3/7/2014 Disclosures • Personal Disclosures : – Consultant: Allergan Corporation, Management of Tone in Cerebral Palsy Orthopediatrics, Merz Pharmaceuticals • Institutional Research Support : Children ’ s Hospital, DePuy Spine, Allergan, Axial NIH, Orthopedic Research and Education Foundation, Major League Baseball, Rady Rady Children ’ s Hospital Hank Chambers, MD Biotech, Ellipse, Alphatec Spine, KFx, Magellan Spine, Zimmer, KCI, Synthes, Syntaxin, K2M, Rady Children ’ s Hospital, DePuy Spine Professor of Clinical Orthopedic Surgery • Institutional Education Support : University of California at San Diego What Is Cerebral Palsy? Off Label Use • Is it brain damage due to obstetrical • All of the medications in this talk are off label trauma? for children with cerebral palsy • Was the baby too big or too small? • The use of an intrathecal baclofen pump for • Cerebral palsy (CP) describes a group of permanent disorders of the development of dystonia is an off label use movement and posture, causing activity limitation, that are attributed to non- progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, behavior, by epilepsy and by secondary musculoskeletal problems Modified after Bax et al. DMCN 2005 1
3/7/2014 Epidemiology: The Cerebral Palsies Some Statistics • 54 million Americans have a disability • Risk is 25-30 times in neonates < 1500g – 1 in 3 children with VLBW will have CP • 72 percent of unemployed adults with – Most children with CP were not premature disabilities would like to work • Prevalence in 8 year olds: 3-4 patients/1000 • Lifetime cost of child born today with – (1 in 278) CP: – 10,000 new diagnoses each year • Prevalence: ~950,000 Americans with CP – $1 million • 87% 30-year survival rate • There are now more adults with CP than children. My clinic has over 2200 adults. Motor Disorders Other Important Problems •Loss of Selective Motor •Spasticity Control •Athetosis •Sensory Deficits •Ataxia •Weakness •Dystonia •Visual Impairment •Rigidity •Mental Health Issues 2
3/7/2014 Current Treatment Options: General • Exercise and physical modalities Oral Medications for the • Systemic drugs Treatment of Spasticity • Anesthetic and neurolytic injections Sequential • Chemodenervation injections • Intrathecal drugs • Orthopedic methods • Neurosurgical methods Integrated Primary and Secondary Myotactic Reflex Antispasticity Drugs • Secondary ASDs • Primary ASDs – Tiagabine – Benzodiazepines – Cyproheptadine – Baclofen SDR – Clonidine – Dantrolene – Lamotrigine – Tizanidine – Gabapentin – Cannibis • Baclofen • Tiagabine • Diazepam Dantrolene • Tizanidine BTX 3
3/7/2014 Primary Oral/Systemic Agents: Primary Oral/Systemic Agents: Diazepam Diazepam • Suggested indications • Suggested starting • Potential side effects dose – Flexor and extensor – Sedation spasms – Infants: 1 mg qhs – Respiratory depression – Stiffness, pain and – Young adults: – Hypotension and bradycardia associated insomnia 5 mg qhs – Paradoxical irritability – Spasticity and – Maximum dose in – Withdrawal syndrome seizures children: – Paradoxical sleep disorders – Combined with • 0.8 to 1.0 mg/kg/d – Increased oral secretions total, q 6-8 h baclofen in patients with severe spasticity – Postoperative spasm – Preprocedure sedation Krach LE. J Child Neurol 2001;16:31-6. Siberry GK, Iannone R. The Harriet Lane Handbook . 15th ed. St. Louis, MO; 2000. Primary Oral/Systemic Agents: Primary Oral/Systemic Agents: Baclofen Baclofen • GABA B agonist • Suggested indications • Suggested dosage – Flexor and extensor • Mechanism of action – Initiate at 2.5 to 5 mg spasms – Alters release of qhs and titrate to – Stiffness excitatory tid or qid neurotransmitters and – Pain and associated – Maximum dose substance P in the insomnia • <2 years = 20 mg/d spinal cord – Severe spasticity in • 2-7 years = 40 mg/d – Depresses mono- and combination with • >8 years = 60 mg/d polysynaptic reflexes diazepam – Enhances Renshaw cell Baclofen activity Lataste X, et al. Neurology 1994;44(suppl 9):S53-9. Krach LE. J Child Neurol 2001;16:31-6. Baclofen Package Insert, 2000. 4
3/7/2014 Primary Oral/Systemic Agents: Primary Oral/Systemic Agents: Dantrolene Baclofen • Hydantoin derivative • Potential side effects • Mechanism of action – Sedation, drowsiness, fatigue – Acts upon skeletal – Decreased seizure threshold muscle fibers – May potentiate weakness – Inhibits release of Ca ++ – Orthostatic hypotension from the sarcoplasmic – Withdrawal syndrome reticulum – Uncouples excitation – Increased oral secretions from contraction – Elevated transaminases Dantrolene Gracies JM, et al. Muscle Nerve 1997;20(suppl 6):S92-120. Baclofen Package Insert, 2000. Primary Oral/Systemic Agents: Primary Oral/Systemic Agents: Dantrolene Dantrolene • Indications • Potential side effects • Dosage in children – Symptomatic relief, – Initial: 0.5 mg/kg qhs especially clonus, in – Hepatotoxicity – Increase slowly all types of UMN to 0.5 mg/kg – Muscle weakness syndromes 2-4 times/d at 4-day – Diarrhea, mild drowsiness, intervals – Then, increase dose by paresthesias 0.5 mg/kg to a maximum of 3 mg/kg/dose – Dysphagia (2-4 times/d) to maximum of 400 mg/d Katrak PH, et al. Arch Phys Med Rehabil 1992;73:4-9. Mayer N, et al. Am J Phys Med 1973;52:18-29. Siberry GK, Iannone R. The Harriet Lane Handbook . 15th ed. St. Louis, MO; 2000. 5
3/7/2014 Primary Oral/Systemic Agents: Primary Oral/Systemic Agents: Tizanidine Tizanidine • An a 2 adrenergic • Dosage in children • Indications agonist – <10 years – Nighttime spasms, • Mechanism of action • 1 mg qhs pain, and clonus – Reduces excitatory • Increase q week to qid dosing as amino acid and tolerated substance P release – >10 years – Depresses polysynaptic • 2 mg qhs reflexes • Increase q week to qid dosing as tolerated – Decreases activity in – Target dose is 0.3 to the locus ceruleus Tizanidine 0.5 mg/kg/d Delwaide PJ, et al. Neurology 1994;44(suppl 9):S21-8. Wagstaff AJ, et al. Drugs 1997;53:435-52. The United Kingdom Tizanidine Trial Group. Neurology 1994;44(suppl 9):S70-8. Primary Oral/Systemic Agents: Secondary Oral/Systemic Agents Tizanidine • Potential side effects • Tiagabine – Sedation • Cyproheptadine – Fatigue and drowsiness • Clonidine – Dry mouth • Lamotrigine – Dizziness • Gabapentin – Visual hallucinations (3%) • Carbidopa-levodopa – Hepatotoxicity (5%) • Cannibis – Orthostatic hypotension • Never use with dantrolene or valproic acid Gracies JM, et al. Muscle Nerve 1997;20(suppl 6):S92-120. Wagstaff AJ, et al. Drugs 1997;53:435-52. Young RR. Neurology 1994:S12-20. 6
3/7/2014 Physiologic Actions of Local Anesthetics and Neurolytics Local Anesthetics, Neurolytics, and • These agents may decrease focal or regional muscle overactivity by decreasing afferent Chemodenervation and efferent nerve impulses for the Patient with Cerebral Palsy and • Local anesthetics Spasticity – Peripheral nerves may be blocked at a distance from the muscle they innervate, close to, or even within the target muscle – Blocks may be transient for diagnostic or other short- term purposes • Neurolytics – Can produce long-term effects through nerve destruction or blockade of neuromuscular transmission Therapeutic Options by Duration of Effect • Short-duration • Long-duration nerve blocks nerve blocks (~2-5 Botulinum Toxins (<half day) months) – Local anesthetics – Neurolytics • Lidocaine • Phenol • Bupivacaine • Ethanol • Etidocaine – Chemodenervation • Botulinum toxin 7
3/7/2014 Botulinum Toxins • Botulinum Toxin A – OnabotulinumtoxinA - Botox (Allergan Corp) – IncobotulinumtoxinA - Xeomin (Merz Corp) – AbobotulinumtoxinA - Dysport (Ipsen Corp) • Botulinum Toxin B Myobloc (Solstice Corp) – rimabotulinumtoxinB • Botulinum Toxins C-H? Botulinum Toxins Black Box Warning • Used for focal spasticity and dystonia •FDA issued black box • Can use for upper or lower extremity warning for children with • 12 Units/kg (Companies suggests 8) severe CP • No more than 400 Units • No more than 100 Units per muscle • No more than 50 Units per injection 8
3/7/2014 Gastrocnemius and Targeting Other Uses of Botulinum Toxins •Pain •Drooling •Bladder and Rectal Sphincter tone Neurosurgical Approaches in Cerebral Palsy • Selective dorsal rhizotomy Neurosurgical Interventions for • Peripheral neurectomy Spasticity in Children with • Myelotomy Cerebral Palsy • Dorsal column electrical stimulation 9
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