A. Epidemiology

1. U-shaped incidence: highest in childhood and old age
2. 50% of events are idiopathic

B. Definitions and Classification [3,4]

1. Seizure is a clinical event
   1. Caused by abnormal cerebral electrical activity that
   2. Results in disturbances of sensorium, motor activity, sensation, and/or autonomic function
2. Epilepsy is recurrent unprovoked seizures
3. Partial Epilepsy: involves only one part of one hemisphere
4. Simple Partial Epilepsy
   1. No loss of consciousness
   2. Presents as convulsive motor activity, sensory alteration, disturbances of thought
   3. Autonomic symptoms may occur
5. Complex
   1. Clouding of consciousness
   2. Often with automatisms
   3. Post-ictal state is common
   4. Electrical activity spreads to the limbic region from the either the temporal or frontal lobes
6. Secondarily generalized partial seizure
7. Generalized: involving all of both hemispheres from the onset
   1. Absence: impairment of sensorium only
   2. Grand mal or tonic clonic
   3. Atonic or akinetic (sudden loss or freezing of posture or tone)
   4. Myoclonic
8. Myoclonic Seizures
   1. Momentary muscle jerking of trunk and arms
   2. No loss of consciousness
9. Status epilepticus
   1. Seizures without return to consciousness lasting more than 30 minutes
   2. Seizures may be generalized, partial, or even non-convulsive

C. Etiology [3,4]

1. Idiopathic
   1. Epilepsy
   2. Febrile Seizures
2. Metabolic
   1. Hypoglycemia
   2. Electrolyte disturbances: Na, Ca, Mg, PO43-
   3. Hypoxemia including complicated breath holding spells
   4. Hyperammonemia
   5. Uremia
3. Inborn errors of metabolism
   1. Pyridoxine dependency
   2. Maple syrup urine disease
   3. Hyperglycinemia
   4. Urea cycle defects
   5. Cerebral folate deficiency (see below)
   6. Other amino and organic acid disorders
4. Infections
   1. Meningitis
   2. Encephalitis
   3. Abscess
   4. Neurocysticerci
   5. Granulomata
5. Vascular
   1. Cerebrovascular Accident (CVA): thrombotic, embolic, or hemorrhagic
   2. Intracranial hemorrhage
   3. Vasculitis
   4. Sinovenous occlusive disease
   5. Malignant hypertension
6. Toxic
   1. Medications
   2. Drug Withdrawal
   3. Toxins
7. Medications
   1. Tricyclic Antidepressants
   2. Phenothiazines
   3. Theophylline
   4. Disufiram
   5. Cocaine and other CNS stimulants
   6. Isoniazid
8. Drug Withdrawal
   1. Alcohol
   2. Narcotics
   3. Benzodiazepines
9. Other toxins
   1. Shiga toxin
   2. Camphor
   3. Lead
   4. Strychinine
10. Inadequate anti-convulsant levels
11. Endocrine
    1. Hypo or hyperthyroidism
    2. Addison's Disease (Adrenal Insufficiency)
12. Structural
    1. Trauma: seizures on impact, early or late after impact
    2. Congenital brain anomaly
    3. CNS tumors
13. Slight (2.7X) increase in risk of febrile seizures in children within 2 weeks of MMR, but no longterm sequellae or increase in epilepsy [7]
14. Idiopathic Seizure Syndromes [6]
    1. Infantile Spasms
    2. Lennox-Gastaut Syndrome
    3. Severe myoclonic epilepsy in infants
15. Infantile Spasms [8]
    1. Also called West's Syndrome
    2. Presents in infants with ictal episodes including spasms
    3. >50% have an associated neuroglocial disorder including:
    4. Periventricular leucomalacia, hypoxic encephalopathy, Down's syndrome, tuberous sclerosis
    5. Prednisolone 40mg qd or intramuscular ACTH (tetracosactide 0.5mg qod) ~70% effective
    6. Vigabatrin, a GABA inhibitor, 100mg/kg qd po, 54% effective
16. Causes of Status Epilepticus in Children [13]
    1. ~45% have underlying neurological abnormality
    2. Febrile seizure in ~55% of children with normal neurological baseline
    3. Of children with febrile seizures, ~10% had acute bacterial meningitis
    4. Recurrence of status epilepticus at 1 year ~16%; ~3% case fatality rate

D. Therapy for a Persistent Seizure [4,5]

1. ABCs of life support
2. Check glucose, replete if low
   1. 4 mL/kg D25 for children
   2. 10 mL/kg D10 for neonates
3. Benzodiazepines
   1. Diazepam
   2. Lorazepam
   3. Midazolam
4. Buccal Midazolam [11]
   1. More effective than rectal diazepam for emergency seizure treatment
   2. No increase in risk for respiratory depression in hospitalized setting
   3. Dose 2.5-10mg according to age
5. Diazepam
6. IV/IO 0.2-0.3 mg/kg; rectally 0.5 mg/kg up to 20 mg
7. May repeat 2-3 times
8. Rapid onset of action but redistributes quickly
9. Action lasts approximately 20 minutes
10. Lorazepam
    1. IV/IO 0.1 mg/kg; rectally give twice the dose
    2. Nearly as rapid onset as diazepam
    3. Longer half-life in the brain than diazepam
    4. Intranasal lorazepam 100µg/kg more effective than paraldehyde 0.2mL/kg IM for protracted convulsions in children [12]
11. Phenytoin and fosphenytoin
    1. Load 15-20 mg/kg IV; can give IM when no IV access
    2. Fosphenytoin IV form safer due to less respiratory depression
    3. Monitor during administration due to risk of arrhythmias or hypotension
12. Phenobarbital
    1. Load 10-20 mg/kg IV; maximum 1 gm
    2. Repeat dosing 2-3 times as needed
    3. Preferred anticonvulsant in neonates
13. Other
    1. Paraldehyde: 0.2-0.5 mL/kg rectally or IM (use limited due to severe side effects; lorazepam intranasal appears more effective and better tolerated) [12]
    2. Consider pyridoxine (B6) in infants
    3. Consider thiamin with alcoholism or malnutrition
    4. Identify and correct electrolyte disturbances
    5. For resistant status consider midazolam drip, propofol, or general anesthesia

E. Laboratory Evaluation After First Seizure Episode

1. History and physical examination (initially brief and then more thorough)
2. Electrolytes, BUN, calcium, magnesium, and phosphate
3. CT or brain MRI
   1. Seizures with no readily identifiable cause
   2. Localizing signs on examination
   3. Persistent alteration of consciousness
4. Electroencephalogram (EEG) to exclude persistent non-convulsive seizures
5. Complete blood count (CBC) for fever evaluation
6. Lumbar puncture
   1. All infants under 9-12 months with high fevers
   2. Older infants with atypical febrile seizures
   3. Clinical meningismus
7. Toxic screen for potential ingestions
8. Electrocardiogram (ECG)
9. Possible metabolic studies
10. Treatment is generally not warranted after a single unprovoked seizure [9]

F. Evaluation for Recurrent Seizures

1. Refer to pediatric neurologist if seizures persist after underlying disturbance is corrected
2. EEG to look for persistent electrical abnormalities
   1. May be provoked with hyperventilation, sleep deprivation, or photic stimulation
   2. Video telemetry useful with frequent paroxysmal spells
3. Consider prophylactic anticonvulsant therapy
   1. Carbamazepine or phenytoin first-line
   2. Phenobarbital used for infants
4. Home rectal diazepam or Diastat can be used for acute seizure management

G. Cerebral Folate Deficiency [10]

1. Infantile onset syndrome with reduced cerebral (normal peripheral) levels of folate metabolite
2. Specifically, reduced levels of 5-methyltetrahydrofolate (5MTHF)
3. Normal folate metabolism outside of CNS
4. Symptoms develop age 4-6 months after birth
   1. Irritability, slow head growth, psychomotor retardation
   2. Cerebellar ataxia, pyramidal tract signs, dyskinesias
   3. Minority of cases with seizures
5. Dysfunctional membrane associated folate receptors in CNS
   1. Receptor is required for folate transport into CNS
   2. Most cases due to blocking autoantibodies to folate receptors
6. Diagnosis with demonstration of reduced CSF (but normal peripheral) 5MTHF levels
7. Effectively treated with 0.25-0.5mg/kg po bid folinic acid

References

1. Evans OB. 1999. Pediatric Annals. 28(4):231
2. Brodie MJ and Dichter MA. 1996. NEJM. 334(3):168
3. Wallace SJ. 1997. Lancet. 349:1009
4. Vedanarayanan VV. 1999. Pediatric Annals. 28(4):218
5. Rivera RF and Laureta E. 1999. Contemp Pediatrics. 16:(7)49
6. Chang BS and Lowenstein DH. 2003. NEJM. 349(13):1257
7. Vestergaard M, Hviid A, Madsen KM, et al. 2004. JAMA. 292(3):351
8. Lux AL, Edwards SW, Hancock E, et al. 2004. Lancet. 364(9447):1773
9. Hirtz D, Berg A, Bettis D, et al. 2003. Neurology. 60:166
10. Ramaekers VT, Rothenberg SP, Sequeria JM, et al. 2005. NEJM. 352(19):1985
11. McIntyre J, Robertson S, Norris E, et al. 2005. Lancet. 366(9481):205
12. Ahmad S, Ellis JC, Kamwendo H, Molyneux E. 2006. Lancet. 367(9522):1591
13. Chin RF, Nieville BG, Peckham C, et al. 2006. Lancet. 368(9531):222