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Clinical Epilepsy. American Epilepsy Society. Definitions.  Seizure: the clinical manifestation of an abnormal, excessive excitation and synchronization of a population of cortical neurons  Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults.

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clinical epilepsy

Clinical Epilepsy

American Epilepsy Society

definitions

Definitions

 Seizure: the clinical manifestation of an abnormal, excessive excitation and synchronization of a population of cortical neurons

 Epilepsy: two or more recurrent seizures unprovoked by systemic or acute neurologic insults

epidemiology of seizures and epilepsy

Epidemiology of Seizures and Epilepsy

 Seizures

Incidence: 80/100,000 per year

Lifetime incidence: 9% (1/3 febrile convulsions)

 Epilepsy

Incidence: 45/100,000 per year

Point prevalence: 0.5-1%

Cumulative lifetime incidence: 3%

complex partial seizures
Complex Partial Seizures

 Impaired consciousness

 Clinical manifestations vary with site of origin and degree of spread

  • Presence and nature of aura
  • Automatisms
  • Other motor activity

 Duration typically < 2 minutes

secondarily generalized seizures
Secondarily Generalized Seizures

 Begins focally, with or without focal neurological symptoms

 Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases

 Typical duration 1-3 minutes

 Postictal confusion, somnolence, with or without transient focal deficit

eeg partial seizure
EEG: Partial Seizure

Right temporal

seizure with

maximal phase

reversal in the

right sphenoidal

electrode

eeg partial seizure1
EEG: Partial Seizure

Continuation of same seizure

Right temporal

seizure with maximal phase reversal in the right sphenoidal electrode

typical absence seizures
Typical Absence Seizures

 Brief staring spells (“petit mal”) with impairment of awareness

  • 3-20 seconds
  • Sudden onset and sudden resolution
  • Often provoked by hyperventilation
  • Onset typically between 4 and 14 years of age
  • Often resolve by 18 years of age

 Normal development and intelligence

 EEG: Generalized 3 Hz spike-wave discharges

atypical absence seizures
Atypical Absence Seizures

 Brief staring spells with variably reduced responsiveness

  • 5-30 seconds
  • Gradual (seconds) onset and resolution
  • Generally not provoked by hyperventilation
  • Onset typically after 6 years of age

 Often in children with global cognitive impairment

 EEG: Generalized slow spike-wave complexes (<2.5 Hz)

 Patients often also have Atonic and Tonic seizures

myoclonic seizures
Myoclonic Seizures

 Brief, shock-like jerk of a muscle or group of muscles

 Epileptic myoclonus

  • Typically bilaterally synchronous
  • Impairment of consciousness difficult to assess (seizures <1 second)
  • Clonic seizure – repeated myoclonic seizures (may have impaired awareness)

 Differentiate from benign, nonepileptic myoclonus (e.g., while falling asleep)

 EEG: Generalized 4-6 Hz polyspike-wave discharges

tonic and atonic seizures
Tonic and Atonic Seizures

Tonic seizures

  • Symmetric, tonic muscle contraction of extremities with tonic flexion of waist and neck
  • Duration - 2-20 seconds.
  • EEG – Sudden attenuation with generalized, low-voltage fast activity (most common) or generalized polyspike-wave.

Atonic seizures

  • Sudden loss of postural tone
    • When severe often results in falls
    • When milder produces head nods or jaw drops.
  • Consciousness usually impaired
  • Duration - usually seconds, rarely more than 1 minute
  • EEG – sudden diffuse attenuation or generalized polyspike-wave
generalized tonic clonic seizures
Generalized Tonic-Clonic Seizures
  • Associated with loss of consciousness and post-ictal confusion/lethargy
  • Duration 30-120 seconds
  • Tonic phase
    • Stiffening and fall
    • Often associated with ictal cry
  • Clonic Phase
    • Rhythmic extremity jerking
  • EEG – generalized polyspikes
epilepsy syndromes
Epilepsy Syndromes

Epilepsy Syndrome

Grouping of patients that share similar:

  • Seizure type(s)
  • Age of onset
  • Natural history/Prognosis
  • EEG patterns
  • Genetics
  • Response to treatment
etiology of seizures and epilepsy
Etiology of Seizures and Epilepsy

 Infancy and childhood

  • Prenatal or birth injury
  • Inborn error of metabolism
  • Congenital malformation

 Childhood and adolescence

  • Idiopathic/genetic syndrome
  • CNS infection
  • Trauma
etiology of seizures and epilepsy1
Etiology of Seizures and Epilepsy

 Adolescence and young adult

  • Head trauma
  • Drug intoxication and withdrawal*

 Older adult

  • Stroke
  • Brain tumor
  • Acute metabolic disturbances*
  • Neurodegenerative

*causes of acute symptomatic seizures, not epilepsy

questions raised by a first seizure
Questions Raised by a First Seizure

 Seizure or not?

 Focal onset?

 Evidence of interictal CNS dysfunction?

 Metabolic precipitant?

 Seizure type? Syndrome type?

 Studies?

 Start AED?

evaluation of a first seizure
Evaluation of a First Seizure
  • History, physical
  • Blood tests: CBC, electrolytes, glucose, calcium, magnesium, phosphate, hepatic and renal function
  • Lumbar puncture

(only if meningitis or encephalitis suspected and potential for brain herniation is excluded)

  • Blood or urine screen for drugs
  • Electroencephalogram
  • CT or MR brain scan
seizure precipitants
Seizure Precipitants

 Metabolic and Electrolyte Imbalance

 Stimulant/other proconvulsant intoxication

 Sedative or ethanol withdrawal

 Sleep deprivation

 Antiepileptic medication reduction or inadequate AED treatment

 Hormonal variations

 Stress

 Fever or systemic infection

 Concussion and/or closed head injury

seizure precipitants cont
Seizure Precipitants (cont.)

Metabolic and Electrolyte Imbalance

  • Low blood glucose

(or high glucose, esp. w/ hyperosmolar state)

  • Low sodium
  • Low calcium
  • Low magnesium
seizure precipitants cont1
Seizure Precipitants (cont.)

Stimulants/Other Pro-convulsant Intoxication

 IV drug use

 Cocaine

 Ephedrine

 Other herbal remedies

 Medication reduction

eeg abnormalities
EEG Abnormalities

 Background abnormalities: significant asymmetries and/or degree of slowing inappropriate for clinical state or age

 Interictal abnormalities associated with seizures and epilepsy

  • Spikes
  • Sharp waves
  • Spike-wave complexes

 May be focal, lateralized, generalized

medical treatment of first seizure
Medical Treatment of First Seizure

Whether to treat first seizure is controversial

 16-62% will recur within 5 years

 Relapse rate might be reduced by antiepileptic drug treatment

 Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk

 Quality of life issues are important (ie driving)

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): 478-483.

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: 851-852.

choosing antiepileptic drugs
Choosing Antiepileptic Drugs

 Seizure type

 Epilepsy syndrome

 Pharmacokinetic profile

 Interactions/other medical conditions

 Efficacy

 Expected adverse effects

 Cost

choosing antiepileptic drugs1
Choosing Antiepileptic Drugs
  • Limited placebo-controlled trials available, particularly of newer AEDs
  • In practice, several drugs are commonly used for indications other than those for which they are officially approved/recommended
  • Choice of AED for partial epilepsy depends largely on drug side-effect profile and patient’s preference/concerns
  • Choice of AED for primary generalized epilepsy depends on predominant seizure type(s) as well as drug side-effect profile and patient’s preference/concerns
  • ILAE and AAN recommendations indications listed in the appendix
choosing antiepileptic drugs2
Broad-Spectrum Agents

Valproate

Felbamate

Lamotrigine

Topiramate

Zonisamide

Levetiracetam

Rufinamide*

Narrow-Spectrum Agents

Partial onset seizures

Phenytoin

Carbamazepine

Oxcarbazepine

Gabapentin

Pregabalin

Tiagabine

Lacosamide*

Absence

Ethosuximide

Choosing Antiepileptic Drugs

* New AEDs (approved 2008) categorization may change

choosing antiepileptic drugs cont
Choosing Antiepileptic Drugs (cont.)Choosing Antiepileptic Drugs (cont.)

Monotherapy for Partial Seizures

Best evidence and FDA indication:

Carbamazepine, Oxcarbazepine, Phenytoin, Topiramate

Similar efficacy, likely better tolerated:

Lamotrigine, Gabapentin, Levetiracetam

Also shown to be effective:

Valproate, Phenobarbital, Felbamate, Lacosamide

Limited data but commonly used:

Zonisamide, Pregabalin

Azar and Abou-Khalil, Seminars in Neurology, 2008 28:305-316

choosing antiepileptic drugs cont1
Choosing Antiepileptic Drugs (cont.)

Monotherapy for Generalized-Onset Tonic-Clonic Seizures

Best evidence and FDA Indication:

Valproate, Topiramate

Also shown to be effective:

Zonisamide, Levetiracetam

Phenytoin, Carbamazepine (may exacerbate absence and myoclonic sz )

Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies)

choosing antiepileptic drugs cont2
Choosing Antiepileptic Drugs (cont.)

Absence seizures

Best evidence:

Ethosuximide (limited spectrum, absence only)

Valproate

Also shown to be effective:

Lamotrigine

May be considered as second-line:

Zonisamide, Levetiracetam, Topiramate, Felbamate, Clonazepam

choosing antiepileptic drugs cont3
Choosing Antiepileptic Drugs (cont.)

Myoclonic Seizures

Best evidence:

Valproate

Levetiracetam (FDA indication as adjunctive tx)

Clonazepam (FDA indication)

Possibly effective:

Zonisamide, Topiramate

choosing antiepileptic drugs cont4
Choosing Antiepileptic Drugs (cont.)

Lennox-Gastaut Syndrome

Best evidence/FDA indication*:

Topiramate, Felbamate, Clonazepam, Lamotrigine, Rufinamide

* FDA approval is for adjunctive treatment for all except clonazepam

Also effective:

Valproate

Some evidence of efficacy:

Zonisamide, Levetiracetam

antiepileptic drug monotherapy
Antiepileptic Drug Monotherapy

 Simplifies treatment

 Reduces adverse effects

 Conversion to monotherapy from polytherapy

  • Eliminate sedative drugs first
  • Withdraw antiepileptic drugs slowly over several months
antiepileptic drug interactions
Antiepileptic Drug Interactions
  • Drugs that may induce metabolism of other drugs:
    • carbamazepine, phenytoin, phenobarbital, primidone
  • Drugs that inhibit metabolism of other drugs:
    • valproate, felbamate
  • Drugs that are highly protein bound:
    • valproate, phenytoin, tiagabine
    • carbamazepine, oxcarbazepine
    • topiramate is moderately protein bound
  • Other drugs may alter metabolism or protein binding of antiepileptic drugs (especially antibiotics, chemotherapeutic agents and antidepressants)
antiepileptic drug interactions1
Antiepileptic Drug Interactions

Drugs that may decrease the efficacy of hormonal contraception

  • Phenytoin
  • Carbamazepine
  • Phenobarbital
  • Topiramate*
  • Oxcarbazepine*
  • Felbamate*

*at high doses

“High-dose” birth control pills are recommended for patients taking

these medications.

Lamotrigine levels decreased by hormonal contraception

aed serum concentrations
AED Serum Concentrations
  • AED serum concentrations are to be used as a guide, not dictate clinical decision making.
  • Serum concentrations are useful when optimizing AED therapy, assessing compliance, monitoring during pregnancy or oral contraceptive use, or teasing out drug-drug interactions.
  • Individual patients define their own “therapeutic” and “toxic” ranges.

Patsalos PN, et al. Epilepsia.2008. 49(7): 1239-1276

adverse effects of aeds common
Adverse Effects of AEDs: Common

Often dose-related:

Dizziness

Fatigue

Ataxia

Diplopia

Irritability

  • levetiracetam

Word-finding difficulty

  • topiramate

Weight loss/anorexia

  • topiramate, zonisamide, felbamate

Weight gain

  • valproate (also associated with polycystic ovarian syndrome in young women)
  • carbamazepine, gabapentin, pregabalin
adverse effects of aeds serious
Adverse Effects of AEDs: Serious

Typically idiosyncratic:

Renal stones

  • topiramate, zonisamide

Hyponatremia

  • carbamazepine, oxcarbazepine

Aplastic anemia

  • felbamate, zonisamide, valproate, carbamazepine

Agranulocytosis

  • carabamazepine

Hepatic Failure

  • valproate, felbamate, lamotrigine, phenobarbital

Anhydrosis, heat stroke

  • topiramate

Acute closed-angle glaucoma

  • topiramate
adverse effects of aeds rash
Adverse Effects of AEDs: Rash
  • 15.9% patients ever experienced a rash attributed to an AED
  • Average rate of AED-related rash for a given AED 2.8%, 2.1% causing AED discontinuation.
  • Predictors significant in multivariate analysis:
    • occurrence of another AED-rash

Arif H et al. Neurology 2007

adverse effects of aeds rash1
Adverse Effects of AEDs: Rash

Stevens-Johnson Syndrome (SJS) and

Toxic Epidermal Necrolysis (TENS)

  • severe life threatening allergic reaction
  • blisters and erosions of the skin, particularly palms/soles and mucous membranes
  • fever and malaise
  • rare: severe risk roughly 1-10/10,000 for many AEDs
    • rapid titration of lamotrigine especially in combination with valproate increases risk
adverse effects of aeds rash2
Adverse Effects of AEDs: Rash

Drugs rarely associated with rash

  • Valproate
  • Gabapentin
  • Pregabalin
  • Levetiracetam
  • Topiramate
aed related rash in adult patients with epilepsy
AED-related rash in adult patients with epilepsy

▲▲= rash rate significantly greater than average of all other AEDs (p<0.003)

▼▼= rash rate significantly lower than average of all other AEDs (p<0.003)

▲= trend towards significantly higher than average rash rate of all other AEDs (0.003

▼= trend towards significantly lower than average rash rate of all other AEDs (0.003

aed related rash in asian patients with epilepsy
AED-related rash in Asian patients with epilepsy

FDA alert 12/2007

Risk of “dangerous or even fatal skin reactions” (SJS and TEN) are

more common in those with HLA-B*1502

This allele is almost exclusively found in Asians

  • In 10-15% of population in China, Thailand, Malaysia, Indonesia, the Phillipines, and Taiwan
  • 2-4% in India
  • <1% in Japan and Korea

59/60 Asian patients w/ SJS/TEN had this allele vs 4% of cbz

tolerant patients

Estimated absolute risk for those with the allele: 5%

Asians “should be screened for the HLA-B*1502 allele before

starting treatment with carbamazepine”

These patients may also be at risk with other AEDs

  • Use drugs not typically associated with rash

www.fda.gov

epilepsy comorbidities and aeds
Epilepsy Comorbidities and AEDs

Osteoporosis

  • Mostly worsened by the enzyme inducers: phenytoin, phenobarbital, primidone. Carbamazepine data equivocal.
  • Equivocal data with valproate, unavailable for other non- inducers.
  • Take calcium 1000-1500/d; Vit D 400-4000/d

Depression

  • Can be exacerbated by levetiracetam (and less so zonisamide)
  • Can be helped by lamotrigine and possibly gabapentin, pregabalin (and vagus nerve stimulator)

Migraine

  • Consider topiramate, valproate

Obesity

  • Weight loss with topiramate and zonisamide
  • Weight gain with valproate > gabapentin/pregabalin, carbamazepine
possible suicide risk with aeds
Possible suicide risk with AEDs

Recent FDA alert (1/2008):

  • Meta-analysis of 199 placebo-controlled add-on tx trials

(44,000 patients)

  • Suicidality with adjunct AEDs than adjunct placebo:
    • 0.43% vs 0.22%
  • Extra 2.1 patients per 1000 more patients will have suicidality
  • 4 suicides with AEDs vs 0 with placebo
  • “generally consistent across the 11 AEDs”

Data analysis is controversial and overall difference is very small

Further investigation is needed

Clinicians should be aware of potential risk and screen for

depression/suicidality

www.fda.gov

dose initiation and monitoring
Dose Initiation and Monitoring

 Discuss likely and unlikely but important adverse effects

 Discuss likelihood of success

 Discuss recording/reporting seizures, adverse effects, potential precipitants

discontinuing aeds
Discontinuing AEDs

 Seizure freedom for 2 yearsimplies overall >60% chance of successful withdrawal in some epilepsy syndromes

 Favorable factors

  • Control achieved easily on one drug at low dose
  • No previous unsuccessful attempts at withdrawal
  • Normal neurologic exam and EEG
  • Primary generalized seizures except JME
  • “Benign” syndrome

 Consider relative risks/benefits (e.g., driving, pregnancy)

evaluation after seizure recurrence
Evaluation After Seizure Recurrence

 Progressive pathology?

 Avoidable precipitant?

 If on AED

  • Problem with compliance?
  • Pharmacokinetic factor?
  • Increase dose?
  • Change medication?

 If not on AED

  • Start therapy?
non drug treatment lifestyle modifications
Non-Drug Treatment/Lifestyle Modifications

 Adequate sleep

 Avoidance of alcohol, stimulants, etc.

 Avoidance of known precipitants

 Stress reduction — specific techniques

ketogenic diet
Ketogenic Diet
  • Main experience with children, especially with multiple seizure types
  • Likely anti-seizure effect of ketosis (beta hydroxybutyrate), but other mechanisms also may be responsible for beneficial effects
  • Low carbohydrate, adequate protein, high fat
  • 50% with a >50% seizure reduction
    • 30% with >90% reduction
  • Side effects include kidney stones, weight loss, acidosis, dyslipidemia
alternative diets
Alternative Diets

 Modified Atkins diet

  • 10 g/day carbohydrates to start, fats encouraged
  • No protein, calorie, fluid restriction
  • 3 reports to date from Johns Hopkins, 1 from South Korea
    • 47% all children with >50% seizure reduction
    • Studies underway for adults

 Low-glycemic index treatment

  • 40-60 g/day low-glycemic carbohydrates
  • Portions generally controlled
  • Single report from Massachusetts General
patient selection for surgery criteria
Patient Selection for Surgery: Criteria

 Epilepsy syndrome not responsive to medical management

  • Unacceptable seizure control despite maximum tolerated doses of 2-3 appropriate drugs as monotherapy

 Epilepsy syndrome amenable to surgical treatment

evaluation for surgery
Evaluation for Surgery

History and Exam: consistency, localization of seizure onset and progression

MRI: 1.5 mm coronal cuts with sequences sensitive to gray-white differentiation and to gliosis

Other neuroimaging options: PET, ictal SPECT

EEG: ictal and interictal, special electrodes

Magnetoencephalography (MEG): interictal, mapping

Neuropsychological battery

Psychosocial evaluation

Intracarotid amobarbital test (Wada)

surgical treatment
Surgical Treatment

 Potentially curative

  • Resection of epileptogenic region (“focus”) avoiding significant new neurologic deficit

 Palliative

  • Partial resection of epileptogenic region
  • Disconnection procedure to prevent seizure spread
    • Callosotomy
    • Multiple subpial transections
epilepsy surgery outcomes
Epilepsy Surgery Outcomes

Reference: Engel, J. et al. Neurology 2003

epilepsy surgery
Epilepsy Surgery

Corpus Callosotomy

  • Palliative surgery for intractable epilepsies with drop attacks (ie Lennox-Gastaut)
  • Up to 75% have > 75% reduction in atonic seizures
  • Risk of disconnection syndromes

Hemispherectomy

  • Indicated for catastrophic hemispheric epilepsies, usually presenting in children (ie Rasmussen’s encephalitis, hemimegalencephaly)
  • 43-79% seizure free (varies by etiology)
  • “Functional hemispherectomy” (disconnection without removal) now more commonly performed

Multiple Subpial Transections

  • Cuts horizontal cortical-cortical connections
  • Generally reserved for epileptogenic regions in functional cortex

Spencer and Huh, Lancet 2008

vagus nerve stimulator
Vagus Nerve Stimulator

 Intermittent programmed electrical stimulation of left vagus nerve

 Option of magnet activated stimulation

 Adverse effects local, related to stimulus (hoarseness, throat discomfort, dyspnea)

 Mechanism unknown

 Clinical trials show that 35% of patients have a 50% reduction in seizure frequency and 20% experience a 75% reduction after 18 months of therapy.

 May improve mood and allow AED reduction

 FDA approved for refractory partial onset seizures and refractory depression

status epilepticus
Status Epilepticus

 Definition

  • More than 10 minutes of continuous seizure activity

or

  • Two or more sequential seizures without full recovery between seizures
status epilepticus1
Status Epilepticus

 A medical emergency

  • Adverse consequences can include hypoxia, hypotension, acidosis, hyperthermia, rhabdomyolysis and neuronal injury
  • Know the recommended sequential protocol for treatment and distribute a written protocol to emergency rooms, ICUs and housestaff.
  • Goal: stop seizures as soon as possible
se treatment algorithm
SE Treatment Algorithm

Arif and Hirsch, Seminars in Neurology, 2008

One commonly used treatment algorithm is:

First 5 minutes:

  • Check emergency ABC’s
  • Give O2
  • Obtain IV access
  • Begin EKG monitoring
  • Check fingerstick glucose
  • Draw blood for Chem-7, Magnesium, Calcium, Phosphate, CBC, LFTs, AED levels, ABG, troponin
  • Toxicology screen (urine and blood).
se treatment algorithm1
SE Treatment Algorithm

Arif and Hirsch, Seminars in Neurology, 2008

6-10 minutes

  • Thiamine 100 mg IV; 50 ml of D50 IV unless adequate glucose known.
  • Lorazepam4 mg IV over 2 mins; if still seizing, repeat X 1 in 5 mins.
  • If no rapid IV access give diazepam 20 mg PR or midazolam 10 mg intranasally, buccally or IM.
se treatment algorithm2
SE Treatment Algorithm

Arif and Hirsch, Seminars in Neurology, 2008

10-20 minutes:

  • If seizures persist, begin fosphenytoin 20 mg/kg IV at 150 mg/min, with blood pressure and EKG monitoring.
  • Reasonable to bypass this step, or perform subsequent step simultaneous with fosphenytoin loading
se treatment algorithm3
SE Treatment Algorithm

Arif and Hirsch, Seminars in Neurology, 2008

10-60 minutes: one (or more) of the following 4 options:

(intubation usually necessary except for valproate)

  • CIV midazolam: Load: 0.2 mg/kg; repeat 0.2-0.4 mg/kg boluses every 5 minutes until seizures stop, up to a maximum total loading dose of 2 mg/kg. Initial cIV rate: 0.1 mg/kg/hr. cIV dose range: 0.05 – 2.9 mg/kg/hr.

OR

  • CIV propofol: Load: 1 mg/kg; repeat 1-2 mg/kg boluses every 3-5 minutes until seizures stop, up to maximum total loading dose of 10 mg/kg. Initial cIV rate: 2 mg/kg/h. cIV dose range: 1-15 mg/kg/hr. Avoid >48 hrs of >5 mg/kg/h (increased risk of propofol infusion syndrome).

OR

  • IV valproate: 40 mg/kg over ~10 minutes. If still seizing, additional 20 mg/kg over ~5 minutes.

OR

  • IV phenobarbital: 20 mg/kg IV at 50-100 mg/min.
se treatment algorithm4
SE Treatment Algorithm

Arif and Hirsch, Seminars in Neurology, 2008

60 minutes:

  • CIV Pentobarbital. Load: 5 mg/kg at up to 50 mg/min; repeat 5 mg/kg boluses until seizures stop. Initial cIV rate: 1 mg/kg/hr. cIV-dose range: 0.5-10 mg/kg/hr; traditionally titrated to suppression-burst on EEG.

Begin EEG monitoringASAP if patient does not

rapidly awaken, or if any CIV treatment is used.

~20% of those successfully treated clinical

status will still be seizing on EEG.

Treiman et al, VA Coop Study, NEJM ‘98

differential diagnosis of non epileptic events physiologic
Differential Diagnosis of Non-epileptic Events: Physiologic
  • Syncope
    • Cardiac (Arrhythmia)
    • Non-Cardiac Syncope (Vasovagal, Dysautonomic)
  • Metabolic (Hypoglycemia)
  • Migraine
  • Sleep Disorders (Narcolepsy)
  • Movement Disorders (Paroxysmal Dyskinesia)
  • Transient Ischemic Attacks
differential diagnosis of non epileptic events psychogenic
Differential Diagnosis of Non-epileptic Events: Psychogenic
  • Psychogenic Seizures
  • Malingering
  • Panic Attacks
  • Intermittent Explosive Disorder
  • Breath-holding Spells
syncope
Syncope

 Characteristic warning, usually gradual (except with cardiac arrhythmia)

 Typical precipitants (except with cardiac arrhythmia)

 Minimal to no postictal confusion/somnolence

 Convulsive syncope — tonic>clonic manifestations, usually < 30 sec; usually from disinhibited brainstem structures (only rarely from cortical hypersynchronous activity)

syncope vs sz before spell
Syncope vs Sz: Before Spell

Hirsch et al, Merritt’s Textbook of Neurology, 2007

syncope vs sz during spell
Syncope vs Sz: During Spell

Hirsch et al, Merritt’s Textbook of Neurology, 2007

syncope vs sz during spell1
Syncope vs Sz: During Spell

Hirsch et al, Merritt’s Textbook of Neurology, 2007

syncope vs sz during spell2
Syncope vs Sz: During Spell

Hirsch et al, Merritt’s Textbook of Neurology, 2007

syncope vs sz after spell
Syncope vs Sz: After spell

Hirsch et al, Merritt’s Textbook of Neurology, 2007

features that are not helpful for differentiating syncope from seizure
Incontinence

Prolactin level

Dizziness

Fear

Injury other than lateral tongue biting

Eye movements (rolling back)

Brief automatisms

Features That Are Not Helpful for Differentiating Syncope from Seizure

Hirsch et al, Merritt’s Textbook of Neurology, 2007

psychogenic nonepileptic seizures
Psychogenic Nonepileptic Seizures
  • 10-45% of patients referred for intractable spells
  • Females > males
  • Psychiatric mechanism — dissociation, conversion
  • Common association with physical, emotional, or sexual abuse
  • Spells with non-epileptic etiology
  • No obvious ictal eeg correlation

(classically normal awake background during episode of impaired consciousness)

Caveats: Diagnosis can be complicated

    • The majority of simple partial seizures have no EEG correlation
    • Frontal lobe seizures may have unusual semiology and no discernable EEG correlation
psychogenic nonepileptic seizures cont
Psychogenic Nonepileptic Seizures (cont.)

FEATURES SUGGESTIVE OF NONEPILEPTIC PSYCHOGENIC SEIZURES

  • Eye Closure
  • Pelvic thrusting
  • Opisthotonus
  • Side-to-side head shaking
  • Prolonged duration (>4 minutes)
  • Stopping and starting
  • Suggestibility
psychogenic nonepileptic seizures cont1
Psychogenic Nonepileptic Seizures (cont.)

 Represents psychiatric disease

 Once recognized, approximately 50% respond well to specific psychiatric treatment

 Epileptic and nonepileptic seizures may co-exist

 Video-EEG monitoring often required for diagnosis

utility of epilepsy video eeg monitoring units
Utility of epilepsy video/EEG monitoring units

Epilepsy Monitoring Unit (EMU):

  • Inpatient unit with specialized personnel
  • Continuous video and EEG recording
  • Utility:
    • Differentiate between epileptic and non-epileptic spells
    • Identification of unrecognized seizures
    • Recording seizures for presurgical evaluation

NAEC Guidelines for EMU evaluation:

  • Treatment failure of 1 year
  • Failure of 2-3 AEDs
utility of epilepsy video eeg monitoring units non epileptic spells
Utility of epilepsy video/EEG monitoring units:Non-epileptic spells

Study of 213 EMU admissions

Smolowitz et al, Am J Med Qual 2007

  • 21% had purely nonepileptic events
    • Treated as if epilepsy for a mean of 9 yrs
    • Half treated w/ >3 AEDs
  • EMU yielded definitive diagnosis in 88%
utility of epilepsy video eeg monitoring units emu epilepsy
Utility of epilepsy video/EEG monitoring units (EMU): Epilepsy

Early Identification of Refractory Epilepsy n=525

Kwan and Brodie, NEJM 200

  • 192 (37%) patients were refractory.
  • Only 11% of patients became seizure-free if the first drug was ineffective.
  • Suggests need for early pre-surgical evaluation

Patient awareness of seizures n=31

Blum et al. Neurology. 1996

  • 30% patients deny all seizures
  • Only 23% were aware of all seizures
sudden unexplained death in epilepsy sudep
Sudden Unexplained Death in Epilepsy: SUDEP

Definition:

“sudden, unexpected, witnessed or unwitnessed, nontraumatic and non-drowning death in a patient with epilepsy where the postmortem examination does not reveal a toxicologic or anatomic cause of death, with or without evidence of a seizure and excluding documented status epilepticus.”

Nashef L, Brown S. Epilepsy and sudden deaths. Lancet. 1996;348:1324-1325.

sudden unexplained death in epilepsy sudep1
Sudden Unexplained Death in Epilepsy: SUDEP

Witnessed SUDEP Langan et al. (2000)

  • 15/135 SUDEP cases were witnessed.
  • 12/15 were associated with a convulsive seizure.
  • One collapse occurred 5 minutes after a GTC seizure and one after an aura.
  • One patient died in a probable postictal state.
  • 12/15 were noted to have experienced respiratory difficulties.
    • Suggests that respiratory dysfunction may be an important contributing factor in SUDEP.
    • Suggests that positioning or stimulation of respiration may be important in the prevention of SUDEP.
epidemiology of sudep
Epidemiology of SUDEP

SUDEP

  • Represents about 2-18% of deaths among the general population of patients with epilepsy.
  • Risk of sudden death in epilepsy patients 24 X that of general population.
  • Mean SUDEP incidence: 3.7/1000 people per year.
    • Higher in patients referred for epilepsy surgery (up to 1 per 100).

Walczak et al. Neurology 2001;56(4):519-525

Ryvlin P, Kahane P. Epilepsy Res. 2003;56(2-3):105-120

Dasheiff RM. J Clin Neurophys. 1991;8(2):216-222

Leestma et al. Ann Neurol 1989;26(2):195-203

epidemiology of sudep1
Epidemiology of SUDEP

SUDEP Risk Factors

  • History of and number of GTCS
  • Frequent seizures
  • Subtherapeutic AED levels
  • Young adults
  • Long epilepsy duration; early epilepsy onset
  • AED polytherapy
  • Frequent AED changes
  • IQ <70

Tomson, 2005; Tellez-Zenteno, 2005; Langan, 2005; So, 2006

recommendations for sudep prevention
Recommendations for SUDEP prevention

Optimize seizure control as promptly as possible

  • Re-evaluate epilepsy diagnosis and treatment as soon as 2 AEDs have failed, or when GTC szs are frequent despite initial AED treatment
  • Consider epilepsy surgery at that point
  • Maximize compliance with AEDs

Use the least number of AEDs needed to control seizures

  • Add AED with the aim of replacing the current AED in a timely fashion (But not at the expense of worsening of seizure control)

Educate patients and families

pregnancy and epilepsy major congenital malformation and aeds
Pregnancy and Epilepsy:Major Congenital Malformation and AEDs
  • Most available data on risk of AEDs comes from pregnancy registries.
  • Main outcome variable of most registries are major congenital malformations (MCM)
  • MCM = malformation that affects physiologic function or requires surgery
    • Neural tube defects
    • Cardiac defects
    • Genitourinary defects
    • Oral clefts
  • MCMs are more common with AED exposure
    • MCM risk in general population 1.6-2.1%
    • MCM risk with AED monotherapy 4.5% (OR 2.6)
    • MCM risk with Polytherapy 8.6% (OR 5.1)

Holmes eta l. NEJM 2001. 344 (15): 1132-8.

pregnancy and epilepsy
Pregnancy and Epilepsy
  • 96% of pregnancies in mothers with epilepsy produce normal children
  • Spontaneous abortions and pre-term birth more common in women with epilepsy
  • Increased rate of fetal malformations associated with antiepileptic drug exposure
  • Seizures during pregnancy may be harmful
    • Tonic-clonic seizures associated with intracranial hemorrhage, fetal bradycardia and lower IQ in children
    • Status associated with increased fetal and maternal mortality in some studies
    • Insufficient data on non-convulsive seizures

Morrow et al. J Neurol Neurosurg Psychiatry. 2006. 77(2):193-8

Holmes eta l. NEJM 2001. 344 (15): 1132-8.

Meador et al. Neurology. 2008; 71:1109-1117

Adab et. al. J Neurol Neurosurg Psychiatry. 2004: 75(11): 1575-1583

pregnancy and epilepsy major congenital malformation and aeds1
Pregnancy and Epilepsy:Major Congenital Malformation and AEDs

Valproate consistently associated with poorer outcomes

  • MCM rate with valproate monotherapy 6.2-13.2% across 5 registries
  • Most studies show dose- related increase in risk with doses > 1000mg/day
  • Polytherapy regimens including valproate also substantially increased risk of MCM
  • Valproate associated with lower IQs in exposed children

Phenobarbital probably also poses higher risk of MCM

compared with other monotherapy regimens.

Meador etal. Neurology 2007; 68 (suppl 1): A337

Meador et al. Neurology 2008; 71:1109-1117

pregnancy and epilepsy major congenital malformation and aeds2
Pregnancy and Epilepsy:Major Congenital Malformation and AEDs

MCM rate similar among other studied AEDs in monotherapy, but not enough data to show significant difference between them

  • Levetiracetam
    • Early data promising (0% in monotherapy, 2.7% in polytx)
  • Carbamazepine (2.2-3.9%)
    • Substantial data available, relatively good track record
  • Lamotrigine (1.4-4.4%)
    • Increased risk (5.4%) with doses > 400/day
  • Gabapentin (0-3.2%)
  • Topiramate (0-4.8%)
  • Phenytoin (3.2-6.7%)
  • Zonisamide, Pregabalin
    • No substantial data on monotherapy

Meador etal. Neurology 2007; 68 (suppl 1): A337

Meador et al. Neurology 2008; 71:1109-1117

pregnancy and epilepsy guidelines for management
Pregnancy and Epilepsy Guidelines for Management

All women of child-bearing potential should receive education and carefully considered management before and during pregnancy to optimize the chances of a good outcome for both mother and child.

Reference: Liporace J, D’Abreu. Epilepsy and Women’s Health: Family Planning, Bone Health,

Menopause, and Menstrual Related Seizures. Mayo Clinic Proceedings 2003; 78: 497-506.

pregnancy and epilepsy major congenital malformation rates in monotherapy
20%

15%

10%

5%

0%

LEV

GBN

CBZ

LTG

TPM

PHT

PHB

VPA

UK Pregnancy Registry

North American AED Pregnancy Registry

Australian Pregnancy Registry

Finland National Birth Registry

Swedish Medical Birth Registry

GSK International Lamotrigine Pregnancy Registry

Pregnancy and Epilepsy: Major Congenital Malformation Rates in Monotherapy
pregnancy and epilepsy guidelines for management1
Pregnancy and Epilepsy Guidelines for Management

Education

  • Most women with epilepsy have normal children
  • Risk of fetal malformations is increased
  • AED teratogenicity is related to exposure in the first trimester of pregnancy
  • Planning should begin well before pregnancy
  • Seizures may be deleterious to the fetus
  • Compliance with AED treatment is important
  • Prenatal diagnosis of fetal malformations is possible
pregnancy and epilepsy guidelines for management2
Pregnancy and Epilepsy Guidelines for Management

Before pregnancy

  • Attempt AED monotherapy with lowest effective dose
  • Consider switching AEDs prior to pregnancy, particularly if on valproate
  • Establish baseline therapeutic levels
  • Folate supplementation
    • At least 1mg/day for women of childbearing age
    • 4mg/day if planning pregnancy or at risk for pregnancy
pregnancy and epilepsy guidelines for management3
Pregnancy and Epilepsy Guidelines for Management

During pregnancy

  • Monitor AED dose requirements to maximize seizure control
    • Particularly with lamotrigine (levels fall > 50% and sz increase)
    • Also increased clearance of levetiracetam, oxcarbazepine, phenobarbital and phenytoin
  • Continue folate supplementation
  • High-risk OB care, consider prenatal diagnosis of malformations
  • Vit K (10 mg/day orally) starting at 36 weeks
breast feeding and epilepsy
Breast Feeding and Epilepsy

Breastfeeding should be encouraged unless clear risk posed

Probably safe:

  • Carbamazepine
  • Phenytoin
  • Valproate
  • Lamotrigine

“Use with caution” in lactating women:

  • Primidone
  • Phenobarbital
  • Ethosuximide

Pennell et al. Epilepsy and Behavior. 2007. 11: 263-9

Newport et al. Pediatrics 2008. 122(1). E223-31

driving and epilepsy
Driving and Epilepsy

 Regulation varies state by state regarding:

  • Reporting requirements
  • Required seizure-free period
  • Favorable/unfavorable modifiers

 Insurance issues

 Employment issues

Resource: www.efa.org

first aid tonic clonic seizure
First AidTonic-Clonic Seizure

 After seizure ends, turn person on side with face turned toward ground to keep airway clear, protect from nearby hazards

 Transfer to hospital needed for:

  • Multiple seizures or status epilepticus
  • Person is pregnant, injured, diabetic
  • New onset seizures

 DO NOT put any object in mouth or restrain

neonatal seizures
Neonatal Seizures

 Incidence: 1.6 – 3.5 per 1000 live births

 Major risk factors are prematurity, low-birth weight, hypoxic-ischemic encephalopathy

 Associated with increased morbidity and mortality

 May be symptomatic of treatable, serious condition (hypoglycemia, meningitis)

 Diagnosis: observation with vs. without EEG

References: Ronen, J Pediatr, 1999; Lanska, Neurology, 1995;

Saliba, Am J Epidemiol, 1999.

recognition of neonatal seizures
Recognition of Neonatal Seizures

 Observation of abnormal, repetitive attacks of movements, postures or behaviors

 Classification

  • subtle
  • tonic
  • clonic
  • myoclonic
  • autonomic

 Evaluation for cause(s) of seizures

 Confirmation/support by EEG

examples of acquired conditions that may provoke neonatal seizures
Examples of Acquired Conditions That May Provoke Neonatal Seizures

 Hypoxia-ischemia

 Physical trauma

 Toxic-metabolic

 Inborn errors of metabolism

 Systemic or CNS infections

 Intracranial hemorrhage

acute treatment of neonatal seizures
Acute Treatment of Neonatal Seizures

 Phenobarbital loading dose: 20 mg/kg

 Fosphenytoin

loading dose: 20 mg/kg [email protected] 1

 Diazepam first dose about 0.25 mg/kg

 Lorazepam first dose about 0.05 to 0.1 mg/kg

selected pediatric epilepsy syndromes
Selected Pediatric Epilepsy Syndromes

 Epileptic Encephalopathies

  • West Syndrome — infantile onset, hypsarrhythmic EEG; infantile spasms; cryptogenic vs. symptomatic
  • Lennox-Gastaut Syndrome — childhood onset, slow spike-wave EEG, tonic, atypical absence, atonic and other seizure types, and mental retardation
  • Myoclonic epilepsies of infancy and early childhood — heterogeneous
slide110
Selected Pediatric Epilepsy Syndromes (cont.)

Febrile convulsions — 6 mo.-5 yrs.

  • Simple: Duration less than 15 minutes, generalized, and do not recur within 24 hours
  • Complex: Duration longer than 15 minutes, focal in nature or recur within 24 hours

Febrile convulsions: Risk Factors for development of epilepsy:

  • Complex febrile seizures
  • Neurodevelopmental abnormalities
  • Afebrile seizures in first-degree relatives
  • Recurrent febrile seizures
  • Febrile seizures following brief and low grade fever
  • Febrile seizure onset in first year
selected pediatric epilepsy syndromes cont
Selected Pediatric Epilepsy Syndromes (cont.)

 Benign epilepsy with centrotemporal spikes — nocturnal oropharyngeal simple partial seizures, with or without secondary generalization

 Childhood epilepsy with occipital paroxysms — visual or autonomic phenomena, especially ictal vomiting, at times with secondary generalization

selected pediatric epilepsy syndromes cont1
Selected Pediatric Epilepsy Syndromes (cont.)

 Idiopathic generalized epilepsies

  • Childhood absence epilepsy — absence, occasionally with tonic-clonic seizures
  • Juvenile myoclonic epilepsy — myoclonic, tonic-clonic, at times absence
aeds in pediatrics
AEDs in Pediatrics

 Extrapolation of efficacy data from adult studies

 Importance of adverse effects relative to efficacy

 Susceptibility to specific adverse effects (valproate hepatotoxicity, lamotrigine rash)

 Age-related pharmacokinetic factors

 Neonate: low protein binding, low metabolic rate, possible decreased absorption if given with milk/formula

 Children: faster metabolism

managing pediatric epilepsy
Managing Pediatric Epilepsy
  • Consider chewable/liquid formulations
  • Weight-based dosing with frequent adjustments to account for growth
  • Minimize missed school
  • Develop safety plan with family
  • For intractable epilepsy consider
    • Ketogenic diet
    • Surgery
    • Vagal nerve stimulation
appendix references for nurses
Appendix: References for Nurses

Reprinted with permission from the American Association of Neuroscience Nurses

appendix references for nurses1
Appendix: References for Nurses

Journals

 Clinical Nursing Practice in Epilepsy

 Epilepsia (the Journal of the International League Against Epilepsy).

 Epilepsy Currents (Bimonthly Journal for American Epilepsy Society. Also on www.aesnet.org)

 Epilepsy USA Magazine, published by the Epilepsy Foundation. Also available on www.epilepsyfoundation.org.

 The Journal of Neuroscience Nursing (the Journal of the American Association of Neuroscience Nurses). There is a yearly index in the December issue by author and by topic (epilepsy) for easy reference.

 Seizure

appendix references for nurses2
Appendix: References for Nurses

Books

 A Guide to Understanding and Living with Epilepsy, Devinsky, O, F.A. Davis Company, 1994.

 Anticonvulsant Prescribing Guide, PDR second edition, 1998, Ortho-McNeil.

 Clinical Epilepsy, Duncan, J.S., Shorvon, S.D., Fish, D.R., Churchill Livingstone, 1995.

 Core Curriculum for Neuroscience Nursing, third ed., American Association of Neuroscience Nursing.

 Epilepsy A to Z: A Glossary of Epilepsy Terminology, Kaplan PW, Loiseau P, Fischer RS, Jallon P, Demos Vermande, 1995.

 Epilepsy in Clinical Practice: A Case Study Approach, Wilner, A., Demos, 2000.

 Managing Seizure Disorders: A Handbook for Health Care Professionals, Santilli, N., Lippincott-Raven, 1996.

appendix references for nurses3
Appendix: References for Nurses

Books, Cont.

  • Seizures and Epilepsy in Childhood A guide for parents, third edition, Freeman JM, Vining EPG, Pillas DJ, Johns Hopkins Press, 2002.
  • The Ketogenic Diet: A Treatment for Children and Others with Epilepsy, Freeman JM, Kossoff EH, Kelly MT, Freeman JB. Demos, 2006.
  • Childhood Seizures, Shinnar, S., Amir N, Branski D, Karger, 1995.
  • Students with Seizures A manual for school nurses, Santilli N, Dodson WE, Walton AV. Health Scan Publications, 1991. (*there is a section in this book that lists references for specific groups.)
  • Treatment of Epilepsy: Principles and Practice, Wyllie E, Gupta A, Lachhwani DK. 2005

Videos

 The Epilepsy Foundation Catalog contains many videos that can be used for education for nurses, families and schools. The “First Aid” video is a good one. (800) EFA-1000 or www.epilepsyfoundation.org. (Spanish videos also available)

appendix references for nurses4
Appendix: References for Nurses

Networking

 American Association of Neuroscience Nurses (AANN), 4700 W. Lake Avenue, Glenview, IL 60025-1485, (847) 375-4733, http://www.aann.org. The professional organization for nurses specializing in the neurosciences.

 American Epilepsy Society, 342 North Main Street, West Hartford, CT 06117-2507, (860) 586-7505, www.aesnet.org. A membership society of professionals interested in epilepsy. Within the society are special interest groups including a nurses group. Contact the Society for more information.

 Association of Child Neurology Nurses (ACNN), 1000 West County Road East, Suite 290, St. Paul, MN, 55126, (651) 486-9447. A membership organization of nurses interested in child neurology. 

 Epilepsy Foundation, eCommunities. Chat rooms for four different groups: Women and Epilepsy; Parents Helping Parents; The Teen Chat Room; and Living Well with Seizures. Located at www.epilepsyfoundation.org

appendix references for nurses5
Appendix: References for Nurses

Web Sites

 American Association of Neuroscience Nurses http://www.aann.org

 American Child Neurology Nurses http://www.acnn.org

 American Epilepsy Society http://www.aesnet.org

 Epilepsy Foundation (National Office) http://www.epilepsyfoundation.org

or http://www.efa.org/education.firstaid.html

 Epilepsy Therapy Development Project/Epilepsy.com

http://www.epilepsy.com

 First Aid for Epilepsy http://www.epinet.org.an/info/general.asp

 Nursing Care Implications

http://www.nurseweek.com/ce/191-sb1.html

 Nursing CEUs for Neurological Nursing http://www.nursecen.com/nur.htm

 Nursing Case Studies http:www.webclinics.org

(log in as AED and use password NURSE)

appendix references for neurologists
Appendix: References for Neurologists

Epidemiology and Classification

  • Herman ST. Classification of Epileptic Seizures. Continuum Neurol. 2007; 13(4): 13-47.
  • Engel J et al. A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001; 42(6): 796-803.
appendix references for neurologists1
Appendix: References for Neurologists

Epidemiology and Management

  • French, JA and Pedley, TA. Management of Epilepsy. N Engl J Med 2008 359: 166-176
  • Krumholz A, Wiebe S, Gronseth G, et al. Evaluating an apparent unprovoked first seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2007;69:1996-2007
  • Blum, DE et al. Patient awareness of seizures. Neurology. 1996 Jul;47(1):260-4
  • Arif, H and Hirsch, L. Treatment of status epilepticus. Semin Neurol. 2008 Jul;28(3):342-54.
appendix references for neurologists2
Appendix: References for Neurologists

Antiepileptic Drugs

  • Azar NJ and BW Abou-Khalil. Considerations in the Choice of an Antiepileptic Drug in the Treatment of Epilepsy. Seminars in Neurology. 28(3): 305-316.
  • French JA, Kanner AM, Bautista J et al., Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society, Neurology 62 (2004), pp. 1252–1260.
  • French JA. Treatment with Antiepileptic Drugs, New and Old. Continuum Neuol 2007; 13(4): 71-90
  • Glauser T, Ben-Menachem, Bourgeois B et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47(7): 1094-1120.
  • Patsalos PN, Berry DJ, Bourgeois BFD et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 49(7): 1239-1276
appendix references for neurologists3
Appendix: References for Neurologists

Intractable Epilepsy and Epilepsy Surgery

  • Kwan P and MJ Brodie. Early Identification of Intractable Epilepsy. N Engl J Med. 2000 Feb 3;342(5):314-9.
  • Wiebe S et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy, N Engl J Med 345 (2001), 311–318
  • Engel J et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons, Neurology 60 (2003), 538–547.
  • Spencer SS and L Huh, The evaluation of surgical outcome in epilepsy, Lancet Neurol 7 (2008), 525–537.
ilae summary guidelines
ILAE Summary Guidelines

Reference: Epilepsia 2006:47; 1094-1120.

aan s recommendation levels
AAN’s Recommendation Levels

References:

Neurology 2004, 62:1252-1260.

Neurology 2004, 62:1261-1273.

summary of aan evidence based guidelines level a or b recommendations
Summary of AAN evidence-based guidelines level A or B recommendations

Reference: Neurology 2004, 62:1252-1260.

summary of aan evidence based guidelines level a or b recommendations1
Summary of AAN evidence-based guidelines level A or B recommendations

Reference: Neurology 2004, 62:1252-1260.

summary of aan evidence based guidelines level a or b recommendation
Summary of AAN evidence-based guidelines level A or B recommendation

References:

Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.

summary of aan evidence based guidelines level a or b recommendation1
Summary of AAN evidence-based guidelines level A or B recommendation

References:

Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273.

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