Epilepsy and Related Disorders

CHAPTER 11

I. Miscellaneous

A. Definitions

1. Seizure: reflects a sudden, sustained, and simultaneous discharge of very large numbers of neurons, either within a region of the brain or throughout the brain

a. Partial: focal cortical onset of epileptiform activity

i. Simple: no definitive loss of awareness

ii. Complex: loss of awareness at some level

b. Generalized: diffuse cortical epileptiform activity

i. Primary: immediate onset of diffuse cortical epileptiform activity

ii. Secondary: spread of focal discharges throughout cortex

2. Epilepsy: a tendency toward recurrent seizures unprovoked by systemic or neurologic insults

B. Incidence and prevalence

1. Seizure: incidence: approximately 80/100,000 per year; lifetime prevalence: 9% (one-third are benign febrile convulsions)

2. Epilepsy

a. Incidence: approximately 45/100,000 per year

b. Point prevalence: 0.5 to 1.0% (2.5 million)

i. Less than or equal to 14 years old (y/o): 13%

ii. 15 to 64 y/o: 63%

iii. Greater than or equal to 65 y/o: 24%

c. Cumulative risk of epilepsy: 1.3% to 3.1%

C. Impact of epilepsy in the United States

1. Economic: the total cost to the nation for seizures and epilepsy is approximately $12.5 billion; direct costs: $1.7 billion (medical costs); indirect costs: $10.8 billion (productivity).

2. Psychosocial: self-esteem and behavior issues; depression and anxiety disorder; sudden unexplained death in epilepsy (annual risk: 1/200–1/500; cause unknown but suspected to be cardiopulmonary arrest)

D. Experimental protocols to induce epilepsy in animal models

1. Aluminum gel

2. Freezing

3. Penicillamine

4. Cobalt

5. Stimulation

6. Kainic acid

E. Etiologies

1. Metabolic

a. Inborn errors: for example, gangliosidoses, glycogen storage diseases

b. Acquired: hyponatremia, hypocalcemia, hypomagnesemia, hypophosphatemia, hypoglycemia or hyperglycemia, hyperthyroidism/thyrotoxicosis, uremia, hyperammonemia

2. Toxic

a. Alcohol toxicity or withdrawal

b. Barbiturate toxicity or withdrawal

c. Benzodiazepine toxicity or withdrawal

d. Cocaine

e. Phencyclidine

f. Amphetamines

g. Common medications that cause seizures

i. Antidepressants (tricyclic antidepressants, bupropion)

ii. Antipsychotics (chlorpromazine, thioridazine, trifluoperazine, perphenazine, haloperidol)

iii. Analgesics (fentanyl, meperidine, pentazocine, propoxyphene, tramadol [Ultram^®])

iv. Local anesthetics (lidocaine, procaine)

v. Sympathomimetics (terbutaline, ephedrine, phenylpropanolamine)

vi. Antibiotics (penicillin, ampicillin, cephalosporins, metronidazole, isoniazid, pyrimethamine)

vii. Antineoplastic agents (vincristine, chlorambucil, methotrexate, bis-chloroethylnitrosourea, cytosine arabinoside)

viii. Bronchodilators (aminophylline, theophylline)

ix. Immunosuppressants: cyclosporine, ornithine-ketoacid transaminase 3

x. Others (insulin, antihistamines, atenolol, baclofen, cyclosporine)

3. Neoplasm (metastasis, primary)

4. Infection

a. Meningitis

b. Encephalitis

i. Herpes simplex virus 1: most commonly causes temporal lobe seizures

ii. Herpes simplex virus 2: infection acquired in birth canal

iii. HIV

iv. Epidemic encephalitides

c. Brain abscess

5. Vascular: stroke (ischemia, hemorrhage), subarachnoid hemorrhage, arteriovenous malformation, cavernous malformation, venous sinus thrombosis, amyloid angiopathy

6. Trauma: closed-head injury: subdural hematoma, contusion nonlesional; open-head injury

7. Eclampsia

8. Idiopathic: mesial-temporal sclerosis

9. Congenital

10. Perinatal insults

11. Phakomatoses: tuberous sclerosis, Sturge-Weber syndrome

12. Neuronal migration disorders

13. Autoimmune: systemic lupus erythematosus; central nervous system (CNS) vasculitis; autoimmune encephalitis (including LGI1, GABAa, GABAb encephalitis and others)

F. Febrile seizures

1. Uncommon before age 6 months and after age 6 years

2. 13% incidence of epilepsy if at least two of the following factors

a. Family history of nonfebrile seizures

b. Abnormal neurologic examination or development

c. Prolonged febrile seizure

d. Focal febrile seizure with Todd’s paralysis

G. Genetic basis for idiopathic epilepsies

CLINICAL PHENOTYPE	LINKAGE
Benign familial neonatal convulsions	8q; 20q
Benign familial infantile convulsions	19q
Autosomal-dominant nocturnal frontal lobe epilepsy (FLE)	20q
Partial epilepsy with auditory features	10q
Juvenile myoclonic epilepsy (JME)	6p
Generalized epilepsy with febrile seizures plus	19q; 2q
Febrile seizures	19p; 8q

H. Differential diagnosis of seizures

1. Hypoglycemia

2. Syncope (convulsive syncope common, often misinterpreted as seizure)

3. Asterixis

4. Tremor

5. Cerebrovascular accident/transient ischemic attack

6. Myoclonus

7. Dystonia

8. Narcolepsy

9. Panic attack/anxiety

10. Migraine

11. Psychogenic seizures

12. Malingering

13. Breath-holding spells

NB:

Breath-holding spells occur in up to 5% of infants, often triggered by frustration or sudden pain. Consciousness is lost prior to (occasional) brief clonic jerking.

I. Emergent evaluation of a patient with seizures

1. Airway, breathing, and circulation: protect airway by turning patient on side to reduce risk of aspiration

2. Examination

Examination	Assess for focal deficits that may indicate a lesion (i.e., tumor, infections, stroke)
	Short-term memory deficits suggestive of temporal lobe epilepsy
	Frontal lobe executive dysfunction suggestive of frontal lobe epilepsy
History	History of seizures (type, duration, frequency)
	Intake of antiepileptic drugs (AEDs) and other medications that may cause seizures
	Family history of seizures
	History of head trauma with loss of consciousness >30 mins or penetrating head injury
	History of febrile seizures
	History of central nervous system infections
	History of substance abuse (especially ethyl alcohol [ETOH] and barbiturate; either intoxication or withdrawal)

3. Basic labs

a. Electrolytes: ↓Na+, Ca²⁺, Mg²⁺

b. ↑ or ↓ glucose

c. Platelets (thrombotic thrombocytopenic purpura, disseminated intravascular coagulopathy)

d. Toxicology screen (especially ETOH and barbiturate intoxication or withdrawal)

e. Antiepileptic drug (AED) levels

f. Erythrocyte sedimentation rate (if vasculitis suspected)

g. Infection: urinalysis, chest x-ray, ± lumbar puncture (LP) (perform if recent fever, atypical mental status changes)

4. Diagnostic tests

a. Radiographic: MRI preferred over CT (either should be acquired with or without contrast); evaluate for tumor, stroke, and/or infectious process; if patient stable, MRI preferred; if focal deficit, CT emergently followed by MRI.

b. LP: if there is any suggestion of fever, meningeal signs (nuchal rigidity), elderly, or behavioral signs → perform LP; once LP is performed, treat empirically if any suggestion of infection clinically even before results are known; if LP cannot be performed and infection suspected, always treat patient and do not await availability of LP or results; may want to treat empirically with acyclovir, 10 mg/kg q8h, and third-generation cephalosporin.

c. Electroencephalography (EEG): obtain within 24 to 48 hours (increased epileptiform potentials are noted postictally within 24–48 hours); if persistent mental status changes, stat EEG to rule out nonconvulsive status epilepticus (SE).

5. Treatment

a. Single seizure

i. None (unless SE)

ii. Recurrence risk after a first unprovoked seizure

(A) Year 1: 14%

(B) Year 2: 29%

(C) Year 3: 34%

iii. AEDs have no effect on risk or disease course.

b. Recurrent seizure or abnormality on evaluation

i. Recommend, in most cases, to load with fosphenytoin, which provides rapid therapeutic effect (unless phenytoin [PHT] or rapid loading dose is contraindicated; may then convert patient to another AED of choice once patient is stabilized)

ii. If recurrent self-limited seizures in emergency room, 1 to 2 mg of lorazepam (Ativan^®) intravenously to max of 10 mg (or respiratory compromise significantly increases)

c. If there is any history of alcohol (ETOH) abuse, administer thiamine, 100 mg intravenously, before glucose administration.

d. If AED level is low, use volume of distribution to calculate bolus dose:

Bolus dose (in mg) = V_d × (desired concentration – current concentration)

V_d is in L/kg × body weight in kg.

Concentration is in mg/L.

V_d: PHT = 0.6 L/kg

Valproic acid (VA) = 0.1–0.3 L/kg

Phenobarbital (PB) = 0.6 L/kg

Carbamazepine (CBZ) = 1–2 L/kg

II. Classifications

A. International classification of epileptic seizures

1. Partial seizures

a. Simple partial seizures

i. With motor signs

ii. With somatosensory or special sensory symptoms

iii. With autonomic symptoms or signs

iv. With psychic symptoms

b. Complex partial seizures (CPSs)

i. Simple partial onset

ii. With impairment of consciousness at onset

c. Partial seizures evolving to secondary generalized seizures

i. Simple partial seizures evolving to generalized seizures

ii. CPS evolving to generalized seizures

iii. Simple partial seizures evolving to CPS evolving to generalized seizures

2. Generalized seizures

a. Absence seizures

i. Typical absence

ii. Atypical absence

b. Myoclonic seizures

c. Clonic seizures

d. Tonic seizures

e. Tonic-clonic seizures

f. Atonic seizures

3. Unclassified seizures

B. Revised international classification of epilepsies, epileptic syndromes, and related seizure disorders

1. Localization related

a. Idiopathic (primary)

i. Benign childhood epilepsy with centrotemporal spikes

ii. Childhood epilepsy with occipital paroxysm

iii. Primary reading epilepsy

b. Symptomatic (secondary)

i. Temporal lobe epilepsies

ii. Frontal lobe epilepsies

iii. Parietal lobe epilepsies

iv. Occipital lobe epilepsies

v. Chronic progressive epilepsia partialis continua of childhood

vi. Reflex epilepsies

c. Cryptogenic

2. Generalized

a. Primary

i. Benign neonatal familial convulsions

ii. Benign neonatal convulsions

iii. Benign myoclonic epilepsy in infancy

iv. Childhood absence epilepsy

v. Juvenile absence epilepsy

vi. Juvenile myoclonic epilepsy

vii. Epilepsy with generalized tonic-clonic (GTC) convulsions on awakening

b. Cryptogenic or symptomatic

i. West’s syndrome

ii. Lennox-Gastaut syndrome

iii. Epilepsy with myoclonic astatic seizures

iv. Epilepsy with myoclonic absences

c. Symptomatic

i. Nonspecific etiology

(A) Early myoclonic encephalopathy

(B) Early infantile epileptic encephalopathy with suppression burst

ii. Specific syndromes

3. Epilepsies undetermined, whether focal or generalized

a. With both focal and generalized seizures

i. Neonatal seizures

ii. Severe myoclonic epilepsy in infancy

iii. Epilepsy with continuous spike waves during slow-wave sleep

iv. Acquired epileptic aphasia (Landau-Kleffner syndrome)

b. Special syndromes

c. Situation-related seizure

d. Febrile convulsions

e. Isolated seizures or isolated SE

f. Metabolic or toxic events

C. Primary generalized epilepsy

1. Absence

a. Typical

i. No aura or warning

ii. Motionless with blank stare

iii. Short duration (usually < 10 seconds)

iv. If seizure prolonged, eyelid fluttering or other automatisms may occur

v. Little or no postictal confusion

vi. 70% of cases: precipitated by hyperventilation

vii. EEG: 3-Hz spike and wave

b. Atypical

i. Similar to simple absence with motor activity or autonomic features

ii. May have clonic, atonic, and tonic seizures

iii. Longer duration

iv. More irregular spike wave with 2.5- to 4.5-Hz spike and wave, and polyspike discharges

2. Tonic

3. Atonic

a. Typical in children with symptomatic or cryptogenic epilepsy syndromes, such as Lennox-Gastaut syndrome

b. Duration: tonic mean, 10 seconds; atonic, usually 1 to 2 seconds

4. Tonic-clonic

5. Myoclonic seizures

a. Brief, shock-like muscle contractions of head or extremities

b. Usually bilaterally symmetric but may be focal, regional, or generalized

c. Consciousness preserved unless progression into tonic-clonic seizure

d. Precipitated by sleep transition and photic stimulation

e. May be associated with a progressive neurologic deterioration

f. EEG: generalized polyspike-wave, spike-wave complexes

g. Subtypes of myoclonic epilepsy

i. NB: Juvenile myoclonic epilepsy (JME)

(A) Onset is often late adolescence (12–16 y/o) with myoclonic events followed by tonic-clonic seizures; within a few years, myoclonic events are more common in the morning shortly after awakening.

(B) Genetically localized to chromosome 6p

(C) Most common seizure induced by photic stimulation; also precipitated by alcohol intake and sleep deprivation

(D) May have severe seizures if missed AEDs

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