MOVEMENT DISORDERS
From the 40th Annual Advances and Controversies in Clinical Pediatrics, presented by the Department of Pediatrics,
University of California, San Francisco, School of Medicine
| MAKING SENSE OF ANTIEPILEPTIC DRUGS—Thomas K. Koch, MD, Professor of Pediatrics and Neurology, Oregon
Health and Science University, and Chief, Pediatric Neurology, Doernbecher Children’s Hospital, Portland, OR
|
| Goals of antiepileptic treatment: balancing act; seizure control—decreased frequency and intensity; making patient
seizure-free not always possible; minimizing side effects—minimize number of medications; if using more than
2 or 3 antiepileptic drugs (AEDs), pharmacokinetics complicated, side effects increased, and antiepileptic control often
no better; increasing compliance—many newer medications have longer half-lives
|
| Therapeutic options: AEDs; vagal nerve stimulator good adjunct in children with difficult epilepsy; ketogenic diet;
resective surgery (curative in appropriate patients); study by Kwan and Brodie (2000)—≈33% of patients medically
intractable; regardless of drug, 47% of patients respond to monotherapy
|
| Standard AEDs: phenobarbital, phenytoin, carbamazepine, valproic acid, and diazepam; all older drugs strong enzymatic
inducers of cytochrome P (CYP)450 system in liver (problem in patients on oral contraceptives [OCs] or steroids,
or undergoing chemotherapy); phenytoin has zero-order kinetics and poorly absorbed from gastrointestinal (GI)
system of young children (especially infants)
|
“Old Dogs Learn New Tricks”
| Diazepam rectal gel (Diastat AcuDial): new delivery system; effective adjunct for acute or cluster seizures; safe,
well tolerated, and pediatric-friendly; formulations—2.5 to 20 mg at 2.5-mg increments
|
| Fosphenytoin: prodrug of phenytoin; infusible twice as fast as phenytoin and safer; well-absorbed when given intramuscularly;
indications—status epilepticus and acute seizures
|
| Carbamazepine: excellent medication for partial seizures; problem—relatively short half-life (6-8 hr); dosing 3 to 4
times/day; more frequent dosing, less compliance (bid, compliance rate ≈70%); Carbatrol—pediatric-friendly delivery
(100-, 200-, or 300-mg sprinkle, given bid); Tegretol XR (extended release)—osmotic bullet (if bitten, osmotic
engineering disrupted); caveat—newer medications being favored over carbamazepine for pediatric use
|
| Valproic acid: Depakon—new delivery (intravenous [IV]); indications include patients in emergency department
(ED) because of noncompliance and those npo for surgery; conversion rate from oral to IV 1:1; half-life ≈8 hr (given
tid); Depakote ER (extended release)—once-daily dosing; used in epilepsy, but also good prophylaxis against migraine;
for conversion from Depakote, increase dose 20%
|
Newer Antiepileptic Drugs
| Possible, not practical: felbamate—problem serious side effects in bone marrow and liver; possible death;
gabapentin—“looking for home”; tiagabine (Gabitril)—never gained foothold as anticonvulsant; zonisamide—weak
anticonvulsant; may have role in certain situations; vigabatrin—excellent medication but not available in United
States (outside United States, first-line drug for infantile spasms)
|
| Lamotrigine (Lamictal): excellent medication
|
 | Pharmacology: relatively long half-life (24 hr); recommended dosing bid (once-daily dosing possible); used with other
enzyme-inducing drugs, half-life decreases; used with valproic acid, half-life increases almost 3-fold; val-proic acid
and lamotrigine powerful antiepileptic combination; linear kinetics (predictable); effective as monotherapy (use caution
in combining with other drugs); broad-spectrum antiepileptic—partial generalized seizures; complex epilepsy
(eg, Lennox-Gastaut syndrome); petit mal or absence seizures
|
| Side effects: interaction with valproic acid (significant prolongation of half-life); most notable side effect rash related
to overly rapid titration (indication to discontinue; worry about Stevens-Johnson syndrome); titration website
lamictal.com/calc1.jsp
|
| Levetiracetam (Keppra): excellent medication; side effects minimal; no drug-drug interactions; safe to start and
stop
|
| Pharmacology: chemically unrelated to other AEDs; linear kinetics; half-life 6-8 hr (administered bid or tid); does not
induce CYP450 system; safe to combine with steroids or OCs; broad spectrum—partial and generalized seizures;
epilepsy secondary to brain tumor, or postoperative neurosurgical procedures; juvenile myoclonic epilepsy; available
as liquid formulation—100 mg/mL; can be given to infants; starting dose in children 10 to 20 mg/kg (maintenance
dose 60-80 mg/kg)
|
| Side effects: possible nightmares, nocturnal agitation, sleeplessness; rarely, psychosis (resolves with discontinuation);
tolerated well by most children; safer than phenobarbital, easier to use than phenytoin, and avoids side effects of
valproic acid
|
| Pharmacology: some induction of CYP450 system (problem in women on OCs); long half-life; administered twice-
daily for epilepsy; broad spectrum—Lennox-Gastaut syndrome; and partial and generalized seizures; excellent
prophylaxis against migraine (dosed once daily); available as sprinkle (not liquid); starting dose ≤10 to 15 mg/kg
per day (bid)
|
| Side effects: cognitive slowing (poor word finding) and difficulty with concentration largely associated with high
doses used in clinical trials (300 and 400 mg/day); dose for children with epilepsy 8 to 15 mg/day (avoids cognitive
problems); paresthesias in hands seen in adults, not children; reports of kidney stones (topiramate carbonic anhydrase
inhibitor; be careful if using with ketogenic diet); glaucoma (incidence low; reversible with discontinuation);
metabolic acidosis not significant
|
| Oxcarbazepine (Trileptal)
|
| Pharmacology: analogue of carbamazepine, but safer and has longer half-life (allows bid dosing); oxcarbazepine and
levetiracetam have largely replaced carbamazepine; new drugs safer, avoid side effects, and have longer half-lives;
indications—partial seizures; secondary generalized seizures
|
| Side effects: avoids enzymatic induction of carbamazepine (different metabolic pathway); no autoinduction; induction
of CYP450 system minimal; can be used in patients on steroids or OCs; available as tablet or liquid (favorable for
pediatric use); Trileptal vs Tegretol—some patients on Tegretol able to switch to Trileptal in one day; conversion
ratio of Tegretol to Trileptal 1:1.5 (switch does not require titration); similar types of side effects as with Tegretol,
but decreased incidence; avoids blood dyscrasias, so rash rare; as with Tegretol, increased incidence of hyponatremia
(unusual in children)
|
| Side effects: lamotrigine (rashes); levetiracetam (nightmares); oxcarbazepine (mild side effects and mild induction of
CYP450 system); topiramate (central nervous system [CNS] effects and renal stones)
|
| AED treatment options: most drugs used for partial seizures (secondarily for generalized); lamotrigine, levetiracetam,
and topiramate can be used for generalized seizures, including absence and partial seizures; most newer drugs broad
spectrum
|
| Prospect for becoming seizure-free on AEDs: partial epilepsies—rate <50% (surgery excellent option in appropriate
patients; excludes benign rolandic seizures [those children do well]); symptomatic generalized epilepsies—eg,
CNS malformation, significant insult at birth from hypoxia or other major catastrophic event; rate ≤25% (these children
hard to control)
|
| TRENDS IN TICS AND TOURETTE’S SYNDROME—Audrey Foster-Barber, MD, PhD, Assistant Professor of Neurology
and Pediatrics, University of California, San Francisco, School of Medicine
|
| Definition of tic: sudden brief involuntary movements with semivoluntary component; natural history variable;
symptoms—wax and wane, and may increase with stress or relaxation; blinking, grimacing, shoulder-shrugging, sounds;
types —movement or motor; phonic
|
| Primary tic disorders (also known as idiopathic tic disorders)
|
| Diagnostic criteria: Tourette’s syndrome (TS)—multiple motor tics and ≥1 sound-based tic >1 yr; onset ≤18 yr of
age; no other pathologic explanation; chronic motor tics—only motor (no sounds) >1 yr; transient tic disorder—
duration <3 mo
|
| Epidemiology: transient tic disorder—affects 3% to 15% of children; TS—0.5% to 1.0%; speaker’s view—rates underestimated;
male predominance—ranges from 2:1 to 10:1
|
Tourette’s Syndrome
| Natural history: onset 3 to 8 yr of age; peak severity 9 to 12 yr of age; tics wax and wane, but worsen; for 60% to
80% of patients, tics decrease or stop by adulthood; many patients outgrow tics, but comorbidities persist; simple tics
first, complex tics later (blink, then sniff, then shoulder shrug)
|
| Comorbidities: affect ≈50% of patients with TS; attention-deficit/hyperactivity disorder (ADHD) most common; obsessive-compulsive
disorder (OCD) comes on as tics abate; learning, mood, and behavior problems (eg, rage attacks);
migraine; sleep disorders
|
| Differential diagnosis: other primary tic disorders—transient or sounds absent; secondary tic disorders—
neurologic disease, eg, tuberous sclerosis; neurodegenerative disorders (eg, Huntington’s disease); Down syndrome;
autism or pervasive developmental delay; toxin exposure; infection or postinfectious exposure (eg, Streptococcus
pneumoniae)
|
| Pathophysiology: dysfunction in circuit regulating voluntary movement—circuit between cortex (frontal lobe),
basal ganglia, and thalamus; overflow of unintended movements (TS believed failure of negative inhibition in circuit);
main neurotransmitter dopamine; serotonin may play role
|
| Experimental diagnostic testing: no diagnostic tests required for diagnosis of TS, but experimental tests support theory
of failure of negative regulation; volumetric magnetic resonance imaging (MRI)—in most people, left-right asymmetry
in striatum (with TS, asymmetry missing); functional positron emission tomography (PET) and MRI—
differences in metabolism in frontal lobe in response to movement stimuli (frontal lobe less active and exhibits less inhibition
of movement circuit); blink reflex and transcranial magnetic stimulation—patients with TS respond faster and
to lower-level stimuli
|
| Genetic and environmental factors: high concordance in twin studies; bilineal inheritance—TS more likely if
maternal and paternal families have symptoms; associated genes—contactin-associated protein 2 (CNTNAP2; relative
of genes mutated in epilepsy syndromes); Slit and TRK-like 1 (SLITRK1) implicated in familial trichotillomania;
risk factors—severe morning sickness; tobacco and caffeine exposure during pregnancy; low birth weight; low
Apgar scores
|
| Neuroimmunologic theory of etiology: controversial; exacerbation of tics with Group A β-hemolytic streptococcal
infection (small cohort of children with TS have exacerbation of symptoms with streptococcal infections); in some
patients—antistreptolysin O (ASO) titer elevation related temporally to clinical exacerbation; antineuronal antibodies
isolated that bind to basal ganglia in pathologic sections; findings not confirmed in all studies; infusion of TS sera in
rats—2 studies; one study found behavior change, other did not
|
| Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS):
affects small subset of children with tics; defined by—1) obsessive-compulsive symptoms or tics, and 2) sudden
onset with marked exacerbations related temporally to streptococcal infection; children more hypotonic and
exhibit chorea
|
| Diagnostic evaluation: if history does not raise red flags about secondary TS and neurologic exam normal, further
testing not needed; test to rule out secondary TS—if history of injury or toxin exposure, or child developmentally delayed
or dysmorphic; includes MRI; consider genetic studies
|
| Treatment: 60% to 80% of affected children do not need treatment of tics (will outgrow); treat—tics causing pain
(neck movement causing subluxation, eye-poking); coprolalia (involuntary cursing) or other disruptive sounds; comorbidities
(eg, ADHD or OCD); educating family—parents must not order child to stop, or punish child for tics; ignoring
tics tends to decrease frequency by decreasing stress; best treatment multimodal—education and social
support; if needed, behavior therapy and medication
|
Treatment of Tics
| Limits of medical therapy: no single medication resolves tics completely; several weeks to achieve effect (exception
benzodiazepines); response confounded by natural waxing and waning; multiple medications (all have side effects);
most effective medication decreases tics ≤60%
|
| First line: α-adrenergic agonists (guanfacine and clonidine); decrease tic frequency 20% to 40%; side effects benign
|
| Second line: selective serotonin reuptake inhibitors (SSRIs); antiepileptics; baclofen, botulinum toxin type A (Botox)
injections; no strong literature showing efficacy; side effects variable
|
| Third line: dopamine receptor blockers (haloperidol, risperidone); 40% to 60% decrease in tics; side effects—benign
to serious; weight gain, hypercholesterolemia; extra-pyramidal symptoms (eg, akathisia); tardive dyskinesia (irreversible
movement disorder with masticatory movements; seen with chronic use)
|
| Immunomodulation: 2 large controlled trials of antibiotics in patients with TS (no change in tics or OCD symptoms);
immunomodulation in children with PANDAS (Swedo et al, 1998)—29 children treated with IV immunoglobulin
(IVIG), saline, or plasmapheresis; with plasmapheresis only, tics decreased ≈30%; with combination IVIG and
plasmapheresis, OCD decreased 40%; no recommendation to apply this regimen (National Institutes of Health [NIH]
guidelines advise against)
|
| Surgical intervention: experimental; published studies small and limited to adults; bottom line—why perform brain
surgery on child who may outgrow tics?
|
| Deep brain stimulation for TS: mainstay in appropriate patients; unilateral or bilateral stimulation of various sites
in brain; 6 published papers involving 7 adult patients; tic reduction 40% to 90%; OCD symptoms reduced; not currently
offered to pediatric patients
|
| Behavior therapy: habit-reversal therapy; awareness training and competing-response training; in controlled trials,
up to 55% reduction in tics; in contrast, first-line medical treatment associated with 20% to 40% reduction
|
| Stimulant treatment: stimulants mainstay treatment of ADHD (many patients with TS have ADHD); in some patients,
stimulants cause tics to emerge or worsen; side effects (Tourette’s Syndrome Study Group, 2002)—136 children
with TS treated with methylphenidate alone, clonidine alone, methylphenidate and clonidine, or placebo; based
on tic severity score, no difference in number of children with worsening at 4 mo when medication compared to placebo;
recommendations—no contraindication to stimulant treatment in TS; if tics increase in first 4 wk of treatment,
perform trial discontinuation and rechallenge (remember natural history of waxing and waning)
|
Suggested Reading
Gilbert D: Treatment of children and adolescents with tics and Tourette syndrome. J Child Neurol 21:690, 2006;
Himle MB et al: Brief review of habit reversal training for Tourette syndrome. J Child Neurol 21:719, 2006;
Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314, 2000; Pellock JM: Understanding
co-morbidities affecting children with epilepsy. Neurology 62:S17, 2004; Scahill L et al: Contemporary
assessment and pharmacotherapy of Tourette syndrome. NeuroRX 3:192, 2006; Shinnar S et al: The risk of
seizure recurrence after a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics 98:216,
1996; Swedo SE et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections:
clinical description of the first 50 cases. Am J Psychiatry 155:264, 1998, Tourette’s Syndrome Study Group:
Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 58:527, 2002.
Educational Objectives
| The goal of this program is to improve the care of patients with movement disorders. After hearing and assimilating
this program, the clinician will be better able to:
|
| 1. Describe newer formulations (eg, new delivery mechanisms) of standard antiepileptic drugs (AEDs).
|
| 2. Describe the safety and efficacy of newer AEDs.
|
| 3. Explain the natural history of childhood tics.
|
| 4. Recognize indications for treatment of tics, including those associated with Tourette’s syndrome.
|
| 5. Choose appropriate therapy for managing tics.
|
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. Koch has participated
in the Speakers’ Bureau for Ortho McNeil Pharmaceuticals and Abbott Laboratories.
Acknowledgements
Drs. Koch and Foster-Barber were recorded at the 40th annual Advances and Controversies in Clinical Pediatrics,
presented May 31 through June 2, 2007, in San Francisco, CA, by the Department of Pediatrics, University of California,
San Francisco, School of Medicine.
|
