Epilepsy in Native Americans

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Epilepsy in Native Americans

• October 16, 2003

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Objectives

• Review etiology of epilepsy and principles of
  therapy
• Identify important aspects to consider when
  treating epilepsy in Native Americans
• Discuss Navajo neuropathy and common
  characteristics of the syndromes

3
Introduction

• Seizure the result of excessive synchronous
  discharge of cortical neurons
• Convulsion violent, involuntary contraction of
  voluntary muscles
• Epilepsy a clinical condition characterized by
  recurrent unprovoked seizures

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Prevalence

• 1.4 M in USA with 8.4 M visits to office-based
  neurologists
• Chronic seizure disorder in 1-2 of general
  population (6.1 per 1000)
• Ten percent of general population have at least
  one seizure in their lifetime
• Minority groups may have higher rate
• Acquired (symptomatic) epilepsy
• Socioeconomic status

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Prevalence in NA

• Survey published in 1987 found prevalence to be
  8.2 per 1000 (Navajos in NM and AZ)
• Acquired (symptomatic)
• Trauma
• alcohol-related head injury
• Post-encephalopathic
• years of excessive alcohol abuse
• Post-inflammatory
• bacterial meningitis

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Epileptic Neuron
Stimulus
Presynaptic Neuron
Repeated influx of sodium ions
Excessive Glutamate Aspartate release
Excessive stimulation leading to a seizure
An increase in the presynaptic release of
glutamate and aspartate may lead to excessive
stimulation of the postsynaptic membrane.
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Triggers

• Hyperventilation (absence)
• Too much sleep
• Too little sleep
• Sensory stimuli
• Emotional stress
• Hormonal changes
• Drug overdose or withdrawal

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Classification

• Partial (focal, local)
• Simple (w/o impairment of consciousness)
• With motor symptoms
• With special sensory or somatosensory symptoms
• With psychic symptoms
• Complex (consciousness impaired)
• Simple partial onset followed by impairment
• Impaired consciousness at onset
• Secondarily generalized

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Classification

• Generalized (convulsive or non-convulsive)
• Onset occurs bilaterally and symmetrically
• absence, atonic, clonic, myoclonic, tonic,
  tonic-clonic, infantile spasms
• Unclassified seizures
• Status epilepticus

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Diagnosis

• Seizure characteristics
• Frequency and duration
• Precipitating factors
• Time of occurrence
• Aura
• Ictal and post-ictal state
• Laboratory
• CBC
• Chem panel with Mg and Ca
• UA
• Lumbar puncture
• PE and NE
• EEG
• MRI or CT

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Treatment Goals

• Normal lifestyle
• Reduce frequency of seizures
• Balance between suppression and AEs
• Encourage compliance
• Assess the concerns of the patient
• Driving
• Education
• Relationships
• Housing
• Social stigma
• Epilepsy Foundation of America

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Principles of Pharmacotherapy

• Positive correlation between the early initiation
  of therapy and the ability to control seizure
  activity
• Failure to control seizures may lead to an
  increase in seizure activity and also the
  occurrence of other seizure types
• No regimen like the first regimen

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Principles of Pharmacotherapy

• Drug choice is based on seizure type and side
  effect profile
• Always start with monotherapy
• 70 of patients can be maintained with one drug
• Of 35 with unsatisfactory control, 10 will be
  well-controlled on two drugs
• 20 will be medically refractory
• 15 will become surgery candidates
• Success rate is 80-90 in properly selected
  patients
• Risks include learning,memory, and general
  intellectual impairment

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Principles of Pharmacotherapy

• Seizure control may be achieved at doses
  corresponding to less than normal therapeutic
  serum levels likewise, doses corresponding to
  higher than normal therapeutic serum levels may
  be tolerated and required by some patients
• Begin dosing at 1/3 to ¼ anticipated maintenance
  dose and titrate over 3-4 weeks

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Treatment Failure

• Number one cause of treatment failure is
• AED is not considered ineffective until patient
  has continued seizures AND some
  concentration-dependent side effects
• Substitute
• Mixed seizure types are more likely to require
  more than one AED
• Seizure chart a must

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Principles of Pharmacotherapy

• Kinetics
• Plasma protein binding
• Measure free instead of total
• DPH
• Age
• Neonates
• Infants, children
• Elderly
• Metabolism
• Induction or inhibition of the CYP450 enzyme
  system
• Many AEDs have active metabolites

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Principles of Pharmacotherapy

• Female patients
• Enzyme-inducing AEDs
• PHT, PHB, CBZ, primidone
• VPA is an inhibitor
• Seizures before or during menses or at time of
  ovulation
• All female patients should take PNV with folate

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Principles of Pharmacotherapy

• Pregnancy
• 25-30 increased or decreased frequency
• Increased VD and clearance
• Altered protein binding
• Increased incidence of adverse outcomes
• Twice the incidence of congenital malformations
  (4-6)
• PB and PHT congenital heart malformations,
  facial clefts
• CBZ and VPA spina bifida and hypospadias
• Monotherapy preferred

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Principles of Pharmacotherapy

• Discontinuation of AEDs
• Seizure-free for 2-5 years
• Single type of primary GTC or partial
• Neurological exam and IQ are normal
• EEG normalized with treatment
• Not possible in all patients
• High frequency
• Repeated SE
• Combination of seizure types
• Development of abnormal functioning

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Mechanism of Action

• Partial and secondary generalized GTC
• Promote inactive state of voltage activated
  sodium channels
• Enhanced GABA-mediated synaptic inhibition
• Absence
• Limit activation of voltage-activated T-type
  calcium channel

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Drugs of Choice First Line

• Partial Seizures
• CBZ, PHT, VPA
• Lamotrigine, oxcarbazepine
• Generalized Seizures
• Tonic-Clonic
• CBZ, PHT, VPA
• Absence
• VPA, ethosuximide
• Myoclonic
• Clonazepam, VPA

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Serum Concentration Monitoring

• Assessment of compliance
• Assessment of appropriate levels in patients
  incapable of reporting adverse effects
• Documenting the level corresponding to the max
  tolerated dose
• Sorting out probable cause of nonspecific
  side-effects for patients taking several AEDs
• Adjustment of dose due to pharmacokinetic drug
  interactions
• Titrating medication dosages during pregnancy

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Basis for the Seizure Clinic

• Extend the services of the neurologist
• Increase the number of patients managed
• AED non-compliance a major consideration
• Pharmacological treatment of epilepsy has changed
  drastically in the last few years
• Provide consistent medical follow-up for patients
  with epilepsy

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Neuro-pharmacists Role

• Obtain seizure frequency description
• Assess medication compliance and side effects
• Evaluate patient for signs of drug toxicity
• Order laboratory testing

• Schedule follow-up appointments
• Complete medical record entry
• Provide education, and support
• Obtain neurologists approval of plan

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Case One

• CC/HPI AB is a 37 yo male presenting to seizure
  clinic for follow-up.
• Subjective PMH
• 9/97 Partial complex seizures with rapid
  generalization CBZ monotherapy toxic at 1800
  mg qd
• 6/99 S/P right temporal lobectomay
• 9/99 Medically refractory epilepsy hospitalized
  with AMS
•  Subjective Home meds
• indomethacin 25 mg
• diphenhydramine 25 mg
• prazosin 1 mg
• acetaminophen 325 mg

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Case One

• Subjective
• Seizure frequency four in last three months
• Description he was with his uncle
• ADEs vomiting X1 no drowsiness no other
  complaints
• Current AEDs
• CBZ 200 mg, 2 tabs tid
• Levetiracetam 500 mg, ½ tab bid
• Zonisamide 100 mg, 3 caps q hs

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Case One

• Objective
• PE no gingival hyperplasia, drift, tremor, or
  nystagmus
• Vitals today Weight 196, BP 136/80, temp 97.7,
  HR 68, RR 16
• Lab
• CBZ 15.6 Hgb 15.8
• Na 139 Hct 43.4
• Cl 115 WBC 5.8
• K 3.6 Plt 228
• CO2 21
• BUN 8
• SCr 1.0

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Case One

• Objective
• Lab
• Ca 8.8
• Alb 4.0
• AST 19 (10-42)
• ALT 16 (10-60)
• Alk Phos 126 (36-136)
• Total bili 0.5 (0.2-1)
• Assessment
• Epilepsy current regimen and seizure control is
  satisfactory to the patient
• Plan
• Refill meds, f/u in six months

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Case Two

• CC/HPI CD is 43 yo female here for seizure
  clinic f/u
• Subjective PMH
• seizure d/o since 1968
• Tubal ligation in 1997
• Major depression, recurrent, severe w/psychotic
  features
• Borderline personality disorder
• Subjective home meds
• Trazodone 100 mq q pm alb inh prn
• Olanzapine 10 mg q hs APAP prn
• Sertraline 200 mg p hs naproxen prn

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Case Two

• Subjective
• Seizure frequency 15/month
• Description LOC post-ictal HA, sleepy
• ADEs confusion, forgetfulness, bruise on left
  elbow X 1 week
• Current AEDs
• DPH 100 mg, 2 po am and 3 po q pm
• CBZ 200 mg, 1 ½ bid
• PB 60 mg, 1 po q am, 2 po hs
• Patient reluctant to change regimen

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Case Two

• Objective
• VS today 236, temp 98.9, HR 78, RR 16, BP
  132/76
• PE mild tremor, strange affect
• Most recent lab
• PB 49.1
• DPH 14.1
• CBZ 4.9
• Alb 3.7
• AST 20
• ALT 19
• Alk Phos 180
• Total bili 0.1

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Case Two

• Objective Lab
• Na 138 Hgb 12.4
• Cl 106 Hct 36.4
• K 4.6 WBC 10
• CO2 26 Plt 266
• BUN 16
• SCr 0.6
• Assessment
• Epilepsy with clinical toxicity
• Plan
• Add lamotrigine 50 mg qd
• Dec CBZ from 500 to 400 X 1 week, then 200 X 1
  week, then DC

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Navajo Neuropathy

• 1976 identification of a neurological condition
  among four Navajo children
• Appenzeller O, et al. Acromutilation, Paralyzing
  Neuropathy with Corneal Ulceration in Navajo
  Children. Arch Neruol 197633733-738.
• Common symptoms among these children
• Anesthesia
• Corneal Ulceration
• Painless fractures
• Acral mutilation
• Weakness

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Navajo Neuropathy

• Biopsy revealed
• Sural nerves devoid of myelinated fibers
• Unmyelinated axons had degenerative and
  regenerative morphologic features
• Non-progressive neuromuscular impairment and
  profound sensory loss
• Modest elevation of CSF protein in some

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Navajo Neuropathy

• Common Symptoms among these patients
• Profound sensory loss
• Injuries and infections of limbs
• Joint degeneration
• A recessive trait or possibly a dominant one with
  incomplete penetrance

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Navajo Neuropathy

• 1985 another group discovered a type of
  hereditary sensorimotor neuropathy in six Navajo
  children from three families
• Johnsen SD et al. A New Hereditary Sensory
  Autonomic Neuropayth in a Navajo Population. Ann
  Neurol 198518400
• Navajo Neuropathy Type B
• Characterized by
• Severe arthropathy
• Autonomic disturbance

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Navajo Neuropathy

• Common symptoms included
• Severe Charcot joints of knees and ankles
• Deforming foot fracture
• Perspiration deficiencies
• Some heat intolerance
• Hyperkeratosis of the palms

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Navajo Neuropathy

• Biopsy of nerves
• Reduction in the density of unmyelinated fibers,
  but relatively normal density of myelinated
  fibers
• In contrast to type A

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Navajo Neuropathy

• Incidence
• 20 per 100,000 births between 1972 and 1986
• Greater in the western half of the reservation
• Twenty-four cases from 13 families six of which
  had more than one affected sibling
• Environment not considered a factor three
  families had common ancestors
• Possibly autosomal recessive

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References

• Labiner DM, Kunkel-Thomas JA, Anderson LR.
  Neurologic Disease. In Galloway JM, Goldberg
  BW, Albert JS, editors. Primary Care of Native
  American Patients diagnosis, therapy and
  epidemiology. 1st ed. Boston
  Butterworth-Heinemann 1998. p. 295-303.
• Graves NM, Garnett WR. Epilepsy. In Dipiro
  JT, Talbert R, Yee GC, Matzke GR, Wells BG, Posey
  LM, editors. Pharmacotherapy a
  pathophysiologic approach. 4th edition. New
  York McGraw-Hill 1999. p. 952-953.
• Mcnamara J. Drugs effective in the therapy of
  the epilepsies. In Hardman JG, Limbird LE,
  editors. Goodman and Gilmans the
  Pharmacological Basis of Therapeutics. 9th ed.
  on CD-ROM, version 1.0. New York McGraw-Hill
  Companies 1996.