharmacokinetic profile
                          • Cost
                          • Efficacy
                          • ALL FEMALES (and also consider in males):
                             – Folate 1 - 4 mg/day
                             – MVI
                             – Calcium (1200-1330 mg per day)
                                                                        16
Stephan Eisenschenk, MD
Department of Neurology
                          Rational Use of AEDs: Flooding the Market

                          First-Generation Branded Agents
                          Dilantin       phenytoin             1938     Parke-Davis
                          Tegretol       carbamazepine         1974     Novartis
                          Depakote       divalproex sodium     1978     Abbott
                          Second-Generation Agents
                          Felbatol     felbamate               1993     Wallace Laboratories
                          Neurontin    gabapentin              1993     Parke-Davis
                          Lamictal     lamotrigine             1994     Glaxo Smith Kline
                          Topamax      topiramate              1997     Ortho-McNeil
                          Gabitril     tiagabine               1997     Abbott Laboratories
                          Trileptal    oxcarbazepine           2000     Novartis
                          Zonegran     zonisamide              2000     Elan
                          Keppra       levetiracetam           2000     UCB Pharma
                          Lyricapregabalin              2005   Pfizer                 17
Stephan Eisenschenk, MD
Department of Neurology
                             FDA Indications for AEDs:
                          Monotherapy and/or Add-On Therapy

                           Monotherapy                                    Add-On Therapy
                           Carbamazepine                          Carbamazepine         Levetiracetam
                           Divalproex ER                          Divalproex ER          Gabapentin
                           Ethosuximide                            Ethosuximide           Phenytoin
                           Oxcarbazepine                          Oxcarbazepine           Tiagabine
                           Phenobarbital                           Phenobarbital         Zonisamide
                             Phenytoin                                Primidone
                             Primidone
                            Lamotrigine1
                             Felbamate1
                             Topiramate
                                                                                                            18
Stephan Eisenschenk, MD
                             1Approved   for conversion to monotherapy.            Physician’s Desk Reference, 2004.
Department of Neurology
                          Treatment of New Onset Epilepsy



                              Refractory/
                           Pharmacoresistant
                                 36%
                                                                          Sz-free w/ 1st AED
                                                                                 47%




                                   Sz-free w/ 3rd
                                  AED/Polytherapy
                                        4%                               Sz-free w/ 1st AED
                                                    Sz-free w/ 2nd AED   Sz-free w/ 2nd AED
                                                           13%           Sz-free w/ 3rd AED/Polytherapy
                                                                         Refractory/Pharmacoresistant

                                                                                                19
Stephan Eisenschenk, MD                                                            Kwan P, Brodie MJ. N Engl J Med
Department of Neurology                                                            2000; 342: 314-9.
                                                                             20
Stephan Eisenschenk, MD   Kwan and Brodie. NEJM 2000; 342: 314-319.
Department of Neurology   Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
                                                          21
Stephan Eisenschenk, MD   Kwan and Brodie. NEJM 2000; 342: 314-319.
Department of Neurology   Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
                                                          22
Stephan Eisenschenk, MD   Kwan and Brodie. NEJM 2000; 342: 314-319.
Department of Neurology   Mohanraj and Brodie. Epil Behav 2005; 6: 382-387
                          Why Should Current Prescribing Practices Change?
                                                                  50   Carbamazepine              Depakote DR
                                                                       Depakote ER                Depakote sprinkles
                                                                       Keppra                     Lamictal




                                    AED Prescription Volume (%)
                                                                       Neurontin                  Phenytoin
                                                                  40   Topomax                    Trileptal



                                                                  30


                                                                  20


                                                                  10


                                                                  0
                                                                        0-17           18-34     35-44        45-54    55-64   >65
                                                                                           Age Group (years)


                                                                                          S z - f ree with 1st AE D

                                                                                          S z - f ree with 2n d AE D

                                                                                          S z - f ree with 3rd
                                                                                          AE D/P olyth erap y
                                                                                          P h arm acoresistan t
                                                                                                                 47%

                                                                                           36%

                                                                                                               13%
                                                                                                         4%


                                                                                                                                                   23
                                                                                                                                     PharMetrics. April 2002 to June 2003
                                                                                                                                     IMS NPA, Dec 2003.
Stephan Eisenschenk, MD                                                                                                              Kwan P, Brodie MJ. N Engl J Med
Department of Neurology                                                                                                              2000; 342: 314-9.
                                                                Rational Use of AEDs: All Prescriptions
                              Market Dynamics for All Indications and Epilepsy
                          450000000


                          400000000

                                                                                                                                                  15%
                          350000000
                                                                                                                                                                           27%
                          300000000                                                                                                          5%                                      Epilepsy
                                                                                                                                                                                     Psychiatric d/o's
                          250000000                                                                                                        9%
                          200000000
                                                                                                                                                                                     Pain disorders

                          150000000
                                                                                                                                                                                     Headache/migraine

                          100000000
                                                                                                                                                                                     Other

                           50000000
                                                                                                                                                            44%

                                  0
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                                  M
                                                                                          Second Gen. AEDs         First Gen. AEDs


                                                                                                                                                           GABITRIL
                                                                                                                                                  KEPPRA     1.8%
                                                                                                                                                   4.7%               ZONEGRAN
                                                                 50   Carbamazepine           Depakote DR
                                  AED Prescription Volume (%)




                                                                                                                                                                        2.1%
                                                                      Depakote ER             Depakote sprinkles
                                                                      Keppra                  Lamictal                                          LAMICTAL
                                                                      Neurontin               Phenytoin                                           8.1%
                                                                 40   Topomax                 Trileptal

                                                                                                                                           TRILEPTAL                                 NEURONTIN
                                                                                                                                              8.0%                                     60.6%
                                                                 30


                                                                 20
                                                                                                                                            TOPAMAX
                                                                                                                                              14.8%
                                                                 10


                                                                 0
                                                                      0-17        18-34     35-44        45-54        55-64          >65


                                                                                      Age Group (years)                                                                                      24
                                                                                                                                                                         PharMetrics. April 2002 to June 2003.
Stephan Eisenschenk, MD                                                                                                                                                  Source: IMS NPA, Dec. 2003
Department of Neurology                                                                                                                                                  MAT 03/2004
                                                   “All substances are
                                                     poisons; there is none
                                                     which is not a poison.
                                                     The right dose
                                                     differentiates a poison
                                                     from a remedy.”

                          Paracelsus (1493-1541)
                                                                      25
Stephan Eisenschenk, MD
Department of Neurology
                              Summary of Serious and Non-serious
                               Adverse Events of the Newer AEDs
                          AED             Serious Adverse Events                             Nonserious Adverse Events
                          Gabapentin      None                                               Weight gain, peripheral edema,
                                                                                             behavioral changes
                          Lamotrigine     Rash, including Stevens Johnson and toxic          Tics and insomnia
                                          epidermal necrolysis (increased risk for
                                          children, also more common with concomitant
                                          valproate use and reduced with slow titration);
                                          hypersensitivity reactions, including risk of
                                          hepatic and renal failure, DIC, and arthritis

                          Levetiracetam   None                                               Irritability/behavior change
                          Oxcarbazepine   Hyponatremia (more common in elderly), rash        None

                          Tiagabine       Stupor or spike wave stupor                        Weakness
                          Topiramate      Nephrolithiasis, open angle glaucoma,              Metabolic acidosis, weight loss,
                                          hypohidrosis (predominantly children)              language dysfunction
                          Zonisamide      Rash, renal calculi, hypohidrosis (predominantly   Irritability, photosensitivity,
                                          children)                                          weight loss

                                                                                                                        26
Stephan Eisenschenk, MD
Department of Neurology
                                  Pregnancy and AED Therapy:
                                Risks of Congenital Abnormalities
                          •   Congenital malformations
                               – Most common: orofacial clefts, heart defects
                               – Less common: microcephaly, neural tube defects
                          •   Major malformations
                               – General population: 2% to 4%
                               – Newborns prenatally exposed to AEDs: 4% to 8%
                               – Multiple AEDs and higher doses may substantially increase malformation rate
                          •   Minor malformations
                               – Increased 2 to 3 fold (10% to 30%)




                                                                                                                        27
                                                                                         So EL. Med Clin North Am. 1993;77:203-214.
                                                                                         Foldvary N. Neurol Clin. 2001;19:409-425.
Stephan Eisenschenk, MD                                                                  Schachter SC. Epilepsia. 1999;40(suppl 9):S20-S25.
Department of Neurology                                                                  Holmes LB, et al. N Engl J Med. 2001;344:1132-1138.
                                              AEDs and Bone Health
                          •       Increased incidence of osteopenia,
                                  osteomalacia, and fracture with some AEDs
                                    – No prospective trials have been performed
                                        to define the frequency of fractures in
                                        epilepsy
                          •       Factors associated with reduced BMD
                                    – Polypharmacy
                                    – Generalized seizures
                          •       All tested AEDs have been shown to reduce
                                  BMD
                                    – Primarily associated with enzyme-
                                        inducing AEDs and phenytoin
                          •       Strong association for decreasing bone mineral
                                  density                                                                        50   Carbamazepine
                                                                                                                      Depakote ER
                                                                                                                                                 Depakote DR
                                                                                                                                                 Depakote sprinkles
                                    – Carbamazepine                                                                   Keppra                     Lamictal




                                                                                   AED Prescription Volume (%)
                                                                                                                      Neurontin                  Phenytoin

                                    – Phenobarbital                                                              40   Topomax                    Trileptal


                                    – Phenytoin
                                                                                                                 30
                                    – Primidone
                          •       Conflicting findings on bone mineral density                                   20
                                    – Divalproex
                                    – Lamotrigine                                                                10

                          •       Limited information on newer AEDs
                                                                                                                 0
                                                                                                                       0-17           18-34     35-44         45-54   55-64   >65
                              PharMetrics. April 2002 to June 2003.
                              Source: IMS NPA, Dec. 2003
                                                                                                                                                                        28
Stephan Eisenschenk, MD       Pack AM, et al. Epilepsy Behav. 2003;4:169-174.                                                             Age Group (years)
Department of Neurology       Ensrud KE, et al. Neurology. 2004;62:2051-2057
                          AEDs and Bone Health




                                                 29
Stephan Eisenschenk, MD
Department of Neurology
                                                      Rational Use of AEDs
                                          So Why Should Prescribing Practices Change?
                          Patients often required long term (or lifetime) treatment due to driving status

                          State of Florida *15A-5.004 Neurological Guidelines for Applicants with Seizures
                               (*the following changes to the seizure guidelines became effective in August 1992 and have been used as policy
                               since that date)
                          1.   Applicants and licensed drivers should be seizure free for a period of 2 years before being approved for
                               licensing; but if under regular medical supervision, may apply at the end of 6 months for review by the
                               Medical Advisory Board. “Petit mal” or absence seizures and partial seizures with complex symptomology will
                               also follow these guidelines. The isolated seizure with a normal EEG may be reviewed after 3 months.
                          2.   Applicants and licensed drivers who have been approved after 6 months seizure free may be required to submit
                               follow-up reports at the end of 1 year from the date of approval.
                          3.   Applicants and licensed drivers who have a chronic recurring seizure disorder (or who have been treated for
                               such for 1 year) and medications have been discontinued will not be licensed to drive during the period of
                               drug withdrawal and for a period of 3 months following complete cessation of treatment. If the patient has
                               seizures during this period, licensing may be considered after a 3 month seizure free interval upon return to
                               adequate therapy.
                          4.   If there is a question about the seizure type or the medications the applicant of licensed driver is on, it is the
                               prerogative of the Medical Advisory Board to question the treating physician further in an effort to clarify the
                               nature of the seizures.
                          5.   Blood levels below therapeutic levels are to be considered on an individual basis.
                          6.   Applicants and licensed drivers with only chronic nocturnal seizures will be considered on an individual basis.
                          7.   Applicants and licensed drivers with syncopal episodes who have no clear diagnosis established will be
                               considered on an individual basis
                                                                                                                                      30
Stephan Eisenschenk, MD
Department of Neurology
                          Treatment/Evaluation Sequence for
                             Pharmacoresistent Epilepsy
                                                       1st Monotherapy AED Trial
                                                                                                 S z - f ree with 1st AE D
                                                                                                 S z - f ree with 2n d AE D
                                                                                                 S z - f ree with 3rd AE D/P olyth erap y

                                                      2nd Monotherapy AED Trial                  P h arm acoresistan t



                                                                                                                                     13%
                                                                                               47%

                                              3rd Monotherapy/Polytherapy AED Trial
                                                                                                                                          4%

                                               Strongly consider videoEEG Monitoring                            36%
                                                                                                                               Kwan P, Brodie MJ.
                                                                                                                               NEJM;342:314-319.
                                           Non-epileptic                            Epilepsy



                               Psychogenic, migraine, syncope,            Epilepsy Surgery/VNS Therapy/
                          sleep disorders, movement disorder’s, etc.           Neuropace Evaluation



                                                           Polytherapy AED Trials   Resective Surgery                31
                                                                                                              Stimulator Therapy
Stephan Eisenschenk, MD
Department of Neurology
                          Other Treatments of Epilepsy
                          • Medical
                             – Experimental AED trials
                             – Ketogenic diet
                          • Surgical
                             – Resective
                             – Multiple Subpial Transection
                             – Vagal Nerve Stimulator
                          • Experimental
                             – Thalamic Stimulators
                             – Stereotactic Radiosurgery
Stephan Eisenschenk, MD
                             – Responsive Neurostimulators    32
Department of Neurology
                           Evaluation for Surgery- Neuroimaging
                          MRI
                            -hippocampal volumetrics
                                greater than ~0.5cc difference increases chances for seizure
                                remission
                            -1.5 mm coronal cuts with sequences sensitive to gray-white
                                 differentiation and to gliosis
                            -inversion recovery/high resonance for cortical dysplasia

                          PET
                          Ictal/interictal SPECT
                          MR Spectroscopy
                                Decreased NAA (due to neuronal loss)
                                Normal to high Cho and Creatine (represents astrocytosis)   33
Stephan Eisenschenk, MD
Department of Neurology
                          Epilepsy Surgery- Neuroimaging




                          Hippocampal atrophy in   Ganglioglioma        DNT
                          temporal lobe epilepsy




                            Cortical Dysplasia          AVM                       34
                                                                   Cavernous Angioma
Stephan Eisenschenk, MD
Department of Neurology
                          Evaluation for Surgery- Subdural Grid Electrodes




                                                                       35
Stephan Eisenschenk, MD
Department of Neurology
                          Left Anterior Temporal Loectomy




                                                       36
Stephan Eisenschenk, MD
Department of Neurology

								
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