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Intrathecal baclofen treatment in children with neurological disorders Bonouvrié, L.A.

2019

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Bonouvrié, L. A. (2019). Intrathecal baclofen treatment in children with neurological disorders.

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neurological disorders

department of Child Neurology, Maastricht University Medical Center, Maastricht, the Netherlands. dŚĞƚƌŝĂůƐŝŶƚŚŝƐƚŚĞƐŝƐǁĞƌĞĨƵŶĚĞĚďLJƚŚĞWŚĞůƉƐ^ƟĐŚƟŶŐǀŽŽƌ^ƉĂƐƟĐŝ;ƉƌŽũĞĐƚŶƵŵďĞƌ ϮϬϭϭϬϯϳ ĂŶĚ ƉƌŽũĞĐƚŶƵŵďĞƌ ϵϵ͘ϬϰϳͿ͕ ,ĂŶĚŝĐĂƉE> ;ƉƌĞǀŝŽƵƐůLJ ZĞǀĂůŝĚĂƚŝĞĨŽŶĚƐͿ ;ƉƌŽũĞĐƚŶƵŵďĞƌZϮϬϭϭϬϯϮͬͿ͕<ŝŶĚĞƌƌĞǀĂůŝĚĂƟĞ&ŽŶĚƐĚƌŝĂĂŶƐƟĐŚƟŶŐ;ƉƌŽũĞĐƚŶƵŵďĞƌ ϭϭ͘ϬϮ͘ϭϳͲϮϬϭϭͬϬϬϯϱͿĂŶĚƚŚĞ:ŽŚĂŶŶĂ<ŝŶĚĞƌ&ŽŶĚƐ;ƉƌŽũĞĐƚŶƵŵďĞƌϮϬϭϭͬϬϬϯϱͲϯϱϳͿ͘ WƌŝŶƟŶŐŽĨƚŚŝƐƚŚĞƐŝƐǁĂƐƐƵƉƉŽƌƚĞĚďLJŶŽŶĐŽŵŵĞƌĐŝĂůŐƌĂŶƚƐĨƌŽŵWŚĞůƉƐ^ƟĐŚƟŶŐ ǀŽŽƌ^ƉĂƐƟĐŝ͕LJƐƚŽŶŝĞǀĞƌĞŶŝŐŝŶŐ͕K/DKƌƚŚŽƉĞĚŝĞ;ƐƐĞŶ͕ƚŚĞEĞƚŚĞƌůĂŶĚƐͿ͕<ĂŵĞƌ KƌƚŚŽƉĞĚŝĞ͕ĂŶĚ/ƉƐĞŶ&ĂƌŵĂĐĞƵƟĐĂůƐ͘ /^E͗ϵϳϴͲϵϰͲϬϮϴϭϰϰϴͲϰ ĞƐŝŐŶĐŽǀĞƌĂŶĚĐŚĂƉƚĞƌƉĂŐĞƐďLJZŝŬsƌŝũŵĂŶ͕ZĞŬůĂŵĞďƵƌĞĂƵ͘ŝƚ >ĂLJŽƵƚĂŶĚĚĞƐŝŐŶďLJĚƵĂƌĚŽdžĞŵ͕ƉĞƌƐŽŽŶůŝũŬƉƌŽĞĨƐĐŚƌŝŌ͘Ŷů͘ WƌŝŶƚĞĚďLJ/ƉƐŬĂŵƉWƌŝŶƟŶŐ͕ƉƌŽĞĨƐĐŚƌŝŌĞŶ͘ŶĞƚ

© L.A. Bonouvrié, Amsterdam, the Netherlands

Intrathecal baclofen treatment in children with

neurological disorders

D/^,WZK&^,Z/&d ƚĞƌǀĞƌŬƌŝũŐŝŶŐǀĂŶĚĞŐƌĂĂĚŽĐƚŽƌĂĂŶ ĚĞsƌŝũĞhŶŝǀĞƌƐŝƚĞŝƚŵƐƚĞƌĚĂŵ͕ ŽƉŐĞnjĂŐǀĂŶĚĞƌĞĐƚŽƌŵĂŐŶŝĮĐƵƐ prof.dr. V. Subramaniam, in het openbaar te verdedigen ƚĞŶŽǀĞƌƐƚĂĂŶǀĂŶĚĞƉƌŽŵŽƟĞĐŽŵŵŝƐƐŝĞ

ǀĂŶĚĞ&ĂĐƵůƚĞŝƚĚĞƌ'ĞŶĞĞƐŬƵŶĚĞ ŽƉǁŽĞŶƐĚĂŐϯϬŽŬƚŽďĞƌϮϬϭϵŽŵϭϯ͘ϰϱƵƵƌ

in de aula van de universiteit, ĞŽĞůĞůĂĂŶϭϭϬϱ

door

  ƉƌŽĨ͘Ěƌ͘Z͘:͘sĞƌŵĞƵůĞŶ

Smith-Chapter 1 'ĞŶĞƌĂůŝŶƚƌŽĚƵĐƟŽŶ ϵ Chapter 2 ůŝŶŝĐĂůƉƌĞƐĞŶƚĂƟŽŶĂŶĚŵĂŶĂŐĞŵĞŶƚŽĨĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂů

palsy

ϯϱ Chapter 3 īĞĐƚƐŽĨŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶŽŶĚĂŝůLJĐĂƌĞŝŶĐŚŝůĚƌĞŶǁŝƚŚ

secondary generalized dystonia: a pilot study

61 ŚĂƉƚĞƌϰ Intrathecal baclofen treatment in dystonic cerebral palsy: a

ƌĂŶĚŽŵŝnjĞĚĐůŝŶŝĐĂůƚƌŝĂů͗ƚŚĞ/z^ƚƌŝĂů

ϳϱ ŚĂƉƚĞƌϱ dŚĞ ĞīĞĐƚ ŽĨ ŝŶƚƌĂƚŚĞĐĂů ďĂĐůŽĨĞŶ ŝŶ ĚLJƐŬŝŶĞƟĐ ĐĞƌĞďƌĂů

ƉĂůƐLJ͗ƚŚĞ/z^ƚƌŝĂů

ϵϯ Chapter 6 Intrathecal baclofen for progressive neurological disease in

ĐŚŝůĚŚŽŽĚ͗ĂƐLJƐƚĞŵĂƟĐƌĞǀŝĞǁŽĨůŝƚĞƌĂƚƵƌĞ

ϭϭϵ Chapter 7 Satisfaction with intrathecal baclofen treatment in

ƉĂĞĚŝĂƚƌŝĐƉĂƟĞŶƚƐǁŝƚŚƉƌŽŐƌĞƐƐŝǀĞŶĞƵƌŽůŽŐŝĐĂůĚŝƐĞĂƐĞ

131 ŚĂƉƚĞƌϴ dŚĞĞīĞĐƚŽĨŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶƚƌĞĂƚŵĞŶƚŽŶĂĐƟǀŝƟĞƐ

of daily life in children and young adults with cerebral palsy and progressive neurological disorders

137 ŚĂƉƚĞƌϵ 'ĞŶĞƌĂůĚŝƐĐƵƐƐŝŽŶ ϭϲϱ Chapter 10 Summary ^ĂŵĞŶǀĂƫŶŐ ϭϳϵ Chapter 11 Appendix /͘LJƐŬŝŶĞƐŝĂŵĞĂƐƵƌĞŵĞŶƚƐĐĂůĞƐ //͘/z^ƐƚƵĚLJŐƌŽƵƉ ϭϵϭ Chapter 12 >ŝƐƚŽĨĂďďƌĞǀŝĂƟŽŶƐ ϭϵϳ Chapter 13 ĂŶŬǁŽŽƌĚͬtŽƌĚŽĨƚŚĂŶŬƐ 201

10

INTRODUCTION

DŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌƐŝŶĐŚŝůĚŚŽŽĚĂƌĞŵŽƐƚůLJĐĂƵƐĞĚďLJĚLJƐĨƵŶĐƟŽŶŽĨƚŚĞĚĞǀĞůŽƉŝŶŐ ďƌĂŝŶĚƵĞƚŽďƌĂŝŶůĞƐŝŽŶƐŽƌďƌĂŝŶĂďŶŽƌŵĂůŝƟĞƐ͘dŚĞƐĞƐŽĐĂůůĞĚĐĞƌĞďƌĂůŵŽǀĞŵĞŶƚ ĚŝƐŽƌĚĞƌƐĐĂŶůĞĂĚƚŽƉŽƐŝƟǀĞƐŝŐŶƐ;ƐŝŐŶƐŽĨĂďŶŽƌŵĂůŵƵƐĐůĞĂĐƟǀŝƚLJͿƐƵĐŚĂƐƐƉĂƐƟĐŝƚLJ ŽƌĚLJƐŬŝŶĞƐŝĂ͕ƚŽŐĞƚŚĞƌǁŝƚŚŶĞŐĂƟǀĞƐŝŐŶƐƐƵĐŚĂƐŵƵƐĐůĞǁĞĂŬŶĞƐƐ͕ĚĞĐƌĞĂƐĞĚƐĞůĞĐƟǀĞ ŵŽƚŽƌĐŽŶƚƌŽůĂŶĚŝŵƉĂŝƌĞĚĐŽŽƌĚŝŶĂƟŽŶ͘1-3 _{Secondary musculoskeletal problems can}

ĂƌŝƐĞĚƵƌŝŶŐŐƌŽǁƚŚŝŶĐůƵĚŝŶŐŵƵƐĐůĞĐŽŶƚƌĂĐƚƵƌĞƐ͕ďŽŶLJĚĞĨŽƌŵŝƟĞƐ͕ƐĐŽůŝŽƐŝƐĂŶĚ hip displacement.3_{ŽŶƐĞƋƵĞŶƚůLJ͕ƚŚĞŝŵƉĂŝƌŵĞŶƚƐŽŶƚŚĞůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚ}

ƐƚƌƵĐƚƵƌĞƐĐĂŶůĞĂĚƚŽƉƌŽďůĞŵƐŝŶĂĐƟǀŝƟĞƐĂŶĚƉĂƌƟĐŝƉĂƟŽŶƐƵĐŚĂƐ;ďƵƚŶŽƚůŝŵŝƚĞĚ ƚŽͿŵŽďŝůŝƚLJ͕ƐĞůĨͲĐĂƌĞ͕ĐŽŵŵƵŶŝĐĂƟŽŶĂŶĚůĞĂƌŶŝŶŐ͘ĐƟǀŝƟĞƐĂŶĚƉĂƌƟĐŝƉĂƟŽŶĂƌĞ ĨƵƌƚŚĞƌŵŽƌĞŝŶŇƵĞŶĐĞĚďLJĞŶǀŝƌŽŶŵĞŶƚĂůĨĂĐƚŽƌƐƐƵĐŚĂƐƚŚĞĂǀĂŝůĂďŝůŝƚLJŽĨĂƐƐŝƐƚĂŶĐĞ for personal care and aids for mobility. To comprehend the extent of problems due ĐĞƌĞďƌĂůŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌƐ͕ƚŚĞ/ŶƚĞƌŶĂƟŽŶĂůůĂƐƐŝĮĐĂƟŽŶŽĨ&ƵŶĐƟŽŶŝŶŐ͕ŝƐĂďŝůŝƚLJ ĂŶĚ,ĞĂůƚŚĨŽƌŚŝůĚƌĞŶĂŶĚzŽƵƚŚ;/&ͲzͿĐĂŶďĞƵƐĞĚĂƐĂĨƌĂŵĞǁŽƌŬ;&ŝŐƵƌĞϭĂŶĚ ϮͿ͘ϰ _{The spectrum of the severity of cerebral movement disorders is broad. This thesis}

11

1

Health Condition

(disorder or disease)

Body Functions

& Structure Activity Participation

Environmental

Factors PersonalFactors

Figure 1.dŚĞ/ŶƚĞƌŶĂƟŽŶĂůůĂƐƐŝĮĐĂƟŽŶŽĨ&ƵŶĐƟŽŶŝŶŐ͕ŝƐĂďŝůŝƚLJĂŶĚ,ĞĂůƚŚĨŽƌŚŝůĚƌĞŶ and Youth model (ICF-CY).ϰ

12

Figure 3. 'ƌŽƐƐDŽƚŽƌ&ƵŶĐƟŽŶŝŶŐůĂƐƐŝĮĐĂƟŽŶ^LJƐƚĞŵ;'D&^Ϳϱ_{. Image on the courtesy of}

13

1

CEREBRAL PALSY

The most common cause of cerebral movement disorders and physical disability in ĐŚŝůĚŚŽŽĚŝƐĐĞƌĞďƌĂůƉĂůƐLJ;WͿ͘dŚĞƉƌĞǀĂůĞŶĐĞŽĨWŝŶtĞƐƚĞƌŶĐŽƵŶƚƌŝĞƐŝƐϮ͘ϭϭ per 1000 livebirths and has been fairly stable for many years.6 _{A European cohort}

ƐƚƵĚLJ ƐŚŽǁĞĚ Ă ƉƌĞǀĂůĞŶĐĞ ŽĨ ϭ͘ϵϲ ƉĞƌ ϭϬϬϬ ůŝǀĞďŝƌƚŚƐ ŝŶ ϮϬϭϬ͘7 _{CP comprises a}

ŐƌŽƵƉ ŽĨ ĚĞǀĞůŽƉŵĞŶƚĂů ĚŝƐŽƌĚĞƌƐ ŽĨ ŵŽǀĞŵĞŶƚ ĂŶĚ ƉŽƐƚƵƌĞ͕ ĂƩƌŝďƵƚĞĚ ƚŽ ŶŽŶͲ progressive disturbances that occurred in the developing fetal or infant brain.ϴ _The

ŵŽƚŽƌŝŵƉĂŝƌŵĞŶƚƐĂƌĞŽŌĞŶĂĐĐŽŵƉĂŶŝĞĚďLJĚŝƐƚƵƌďĂŶĐĞƐŽĨƐĞŶƐĂƟŽŶ͕ƉĞƌĐĞƉƟŽŶ͕ ĐŽŐŶŝƟŽŶ͕ĐŽŵŵƵŶŝĐĂƟŽŶĂŶĚďĞŚĂǀŝŽƵƌ͕ďLJĞƉŝůĞƉƐLJĂŶĚďLJƐĞĐŽŶĚĂƌLJŵƵƐĐƵůŽƐŬĞůĞƚĂů problems.ϴͲϭϬ

EĞƵƌŽŝŵĂŐŝŶŐŝŶWƌĞǀĞĂůƐƐĞǀĞƌĂůƚLJƉĞƐŽĨƵŶĚĞƌůLJŝŶŐďƌĂŝŶůĞƐŝŽŶƐ;&ŝŐƵƌĞϰͿ͘dŚĞ ƉĂƩĞƌŶ ŽĨ ůĞƐŝŽŶƐ ŝƐ ƐƚƌŽŶŐůLJ ƌĞůĂƚĞĚ ƚŽ ƚŚĞ ƐƚĂŐĞƐ ŽĨ ďƌĂŝŶ ĚĞǀĞůŽƉŵĞŶƚ ŝŶ ǁŚŝĐŚ they occurred: prenatal, perinatal or neonatal.11_{&ƵƌƚŚĞƌŵŽƌĞ͕ƚŚĞƉĂƩĞƌŶŽĨůĞƐŝŽŶƐ}

ĐŽƌƌĞƐƉŽŶĚƐǁŝƚŚĐůŝŶŝĐĂůĮŶĚŝŶŐƐ͘12

ƌĂŝŶ ŵĂůĚĞǀĞůŽƉŵĞŶƚ ŽƌŝŐŝŶƐ ĨƌŽŵ ƚŚĞ ĮƌƐƚ ĂŶĚ ƐĞĐŽŶĚ ƚƌŝŵĞƐƚĞƌ͘13_{ ŝƐŽƌĚĞƌƐ ŽĨ}

ƉƌŽůŝĨĞƌĂƟŽŶ͕ŵŝŐƌĂƟŽŶŽƌŽƌŐĂŶŝnjĂƟŽŶĐĂŶŽĐĐƵƌĂƚƚŚŝƐƐƚĂŐĞ͘hŶĚĞƌůLJŝŶŐĐĂƵƐĞƐĐĂŶ ďĞŐĞŶĞƟĐ͕ǀĂƐĐƵůĂƌĂŶĚŝŶĨĞĐƟŽƵƐ͘ĞƉĞŶĚŝŶŐŽŶƚŚĞůŽĐĂůŝƐĂƟŽŶĂŶĚĞdžƚĞŶƚŽĨƚŚĞ maldevelopment clinical symptoms range from easily controllable epilepsy without ĨƵƌƚŚĞƌ ĂďŶŽƌŵĂůŝƟĞƐ ƚŽ ƵŶĐŽŶƚƌŽůůĂďůĞ ĞƉŝůĞƉƐLJ ĂĐĐŽŵƉĂŶŝĞĚ ďLJ ƐƉĂƐƟĐŝƚLJ ĂŶĚ͕ ƐĞǀĞƌĞůLJŝŵƉĂŝƌĞĚŵŽƚŽƌĂŶĚĐŽŐŶŝƟǀĞĚĞǀĞůŽƉŵĞŶƚ͘ϭϰ

/ŶƚŚĞĞĂƌůLJƚŽŵŝĚͲƚŚŝƌĚƚƌŝŵĞƐƚĞƌƉĞƌŝǀĞŶƚƌŝĐƵůĂƌǁŚŝƚĞŵĂƩĞƌůĞƐŝŽŶƐĂƌĞƚŚĞĚŽŵŝŶĂŶƚ ĮŶĚŝŶŐ͘13_{dŚŝƐƚLJƉĞŽĨĚĂŵĂŐĞŽĐĐƵƌƐĂƉƉƌŽdžŝŵĂƚĞůLJďĞĨŽƌĞϯϰǁĞĞŬƐŽĨŐĞƐƚĂƟŽŶĂŶĚ}

ŝƐƚŚĞŵĂŝŶƉĂƩĞƌŶŝŶƉƌĞƚĞƌŵďŽƌŶĐŚŝůĚƌĞŶ͘ϭϮ͕ϭϰ͕ϭϱ_{,ŽǁĞǀĞƌ͕ϮϱйŽĨĐŚŝůĚƌĞŶǁŝƚŚƚŚĞƐĞ}

lesions are born at term.12,13 _{In this last group of children the origin of the lesions is}

ƉƌĞƐƵŵĂďůLJƉƌĞŶĂƚĂůĚƵĞƚŽĐŚƌŽŶŝĐƉůĂĐĞŶƚĂůŝŶƐƵĸĐŝĞŶĐLJǁŝƚŚƉƌŽůŽŶŐĞĚƉĞƌŝŽĚƐŽĨ ŵŽĚĞƌĂƚĞŝŶƚĞŶƐŝƚLJŝŶƐƵĸĐŝĞŶƚŽdžLJŐĞŶĂƟŽŶ͘ϭϭ͕ϭϰ_{/ƐĐŚĞŵŝĂĂŶĚŝŶŇĂŵŵĂƟŽŶ͕ǁŚŝĐŚĐĂŶ} ďĞĚƵĞƚŽƉĞƌĨƵƐŝŽŶĨĂŝůƵƌĞ͕ŝŶĨĞĐƟŽŶŽƌďŽƚŚĐĂŶĐĂƵƐĞƉĞƌŝǀĞŶƚƌŝĐƵůĂƌůĞƵŬŽŵĂůĂĐŝĂ ;Ws>Ϳ͘ϭϱ_{ůĞƐƐĐŽŵŵŽŶĐĂƵƐĞŽĨǁŚŝƚĞŵĂƩĞƌůĞƐŝŽŶƐŝƐƉĞƌŝǀĞŶƚƌŝĐƵůĂƌŚĂĞŵŽƌƌŚĂŐŝĐ} ŝŶĨĂƌĐƟŽŶ;W,/Ϳ͘W,/ŝƐĂĐŽŵƉůŝĐĂƟŽŶŽĨŝŶƚƌĂǀĞŶƚƌŝĐƵůĂƌŚĂĞŵŽƌƌŚĂŐĞǁŚŝĐŚŽĐĐƵƌƐŝŶ ƚŚĞĮƌƐƚĚĂLJƐĂŌĞƌďŝƌƚŚ͕ĞƐƉĞĐŝĂůůLJŝŶǀĞƌLJƉƌĞƚĞƌŵĐŚŝůĚƌĞŶĚƵĞƚŽƐƵƐĐĞƉƟďŝůŝƚLJĨŽƌ haemorrhage of the germinal layer.16_{tŚŝƚĞŵĂƩĞƌůĞƐŝŽŶƐƌĞƐƵůƚŵŽƐƚůLJŝŶƐƉĂƐƟĐŝƚLJ͘}12,17

ϭϰ

ǀĞŶƚƐŝŶƚŚĞůĂƚĞƚŚŝƌĚƚƌŝŵĞƐƚĞƌŵŽƐƚůLJĐĂƵƐĞĐŽƌƟĐĂůͬƐƵďĐŽƌƟĐĂůĂŶĚďĂƐĂůŐĂŶŐůŝĂ ŐƌĂLJŵĂƩĞƌůĞƐŝŽŶƐ͘ϭϯ͕ϭϰ_{>ĞƐŝŽŶŽĨƚŚĞďĂƐĂůŐĂŶŐůŝĂĂŶĚŝŶƐŽŵĞĐĂƐĞƐĂĚĚŝƟŽŶĂůĚĂŵĂŐĞ}

ƚŽƚŚĞĐĞŶƚƌĂůĐŽƌƚĞdžŝƐĂĐŽŵŵŽŶƉĂƩĞƌŶŝŶĂƐƉŚLJdžŝĂƚĞĚŝŶĨĂŶƚƐďŽƌŶĂƚƚĞƌŵǁŚŽ ƉƌĞƐĞŶƚǁŝƚŚůŽǁƉŐĂƌƐĐŽƌĞƐĂŌĞƌďŝƌƚŚ͘ϭϭ͕ϭϰ͕ϭϳ͕ϭϴ_{WŽƐƐŝďůĞŵĞĐŚĂŶŝƐŵƐŽĨƚŚĞƐĞůĞĐƟǀĞ}

vulnerability are the high glucose metabolism during the neonatal period and the ƉĂƩĞƌŶŽĨŵLJĞůŝŶĂƟŽŶƐƚĂƌƟŶŐŝŶƚŚĞĂīĞĐƚĞĚĐĞŶƚƌĂůĐŽƌƟĐĂůƌĞŐŝŽŶ͘ϭϰ _{Children with}

ďĂƐĂůŐĂŶŐůŝĂůĞƐŝŽŶƐƉƌĞƐĞŶƚǁŝƚŚƚŚĞĚLJƐŬŝŶĞƟĐĨŽƌŵŽĨW͘ϭϭ͕ϭϮ͕ϭϴ _{Imaging studies show}

ŝŶǀŽůǀĞŵĞŶƚŽĨƚŚĞůĞŶƟĨŽƌŵŶƵĐůĞŝ;ƉƵƚĂŵĞŶĂŶĚŐůŽďƵƐƉĂůůŝĚƵƐͿŝŶĂůůĐŚŝůĚƌĞŶǁŝƚŚ ĚLJƐŬŝŶĞƟĐW͘dŚĞƌĞĂƉƉĞĂƌƚŽďĞƚǁŽƉĂƩĞƌŶƐ͗ůĞƐŝŽŶƐŝŶƚŚĞƉƵƚĂŵĞŶŽŶůLJŽƌŝŶďŽƚŚ the putamen and globus pallidus.ϭϵ_{ŽŐŶŝƟǀĞĚĞĮĐŝƚƐĂƌĞůĞƐƐƉƌŽĨŽƵŶĚŝŶĐŚŝůĚƌĞŶǁŝƚŚ}

ďĂƐĂůŐĂŶŐůŝĂĐŽŵƉĂƌĞĚƚŽĐŚŝůĚƌĞŶǁŝƚŚǁŚŝƚĞŵĂƩĞƌůĞƐŝŽŶƐ͕ďƵƚǁŚĞŶĂĚĚŝƟŽŶĂů;ŝ͘Ğ͘ ƐĞǀĞƌĞͿĐĞŶƚƌĂů͕;ƐƵďͿĐŽƌƟĐĂůĂŶĚͬŽƌŚŝƉƉŽĐĂŵƉĂůŝŶǀŽůǀĞŵĞŶƚŝƐƉƌĞƐĞŶƚ͕ƐƉĂƐƟĐŝƚLJĐĂŶ ďĞƚŚĞĚŽŵŝŶĂŶƚŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌǁŝƚŚĂĚĚŝƟŽŶĂůůLJĐŽŐŶŝƟǀĞŝŵƉĂŝƌŵĞŶƚ͘ϭϴ͕ϮϬ _Lesions

to the globus pallidus can also occur due to postnatal hyperbilirubinemia-induced ŬĞƌŶŝĐƚĞƌƵƐ͘/ŶƚŚĞƐĞĐŚŝůĚƌĞŶŚĞĂƌŝŶŐŝŵƉĂŝƌŵĞŶƚŝƐŽŌĞŶĂĐĐŽŵƉĂŶLJŝŶŐƚŚĞŵŽǀĞŵĞŶƚ disorder.21,22_{<ĞƌŶŝĐƚĞƌƵƐĐĂŶďŽƚŚŽĐĐƵƌŝŶƉƌĞƚĞƌŵĂŶĚƚĞƌŵďŽƌŶŝŶĨĂŶƚƐ͘}Ϯϯ͕Ϯϰ _The

bilirubin threshold for development of basal ganglia lesions is lower in very preterm ŝŶĨĂŶƚƐ;ϮϱƚŽϮϵǁĞĞŬŽĨŐĞƐƚĂƟŽŶͿŵĂŬŝŶŐƚŚĞŵŵŽƌĞƐƵƐĐĞƉƟďůĞƚŽƚŚĞŽĐĐƵƌƌĞŶĐĞ of kernicterus.ϮϮ͕Ϯϰ_{/ŶŚŝŐŚŝŶĐŽŵĞĐŽƵŶƚƌŝĞƐƚŚŝƐĐŽŶĚŝƟŽŶŚĂƐďĞĐŽŵĞůĞƐƐĐŽŵŵŽŶ}

16

ůĂƐƐŝĮĐĂƟŽŶŽĨĐĞƌĞďƌĂůƉĂůƐLJ

dŚĞƐĞǀĞƌŝƚLJŽĨƚŚĞŝŵƉĂŝƌŵĞŶƚŽĨĨƵŶĐƟŽŶĂůŵŽďŝůŝƚLJŝŶWŝƐĐůĂƐƐŝĮĞĚƵƐŝŶŐƚŚĞ'D&^ ;&ŝŐƵƌĞϯͿ͘ϱ_{^ŝŵŝůĂƌϱƉŽŝŶƚƐĐĂůĞƐĂƌĞƵƐĞĚƚŽĚĞƐĐƌŝďĞƚŚĞůĞǀĞůŽĨŵĂŶƵĂůĨƵŶĐƟŽŶ}

;DĂŶƵĂůďŝůŝƚLJůĂƐƐŝĮĐĂƟŽŶ^LJƐƚĞŵ͕D^Ϳ͕ĂŶĚƚŚĞůĞǀĞůŽĨĐŽŵŵƵŶŝĐĂƟŽŶĨƵŶĐƟŽŶ ;ŽŵŵƵŶŝĐĂƟŽŶ&ƵŶĐƟŽŶůĂƐƐŝĮĐĂƟŽŶ^LJƐƚĞŵ͕&^Ϳ͘Ϯϱ26 _{This thesis will focus on CP}

ƉĂƟĞŶƚƐǁŝƚŚ'D&^ůĞǀĞů/sĂŶĚs͘ WŝƐĨƵƌƚŚĞƌŵŽƌĞĐĂƚĞŐŽƌŝƐĞĚďLJƚŚĞĚŽŵŝŶĂŶƚŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌ͗ƐƉĂƐƟĐ͕ĚLJƐŬŝŶĞƟĐ or ataxic.10_{^ƉĂƐƟĐŝƚLJŝƐƚŚĞĚŽŵŝŶĂŶƚŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌŝŶϳϮƚŽϵϭйŽĨWƉĂƟĞŶƚƐ͕}ϵ͕ϭϭ ĂŶĚĚLJƐŬŝŶĞƐŝĂŝŶĂƉƉƌŽdžŝŵĂƚĞůLJϭϱй͘11 ^ƉĂƐƟĐŝƚLJ ^ƉĂƐƟĐŝƚLJŝƐĚĞĮŶĞĚĂƐĂǀĞůŽĐŝƚLJͲĚĞƉĞŶĚĞŶƚ͕ŝŶĐƌĞĂƐĞĚƌĞƐŝƐƚĂŶĐĞƚŽĞdžƚĞƌŶĂůůLJĂƉƉůŝĞĚ ƉĂƐƐŝǀĞŵƵƐĐůĞƐƚƌĞƚĐŚǁŚŝĐŚŝƐĨŽƌƚŚĐŽŵŝŶŐĚƵƌŝŶŐƉŚLJƐŝĐĂůĞdžĂŵŝŶĂƟŽŶ͘3,27_{^ƉĂƐƟĐŝƚLJ}

is the result of an imbalance of the excitatory and inhibitory responses to a sensory input signal. Lesions of the central nervous system result in loss of descending inhibitory ĐŽŵŵĂŶĚƐĂŶĚĂďŶŽƌŵĂůŝŵƉƵůƐĞƐ͕ƐƵďƐĞƋƵĞŶƚůLJƌĞƐƵůƟŶŐŝŶŽǀĞƌĂĐƟǀĞĂŶĚƐƉĂƐƟĐ muscles.2_{dŚĞŝŶƚĞŶƐŝƚLJŽĨƐƉĂƐƟĐŝƚLJĐĂŶǀĂƌLJĚĞƉĞŶĚŝŶŐŽŶƉŽƐƚƵƌĞ͕ĂĐƟǀŝƚLJ͕ĞŵŽƟŽŶĂů}

state, pain and other triggers.27

LJƐŬŝŶĞƐŝĂ

LJƐŬŝŶĞƐŝĂ ŝƐ ĐŚĂƌĂĐƚĞƌŝnjĞĚ ďLJ ŝŶǀŽůƵŶƚĂƌLJ͕ ƵŶĐŽŶƚƌŽůůĞĚ͕ ƌĞĐƵƌƌŝŶŐ͕ ŽĐĐĂƐŝŽŶĂůůLJ ƐƚĞƌĞŽƚLJƉĞĚŵŽǀĞŵĞŶƚƐǁŝƚŚŇƵĐƚƵĂƟŶŐŵƵƐĐůĞƚŽŶĞ͘Ϯϴ_{LJƐŬŝŶĞƐŝĂĐĂŶďĞĨƵƌƚŚĞƌ}

separated in dystonia and choreo-athetosis.Ϯϴ͕Ϯϵ_{LJƐƚŽŶŝĂŝƐĂŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌǁŝƚŚ}

involuntary movements, distorted voluntary movements and abnormal postures due to ƐƵƐƚĂŝŶĞĚŽƌŝŶƚĞƌŵŝƩĞŶƚŵƵƐĐůĞĐŽŶƚƌĂĐƟŽŶƐƐƵĐŚĂƐƐůŽǁƌŽƚĂƟŽŶ͕ĞdžƚĞŶƐŝŽŶŽƌŇĞdžŝŽŶ of body parts.Ϯϴ͕Ϯϵ _{The abnormal postures can give the impression of hypokinesia while}

ƚŚĞLJĂƌĞĂĐƚƵĂůůLJĐĂƵƐĞĚďLJƐƵƐƚĂŝŶĞĚŵƵƐĐůĞĐŽŶƚƌĂĐƟŽŶƐ͘dŽŶĞŝƐŇƵĐƚƵĂƟŶŐďƵƚĞĂƐŝůLJ ŝŶĐƌĞĂƐĞĚ;ŚLJƉĞƌƚŽŶŝĂͿ͘Ϯϴ_{ŚŽƌĞŽͲĂƚŚĞƚŽƐŝƐŝƐĐŚĂƌĂĐƚĞƌŝƐĞĚďLJ;ĨĂƐƚĞƌͿŚLJƉĞƌŬŝŶĞƟĐ} ŵŽǀĞŵĞŶƚƐĂŶĚƚŽŶĞŇƵĐƚƵĂƟŽŶ;ŵĂŝŶůLJŚLJƉŽƚŽŶŝĂͿ͘Ϯϴ_{LJƐƚŽŶŝĂĂŶĚĐŚŽƌĞŽĂƚŚĞƚŽƐŝƐ} ĐĂŶďĞƐŝŵƵůƚĂŶĞŽƵƐůLJƉƌĞƐĞŶƚǁŝƚŚĚLJƐƚŽŶŝĂŽŌĞŶďĞŝŶŐƚŚĞŵŽƌĞĚŽŵŝŶĂŶƚĨĞĂƚƵƌĞ͘ dŚĞLJĐĂŶďŽƚŚŵĂŶŝĨĞƐƚĚƵƌŝŶŐƌĞƐƚĂŶĚďŽƚŚŝŶĐƌĞĂƐĞĚƵƌŝŶŐĂĐƟǀŝƟĞƐ͘30 _{Studies shows} ƚŚĂƚĚLJƐƚŽŶŝĂŝƐ͕ŝŶĐŽŶƚƌĂƐƚƚŽĐŚŽƌĞŽͲĂƚŚĞƚŽƐŝƐ͕ƐŝŐŶŝĮĐĂŶƚůLJƌĞůĂƚĞĚƚŽĂĐƟǀŝƟĞƐŽĨĚĂŝůLJ ůŝĨĞ͕ƉĂƌƟĐŝƉĂƟŽŶŝŶƐŽĐŝĞƚLJĂŶĚƋƵĂůŝƚLJŽĨůŝĨĞ͘31 ůŝŶŝĐŝĂŶƐĮŶĚĚLJƐŬŝŶĞƐŝĂĚŝĸĐƵůƚƚŽƌĞĐŽŐŶŝnjĞĂŶĚƚŚĞĚŝƐƟŶĐƟŽŶďĞƚǁĞĞŶĚLJƐƚŽŶŝĂ and choreo-athetosis troublesome.32 _{Measurement scales are therefore not used}

17

1

ĂƌƌLJͲůďƌŝŐŚƚLJƐƚŽŶŝĂ^ĐĂůĞ;^ͿĂŶĚƚŚĞLJƐŬŝŶĞƐŝĂ/ŵƉĂŝƌŵĞŶƚ^ĐĂůĞ;/^Ϳ͘ϯϯͲϯϱ

dŚĞƵƌŬĞͲ&ĂŚŶͲDĂƌƐĚĞŶLJƐƚŽŶŝĂZĂƟŶŐƐĐĂůĞǁĂƐĚĞƐŝŐŶĞĚƚŽĂƐƐĞƐƐƉƌŝŵĂƌLJĚLJƐƚŽŶŝĂ but is frequently used in CP as well.ϯϱ _{Scales are presented at the end of this thesis}

;ƉƉĞŶĚŝdž/͘LJƐŬŝŶĞƐŝĂDĞĂƐƵƌĞŵĞŶƚ^ĐĂůĞƐͿ͘ůůƚŚƌĞĞƐĐĂůĞƐĂƐƐĞƐƐĚLJƐŬŝŶĞƐŝĂŽŶ ƚŚĞ/&ͲzůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚƐƚƌƵĐƚƵƌĞƐ͘&ŽƌĂůůƐĐĂůĞƐ͕ƐƚƵĚŝĞƐůŽŽŬŝŶŐĂƚƚŚĞ ǀĂůŝĚŝƚLJ͕ƌĞůŝĂďŝůŝƚLJ͕ƌĞƐƉŽŶƐŝǀĞŶĞƐƐĂŶĚĐůŝŶŝĐĂůƵƟůŝƚLJŝŶĐŚŝůĚƌĞŶǁŝƚŚWĂƌĞůŝŵŝƚĞĚŝŶ ŶƵŵďĞƌĂŶĚͬŽƌƋƵĂůŝƚLJ͘dŚĞƌĞĂƌĞŶŽƚĞƐƚͲƌĞƚĞƐƚƐƚƵĚŝĞƐ͘&ŽƌĐůŝŶŝĐĂůƵƟůŝƚLJƚŚĞ^ ƐĞĞŵƐƚŚĞĞĂƐŝĞƐƚĂŶĚƋƵŝĐŬĞƐƚƐĐĂůĞƚŽƵƐĞ͘dŚĞ/^ŝƐƚŚĞŵŽƐƚĞdžƚĞŶƐŝǀĞĂŶĚƟŵĞ ĐŽŶƐƵŵŝŶŐƐĐĂůĞŵĂŬŝŶŐŝƚůĞƐƐƐƵŝƚĂďůĞĨŽƌĐůŝŶŝĐĂůƉƌĂĐƟĐĞďƵƚŝƚĐŽƵůĚďĞŽĨĂĚĚĞĚ ǀĂůƵĞŝŶƌĞƐĞĂƌĐŚ͘dŚĞ/^ŝƐĂůƐŽƚŚĞŽŶůLJƐĐĂůĞĂĚĚƌĞƐƐŝŶŐĐŚŽƌĞŽͲĂƚŚĞƚŽƐŝƐĂŶĚƚŚĞ ŽŶůLJƐĐĂůĞĐŽŵƉĂƌŝŶŐƌĞƐƚǀĞƌƐƵƐĂĐƟǀŝƚLJ͘ϯϱ LJƐŬŝŶĞƟĐWŝƐƚŚĞŵŽƐƚĚŝƐĂďůŝŶŐĨŽƌŵŽĨWǁŝƚŚϱϵͲϴϬйŽĨƉĂƟĞŶƚƐďĞŝŶŐ'D&^ level IV or V.36,37_{dŚŝƐŝƐƐƵďƐƚĂŶƟĂůůLJŚŝŐŚĞƌĐŽŵƉĂƌĞĚƚŽĐŚŝůĚƌĞŶǁŝƚŚďŝůĂƚĞƌĂůƐƉĂƐƟĐ}

WŝŶǁŚŽŵ'D&^/sĂŶĚsĂĐĐŽƵŶƚĨŽƌƵŶĚĞƌϮϬйŽĨĐĂƐĞƐ͘37 _{Comprehensive studies}

ŽŶĚLJƐŬŝŶĞƟĐWĂƌĞƌĂƌĞĂŶĚŽƵƚĐŽŵĞƐĂƌĞŵŽƐƚůLJŽŶƚŚĞůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚ ƐƚƌƵĐƚƵƌĞƐ;Ğ͘Ő͘ĚLJƐƚŽŶŝĂͿ͘ZĞƉŽƌƚĞĚŐŽĂůƐĨŽƌƚƌĞĂƚŵĞŶƚŽĨƉĂƟĞŶƚƐǁŝƚŚĚLJƐƚŽŶŝĂĂƌĞŽŶ ĂůůĚŽŵĂŝŶƐŽĨƚŚĞ/&Ͳz͗ŝŵƉƌŽǀĞƉĂŝŶĂŶĚĐŽŵĨŽƌƚ͕ƉƌĞǀĞŶƚǁŽƌƐĞŶŝŶŐŽĨĚĞĨŽƌŵŝƟĞƐ ;ůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚƐƚƌƵĐƚƵƌĞƐͿ͕ŝŵƉƌŽǀĞƉŽƐŝƟŽŶŝŶŐĂŶĚƚƌĂŶƐĨĞƌƐ;ůĞǀĞůŽĨ ĂĐƟǀŝƟĞƐ ĂŶĚ ƉĂƌƟĐŝƉĂƟŽŶͿ͕ ĂŶĚ ŝŵƉƌŽǀĞ ĞĂƐĞ ŽĨ ƉĞƌƐŽŶĂů ĐĂƌĞ ĨŽƌ ďŽƚŚ ƉĂƟĞŶƚƐ ĂŶĚĐĂƌĞŐŝǀĞƌƐ;ŝŶĐůƵĚŝŶŐĚƌĞƐƐŝŶŐĂŶĚŚLJŐŝĞŶŝĐƌĞůĂƚĞĚĐĂƌĞͿ;ůĞǀĞůŽĨĂĐƟǀŝƟĞƐĂŶĚ ƉĂƌƟĐŝƉĂƟŽŶĂŶĚůĞǀĞůŽĨĞŶǀŝƌŽŶŵĞŶƚĂůĨĂĐƚŽƌƐͿ͘ϯϴ͕ϯϵ

WZK'Z^^/sEhZK>K'/>/^^K&,/>,KK

^ƉĂƐƟĐŝƚLJĂŶĚĚLJƐŬŝŶĞƐŝĂŝŶĐŚŝůĚƌĞŶĐĂŶĂůƐŽďĞĐĂƵƐĞĚďLJƉƌŽŐƌĞƐƐŝǀĞŶĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ ŽƌŶĞƵƌŽŵĞƚĂďŽůŝĐĚŝƐĞĂƐĞƐ;WEͿ͘ϰϬͲϰϮ_{EĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞĚŝƐĞĂƐĞƐĂƌĞĚŝƐŽƌĚĞƌƐǁŝƚŚ} ƉƌŽŐƌĞƐƐŝǀĞůŽƐƐŽĨŶĞƵƌŽůŽŐŝĐĂůĨƵŶĐƟŽŶĚƵĞƚŽƐƚƌƵĐƚƵƌĂůĂďŶŽƌŵĂůŝƟĞƐŽĨƚŚĞĐĞŶƚƌĂů nervous system.ϰϮ _{Neurometabolic diseases refer to a group of disorders that are}

ϭϴ

ůĂƌŐĞůLJƐŝŵŝůĂƌƚŽƚŚĂƚŽĨĐĞƌĞďƌĂůƉĂůƐLJ͘&ŽƌƐŽŵĞĚŝĂŐŶŽƐĞƐƉƌŽŵŝƐŝŶŐŽƉƟŽŶƐĂƌĞ available when early treatment is possible such as enzyme replacement, bone marrow ƚƌĂŶƐƉůĂŶƚĂƟŽŶŽƌƐƵďƐƚƌĂƚĞŝŶŚŝďŝƟŽŶ͘ĂƌůLJƌĞĐŽŐŶŝƟŽŶŽĨƚŚĞĚŝƐĞĂƐĞĂŶĚĞĂƌůLJƐƚĂƌƚ ŽĨƚŚĞƐĞƐƉĞĐŝĮĐƚƌĞĂƚŵĞŶƚƐŵĂLJďĞŶĞĮƚŽƵƚĐŽŵĞ͘ϰϰ

Table 1.  ƐĞůĞĐƟŽŶ ŽĨ ƉƌŽŐƌĞƐƐŝǀĞ ŶĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ ĂŶĚ ŶĞƵƌŽŵĞƚĂďŽůŝĐ ĚŝƐĞĂƐĞƐ ŽĨ ĐŚŝůĚŚŽŽĚĐĂƵƐŝŶŐƐƉĂƐƟĐŝƚLJĂŶĚͬŽƌĚLJƐƚŽŶŝĂϰϬͲϰϯ

Diagnosis Pathogenic features ^ƉĂƐƟĐŝƚLJͬ LJƐƚŽŶŝĂ Leucodystrophy ͲDĞƚĂĐŚƌŽŵĂƟĐůĞƵĐŽĚLJƐƚƌŽƉŚLJ - Adrenoleucodystrophy ͲsĂŶŝƐŚŝŶŐǁŚŝƚĞŵĂƩĞƌ - Pelizeus-Merzbacher disease tŚŝƚĞŵĂƩĞƌĂďŶŽƌŵĂůŝƟĞƐĚƵĞƚŽ ĚĞŵLJĞůŝŶŝĂƟŽŶĐĂƵƐĞĚďLJĚĞĮĐŝĞŶƚĂĐƟǀŝƚLJŽĨ ĚŝīĞƌĞŶƚůLJƐŽƐŽŵĂůĞŶnjLJŵĞƐ Both

ZĞƩ͛ƐƐLJŶĚƌŽŵĞ Cerebral atrophy and hyperammonaemia Both

Neuronal ceroid-lipofuscinosis &ĂŝůƵƌĞŽĨĨĂƩLJŽdžŝĚĂƟŽŶ Both

EŝĞŵĂŶŶͲWŝĐŬͲƚLJƉĞ;ĚLJƐƚŽŶŝĐ ůŝƉŝĚŽƐŝƐͿ

ĞĨĞĐƟǀĞĐŚŽůĞƐƚĞƌŽůĞƐƚĞƌŝĮĐĂƟŽŶ͕ŶĞƵƌŽŶĂů storage

LJƐƚŽŶŝĂ

Niemann Pick type A ^ƉŚŝŶŐŽŵLJĞůŝŶĂƐĞĂĐƟǀŝƚLJĚĞĮĐŝĞŶƚ͕ŶĞƵƌŽŶĂů

and visceral storage of sphingomyeline

^ƉĂƐƟĐŝƚLJ

Mucopolysaccharidosis ĞĮĐŝĞŶƚĂĐƟǀŝƚLJŽĨƐƉĞĐŝĮĐůLJƐŽƐŽŵĂů

ĞŶnjLJŵĞƐĐĂƵƐŝŶŐĂĐĐƵŵƵůĂƟŽŶŽĨĂĐŝĚŝĐ polysaccharides in various organs including the brain

Both

Lesh Nyhan Syndrome ,LJƉŽdžĂŶƚŚŝŶĞͲŐƵĂŶŝŶĞ

ϭϵ

1

^ƉĂƐƟĐŝƚLJ

KƌĂůƉŚĂƌŵĂĐŽůŽŐŝĐĂůƚƌĞĂƚŵĞŶƚǁŝƚŚďĂĐůŽĨĞŶ͕ƟnjĂŶŝĚŝŶĞ͕ĚĂŶƚƌŽůĞŶĞŽƌĚŝĂnjĞƉĂŵŚĂƐ ďĞĞŶĚĞƐĐƌŝďĞĚŝŶůŝƚĞƌĂƚƵƌĞ͘dŚĞƌĞŝƐŝŶƐƵĸĐŝĞŶƚĚĂƚĂƚŽŵĂŬĞĐůĞĂƌƌĞĐŽŵŵĞŶĚĂƟŽŶƐ for oral pharmacological treatment since study numbers are low and the described ƉŽƉƵůĂƟŽŶƐƐŵĂůů͘ϰϱ_{ĂĐůŽĨĞŶŝƐƚŚĞĂŐĞŶƚŵŽƐƚĐŽŵŵŽŶůLJƉƌĞƐĐƌŝďĞĚŝŶĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͕}

ŚŽǁĞǀĞƌ͕ƚŚĞƌĞŝƐŝŶƐƵĸĐŝĞŶƚĞǀŝĚĞŶĐĞĨŽƌƚŚĞƵƐĞĨŽƌĞŝƚŚĞƌĚĞĐƌĞĂƐŝŶŐƐƉĂƐƟĐŝƚLJŽƌ ŝŵƉƌŽǀŝŶŐ ŵŽƚŽƌ ĨƵŶĐƟŽŶ ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ƐƉĂƐƟĐ ĐĞƌĞďƌĂů ƉĂůƐLJ͘ϰϱ͕ϰϲ _{The working}

mechanism of baclofen and intrathecal use are described later in this chapter.

ƐƵƌŐŝĐĂůŽƉƟŽŶĨŽƌƚŚĞƚƌĞĂƚŵĞŶƚŽĨƐĞǀĞƌĞƐƉĂƐƟĐŝƚLJŽĨƚŚĞůŽǁĞƌůŝŵďƐŝƐƐĞůĞĐƟǀĞ ĚŽƌƐĂůƌŚŝnjŽƚŽŵLJ;^ZͿ͘^ZŝƐŵŽƐƚůLJƵƐĞĚŝŶĐŚŝůĚƌĞŶǁŝƚŚ'D&^/ĂŶĚ//ĂŶĚĂŝŵƐƚŽ preserve or even improve mobility during growth.ϰϳ_{/ŶĐŚŝůĚƌĞŶǁŝƚŚ'D&^/sĂŶĚs}

ĚĂŝůLJĐŽŵĨŽƌƚĂŶĚĐĂƌĞ;ĚƌĞƐƐŝŶŐĂŶĚǁĂƐŚŝŶŐͿĐĂŶŝŵƉƌŽǀĞĂŌĞƌ^Z͘ϰϴ

LJƐŬŝŶĞƐŝĂ

^ŝŶĐĞĚLJƐƚŽŶŝĂŝƐƚŚĞĚŽŵŝŶĂŶƚĨĞĂƚƵƌĞŝŶĚLJƐŬŝŶĞƟĐW͕ƚƌĞĂƚŵĞŶƚŝƐŵŽƐƚůLJĂŝŵĞĚƚŽ decrease dystonia and not choreo-athetosis.30_{&ŽƌŐĞŶĞƌĂůŝnjĞĚĚLJƐƚŽŶŝĂ͕ƚŚĞƵƐĞŽĨ}

20

dŚĞƐŝƚĞŽĨĂĐƟŽŶŽĨďĂĐůŽĨĞŶŝŶƚƌĞĂƚŵĞŶƚŽĨƐƉĂƐƟĐŝƚLJŝƐƚŚŽƵŐŚƚƚŽďĞƚŚĞƐƵƉĞƌĮĐŝĂů layers of the dorsal spinal cord.ϱϳ_{dŚŝƐŝƐĚŝīĞƌĞŶƚĨŽƌƚƌĞĂƚŵĞŶƚŽĨĚLJƐƚŽŶŝĂǁŚĞƌĞ}

baclofen is thought to act on the intracranial levelϱϱ͕ϱϴ_{͘ůŝŶŝĐĂůĮŶĚŝŶŐƐƐƵƉƉŽƌƚƚŚŝƐ}

ŚLJƉŽƚŚĞƐŝƐ͗ ŝŶ ĐŽŶƚƌĂƐƚ ƚŽ ƐƉĂƐƟĐŝƚLJ͕ Ă ƐŝŶŐůĞ ŝŶƚƌĂƚŚĞĐĂů ůƵŵďĂƌ ďŽůƵƐ ŽĨ ďĂĐůŽĨĞŶ ĚŽĞƐŶŽƚĚĞĐƌĞĂƐĞĚLJƐƚŽŶŝĂ͘/ƚĂĐƚƵĂůůLJƚĂŬĞƐƐĞǀĞƌĂůĚĂLJƐĂŌĞƌĐŽŶƟŶƵŽƵƐŝŶƚƌĂƚŚĞĐĂů ŝŶĨƵƐŝŽŶƚŽƐĞĞŝŵƉƌŽǀĞŵĞŶƚŽĨĚLJƐƚŽŶŝĂ͕ƟŵĞŶĞĞĚĞĚĨŽƌƚŚĞďĂĐůŽĨĞŶƚŽƐƉƌĞĂĚƚŽ the intracranial level.ϱϵ

LJƐƚŽŶŝĂ ŝŶ W ŝƐ ƚŚĞ ƌĞƐƵůƚ ŽĨ ůĞƐŝŽŶƐ ŝŶ ƚŚĞ ďĂƐĂů ŐĂŶŐůŝĂ ĐĂƵƐŝŶŐ ĚŝƐƚƵƌďĂŶĐĞ ŽĨ the indirect basal ganglia pathway. Lesions of the putamen and globus pallidus ĐĂƵƐĞĚĞĐƌĞĂƐĞĚŝŶŚŝďŝƟŽŶŽĨƚŚĞƚŚĂůĂŵƵƐ͘^ƵďƐĞƋƵĞŶƚůLJƚŚĞƚŚĂůĂŵƵƐƐƟŵƵůĂƚĞƐ ƚŚĞƐƵƉƉůĞŵĞŶƚĂƌLJŵŽƚŽƌĂŶĚƉƌĞŵŽƚŽƌĐŽƌƚĞdžĐĂƵƐŝŶŐĞdžĐĞƐƐŝǀĞŵŽǀĞŵĞŶƚƐ;Ğ͘Ő͘ ĚLJƐƚŽŶŝĂͿ͘/ŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶĐĂŶŚLJƉŽƚŚĞƟĐĂůůLJĂĐƚƵƉŽŶĚŝīĞƌĞŶƚŝŶƚƌĂĐƌĂŶŝĂůůĞǀĞůƐ͘ KŶĞŝĚĞĂŝƐƚŚĂƚďLJĂĚŵŝŶŝƐƚƌĂƟŶŐďĂĐůŽĨĞŶ͕ƚŚĞĞdžƚĞƌŶĂůŐůŽďƵƐƉĂůůŝĚƵƐŝƐĞdžŽŐĞŶŽƵƐůLJ ƐƵƉƉƌĞƐƐĞĚ͕ ƌĞƐƵůƟŶŐ ŝŶ ŶŽƌŵĂůŝnjĂƟŽŶ ŽĨ ƚŚĞ ŝŶĚŝƌĞĐƚ ďĂƐĂů ŐĂŶŐůŝĂ ƉĂƚŚǁĂLJ ǁŝƚŚ ŝŶŚŝďŝƟŽŶŽĨƚŚĞƚŚĂůĂŵƵƐĂŶĚƚŚĞƌĞďLJŝŶŚŝďŝƟŽŶŽĨƐƟŵƵůĂƟŽŶŽĨƚŚĞƐƵƉƉůĞŵĞŶƚĂƌLJ motor and premotor cortex, decreasing dystonia.ϱϱ _{Another working mechanism could}

ďĞƚŚĂƚ'ŝƐĂŶŝŶŚŝďŝƚŽƌLJŶĞƵƌŽƚƌĂŶƐŵŝƩĞƌŝŶƚŚĞŚƵŵĂŶĐĞƌĞďƌĂůĐŽƌƚĞdž͕ϱϳ͕ϲϬ _and

ƚŚĂƚďĂĐůŽĨĞŶĚŝƌĞĐƚůLJŝŶŚŝďŝƚƐƉŽƐƚͲƐLJŶĂƉƟĐƐŝŐŶĂůƚƌĂŶƐŵŝƐƐŝŽŶĨƌŽŵƚŚĞĐŽƌƚĞdž͘ ƚŚŝƌĚŽƉƟŽŶŝƐƚŚĂƚďĂĐůŽĨĞŶŝŶŚŝďŝƚƐƚŚĞƚŚĂůĂŵƵƐ͘ŶŽǀĞƌǀŝĞǁŽĨĚŝīĞƌĞŶƚǁŽƌŬŝŶŐ ŵĞĐŚĂŶŝƐŵƐŝƐƉƌĞƐĞŶƚĞĚŝŶĮŐƵƌĞϱ͘

ƵĞƚŽŝƚƐůŽǁůŝƉŝĚƐŽůƵďŝůŝƚLJ͕ŽƌĂůůLJĂĚŵŝŶŝƐƚĞƌĞĚďĂĐůŽĨĞŶĚŽĞƐŶŽƚƉĂƐƐƚŚĞďůŽŽĚ brain barrier well.ϱϳ_{ WůĂƐŵĂ ĐŽŶĐĞŶƚƌĂƟŽŶ ůĞǀĞůƐ ƌĂŶŐŝŶŐ ĨƌŽŵ ϱϬ ƚŽ ϰϰϱ ;ŶŐͬŵůͿ}

ƌĞŶĚĞƌĐĞƌĞďƌŽƐƉŝŶĂůŇƵŝĚ;^&ͿĐŽŶĐĞŶƚƌĂƟŽŶůĞǀĞůƐďĞƚǁĞĞŶфϭϮĂŶĚϲϰŶŐͬŵů͘ ŚŝŐŚĞƌƉůĂƐŵĂĐŽŶĐĞŶƚƌĂƟŽŶĚŽĞƐŶŽƚĐŽƌƌĞƐƉŽŶĚƚŽĂŚŝŐŚĞƌ^&ĐŽŶĐĞŶƚƌĂƟŽŶ͘61

dŚŝƐŵĞĂŶƐƚŚĂƚŝŶŵĂŶLJĐĂƐĞƐ͕ŚŝŐŚŽƌĂůĚŽƐĂŐĞƐĂƌĞŶĞĞĚĞĚƚŽĂĐƋƵŝƌĞƐƵĸĐŝĞŶƚ ^&ĐŽŶĐĞŶƚƌĂƟŽŶƐ͘/ŶƐĞǀĞƌĞĐĂƐĞƐƚŚĞƚŚĞƌĂƉĞƵƟĐĞīĞĐƚƌĞŵĂŝŶƐŝŶƐƵĸĐŝĞŶƚǁŚŝůĞ ĂĚĚŝƟŽŶĂůĂĚǀĞƌƐĞĞīĞĐƚƐ͕ƐƵĐŚĂƐƐĞĚĂƟŽŶ͕ŽĐĐƵƌ͘ϱϳ͕ϲϭ

Intrathecal baclofen treatment

The blood brain barrier can be bypassed by delivering baclofen intrathecally using ĂŶŝŵƉůĂŶƚĞĚŵŝĐƌŽͲŝŶĨƵƐŝŽŶƉƵŵƉ;&ŝŐƵƌĞϲͿ͘,ŝŐŚĞƌůĞǀĞůƐŽĨ^&ĐŽŶĐĞŶƚƌĂƟŽŶǁŝƚŚ ƐŝŵƵůƚĂŶĞŽƵƐ ǀĞƌLJ ůŽǁ ƉůĂƐŵĂ ĐŽŶĐĞŶƚƌĂƟŽŶƐ ĐĂŶ ďĞ ĞĂƐŝůLJ ĂĐŚŝĞǀĞĚ ǁŝƚŚŽƵƚ ƚŚĞ ůŝŵŝƚĂƟǀĞĂĚǀĞƌƐĞĞīĞĐƚƐƐĞĞŶǁŝƚŚŽƌĂůĂĚŵŝŶŝƐƚƌĂƟŽŶ͘ϱϳ͕ϲϮ_{^ĞĚĂƟŽŶĨŽƌŝŶƐƚĂŶĐĞŽĐĐƵƌƐ}

21

1

Figure 5.ĂĐůŽĨĞŶǁŽƌŬŝŶŐŵĞĐŚĂŶŝƐŵ͘ KŶƚŚĞƐƉŝŶĂůĐŽƌĚůĞǀĞůďĂĐůŽĨĞŶďŝŶĚƐƚŽƚŚĞƉƌĞƐLJŶ-ĂƉƟĐ'_BƌĞĐĞƉƚŽƌƐĂŶĚŚĞƌĞďLJŝŶŚŝďŝƚƐƚŚĞƌĞůĞĂƐĞŽĨƚŚĞŶĞƵƌŽƚƌĂŶƐŵŝƩĞƌŐůƵƚĂŵĂƚĞ͘ƐĂ consequence, neuronal transmission onto the lower motor neurons is inhibited. It also binds to ƚŚĞƉŽƐƚƐLJŶĂƉƟĐ' _BƌĞĐĞƉƚŽƌƐŝŶŚŝďŝƟŶŐƚŚĞƐŝŐŶĂůƚƌĂŶƐŵŝƐƐŝŽŶŝŶƚŚĞůŽǁĞƌŵŽƚŽƌŶĞƵƌŽŶ͘ dŚŝƐŝƐƚŚĞǁŽƌŬŝŶŐŵĞĐŚĂŶŝƐŵŝŶƚŚĞƚƌĞĂƚŵĞŶƚŽĨƐƉĂƐƟĐŝƚLJ;ůŽǁĞƌƌŝŐŚƚŝŵĂŐĞͿ͘KŶƚŚĞĐĞƌĞďƌĂů ůĞǀĞůďĂĐůŽĨĞŶŝŶŚŝďŝƚƐƚŚĞĞdžĐĞƐƐŝǀĞƐƟŵƵůĂƟŽŶŽĨƚŚĞĐŽƌƚĞdžďLJŝŶŚŝďŝƟŶŐƚŚĞŐůŽďƵƐƉĂůůŝĚƵƐ͕ ƚŚĂůĂŵƵƐŽƌƐƵƉƉůĞŵĞŶƚĂƌLJŵŽƚŽƌĂŶĚƉƌĞŵŽƚŽƌĐŽƌƚĞdž;ƵƉƉĞƌƌŝŐŚƚŝŵĂŐĞͿ͘dŚŝƐŝƐƚŚĞƉƌĞƐƵŵĞĚ working mechanism of intrathecal baclofen in the treatment of dystonia.

22

ƐLJŵƉƚŽŵƐŽĨŽǀĞƌĚŽƐĞŝŶĂŶŽƚŚĞƌ͘dŚĞƉƵŵƉŚĂƐƚŽďĞƌĞĮůůĞĚĂƉƉƌŽdžŝŵĂƚĞůLJĞǀĞƌLJϮ to 6 months by puncture through the skin and a small membrane located in the center ŽĨƚŚĞƉƵŵƉ͘ŌĞƌĂƉƉƌŽdžŝŵĂƚĞůLJϳLJĞĂƌƐ͕ƚŚĞďĂƩĞƌLJĞdžƉŝƌĞƐĂŶĚƚŚĞƉƵŵƉŚĂƐƚŽďĞ replaced.

Figure 6. The intrathecal baclofen pump

͘dŚĞďĂĐůŽĨĞŶƉƵŵƉ;DĞĚƚƌŽŶŝĐ͕^LJŶĐŚƌŽŵĞĚ//ͿĂŶĚĐĂƚŚĞƚĞƌ͘^ŽƵƌĐĞ͗ǁǁǁ͘ŵĞĚƚƌŽŶŝĐ͘ĐŽŵ B. X-ray of an implanted pump in the abdomen of a 10 year old boy with cerebral palsy, frontal and lateral view.

dŚĞŵŽƐƚĐŽŵŵŽŶĐŽŵƉůŝĐĂƟŽŶƐŽĨ/dĂƌĞŝŶĨĞĐƟŽŶ;ϭϰͲϮϴйͿ͕^&ůĞĂŬ;ϯϯй͕ǁŝƚŚ ϴйƌĞƋƵŝƌŝŶŐƐƵƌŐĞƌLJͿĂŶĚĐĂƚŚĞƚĞƌƌĞůĂƚĞĚƉƌŽďůĞŵƐ;ŝŶĐůƵĚŝŶŐĐĂƚŚĞƚĞƌŵŝŐƌĂƟŽŶ͕ ŽĐĐůƵƐŝŽŶĂŶĚĚŝƐĐŽŶŶĞĐƟŽŶͿ;ϮϭͲϮϯйͿ͘ϱϴ͕ϲϵ͕ϳϬ _{Signs of underdosing or acute withdrawal}

23

1

Table 2. ^ĞůĞĐƟŽŶĐƌŝƚĞƌŝĂĨŽƌ/d Ͳ/ŶƚƌĂĐƚĂďůĞƐƉĂƐƟĐŝƚLJor dystonia ŽtŝƚŚƉƌĞĨĞƌĂďůLJŬŶŽǁŶĞƟŽůŽŐLJ ŽEŽƚŽƉƟŵĂůůLJŵĂŶĂŐĞĚďLJŽƚŚĞƌƚƌĞĂƚŵĞŶƚŽƉƟŽŶƐ ŽtŚŝĐŚŝŵƉĞĚĞƐĂĐƟǀŝƟĞƐŽĨĚĂŝůLJůŝĨĞŽƌƋƵĂůŝƚLJŽĨůŝĨĞ ͲůĞĂƌĂŶĚƌĞĂůŝƐƟĐƚƌĞĂƚŵĞŶƚŐŽĂůƐ ͲďŝůŝƚLJĂŶĚŵŽƟǀĂƟŽŶƚŽĂƩĞŶĚĨŽůůŽǁͲƵƉĂŶĚŵŽŶŝƚŽƌŝŶŐ Ͳ^ƵĸĐŝĞŶƚďŽĚLJƐŝnjĞƚŽĂůůŽǁƉƵŵƉŝŵƉůĂŶƚĂƟŽŶĂŶĚĮůůŝŶŐ dŚĞŝƚĂůŝĐǁƌŝƩĞŶĐƌŝƚĞƌŝĂĂƌĞĐƌŝƚĞƌŝĂŶŽƚƐƉĞĐŝĮĐĂůůLJĚĞƐĐƌŝďĞĚŝŶƚŚĞĐŽŶƐĞŶƐƵƐďƵƚĂƌĞĐƌŝƚĞƌŝĂ ƚŚĂƚĂƌĞƵƐĞĚĂĚĚŝƟŽŶĂůůLJŝŶŽƵƌĐůŝŶŝĐĂůƉƌĂĐƟĐĞ͘

dŚĞĞĸĐĂĐLJŽĨŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶƚƌĞĂƚŵĞŶƚ

^ƉĂƐƟĐĐĞƌĞďƌĂůƉĂůƐLJ ^ƉĂƐƟĐŝƚLJŝƐƚŚĞŵŽƐƚĐŽŵŵŽŶŽƵƚĐŽŵĞŵĞĂƐƵƌĞŽŶƚŚĞůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚ ƐƚƌƵĐƚƵƌĞƐ͘ĨĞǁƉůĂĐĞďŽĐŽŶƚƌŽůůĞĚĚŽƵďůĞďůŝŶĚƌĂŶĚŽŵŝnjĞĚƚƌŝĂůƐůŽŽŬŝŶŐĂƚƚŚĞĞīĞĐƚ ŽĨ/dƚĞƐƚƚƌĞĂƚŵĞŶƚǁŝƚŚŵƵůƟƉůĞƐŝŶŐůĞďŽůƵƐŝŶũĞĐƟŽŶƐ͕ƐŚŽǁĂƐŝŐŶŝĮĐĂŶƚĚĞĐƌĞĂƐĞŽĨ ƐƉĂƐƟĐŝƚLJĂŌĞƌ/dŝŶũĞĐƟŽŶƐ͘ϳϮͲϳϰ_{^ĞǀĞƌĂůŽƚŚĞƌƐƚƵĚŝĞƐǁŝƚŚǀĂƌŝŽƵƐĚĞƐŝŐŶƐ;ƉƌŽƐƉĞĐƟǀĞ} ĂŶĚƌĞƚƌŽƐƉĞĐƟǀĞ͕ƐŵĂůůĐŽŚŽƌƚŽƌĐĂƐĞƐĞƌŝĞƐƐƚƵĚŝĞƐ͕ƐŽŵĞǁŝƚŚĂŶĚƐŽŵĞǁŝƚŚŽƵƚĂ ĐŽŶƚƌŽůŐƌŽƵƉĂǁĂŝƟŶŐ/dƚƌĞĂƚŵĞŶƚͿƌĞƉŽƌƚĂƐŝŐŶŝĮĐĂŶƚĚĞĐƌĞĂƐĞŝŶƐƉĂƐƟĐŝƚLJĂŌĞƌ ĐŽŶƟŶƵŽƵƐ/dƚƌĞĂƚŵĞŶƚǀŝĂĂŶŝŵƉůĂŶƚĞĚƉƵŵƉ;ĨŽůůŽǁƵƉƌĂŶŐŝŶŐĨƌŽŵƐŝdžŵŽŶƚŚƐ ƚŽŶŝŶĞLJĞĂƌƐͿ͘ϯϴ͕ϳϯͲϴϬ WĂŝŶĂŶĚĚŝƐĐŽŵĨŽƌƚĂƌĞƉƌŽďůĞŵƐǁŚŝĐŚĂƌĞŽŌĞŶƌĞƉŽƌƚĞĚŝŶĐŚŝůĚƌĞŶǁŝƚŚƐĞǀĞƌĞ ƐƉĂƐƟĐ W͘ dŚĞ ƐĂŵĞ ƐƚƵĚŝĞƐ ĂƐ ĚĞƐĐƌŝďĞĚ ĂďŽǀĞ ƌĞƉŽƌƚ ŝŵƉƌŽǀĞŵĞŶƚ ŽĨ ƉĂŝŶ ĂŶĚ comfort during ITB test treatment.ϳϮ͕ϳϰ _{Similar results are found with long term}

ĐŽŶƟŶƵŽƵƐ/dƚƌĞĂƚŵĞŶƚ͘ϳϴͲϴϬ _{Quality of life is assessed in several of the described}

ƐƚƵĚŝĞƐ͘sĂƌŝŽƵƐƋƵĞƐƟŽŶŶĂŝƌĞƐĂƌĞƵƐĞĚĂŶĚĂůůƐƚƵĚŝĞƐƌĞƉŽƌƚŝŵƉƌŽǀĞŵĞŶƚŽĨƋƵĂůŝƚLJ of life.ϯϴ͕ϳϱ͕ϳϵ͕ϴϬ KƵƚĐŽŵĞƐ ŽŶ ƚŚĞ ůĞǀĞů ŽĨ ĂĐƟǀŝƟĞƐ ĂŶĚ ƉĂƌƟĐŝƉĂƟŽŶ ĂƌĞ ŽŌĞŶ ŶŽƚ ƐLJƐƚĞŵĂƟĐĂůůLJ ŵĞĂƐƵƌĞĚ͘&ƵƌƚŚĞƌŵŽƌĞ͕ŽƵƚĐŽŵĞŵĞĂƐƵƌĞƐĂƌĞŚĞƚĞƌŽŐĞŶĞŽƵƐ͕ŵĂŬŝŶŐĐŽŵƉĂƌŝƐŽŶ ďĞƚǁĞĞŶƐƚƵĚŝĞƐĚŝĸĐƵůƚ͘/ŶĚŝǀŝĚƵĂůůLJĨŽƌŵƵůĂƚĞĚƉƌŽďůĞŵƐŽĨĚĂŝůLJůŝĨĞŵĞĂƐƵƌĞĚŽŶĂ ǀŝƐƵĂůĂŶĂůŽŐƵĞƐĐĂůĞ;s^ͿĂƌĞĚĞƐĐƌŝďĞĚƚŽƐŝŐŶŝĮĐĂŶƚůLJŝŵƉƌŽǀĞĂŌĞƌ/dďŽůƵƐƚĞƐƚ treatment compared to placebo, as did VAS scores for ease of care.72_{WƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚ}

ƐƚƵĚŝĞƐƐŚŽǁƚŚĂƚŝŵƉƌŽǀĞŵĞŶƚƐŵĂŝŶƚĂŝŶĂŌĞƌϲŵŽŶƚŚƐ͕ϭϮŵŽŶƚŚƐ͕ĂŶĚĞǀĞŶĂŌĞƌ ϲƚŽϵLJĞĂƌƐŽĨĐŽŶƟŶƵŽƵƐ/dƚƌĞĂƚŵĞŶƚ͘ϳϴͲϴϬ _{In individual cases, improvements were}

Ϯϰ

survey, parents indicated that seventy-two percent of pre-set goals were completely achieved during ITB treatment.ϯϴ

ĐƟǀĞĨƵŶĐƟŽŶŝŶŐĂŶĚƐŽĐŝĂůƉĂƌƟĐŝƉĂƟŽŶĂƌĞĨŽƵŶĚŶŽƚƚŽŝŵƉƌŽǀĞŝŶĐŚŝůĚƌĞŶǁŝƚŚ 'D&^/sĂŶĚsĚƵƌŝŶŐ/dƚƌĞĂƚŵĞŶƚ͘76_{KŶŐůŽďĂůƐĐĂůĞƐŽĨĨƵŶĐƟŽŶŝŶŐ͕ƐƵĐŚĂƐƚŚĞ} 'ƌŽƐƐ DŽƚŽƌ &ƵŶĐƟŽŶ DĞĂƐƵƌĞ ;'D&DͿ ĂŶĚ ƚŚĞ WĞĚŝĂƚƌŝĐ ǀĂůƵĂƟŽŶ ŽĨ ŝƐĂďŝůŝƚLJ /ŶǀĞŶƚŽƌLJ;W/Ϳ͕ŶŽĐŚĂŶŐĞƐĂƌĞƌĞƉŽƌƚĞĚǁŝƚŚ/d͘ϯϴ͕ϳϲ͕ϳϴ_{&ŽƌƐĞǀĞƌĞůLJĂīĞĐƚĞĚ'D&^} /sĂŶĚsƉĂƟĞŶƚƐ͕ŶŽƐŝŐŶŝĮĐĂŶƚĐŚĂŶŐĞƐŽŶƐƚĂŶĚĂƌĚŝnjĞĚƋƵĞƐƟŽŶŶĂŝƌĞƐĂƌĞĞdžƉĞĐƚĞĚ ƐŝŶĐĞƚŚĞLJĚŽŶŽƚĂĚĞƋƵĂƚĞůLJŵĞĞƚƚŚĞĨƵŶĐƟŽŶĂůůĞǀĞůŽĨƚŚĞƐĞĐŚŝůĚƌĞŶ͘ dĂŬŝŶŐĐĂƌĞŽĨĂĐŚŝůĚǁŝƚŚƐĞǀĞƌĞĚŝƐĂďŝůŝƚLJƉƵƚƐĂďƵƌĚĞŶŽŶ ƚŚĞĐĂƌĞŐŝǀĞƌƐ;ůĞǀĞů ŽĨĞŶǀŝƌŽŶŵĞŶƚĂůĨĂĐƚŽƌƐͿĂŶĚĂƉƌŽƐƉĞĐƟǀĞĐŽŚŽƌƚƐƚƵĚLJƐŚŽǁƐƚŚĂƚǁŝƚŚůŽŶŐƚĞƌŵ /dƚƌĞĂƚŵĞŶƚ͕ĐĂƌĞŐŝǀĞƌƐƌĞƉŽƌƚƚŽĞdžƉĞƌŝĞŶĐĞĨĞǁĞƌĞŵŽƟŽŶĂůĐŽŶĐĞƌŶƐĂŶĚĨĞǁĞƌ ůŝŵŝƚĂƟŽŶŝŶƟŵĞ͘ϴϬ_{KŶĞŽƚŚĞƌƐƚƵĚLJƌĞƉŽƌƚĞĚŶŽĐŚĂŶŐĞŝŶƚŚĞŝŵƉĂĐƚŽĨĚŝƐĂďŝůŝƚLJĨŽƌ}

children and parents.76_{ĂƌĞŐŝǀĞƌƐĂƟƐĨĂĐƟŽŶŝƐŚŝŐŚ͕ĂŶĚŵŽƐƚŽĨƚŚĞŵǁŽƵůĚĐŚŽŽƐĞ}

for ITB treatment again.ϯϴ͕ϳϱ͕ϴϬ

LJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ &ŽƌƚŚĞĞīĞĐƚŽĨ/dŝŶĐŚŝůĚƌĞŶǁŝƚŚĚLJƐŬŝŶĞƟĐWĨĞǁƐƚƵĚŝĞƐĂƌĞĂǀĂŝůĂďůĞ͘^ƚƵĚŝĞƐ ĐŽŶƚĂŝŶ ŽŶůLJ ƉƌŽƐƉĞĐƟǀĞ ĂŶĚ ƌĞƚƌŽƐƉĞĐƟǀĞ ĐĂƐĞ ƐĞƌŝĞƐ͕ ƌĞƐƵůƟŶŐ ŝŶ Ă ůŽǁ ůĞǀĞů ŽĨ ĞǀŝĚĞŶĐĞĨŽƌƚŚĞĞīĞĐƚŽĨ/dŝŶƚŚĞƐĞƉĂƟĞŶƚƐ͘ϱϴ͕ϴϭ͕ϴϮ KŶƚŚĞůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚƐƚƌƵĐƚƵƌĞƐĚLJƐƚŽŶŝĂ;^ͿŝƐƚŚĞŵŽƐƚĐŽŵŵŽŶ ŽƵƚĐŽŵĞ ŵĞĂƐƵƌĞ͘ ^ ƐĐŽƌĞƐ ĂƌĞ ƌĞƉŽƌƚĞĚ ƚŽ ĚĞĐƌĞĂƐĞ ŝŶ Ăůů ƐƚƵĚŝĞƐ͘ϱϴ͕ϴϭ͕ϴϮ _A ƐŝŐŶŝĮĐĂŶƚůLJŚŝŐŚĞƌĚĞĐƌĞĂƐĞŝŶ^ƐĐŽƌĞƐǁĂƐƐĞĞŶǁŝƚŚĂŚŝŐŚĞƌƉůĂĐĞĚĐĂƚŚĞƚĞƌ ƟƉ;dϰĂŶĚŚŝŐŚĞƌͿĐŽŵƉĂƌĞĚƚŽĂůŽǁĞƌƉůĂĐĞĚƟƉ;dϲĂŶĚůŽǁĞƌͿ͘ϱϴ_{KƚŚĞƌƌĞƉŽƌƚĞĚ} ŽƵƚĐŽŵĞƐŽŶƚŚĞůĞǀĞůŽĨďŽĚLJĨƵŶĐƟŽŶƐĂŶĚƐƚƌƵĐƚƵƌĞƐĂƌĞƌĞĚƵĐƟŽŶŝŶƉĂŝŶ͕ďĞƩĞƌ ŵŽŽĚ͕ŝŵƉƌŽǀĞĚƐůĞĞƉ͕ĂŶĚĂƐƚĂďůĞƌĂŶŐĞŽĨŵŽƟŽŶ͘ϱϴ͕ϴϭ͕ϴϮ _{Quality of life improved in}

ϴϲйŽĨƚŚĞƋƵĞƐƟŽŶĞĚƉĂƟĞŶƚƐ͘ϱϴ͕ϴϭ͕ϴϮ

KŶƚŚĞůĞǀĞůŽĨĂĐƟǀŝƟĞƐĂŶĚƉĂƌƟĐŝƉĂƟŽŶƐĞǀĞƌĂůĐĂƐĞƐĞƌŝĞƐƌĞƉŽƌƚƚŚĞŽƵƚĐŽŵĞƐŽĨ ƐƚƌƵĐƚƵƌĞĚŝŶƚĞƌǀŝĞǁƐŽƌƋƵĞƐƟŽŶŶĂŝƌĞƐ͘ϱϴ͕ϴϭ͕ϴϮ _{Improvement is reported for feeding and}

ƐǁĂůůŽǁŝŶŐ͕ƐŝƫŶŐĂŶĚƉŽƐƚƵƌĞĐŽŶƚƌŽů͕ƵƉƉĞƌůŝŵďƵƐĞ͕ĐŽŵŵƵŶŝĐĂƟŽŶͬƐƉĞĞĐŚ͘/ŶƚŚĞ ŵĂũŽƌŝƚLJŽĨƉĂƟĞŶƚƐŶŽĐŚĂŶŐĞŝŶĂƵƚŽŶŽŵLJŽĨĐĂƌƌLJŝŶŐŽƵƚĚĂŝůLJĂĐƟǀŝƟĞƐǁĂƐƐĞĞŶ͘ϴϮ

&ƵƌƚŚĞƌŵŽƌĞ͕ƚŚĞƌĞǁĂƐŶŽĐŚĂŶŐĞŝŶŐƌŽƐƐŵŽƚŽƌĨƵŶĐƟŽŶ͘ϴϭ

Ϯϱ

1

dƌĞĂƚŵĞŶƚŐŽĂůƐĂƌĞĨƵůůLJƌĞĂĐŚĞĚŝŶϳϲйĂŶĚƉĂƌƚůLJŝŶƚŚĞƌĞŵĂŝŶĚĞƌŽĨƉĂƟĞŶƚƐ͘ϴϭ

ůŵŽƐƚϴϬйŽĨƉĂƟĞŶƚƐǁĞƌĞƐĂƟƐĮĞĚǁŝƚŚ/dƚƌĞĂƚŵĞŶƚĂŶĚϳϰйŽĨƉĂƟĞŶƚƐǁŽƵůĚ choose for ITB treatment again.ϴϮ

26

Khd>/EK&d,/^d,^/^

27

1

REFERENCES

ϭ͘ 'ƌĂŚĂŵ,<͕ZŽƐĞŶďĂƵŵW͕WĂŶĞƚŚE͕ĂŶ ͕>ŝŶ:W͕ĂŵŝĂŶŽ>͕ĞƚĂů͘ĞƌĞďƌĂůƉĂůƐLJ͘ EĂƚZĞǀŝƐWƌŝŵĞƌƐ͘ϮϬϭϲ͖Ϯ͘ Ϯ͘ /ǀĂŶŚŽĞ͕ZĞŝƐƚĞƩĞƌd͘^ƉĂƐƟĐŝƚLJ͗dŚĞ misunderstood part of the upper motor ŶĞƵƌŽŶƐLJŶĚƌŽŵĞ͘ŵ:WŚLJƐDĞĚZĞŚĂďŝů͘ ϮϬϬϰ͖ϴϯ;ƐƵƉƉůͿ͗^ϯͲ^ϵ͘

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16. de Vries LS. Neurological assessment of the preterm infant. Accta Paediatr. ϭϵϵϲ͖ϴϱ͗ϳϲϱͲϳϭ͘

ϭϳ͘ ,ŝŵŵĞůŵĂŶŶ<͕hǀĞďƌĂŶƚW͘dŚĞƉĂŶŽƌĂŵĂ of cerbral palsy in Sweden. XI. Changing ƉĂƩĞƌŶƐ ŝŶ ƚŚĞ ďŝƌƚŚͲLJĞĂƌ ƉĞƌŝŽĚ ϮϬϬϯͲ ϮϬϬϲ͘ĐƚĂWĂĞĚŝĂƚƌŝĐĂ͘ϮϬϭϰ͖ϭϬϯ͗ϲϭϴͲϮϰ͘ ϭϴ͘<ƌćŐĞůŽŚͲDĂŶŶ/͕,ĞůďĞƌ͕DĂĚĞƌ/͕^ƚĂƵĚƚ

Ϯϴ

ϭϵ͘ƌĂǀĂŵƵƚŚĂŶZ͕tĂƵŐŚ:>͘>ŽĐĂůŝnjĂƟŽŶ of basal ganglia and thalamic damage in ĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘WĞĚŝĂƚƌEĞƵƌŽů͘ ϮϬϭϲ͖ϱϰ͗ϭϭͲϮϭ͘

ϮϬ͘'ĞLJƚĞŶďĞĞŬ::͕sĞƌŵĞƵůĞŶZ:͕ĞĐŚĞƌ:'͕ KŽƐƚƌŽŵ<:͘ŽŵƉƌĞŚĞŶƐŝŽŶŽĨƐƉŽŶŬĞŶ language in non-speaking children with severe cerebral palsy: an explorative ƐƚƵĚLJ ŽŶ ĂƐƐŽĐŝĂƟŽŶƐ ǁŝƚŚ ŵŽƚŽƌ ƚLJƉĞ ĂŶĚ ĚŝƐĂďŝůŝƟĞƐ͘ Ğǀ DĞĚ ŚŝůĚ EĞƵƌŽů͘ ϮϬϭϱ͖ϱϳ;ϯͿ͗ϮϵϰͲϯϬϬ͘ Ϯϭ͘ŚŽŝ:z͕ŚŽŝz^͕ZŚĂ͕WĂƌŬ^͘dŚĞĐůŝŶŝĐĂů ŽƵƚĐŽŵĞƐ ŽĨ ĚĞĞƉ ŐƌĂLJ ŵĂƩĞƌ ŝŶũƵƌLJ ŝŶ ĐŚŝůĚƌĞŶ ǁŝƚŚ ĐĞƌĞďƌĂů ƉĂůƐLJ ŝŶ ƌĞůĂƟŽŶ ǁŝƚŚ ďƌĂŝŶ ŵĂŐŶĞƟĐ ƌĞƐŽŶĂŶĐĞ ŝŵĂŐŝŶŐ͘ ZĞƐĞǀŝƐĂďŝů͘ϮϬϭϲ͖ϱϱ͗ϮϭϴͲϮϱ͘ ϮϮ͘KůĚƐ ͕ KŐŚĂůĂŝ :^͘ ŝůŝƌƵďŝŶͲŝŶĚƵĐĞĚ ĂƵĚŝŽůŽŐŝĐŝŶũƵƌLJŝŶƉƌĞƚĞƌŵŝŶĨĂŶƚƐ͘ůŝŶ WĞƌŝŶĂƚŽů͘ϮϬϭϲ͖ϰϯ;ϮͿ͗ϯϭϯͲϮϯ͘ Ϯϯ͘ZŽƐĞ:͕sĂƐƐĂƌZ͘DŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌƐĚƵĞ ƚŽďŝůŝƌƵďŝŶƚŽdžŝĐŝƚLJ͘^ĞŵŝŝŶ&ĞƚĂůEĞŽŶĂƚĂů DĞĚ͘ϮϬϭϱ͖ϮϬ;ϭͿ͗ϮϬͲϱ͘ Ϯϰ͘'ŽǀĂĞƌƚ W͕ >ĞƋƵŝŶ D͕ ^ǁĂƌƚĞ Z͕ ZŽďďĞŶ ^͕ ĚĞ ŽŽ Z͕ tĞŝƐŐůĂƐͲ<ƵƉĞƌƵƐ E͕ Ğƚ Ăů͘ ŚĂŶŐĞƐŝŶŐůŽďƵƐƉĂůůŝĚƵƐǁŝƚŚ;ƉƌĞͿĞƌŵ ŬĞƌŶŝĐƚĞƌƵƐ͘WĞĚŝĂƚƌŝĐƐ͘ϮϬϬϯ͖ϭϭϮ͗ϭϮϱϲͲϲϯ͘ Ϯϱ͘ůŝĂƐƐŽŶ ͕ <ƌƵŵůŝŶĚĞͲ^ƵŶĚŚŽůŵ >͕ ZƂƐďůĂĚ ͕ ĞĐŬƵŶŐ ͕ ƌŶĞƌ D͕ KŚƌǀĂůů D͕ĞƚĂů͘dŚĞDĂŶƵĂůďŝůŝƚLJůĂƐƐŝĮĐĂƟŽŶ ^LJƐƚĞŵ;D^ͿĨŽƌĐŚŝůĚƌĞŶǁŝƚŚĐĞƌĞďƌĂů palsy: scale development and evidence ŽĨǀĂůŝĚŝƚLJĂŶĚƌĞůŝĂďŝůŝƚLJ͘ĞǀDĞĚŚŝůĚ EĞƵƌŽů͘ϮϬϬϲ͖ϰϴ;ϳͿ͗ϱϰϵͲϱϰ͘ Ϯϲ͘,ŝĚĞĐŬĞƌ D:͕ WĂŶĞƚŚ E͕ ZŽƐĞŶďĂƵŵ W>͕ <ĞŶƚ Z͕ >ŝůůŝĞ :͕ ƵůĞŶďĞƌŐ :͕ Ğƚ Ăů͘ ĞǀĞůŽƉŝŶŐ ĂŶĚ ǀĂůŝĚĂƚŝŶŐ ƚŚĞ ŽŵŵƵŶŝĐĂƚŝŽŶ &ƵŶĐƚŝŽŶ ůĂƐƐŝĨŝĐĂƚŝŽŶ System for individuals with cerebral palsy. ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ϮϬϭϭ͖ϱϯ;ϴͿ͗ϳϬϰͲϭϬ͘ Ϯϳ͘ ^ĂŶŐĞƌ d͕ ĞůŐĂĚŽ DZ͕ 'ĂĞďůĞƌͲ^ƉŝƌĂ ͕,ĂůůĞƩD͕DŝŶŬ:t͘ůĂƐƐŝĮĐĂƟŽŶĂŶĚ ĚĞĮŶŝƟŽŶŽĨĚŝƐŽƌĚĞƌƐĐĂƵƐŝŶŐŚLJƉĞƌƚŽŶŝĂ ŝŶĐŚŝůĚŚŽŽĚ͘WĞĚŝĂƚƌŝĐƐ͘ϮϬϬϯ͖ϭϭϭ;ϭͿ͗ĞϴϵͲ Ğϵϳ͘ Ϯϴ͘<ƌćŐĞůŽŚͲDĂŶŶ/͕WĞƚƌƵĐŚh͕tĞďĞƌWD͘ SCPE Reference and Training Manual ;ZΘdDͿ͘'ƌĞŶŽďůĞ͗^ƵƌǀĞŝůůĂŶĐĞŽĨĞƌĞďƌĂů WĂůƐLJŝŶƵƌŽƉĞ͖ϮϬϬϱ͘ Ϯϵ͘^ĂŶŐĞƌ d͕ ŚĞŶ ͕ &ĞŚůŝŶŐƐ >͕ ,ĂůůĞƩ D͕ >ĂŶŐ ͕ DŝŶŬ :t͕ Ğƚ Ăů͘ ĞĮŶŝƟŽŶ ĂŶĚ ůĂƐƐŝĨŝĐĂƚŝŽŶ ŽĨ ,LJƉĞƌŬŝŶĞƚŝĐ DŽǀĞŵĞŶƚƐ ŝŶ ŚŝůĚŚŽŽĚ͘ DŽǀ ŝƐŽƌĚ͘ ϮϬϭϬ͖Ϯϱ;ϭϭͿ͗ϭϱϯϴʹϰϵ͘ ϯϬ͘DŽŶďĂůŝƵ͕ĚĞŽĐŬW͕KƌƟďƵƐ͕,ĞLJƌŵĂŶ >͕ <ůŝŶŐĞůƐ <͕ &ĞLJƐ ,͘ ůŝŶŝĐĂů ƉĂƚƚĞƌŶƐ of dystonia and choreoathetosis in ƉĂƌƟĐŝƉĂŶƚƐǁŝƚŚĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘ ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ϮϬϭϲ͖ϱϴ;ϮͿ͗ϭϯϴͲϰϰ͘ ϯϭ͘ DŽŶďĂůŝƵ ͕ Ğ ŽĐŬ W͕ DĂŝůůĞƵdž >͕ ĂŶ

͕ &ĞLJƐ ,͘ dŚĞ ƌĞůĂƟŽŶƐŚŝƉ ŽĨ ĚLJƐƚŽŶŝĂ and choreoathetosis with activity, ƉĂƌƟĐŝƉĂƟŽŶĂŶĚƋƵĂůŝƚLJŽĨůŝĨĞŝŶĐŚŝůĚƌĞŶ ĂŶĚLJŽƵƚŚǁŝƚŚĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘ ƵƌŽƉĞĂŶ:ŽƵƌŶĂůŽĨWĂĞĚŝĂƚƌŝĐEĞƵƌŽůŽŐLJ͘ ϮϬϭϳ͖Ϯϭ;ϮͿ͗ϯϮϳͲϯϱ͘

ϯϮ͘^ƚĞǁĂƌƚ <͕ dĂǀĞŶĚĞƌ ͕ ZŝĐĞ :͕ ,ĂƌǀĞLJ A. Identification, classification and assessment of dyskinesia in children with ĐĞƌĞďƌĂů ƉĂůƐLJ͗  ƐƵƌǀĞLJ ŽĨ ĐůŝŶŝĐŝĂŶƐ͘ : WĂĞĚŝĂƚƌŚŝůĚ,ĞĂůƚŚ͘ϮϬϭϳ͘

ϯϯ͘ĂƌƌLJ D:͕ sĂŶ^ǁĞĂƌŝŶŐĞŶ :D͕ ůďƌŝŐŚƚ AL. Reliability and responsiveness of the ĂƌƌLJͲůďƌŝŐŚƚ LJƐƚŽŶŝĂ ^ĐĂůĞ͘ Ğǀ DĞĚ ŚŝůĚEĞƵƌŽů͘ϭϵϵϵ͖ϰϭ͗ϰϬϰͲϭϭ͘

ϯϰ͘DŽŶďĂůŝƵ ͕ KƌƟďƵƐ ͕ ĚĞ Ăƚ :͕ ĂŶ ͕ ,ĞLJƌŵĂŶ>͕WƌŝŶnjŝĞW͕ĞƚĂů͘dŚĞĚLJƐŬŝŶĞƐŝĂ Impairment Scale: a new instrument to measure dystonia and choreoathetosis in ĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘ĞǀDĞĚŚŝůĚ EĞƵƌŽů͘ϮϬϭϮ͖ϱϰ͗ϮϳϴͲϴϯ͘

Ϯϵ

1

ϯϲ͘,ŝŵŵĞůŵĂŶŶ<͕DĐDĂŶƵƐs͕,ĂŐďĞƌŐ'͕ hǀĞďƌĂŶƚW͕<ƌćŐĞůŽŚͲDĂŶŶ/͕ĂŶƐ͕ĞƚĂů͘ LJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJŝŶƵƌŽƉĞ͗ƚƌĞŶĚƐ ŝŶƉƌĞǀĂůĞŶĐĞĂŶĚƐĞǀĞƌŝƚLJ͘ƌĐŚŝƐŚŝůĚ͘ ϮϬϬϵ͖ϵϰ͗ϵϮϭͲϲ͘ ϯϳ͘ ,ŝŵŵĞůŵĂŶŶ<͕,ĂŐďĞƌŐ'͕tŝŬůƵŶĚ>D͕ ĞŬDE͕hǀĞďƌĂŶƚW͘LJƐŬŝŶĞƟĐĐĞƌĞďƌĂů ƉĂůƐLJ͗ĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚƐƚƵĚLJŽĨĐŚŝůĚƌĞŶ ďŽƌŶďĞƚǁĞĞŶϭϵϵϭĂŶĚϭϵϵϴ͘ĞǀDĞĚ ŚŝůĚEĞƵƌŽů͘ϮϬϬϳ͖ϰϵ͗ϮϰϲͲϱϭ͘ ϯϴ͘ĂŵƉďĞůůtD͕DĐ>ĂƵŐŚůŝŶ:&͕'ƌĂŶƚ'͕ >ŽĞƐĞƌ:͕'ƌĂƵďĞƌƚ͕ũŽƌŶƐŽŶ<͘>ŽŶŐͲ term safety and efficacy of continous ŝŶƚƌĂƚŚĞĐĂů ďĂĐůŽĨĞŶ͘ Ğǀ DĞĚ ŚŝůĚ EĞƵƌŽů͘ϮϬϬϮ͖ϰϰ͗ϲϲϬͲϱ͘

ϯϵ͘ >ŝĞǁ Wz͕ ^ƚĞǁĂƌƚ <͕ <ŚĂŶ ͕ ƌŶƵƉ ^:͕ Scheinberg A. Intrathecal baclofen therapy in children: an analysis of ŝŶĚŝǀŝĚƵĂůŝnjĞĚŐŽĂůƐ͘ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ ϮϬϭϴ͖ϲϬ;ϰͿ͗ϯϲϳͲϳϯ͘ ϰϬ͘<ůĞŝŶ͕DƺŶĐŚĂƵ͘WƌŽŐƌĞƐƐŝǀĞĚLJƐƚŽŶŝĂ͘ ,ĂŶĚďůŝŶEĞƵƌŽů͘ϮϬϭϯ͖ϭϭϯ͗ϭϴϴϵͲϭϵϳ͘ ϰϭ͘ ƌĞƩD͘WĂĞĚŝĂƚƌŝĐEĞƵƌŽůŽŐLJ͘EĞǁzŽƌŬ͗ WĞĂƌŽŶWƌŽĨĞƐƐŝŽŶĂů>ŝŵŝƚĞĚ͖ϭϵϵϳ͘ ϰϮ͘LJŬĞŶW͕<ƌĂǁŝĞĐŬŝE͘EĞƵƌŽĚĞŐĞŶĞƌĂƟǀĞ diseases of infancy and childhood. Ann EĞƵƌŽů͘ϭϵϴϯ͖ϭϯ;ϰͿ͗ϯϱϭͲϲϰ͘

ϰϯ͘<ĂƌŝŵnjĂĚĞŚW͘ƉƉƌŽĂĐŚƚŽŶĞƵƌŽŵĞƚĂďŽůŝĐ diseases from a pediatric neurologiccal ƉŽŝŶƚ ŽĨ ǀŝĞǁ͘ /ƌĂŶ : ŚŝůĚ EĞƵƌŽů͘ ϮϬϭϱ͖ϵ;ϭͿ͗ϭͲϭϲ͘

ϰϰ͘DƺůůĞƌǀŽŵ,ĂŐĞŶ:͕<ĂƌůĞ<E͕^ĐŚƺůĞZ͕ <ƌćŐĞůŽŚͲDĂŶ/͕^ĐŚƂůƐ>͘>ĞƵŬŽĚLJƐƚƌŽƉŚŝĞƐ underlying cryptic spastic paraparesis: ĨƌĞƋƵĞŶĐLJĂŶĚƉŚĞŶŽƚLJƉĞŝŶϳϲƉĂƟĞŶƚƐ͘ ƵƌŽƉĞĂŶ :ŽƵƌŶĂů ŽĨ EĞƵƌŽůŽŐLJ͘ ϮϬϭϰ͖Ϯϭ͗ϵϴϯͲϴ͘

ϰϱ͘ĞůŐĂĚŽDZ͕,ŝƌƚnj͕ŝƐĞŶD͕^ƐŚǁĂů^͕ &ĞŚůŝŶŐƐ>͕DĐ>ĂƵŐŚůŝŶ:͕ĞƚĂů͘WƌĂĐƟĐĞ parameter: pharmacologic treatment of ƐƉĂƐƟĐŝƚLJ ŝŶ ĐŚŝůĚƌĞŶ ĂŶĚĚ ĂĚŽůĞƐĐĞŶƚƐ ǁŝƚŚ ĐĞƌĞďƌĂů ƉĂůƐLJ ;ĂŶ ĞǀŝĚĞŶĐĞͲďĂƐĞĚͿ ƌĞǀŝĞǁ͘EĞƵƌŽůŽŐLJ͘ϮϬϭϬ͖ϳϰ͗ϯϯϲͲϰϯ͘ ϰϲ͘ĞŶŝŶŝ Z͕ ^ŚĞǀĞůů D/͘ hƉĚĂƚĞƐ ŝŶ ƚŚĞ ƚƌĞĂƚŵĞŶƚ ŽĨ ƐƉĂƐƟĐŝƚLJ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ĐĞƌĞďƌĂůƉĂůƐLJ͘ƵƌƌdƌĞĂƚKƉƟŽŶƐEĞƵƌŽů͘ ϮϬϭϮ͖ϭϰ;ϲͿ͗ϲϱϬͲϵ͘ ϰϳ͘ ŽůƐƚĞƌ D͕ ǀĂŶ ^ĐŚŝĞ WD͕ ĞĐŚĞƌ :'͕ ǀĂŶ KƵǁĞƌŬĞƌŬ t:Z͕ ^ƚƌŝũĞƌƐ Z>D͕ sĞƌŵĞƵůĞŶ Z:͘ >ŽŶŐͲƚĞƌŵ ĞĨĨĞĐƚ ŽĨ ƐĞůĞĐƟǀĞĚŽƌƐĂůƌŚŝnjŽƚŽŵLJŽŶŐƌŽƐƐŵŽƚŽƌ ĨƵŶĐƟŽŶŝŶĂŵďƵůĂŶƚĐŚŝůĚƌĞŶǁŝƚŚƐƉĂƐƟĐ bilateral cerebral palsy, compared with ƌĞĨĞƌĞŶĐĞĐĞŶƟůĞƐ͘ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ ϮϬϭϯ͖ϱ͗ϲϭϬͲϲ͘

ϰϴ͘ƵŝnjĞƌ /͕ ǀĂŶ ^ĐŚŝĞ WD͕ ŽůƐƚĞƌ D͕ ǀĂŶ KƵǁĞƌŬĞƌŬ t:Z͕ ^ƚƌŝũĞƌƐ Z>͕ ǀĂŶ ĚĞ WŽů >͕ Ğƚ Ăů͘ īĞĐƚ ŽĨ ƐĞůĞĐƟǀĞ ĚŽƌƐĂů rhizotomy on daily care and comfort in non-walking children and adolescents with ƐĞǀĞƌĞ ƐƉĂƐƟĐŝƚLJ͘ Ƶƌ : WĂĞĚŝĂƚƌ EĞƵƌŽů͘ ϮϬϭϳ͖Ϯϭ͗ϯϱϬͲϳ͘ ϰϵ͘ :ĂŶŬŽǀŝĐ:͘DĞĚŝĐĂůƚƌĞĂƚŵĞŶƚŽĨĚLJƐƚŽŶŝĂ͘ DŽǀĞŵĞŶƚŝƐŽƌĚĞƌƐ͘ϮϬϭϯ͖Ϯϴ;ϳͿ͗ϭϬϬϭͲϭϮ͘ ϱϬ͘&ĞŚůŝŶŐƐ ͕ ƌŽǁŶ >͕ ,ĂƌǀĞLJ ͕ ,ŝŵŵĞůŵĂŶŶ<͕>ŝŶ:W͕DĂĐŝŶƚŽƐĐŚ͕Ğƚ al. Pharmacological and neurosurgical ŝŶƚĞƌǀĞŶƟŽŶƐ ĨŽƌ ŵĂŶĂŐŝŶŐ ĚLJƐƚŽŶŝĂ ŝŶ ĐĞƌĞďƌĂů ƉĂůƐLJ͗ Ă ƐLJƐƚĞŵĂƟĐ ƌĞǀŝĞǁ͘ Ğǀ DĞĚŚŝůĚEĞƵƌŽů͘ϮϬϭϴ͖ĞƉƵďďĞĨŽƌĞƉƌŝŶƚ͘ ϱϭ͘ DĂƐƐŽŶ Z͕ WĂŐůŝĂŶŽ ͕ ĂƌĂŶĞůůŽ '͘

Efficacy of oral pharmaccological ƚƌĞĂƚŵĞŶƚƐŝŶĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ͗Ă ƐLJƐƚĞŵĂƟĐƌĞǀŝĞǁ͘ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ ϮϬϭϳ͖ϱϵ͗ϭϮϯϳͲϰϴ͘

30 ϱϰ͘ůŝĂ ͕ ĂŐĞůůĂ ͕ &ĞƌƌĞ &͕ Žƌnjŝ '͕ ĂůĂŶĚƌĞůůĂ ͕ ZŽŵŝƚŽ >D͘ ĞĞƉ ďƌĂŝŶ ƐƟŵƵůĂƟŽŶ ĨŽƌ ĚLJƐƚŽŶŝĂ ĚƵĞ ƚŽ ĐĞƌĞďƌĂů ƉĂůƐLJ͗ Ă ƌĞǀŝĞǁ͘ Ƶƌ : WĂĞĚŝĂƚƌ EĞƵƌŽů͘ ϮϬϭϴ͖ϮϮ͗ϯϬϴͲϭϱ͘ ϱϱ͘ůďƌŝŐŚƚ>͘/ŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶŝŶĐĞƌĞďƌĂů ƉĂůƐLJŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌƐ͘:ŽƵƌŶĂůŽĨŚŝůĚ EĞƵƌŽůŽŐLJ͘ϭϵϵϲ͖ϭϭ;ƐƵƉƉůϭͿ͗^ϮϵͲ^ϯϱ͘ ϱϲ͘ƌĞŶŶĂŶ WD͕ tŚŝƚƚůĞ /Z͘ /ŶƚƌĂƚŚĞĐĂů

baclofen therapy for neurological disorders: a sound knowledge base but ŵĂŶLJĐŚĂůůĞŶŐĞƐƌĞŵĂŝŶ͘ƌŝƟƐĐŚ:ŽƵƌŶĂů ŽĨEĞƵƌŽƐƵƌŐĞƌLJ͘ϮϬϬϴ͖ϮϮ;ϰͿ͗ϱϬϴͲϭϵ͘ ϱϳ͘ ůďƌŝŐŚƚ>͘ĂĐůŽĨĞŶŝŶƚŚĞƚƌĞĂƚŵĞŶƚŽĨ ĐĞƌĞďƌĂůƉĂůƐLJ͘:ŚŝůĚEĞƵƌŽů͘ϭϵϵϲ͖ϭϭ͗ϳϳͲ ϴϯ͘ ϱϴ͘ůďƌŝŐŚƚ>͕ĂƌƌLJD:͕^ŚĂŐƌŽŶ,͕&ĞƌƐŽŶ SS. Intrathecal baclofen for generalized ĚLJƐƚŽŶŝĂ͘ Ğǀ DĞĚ ŚŝůĚ EĞƵƌŽů͘ ϮϬϬϭ͖ϰϯ͗ϲϱϮͲϳ͘

ϱϵ͘ ůďƌŝŐŚƚ>͕ĂƌƌLJD:͕&ĂƐŝĐŬW͕ĂƌƌŽŶt͕ ^ĐŚƵůnj͘ŽŶƟŶŽƵƐŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶ infusion for symptomatic generalized ĚLJƐƚŽŶŝĂ͘EĞƵƌŽƐƵƌŐ͘ϭϵϵϲ͖ϯϴ;ϱͿ͗ϵϯϰͲϵ͘ ϲϬ͘DĐŽƌŵŝĐŬ ͘ ' ĂƐ ĂŶ ŝŶŚŝďŝƚŽƌLJ

neurotransmitter in human cerebral ĐŽƌƚĞdž͘:EĞƵƌŽƉŚLJƐŝŽů͘ϭϵϴϵ͖ϲϮ;ϱͿ͗ϭϬϭϴͲ 27. ϲϭ͘ <ŶƵƚƐƐŽŶ ͕ >ŝŶĚďůŽŵ h͕ DĂƌƚĞŶƐƐŽŶ ͘ WůĂƐŵĂ ĂŶĚ ĐĞƌĞďƌŽƐƉŝŶĂů ŇƵŝĚ ůĞǀĞůƐ ŽĨ ďĂĐůŽĨĞŶ;>ŝŽƌĞƐĂůΠͿĂƚŽƉƟŵĂůƚŚĞƌĂƉĞƵƟĐ ƌĞƐƉŽŶƐĞƐŝŶƐƉĂƐƟĐƉĂƌĞƐŝƐ:ŽƵƌŶĂůŽĨƚŚĞ EĞƵƌŽůŽŐŝĐĂů^ĐŝĞŶĐĞƐ͘ϭϵϳϰ͖Ϯϯ͗ϰϳϯͲϴϰ͘ 62. Albright AL, Shultz BL. Plasma baclofen

levels in children receiving continuous ŝŶƚƌĂƚŚĞĐĂů ďĂĐůŽĨĞŶ ŝŶĨƵƐŝŽŶ͘ :ŽƵƌŶĂů ŽĨ ŚŝůĚEĞƵƌŽůŽŐLJ͘ϭϵϵϵ͖ϭϰ͗ϰϬϴͲϵ͘ ϲϯ͘<ƌŽŝŶ :^͕ ůŝ ͕ zŽƌŬ DZE͕ WĞŶŶ Z͘ dŚĞ ĚŝƐƚƌŝďƵƟŽŶŽĨŵĞĚŝĐĂƟŽŶĂůŽŶŐƚŚĞƐƉŝŶĂů ĐĂŶĂůĂŌĞƌĐŚƌŽŶŝĐŝŶƚƌĂƚŚĞĐĂůĂĚŵŝƐƐŝŽŶ͘ EĞƵƌŽƐƵƌŐ͘ϭϵϵϯ͖ϯϯ;ϮͿ͗ϮϮϲͲϯϬ͘ ϲϰ͘sĞŶĚĞƌ:Z͕,ĞƐƚĞƌ^͕tĂůůĞƌ:>͕ZĞŬŝƚŽ͕ >ĞĞDZ͘/ĚĞŶƟĮĐĂƟŽŶĂŶĚŵĂŶĂŐĞŵĞŶƚŽĨ ŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶƉƵŵƉĐŽŵƉůŝĐĂƟŽŶƐ͗Ă ĐŽŵƉĂƌŝƐŽŶŽĨƉĞĚŝĂƚƌŝĐĂŶĚĂĚƵůƚƉĂƟĞŶƚƐ͘ :EĞƵƌŽƐƵƌŐ͗WĞĚŝĂƚƌŝĐƐ͘ϮϬϬϲ͖ϭϬϰ͗ϵͲϭϱ͘ ϲϱ͘ůďƌŝŐŚƚ >͕ dƵƌŶĞƌ D͕ WĂƚƚŝƐĂƉƵ :s͘

Best-practice surgical techniques for ŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶƚŚĞƌĂƉLJ͘:EĞƵƌŽƐƵƌŐ͘ ϮϬϬϲ͖ϭϬϰ͗ϮϯϯͲϵ͘

ϲϲ͘ůďƌŝŐŚƚ >͕ &ĞƌƐŽŶ ^^͘ /ŶƚƌĂǀĞŶƚƌŝĐƵůĂƌ baclofen for dystonia: techniques and ŽƵƚĐŽŵĞƐ͘ : EĞƵƌŽƐƵƌŐ WĞĚŝĂƚƌŝĐƐ͘ ϮϬϬϵ͖ϯ;ϭͿ͗ϭϭͲϰ͘

ϲϳ͘ ZŽĐƋƵĞ '͕ ůďƌŝŐŚƚ >͘ /ŶƚƌĂǀĞŶƚƌŝĐƵůĂƌ versus intrathecal baclofen for secondary dystonia: a comparison of ĐŽŵƉůŝĐĂƟŽŶƐ͘EĞƵƌŽƐƵƌŐ͘ϮϬϭϮ͖ϳϬ;Ϯ^ƵƉƉů KƉĞƌĂƟǀĞͿ͗ϯϮϱͲϲ͘

ϲϴ͘ŽůůŽZ:͕'ŽŽĐŚ:>͕tĂůŬĞƌD>͘^ƚĞƌĞŽƚĂĐƟĐ endoscopic placement of third ventricle catheter for long-term infusion of baclofen ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ƐĞĐŽŶĚĂƌLJ ŐĞŶĞƌĂůŝnjĞĚ ĚLJƐƚŽŶŝĂ͘ : EĞƵƌŽƐƵƌŐ WĞĚŝĂƚƌŝĐƐ͘ ϮϬϭϮ͖ϭϬ;ϭͿ͗ϯϬͲϯ͘

ϲϵ͘'ŽŽĐŚ:>͕KďĞƌŐt͕'ƌĂŵƐ͕tĂƌĚ>͕ tĂůŬĞƌD>͘ŽŵƉůŝĐĂƟŽŶƐŽĨŝŶƚƌĂƚŚĞĐĂů baclofen pumps in children. Pediatr EĞƵƌŽƐƵƌŐ͘ϮϬϬϯ͖ϯϵ͗ϭͲϲ͘

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ϳϮ͘,ŽǀŝŶŐD͕sĂŶZĂĂŬWD͕^ƉŝŶĐĞŵĂŝůůĞ ',::͕ WĂůŵĂŶƐ >:͕ ^ůĞLJƉĞŶ &D͕ sůĞƐ :^,͘ /ŶƚƌĂƚŚĞĐĂů ďĂĐůŽĨĞŶ ŝŶ ĐŚŝůĚƌĞŶ with spastic cerebral palsy: a double-blind, randomized, placebocontrolled, ĚŽƐĞĮŶĚŝŶŐƐƚƵĚLJ͘ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ ϮϬϬϳ͖ϰϵ͗ϲϱϰͲϵ͘

ϳϯ͘ůďƌŝŐŚƚ >͕ Ğƌǀŝ ͕ ^ŝŶŐůĞƚĂƌLJ :͘ Intrathecal baclofen for spasticity in ĐĞƌĞďƌĂůƉĂůƐLJ͘:D͘ϭϵϵϭ͖Ϯϲϱ;ϭϭͿ͗ϭϰϭϴͲ 22.

ϳϰ͘ ǀĂŶ ^ĐŚĂĞLJďƌŽĞĐŬ W͕ EƵƚƚŝŶ ͕ >ĂŐĂĞ >͕ ^ĐŚƌŝũǀĞƌƐ ͕ ŽƌŐŚŐƌĂĞĨ ͕ &ĞLJƐ W͘ Intrathecal baclofen for intractable ccerebral spasticity: a prospective placebo-controlled, double-blind study. EĞƵƌŽƐƵƌŐ͘ϮϬϬϬ͖ϰϲ;ϯͿ͗ϲϬϯͲϭϮ͘

ϳϱ͘<ƌĂƵƐ d͕ 'ĞŐĞŶůĞŝƚŶĞƌ <͕ ^ǀĞŚůŝŬ͕ EŽǀĂŬ D͕ ^ƚĞŝŶǁĞŶĚĞƌ '͕ ^ŝŶŐĞƌ '͘ >ŽŶŐͲƚĞƌŵ therapy with intrathecal bacclofen improves quality of life in children with ƐĞǀĞƌĞƐƉĂƐƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘Ƶƌ:WĂĞĚŝĂƚƌ EĞƵƌŽů͘ϮϬϭϳ͖Ϯϭ͗ϱϲϱͲϵ͘

ϳϲ͘DŽƌƚŽŶ Z͕ 'ƌĂLJ E͕ sůŽĞďĞƌŐŚƐ D͘ Controlled study of the effects of ĐŽŶƟŶƵŽƵƐŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶŝŶĨƵƐŝŽŶŝŶ non-ambulant children with cerebral palsy. ĞǀDĞĚŚŝůĚEĞƵƌŽů͘ϮϬϭϭ͖ϱϯ;ϴͿ͗ϳϯϲͲϰϭ͘ ϳϳ͘ DƵƌƉŚLJ E͕ EŝĐŽůĞ /ƌǁŝŶ D͕ ,ŽĨĨ ͘

Intrathecal baclofen therapy in children with cerebral palsy: efficcacy and ĐŽŵƉůŝĐĂƟŽŶƐ͘ ƌĐŚ WŚLJƐ DĞĚ ZĞŚĂďŝů͘ ϮϬϬϮ͖ϴϯ͗ϭϳϮϭͲϱ͘ ϳϴ͘,ŽǀŝŶŐD͕sĂŶZĂĂŬWD͕^ƉŝŶĐĞŵĂŝůůĞ ',::͕WĂůŵĂŶƐ>:͕ĞĐŚĞƌ:'͕sůĞƐ:^,͕Ğƚ Ăů͘ĸĐĂĐLJŽĨŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶƚŚĞƌĂƉLJ ŝŶĐŚŝůĚĞŶǁŝƚŚŝŶƚƌĂĐƚĂďůĞƐƉĂƐƟĐĐĞƌĞďƌĂů ƉĂůƐLJ͗ĂƌĂŶĚŽŵŝƐĞĚĐŽŶƚƌŽůůĞĚƚƌŝĂů͘Ƶƌ: WĂĞĚŝĂƚƌEĞƵƌŽů͘ϮϬϬϵ͖ϭϯ͗ϮϰϬͲϲ͘ ϳϵ͘,ŽǀŝŶŐD͕sĂŶZĂĂŬWD͕^ƉŝŶĐĞŵĂŝůůĞ ',::͕ sĂŶ <ƌĂŶĞŶͲDĂƐƚĞŶďƌŽĞŬ s,:D͕ ǀĂŶ<ůĞĞĨD͕'ŽƌƚĞƌ:t͕ĞƚĂů͘^ĂĨĞƚLJĂŶĚ ŽŶĞͲLJĞĂƌĞĸĐĂĐLJŽĨŝŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶ ƚŚĞƌĂƉLJŝŶĐŚŝůĚƌĞŶǁŝƚŚŝŶƚƌĂĐƚĂďůĞƐƉĂƐƟĐ ĐĞƌĞďƌĂů ƉĂůƐLJ͘ Ƶƌ : WĂĞĚŝĂƚƌ EĞƵƌŽů͘ ϮϬϬϵ͖ϭϯ͗ϮϰϳͲϱϲ͘ ϴϬ͘sůĞƐ'&͕^ŽƵĚĂŶƚ͕,ŽǀŝŶŐD͕sĞƌŵĞƵůĞŶ Z:͕ ŽŶŽƵǀƌŝĞ >͕ ǀĂŶ KŽƐƚĞŶďƌƵŐŐĞ Z:͕ Ğƚ Ăů͘ >ŽŶŐͲƚĞƌŵ ĨŽůůŽǁͲƵƉ ŽĨ ĐŽŶƟŶŽƵƐ intrathecal baclofen therapy in non-ĂŵďƵůĂŶƚĐŚŝůĚƌĞŶǁŝƚŚŝŶƚƌĂĐƚĂďůĞƐƉĂƐƟĐ ĐĞƌĞďƌĂů ƉĂůƐLJ͘ Ƶƌ : WĂĞĚŝĂƚƌ EĞƵƌŽů͘ ϮϬϭϯ͖ϭϳ͗ϲϯϵͲϰϰ͘ ϴϭ͘ĞŬ DE͕ KůƐƐŽŶ <͕ >ŝŶĚŚ <͕ ƐŬůũƵŶŐ ͕ WĂŚůŵĂŶ D͕ ŽƌŶĞůŝƵƐƐŽŶ K͕ Ğƚ Ăů͘ /ŶƚƌĂƚŚĞĐĂůďĂĐůŽĨĞŶŝŶĚLJƐŬŝŶĞƟĐĐĞƌĞďƌĂů ƉĂůƐLJ͗ĞīĞĐƚƐŽŶĨƵŶĐƟŽŶĂŶĚĂĐƟǀŝƚLJ͘Ğǀ DĞĚŚŝůĚEĞƵƌŽů͘ϮϬϭϴ͖ϲϬ;ϭͿ͗ϵϰͲϵ͘ ϴϮ͘DŽƩĂ&͕^ƟŐŶĂŶŝ͕ŶƚŽŶĞůůŽ͘īĞĐƚƐ

of intrathecal baclofen on dystonia in children with cerebral palsy and the use ŽĨ ĨƵŶĐƟŽŶĂů ƐĐĂůĞƐ͘ :ŽƵƌŶĂů ŽĨ WĞĚŝĂƚƌŝĐ KƌƚŚŽƉĂĞĚŝĐƐ͘ϮϬϬϴ͖Ϯϴ͗ϮϭϯͲϳ͘

ϴϯ͘ĞŶ ^ŵĂŝů ͕ :ĂĐƋ ͕ ĞŶLJƐ W͕ ƵƐƐĞů ͘ Intrathecal baclofen in the treatment of ƉĂŝŶĨƵů͕ ĚŝƐĂďůŝŶŐ ƐƉĂƐŵƐ ŝŶ &ƌĞŝĚƌĞŝĐŚƐ ĂƚĂdžŝĂ͘DŽǀŝƐŽƌĚ͘ϮϬϬϱ͖ϮϬ;ϲͿ͗ϳϱϴͲϵ͘ ϴϰ͘ŚƵD>z͕^ĂůĂ͕tĞŝŶĞƌ,>͘/ŶƚƌĂƚŚĞĐĂů

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ABSTRACT

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INTRODUCTION

Cerebral palsy comprises a group of developmental disorders of movement and ƉŽƐƚƵƌĞ͕ĂƩƌŝďƵƚĞĚƚŽŶŽŶͲƉƌŽŐƌĞƐƐŝǀĞĚŝƐƚƵƌďĂŶĐĞƐƚŚĂƚŽĐĐƵƌƌĞĚŝŶƚŚĞĚĞǀĞůŽƉŝŶŐ ĨĞƚĂůŽƌŝŶĨĂŶƚďƌĂŝŶ͘dŚĞŵŽƚŽƌŝŵƉĂŝƌŵĞŶƚƐĂƌĞŽŌĞŶĂĐĐŽŵƉĂŶŝĞĚďLJĚŝƐƚƵƌďĂŶĐĞƐ ŽĨƐĞŶƐĂƟŽŶ͕ƉĞƌĐĞƉƟŽŶ͕ĐŽŐŶŝƟŽŶ͕ĐŽŵŵƵŶŝĐĂƟŽŶ͕ĂŶĚďĞŚĂǀŝŽƵƌ͕ďLJĞƉŝůĞƉƐLJ͕ĂŶĚ by secondary musculoskeletal problems.1

Cerebral palsy is the most common cause of severe physical disability in early childhood, ǁŝƚŚĂƉƌĞǀĂůĞŶĐĞŽĨϭ͘ϳʹϯ͘ϭƉĞƌϭϬϬϬůŝǀĞďŝƌƚŚƐŝŶŚŝŐŚͲŝŶĐŽŵĞĐŽƵŶƚƌŝĞƐ͕ĂŶĚŚŝŐŚĞƌ prevalence in low-income countries.2,3_{ĞƌĞďƌĂůƉĂůƐLJŝƐĐůŝŶŝĐĂůůLJĐĂƚĞŐŽƌŝƐĞĚŝŶƚŽƐƉĂƐƟĐ͕}

ĚLJƐŬŝŶĞƟĐ͕ĂŶĚĂƚĂdžŝĐĐĞƌĞďƌĂůƉĂůƐLJŽŶƚŚĞďĂƐŝƐŽĨƚŚĞƉƌĞĚŽŵŝŶĂŶƚŵŽƚŽƌĚŝƐŽƌĚĞƌ͘1 LJƐŬŝŶĞƟĐĐĞƌĞďƌĂůƉĂůƐLJ;WͿŝƐĐŚĂƌĂĐƚĞƌŝƐĞĚďLJĂďŶŽƌŵĂůƉŽƐƚƵƌĞƐŽƌŵŽǀĞŵĞŶƚƐ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚŝŵƉĂŝƌĞĚŵƵƐĐůĞƚŽŶĞƌĞŐƵůĂƟŽŶ͕ŵŽǀĞŵĞŶƚĐŽŶƚƌŽů͕ĂŶĚĐŽŽƌĚŝŶĂƟŽŶ ĐŽŵƉƌŝƐŝŶŐƚǁŽŵĂũŽƌŵŽǀĞŵĞŶƚĚŝƐŽƌĚĞƌƉĂƩĞƌŶƐ͗ĚLJƐƚŽŶŝĂĂŶĚĐŚŽƌĞŽĂƚŚĞƚŽƐŝƐ͘ϰ WŝƐƐŽŵĞƟŵĞƐƌĞĨĞƌƌĞĚƚŽĂƐĚLJƐƚŽŶŝĐ͕ĂƚŚĞƚŽŝĚ͕ĞdžƚƌĂƉLJƌĂŵŝĚĂů͕ĐŚŽƌĞŽĂƚŚĞƚŽƟĐ͕ ŽƌĐŚŽƌĞŽĂƚŚĞƚŽŝĚĐĞƌĞďƌĂůƉĂůƐLJ͘WĂĐĐŽƵŶƚƐĨŽƌƵƉƚŽϭϱйŽĨĐĞƌĞďƌĂůƉĂůƐLJĐĂƐĞƐ͕ ŵĂŬŝŶŐŝƚƚŚĞƐĞĐŽŶĚŵŽƐƚĐŽŵŵŽŶƚLJƉĞĂŌĞƌƐƉĂƐƟĐĐĞƌĞďƌĂůƉĂůƐLJ͘Ϯ͕ϱ W ĐĂŶ ŚĂǀĞ ŵĂŶLJ ĐĂƵƐĞƐ͕ ŝŶĐůƵĚŝŶŐ ƉĞƌŝŶĂƚĂů ŚLJƉŽdžŝĂʹŝƐĐŚĂĞŵŝĂ ŝŶ ŝŶĨĂŶƚƐ ďŽƌŶ near to term, neonatal hyperbilirubinaemia, brain maldevelopment, intracranial ŚĂĞŵŽƌƌŚĂŐĞ͕ƐƚƌŽŬĞ͕ŽƌĐĞƌĞďƌĂůŝŶĨĞĐƟŽŶ͘ϱ_{,LJƉĞƌďŝůŝƌƵďŝŶĂĞŵŝĂͲŝŶĚƵĐĞĚŬĞƌŶŝĐƚĞƌƵƐ} ;ŝĞ͕ĚĞƉŽƐŝƟŽŶŽĨďŝůŝƌƵďŝŶŝŶƚŚĞďĂƐĂůŐĂŶŐůŝĂͿĐĂŶŽĐĐƵƌĚƵƌŝŶŐƚŚĞƉƌĞƚĞƌŵĂŶĚƚĞƌŵ ƉĞƌŝŽĚ͘dŚŝƐĐŽŶĚŝƟŽŶŚĂƐďĞĐŽŵĞůĞƐƐĐŽŵŵŽŶŝŶŚŝŐŚͲŝŶĐŽŵĞĐŽƵŶƚƌŝĞƐďĞĐĂƵƐĞŽĨ ƉƌĞǀĞŶƟǀĞƐƚƌĂƚĞŐŝĞƐ͕ďƵƚŝƐƐƟůůĂŶŽƚĂďůĞŝƐƐƵĞŝŶůŽǁͲŝŶĐŽŵĞĐŽƵŶƚƌŝĞƐ͘/ŶĂĚĚŝƟŽŶ ƚŽƉƌŝŵĂƌLJƉƌĞǀĞŶƟŽŶŽĨŚLJƉĞƌďŝůŝƌƵďŝŶĂĞŵŝĂ͕ƉŽƐƚŶĂƚĂůŵŽŶŝƚŽƌŝŶŐƌĞŵĂŝŶƐĞƐƐĞŶƟĂů͕ ĂŶĚƉƌŽŵŝƐŝŶŐƉƌĞǀĞŶƟŽŶĂƉƉƌŽĂĐŚĞƐŚĂǀĞďĞĞŶĚĞǀĞůŽƉĞĚŝŶƌĞƐŽƵƌĐĞͲĐŽŶƐƚƌĂŝŶĞĚ ƐĞƫŶŐƐ͘6 _{Causes outside the neonatal period, such as cardiorespiratory arrest or near}

ĚƌŽǁŶŝŶŐŝŶƚŚĞĮƌƐƚLJĞĂƌ͕ĂƌĞƌĂƌĞƌ͘

ϯϴ

CLINICAL PRESENTATION

DŽƚŽƌŝŵƉĂŝƌŵĞŶƚƐĂƌĞŽŌĞŶŵŽƌĞƐĞǀĞƌĞŝŶƉĞŽƉůĞǁŝƚŚWƚŚĂŶŝŶƉĂƟĞŶƚƐǁŝƚŚ the other types of cerebral palsy.7_{EŽŶͲŵŽƚŽƌĐŽŵŽƌďŝĚŝƟĞƐĂƌĞĂůƐŽĐŽŵŵŽŶ͖ŵŽƌĞ}

ƚŚĂŶŚĂůĨŽĨƉĂƟĞŶƚƐǁŝƚŚWŚĂǀĞĂĐŽŵďŝŶĂƟŽŶŽĨƐĞǀĞƌĞŝŶƚĞůůĞĐƚƵĂůŝŵƉĂŝƌŵĞŶƚ͕ anarthria, and epilepsy.ϰ͕ϱ͕ϳ _{Visual and hearing impairments are also common.}ϱ_{ĞƐƉŝƚĞ}

ŶŽƌŵĂůďŝƌƚŚǁĞŝŐŚƚŝŶŵŽƐƚĐĂƐĞƐ͕ŵŽƌĞƚŚĂŶŚĂůĨŽĨƉĂƟĞŶƚƐďĞĐĂŵĞƵŶĚĞƌǁĞŝŐŚƚĂƚ ĨŽůůŽǁͲƵƉŝŶĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚƐƚƵĚLJĨƌŽŵǁĞƐƚĞƌŶ^ǁĞĚĞŶ͕ƉƌĞƐƵŵĂďůLJĂƐĂƌĞƐƵůƚŽĨ high energy expenditure due to involuntary movements combined with poor feeding, ĚLJƐƉŚĂŐŝĂ͕ŐĂƐƚƌŽͲŽĞƐŽƉŚĂŐĞĂůƌĞŇƵdž͕ĂŶĚƐƵďŽƉƟŵĂůŶƵƚƌŝƟŽŶĂůŝŶƚĂŬĞ͘ϳ͕ϴ _{Sleep and}

ƌĞƐƉŝƌĂƚŽƌLJ ĨƵŶĐƟŽŶ ĂƌĞ ŽŌĞŶ ĚŝƐƚƵƌďĞĚ͘ ƌŽŽůŝŶŐ͕ ĚĞŶƚĂů ƉƌŽďůĞŵƐ͕ ĐŽŶƐƟƉĂƟŽŶ͕ ĨĂĞĐĂů ĂŶĚ ƵƌŝŶĂƌLJ ŝŶĐŽŶƟŶĞŶĐĞ͕ ƉĂŝŶ͕ ĂŶĚ ŵƵƐĐƵůŽƐŬĞůĞƚĂů ĚĞĨŽƌŵŝƟĞƐϵ_{ ;ŝŶĐůƵĚŝŶŐ}

ƐĐŽůŝŽƐŝƐͿĂƌĞĐŽŵŵŽŶ͕ĂŶĚĚĞŐĞŶĞƌĂƟǀĞĐĞƌǀŝĐĂůĐŚĂŶŐĞƐĐĂƵƐŝŶŐŵLJĞůŽƉĂƚŚLJĂŶĚ ŵŽƚŽƌĚĞƚĞƌŝŽƌĂƟŽŶŚĂǀĞďĞĞŶĚĞƐĐƌŝďĞĚŝŶĂĚƵůƚƐ͘10 _{Mental health problems, including}

ĚĞƉƌĞƐƐŝŽŶ͕ĂƌĞŝŶĐƌĞĂƐŝŶŐůLJƌĞĐŽŐŶŝƐĞĚ͘dŚĞƌŝƐŬĨŽƌĞĂƌůLJĚĞĂƚŚŝŶƚŚĞƐĞƉĂƟĞŶƚƐŝƐ higher than in other types of cerebral palsy,11_{ĂŶĚŝŶƚŚĞŐĞŶĞƌĂůƉŽƉƵůĂƟŽŶ͕ŵŽƐƚ}