NEUROLOGIC UPDATE
| FIRST AND SECOND SEIZURES: WHAT TO KNOW, WHAT TO DO —Paul G. Fisher, MD, Associate Professor of Neurology and Pediatrics, Stanford University School of Medicine, Palo Alto, CA |
Verification of Seizure
| Paroxysmal events (not everything that shakes is seizure): neonatal apnea; breath-holding spells; migraines; acute confusional state; sleep disorders; tics; masturbation; hyperekplexia (exaggerated startle reflex); spasmus nutans (benign idiopathic nystagmus; resolves spontaneously); behavioral disorders |
| Definitions: seizure—abnormal excessive discharge of neurons; types (focal or generalized); epilepsy—recurring seizures without known precipitant (eg, febrile seizures not epilepsy) |
| Seizure classification: generalized (whole brain seizes at once); partial (abnormal focal discharge in one hemisphere); adults have more focal pathology and partial seizures; children have more generalized seizures; generalized seizures more refractory than partial; types of partial seizures—simple; complex; secondarily generalized; complex partial seizures cause impairment in consciousness; types of generalized seizures—tonic-clonic (grand mal); tonic; clonic; absence (petit mal); myoclonic; atonic (drop attacks) |
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More definitions: clonus—alternating depolarization and repolarization results in involuntary rhythmic contraction and relaxation of muscles; myoclonus—shock-like contraction; multiple etiologies; irregular rhythmicity; aura— sensation that precedes focal or partial seizure; sensation usually focal (eg, unusual smell); prodrome—feeling (change in physiologic state) that precedes generalized seizure; automatism—integrated complex actions or behaviors during or immediately after seizure (patient has no recall afterward) |
| Pearls: home video excellent way to capture seizure episodes; during seizure, eyes open, not closed (if eyes closed, event nonelectrical); patients with new-onset daily seizures rarely have completely normal findings on electroencephalography (EEG); seizures rarely produce negative phenomena (eg, pallor, cold, apnea, bradycardia; instead, consider syncope, breath-holding spells, prematurity); directed acts of violence rarely seizures; conversion disorder and malingering rarely occur during first decade of life |
Investigations
| Febrile seizures: partial or generalized seizures that occur in patients 6 mo to 5 yr of age; complex—focal, lasting >15 min, or >2 events in 24 hr; benign; lumbar puncture (LP)—appropriate for patients <12 mo of age (concern about meningitis); other tests—performed only to address underlying illness; emergent computed tomography (CT) of head not warranted, even for patients with complex seizures, unless patient toxic, ill-appearing, or not waking up; routine EEG not warranted |
| Afebrile seizures: complete blood cell count (CBC) or electrolytes only in response to vomiting, diarrhea, dehydration, or failure to return to baseline; LP if concerned about meningitis or encephalitis; toxicology screening warranted; emergent CT if focal deficit or clouded mental status does not resolve over 1 to 2 hr; for repetitive seizures, order MRI (no contrast) to detect subtle malformations in brain; EEG—practice parameter from American Academy of Neurology (Hirtz et al, 2000) states every child should get EEG after first seizure (controversial and not evidence-based); 20% of all comers have abnormal findings on EEG; classic findings associated with petit mal seizures and benign epilepsy of childhood, but history generally sufficient |
When to Treat
| Febrile seizures: according to practice parameter from American Academy of Pediatrics (1996), treatment almost never indicated; seizures fleeting; recurrence—after first episode, ≈33% of children have second episode; ≈50% of those have subsequent episodes; risk for epilepsy—only 3% of children with febrile seizures develop epilepsy by 7 yr of age; risk increases with positive family history, preexisting neurologic deficit, or developmental delay; patients with complex febrile seizures have higher risk for epilepsy, but most of these patients do not develop epilepsy; side effects of treatment (eg, phenobarbital) significant |
| Afebrile seizures: often isolated events; therapy generally reserved for patients with recurrent episodes; antiepileptic drugs do not eliminate recurrences |
Choice of Medication
| Seizure type: partial (focal) seizures—carbamazepine (Tegretol); oxcarbazepine (Trileptal; better efficacy with fewer side effects); valproic acid (eg, Depakote); levetiracetam (Keppra); topiramate (Topamax); generalized nonconvulsive— ethosuximide good for absence seizures; generalized convulsive—oxcarbazepine; levetiracetam; lamotrigine (Lamictal); topiramate |
| New drugs: fosphenytoin—preferred form of intravenous (IV) phenytoin; expensive; used in urgent setting as bolus; associated with lower incidence of skin sloughs and less precipitation with IV fluids than phenytoin (phenytoin precipitates with dextrose); IV valproic acid (Depacon)—not commonly used for treating status epilepticus; diazepam (eg, Diastat)—rectal gel; not used routinely, unless patient far from ED; oxcarbazepine—lacks hepatic autoinduction of carbamazepine, but similarly subject to interference by macrolides (eg, azithromycin, erythromycin); topiramate—high doses associated with cognitive dulling and anorexia; most children tolerate it well; lamotrigine—good medication, but titration slow (rapid titration may cause Stevens-Johnson syndrome); formulations—oxcarbazepine pills scored (can be split); gabapentin (Neurontin) available as liquid; lamotrigine available as dispersible tablets; topiramate and Depakote available as sprinkles; levetiracetam—does not inhibit cytochrome P (CYP)450 system; useful in patients on multiple hepatically metabolized medications (older drugs, [eg, phenobarbital, carbamazepine, phenytoin] have more interactions); available as liquid; associated with behavioral side effects (eg, aggression) in some children; vigabatrin—not available in United States; drug of choice for infantile spasms (particularly in children with tuberous sclerosis) |
Clinical Implications of Status Epilepticus
| Status epilepticus: longer seizures (longer than 15-30 min) or multiple seizures in 24-hr period; convulsive or nonconvulsive |
| Etiology: ≈25% of patients have history of seizure; 25% febrile; 25% new onset; 25% idiopathic; routine imaging not warranted (unless patient not waking up or has persistent focal deficit) |
| Management: follow well-conceptualized protocol (eg, see Harriet Lane Handbook); evaluate airway, breathing, circulation; consider laboratory tests; obtain IV access; medical therapy—begin with 1 or 2 doses of benzodiazepine (lorazepam preferred over diazepam because it enters central nervous system [CNS] more quickly); follow with fosphenytoin, phenytoin, or phenobarbital; benzodiazepines—bind γ-aminobutyric acid (GABA) receptors (after 1 or 2 doses, receptors full; move on to other medications); excessive doses cause respiratory suppression; child on long-term regimen—give more of same medication; after febrile status epilepticus, do not treat |
| Counseling: most children with epilepsy lead normal lives; activity restrictions generally unnecessary; only those who have drop attacks (atonic seizures) require helmets or other protective wear; no bathing or swimming unattended (risk of drowning; showering fine); driving laws vary by state; if seizures absent 3 mo, risk for recurrence extremely low; parents should know first aid for seizures (not necessarily cardiopulmonary resuscitation [CPR]); child positioned on side to prevent aspiration of vomit; adolescents—significant impact on self-esteem and image; poor academic performance may be related to medication (or self-esteem issue); oral folate indicated in postpubertal girls taking anticonvulsants (in case of pregnancy) |
| CEREBRAL PALSY: PATHOPHYSIOLOGY, MANAGEMENT, AND PREVENTION —Raman Sankar, MD, PhD, Associate Professor and Chief, Pediatric Neurology, and Rubin Brown Distinguished Chair, David Geffen School of Medicine at the University of California, Los Angeles |
| Definition of cerebral palsy (CP): disorder of posture and/or movement due to nonprogressive lesion of developing brain; different from neurodegenerative conditions (eg, Tay-Sachs disease); neonatal meningitis may cause CP; mental retardation not part of definition |
| Incidence: 1.5 to 2.5 children per 1000; ≈5000 new cases per year; rate increasing among low birth weight infants due to increased rate of survival |
| Classification: spastic—diplegia predominantly involves lower extremities; hemiplegia involves one side of brain; quadriplegia; dyskinetic—includes dystonic, athetoid, and choreoathetoid CP; ataxic—low tone rather than spasticity; eg, Dandy-Walker syndrome |
| Associated disabilities: mental retardation—affects 50% of patients with CP; choreoathetosis (involuntary movements) associated with better intellectual performance; seizures—up to one-third of patients with CP have seizures; onset usually within first 2 yr; visual or visual-motor problems—retinopathy of prematurity; strabismus; esotropia; refractive errors; cataracts; chorioretinitis; other conditions—sensorineural deafness; speech and learning disabilities |
| Etiology: unknown in most cases; only ≈10% of cases of CP related to intrapartum asphyxia (most cases likely due to other prenatal causes); CP difficult to predict or prevent |
Syndromes
| Distinct natural histories and probable causes |
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1) CP in premature infants of low birth weight |
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2) CP in systemically sick full-term infants |
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3) Delayed CP in children who were apparently healthy as newborns |
| CP in infants small for gestational age (SGA) and/or premature infants: largest category; intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) give rise to spastic diplegia; of children with good hand function and diplegia, most born premature; diplegia occurs when patient extremely premature; IVH and PVL can occur weeks before or after birth; role of asphyxia unclear; defects in autoregulation of cerebral blood flow probably important; chorionitis major risk factor; ≥80% of very premature births have evidence of placental infection; congenital malformations of brain may cause CP; twins have increased risk |
| CP in sick full-term infants: low Apgar scores alone not sufficient to meet criteria for CP |
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Intrapartum asphyxia: American College of Obstetrics and Gynecology (ACOG) criteria—cord blood pH <7; persistently suppressed Apgar scores; injury to other organ systems (brain relatively protected; look for changes in liver enzymes or compromised kidney function); severe asphyxia (case)—patient has severe cerebral edema; brain “plastered” against cranial vault; poor differentiation between gray and white matter; following visit, patient exhibited classic severe bilateral leukomalacia; neonatal seizures may play role |
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Electrographic seizures in neonates correlate with poor neurodevelopmental outcome (McBride et al, 2000): of 68 infants, 40 had EEG-proven seizures; Apgar scores, initial pH, and base deficits not significantly different between groups with and without history of seizure; findings—death occurred in 7 of 23 infants with severe seizures vs 0 of 14 infants without seizures; severe CP occurred in 6 of 16 infants with seizures vs 1 of 14 without seizures; large differences in rates of delayed walking and microcephaly; conclusion—prolonged seizure activity affects morbidity and mortality; speaker’s recommendation—all children at risk should have continuous EEG monitoring; EEG shows evidence of seizure even after treatment with phenobarbital; with continuous depolarizations, cells flooded with calcium; when mitochondria overwhelmed, process leading to apoptosis initiated |
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Clinical predictors: classic predictors (eg, brief fetal bradycardia and delayed first cry) associated with high false-positive rate; ACOG criteria and careful monitoring more important; other possible etiologies—cerebral malformations (motor problems and seizures); metabolic disorders may present postnatally; infection of placental membranes |
| CP in term infants who were well as newborns: cortical dysgenesis common etiology (encephalization occurs later); Volpe, 1992—up to one-third of term infants with CP had cortical dysgenesis; kernicterus can cause athetoid-type CP |
| Diffusion tensor imaging (DTI) with tractography: assesses changes in white matter before CP fully manifests clinically |
| Management options: physical and occupational therapy—refer for needs assessment early on; pharmacologic armamentarium—includes baclofen, tizanidine (Zanaflex), and clonazepam; benzodiazepines effective in reducing spasticity, but sedating; excessive use associated with increased secretions (many highly disabled children cannot keep lungs clear); baclofen and tizanidine sedating; tizanidine has short half-life (dosed up to 4 times/day); intrathecal therapy with baclofen pump sometimes indicated; botulinum toxin (focal injections); orthopedic procedures—numerous; neurosurgical procedures (eg, dorsal rhizotomy)—controversial |
| Other management issues: nutritional counseling and adjustments (many patients need calcium and vitamin D supplements); physical therapy should promote weight-bearing to reduce risk for osteomalacia and rickets; vision evaluation; special education or assistance with communication when appropriate |
Pathogenesis and Prevention
| Progress in prevention: has not substantially reduced rate of PVL; under study—maturation processes in oligodendrocytes (which make myelin) may play role; oxidative and free radical injury; inflammation may accompany ischemia, reperfusion, and infection |
| Role of magnesium sulfate (MgSO4): conflicting data; Nelson and Grether, 1995—epidemiologic study looking at >150,000 births in California; among smaller singletons, in utero exposure to MgSO4 more common among controls than those with CP; Schendel et al, 1996—those exposed to MgSO4 had lower prevalence of CP (0.9 vs 7.7); Leviton et al— prospective trial using cranial ultrasonography concluded that maternal supplementation with MgSO4 not associated with reduced incidence of CP; Mittendorf et al, 2002—MgSO4 associated with worse prognosis |
| Role of maternal infection: Grether and Nelson, 1997—maternal temperature and chorioamnionitis associated with CP; Yoon et al, 1997—gravid rabbits inoculated with Escherichia coli (many developed white-matter injury) |
| Role of mediators of inflammation: inflammation may jointly produce injury with seizures; Yoon et al, 1997— TNF-α and interleukin-6 more frequent in brain lesions with PVL than those without PVL; Sankar et al, 2006— inflammation contributes to seizure-induced hippocampal injury in neonatal brain (animal study) |
| Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury (Back et al, 2006): caffeine reduced injury in rats; neonates often treated with caffeine if apnea of prematurity suspected |
Suggested Reading
Back SA et al: Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol 60:696, 2006; Bonekamp D et al: Diffusion tensor imaging in children and adolescents: reproducibility, hemisphere, and age-related differences. Neuroimage 34:733, 2007; DiMario FJ Jr: Children presenting with complex febrile seizures do not routinely need computed tomography scanning in the emergency department. Pediatrics 117:528, 2006; Hirtz D et al: Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, The Canadian Neurology Society, and The American Epilepsy Society. Neurology 55:616, 2000; Leviton A et al: Maternal receipt of magnesium sulfate does not seem to reduce the risk of neonatal white matter damage. Pediatrics 99:E2, 1997; McBride MC et al: Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology 55:506, 2000; Mittendorf R et al: Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 186:1111, 2002; Nelson KB, Grether JK: Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 95:263, 1995; Schendel DE et al: Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low birthweight children aged 3 to 5 years. JAMA 276:1805, 1996; Shevell M et al: Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 11:367, 2003; Yoon BH et al: Experimentally induced intrauterine infection causes fetal brain white matter less in rabbits. Am J Obstet Gynecol 177:797, 1997.
Educational Objectives
| The goal of this program is to improve primary care management of seizures and cerebral palsy (CP). After hearing and assimilating this program, the clinician will be better able to: |
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1. Apply a systematic approach to evaluating a patient who presents with a possible first or second seizure. |
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2. Compare appropriate management of febrile seizures to that of afebrile seizures. |
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3. Describe the pathophysiology of CP. |
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4. Recognize signs and symptoms of CP. |
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5. Choose appropriate therapy for managing CP. |
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Fisher has participated in the Speaker’s Bureau for UCB-Pharma; Dr. Sankar has received research funding from Marinus Pharmaceuticals; he has also been a consultant and/or member of a Speaker’s Bureau for GlaxoSmithKline, Ortho-McNeil Neurologics, UCB-Pharma, Valeant Pharmaceuticals, and Cyberonics.
Acknowledgments
Dr. Fisher was recorded at the 18th annual Las Vegas Postgraduate Pediatric Meeting, Advances in Pediatrics, presented May 17-20, 2007, in Las Vegas, NV, by the American Academy of Pediatrics, California Chapter 2; Dr. Sankar was recorded at the 64th Brennemann Lectures, presented September 6-9, 2007, in Anaheim, CA, by the Los Angeles Pediatric Society. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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