הפרעות תנועה והטיפול בבוטולינום טוקסין

• ד" ר מריאטה אנקה הרשקוביץ

• מנהלת מרפאה להפרעות תנועה

• מרפאה נוירולוגית

• בית חולים ע"ש אדית וולפסון

In 1822 Justus Kerner described the signs and symptoms of ”botulism”, which became known as Kerner's disease. He also predicted the therapeutic use of the toxin.

The word botulinum comes from the Latin word botulus, meaning sausage, as infected food was recognised early on as being responsible for the food intoxication syndrome originally referred to as Kerner's disease, but known as botulism since 1897.

In 1970s Dr Allan B Scott at the Smith-Kettelwell Eye Research Institute in California used purified type A toxin to induce strabismus in animals by local injection into eye muscles. In the same period, he started to treat squinting in humans using a similar technique. He also introduced local injections of botulinum in the treatment of dystonias, first blepharospasm and later torticollis in collaboration with neurologists.

Up to now torticollis has been the main indication for therapy.

Botulinum toxin history

Botulinum toxin(I)• Clostridium botulium : produce immunologically distinct toxin(A-G)

• cleaved into a heavy chain(100K) & light chain(50K) , linked by a disulfide bond, by trypsin or bacterial enzyme

• BTX A & E : cleave SNAP-25(synaptosome associated protein), a protein for synaptic vesicle targeting & fusion with presynaptic membrane

• BTX B, D & F : cleave synaptobrevin-2(VAMP, vesicle associated membrane protein)

• BTX C : cleave syntaxin, plasma membrane associated protein

Botulinum toxin(II)

Mechanism of action

• blocks acetylcholine release by cleaving SNAP-25

• not affect the synthesis or storage of acetylcholine or the conduction of electrical signals

Side effect : transient, mild* in blepharospasm, ptosis, blurring of vision, tearing, local hematoma(< 2 wks)

Contraindication

• previous allergic reaction

• motor neuron disease

• myasthenia gravis or Eaton-Lambert syndrome

• Pregnancy

• aminoglycoside use : increased effects of Botox therapy

• presence of infection at the proposed injection site

Pharmacology of Botulinum ToxinPharmacology of Botulinum Toxin

• 7 distinct antigenic types (serotypes): – A, B, C, D, E, F, G

• Serotypes differ– Biochemical structure and molecular weight

– Potency (ED50)

– Intracellular target

• 7 distinct antigenic types (serotypes): – A, B, C, D, E, F, G

• Serotypes differ– Biochemical structure and molecular weight

– Potency (ED50)

– Intracellular target

NT = Pure neurotoxin protein

HA = Hemagglutinin protein

NTNH = Nontoxic, non-HA protein

NT = Pure neurotoxin protein

HA = Hemagglutinin protein

NTNH = Nontoxic, non-HA protein

HANTNH

HA

HA

HA

HA

HA

-S-S-

Light chain Heavy chain

NH2

NH2

COOH

COOH

NPNT

NT

Biochemistry of Botulinum Toxin Type ABiochemistry of Botulinum Toxin Type A

The Neuromuscular J unctionThe Neuromuscular J unction

Reproduced with permission from Arnon SS, et al. JAMA. 2001;285:1061.Reproduced with permission from Arnon SS, et al. JAMA. 2001;285:1061.

Botulinum Toxin Type A Mechanism of Action: Current HypothesisBotulinum Toxin Type A Mechanism of Action: Current Hypothesis

Reproduced with permission from Arnon SS, et al. JAMA. 2001;285:1061.Reproduced with permission from Arnon SS, et al. JAMA. 2001;285:1061.

Craniofacial Movement Disorders

Diagnostic Group Area affected

Hemifacial Spasm

Blepharospasm

Oromandibular Dystonia

Tardive Dyskinesia

Craniofacial Tics

Craniofacial Tremor

Craniofacial Chorea

Craniofacial Myoclonus

Unilateral eye and face

Bilateral eyes

Masticatory muscles

Face, lips, tongue

Eyes, face, lip

Chin or jaw

Mouth and lips

facial or palatal

• Age 50-60 at onset• Female = 2x male• Frontalis muscle

involvement in 15%• Persists while sleeping

(D/D with EBS)

• 66% associated with HTN

Hemifacial spasm

• Bilateral• Affects orbicularis oculi muscle• Central in origin• Progresses to functional

blindness• Onset > 50 y/o• Female > male• Absent during sleep• Associated with anxiety disorder

Benign essential blepharospasm( EBS)

BOTULINUM INJECTION SITES FOR EBS

Oromandibular dystonia

• rarely improve with medication, no surgical treatment

• average latency : 5.5 days, average duration : 11.5 wks

• transient swallowing problem : 1/3

• in jaw-closure dystonia : masseter muscle* in jaw-opening dystonia : submental muscle or lateral pterygoid muscle

Spasmodic dysphonia

• unilateral injection : superior & longer lasting benefit than bilateral(Adams, 1993)

• unilateral : 5 - 30 U

• adverse effect : transient breathy hypophonia, hoarseness & rare dysphagia with aspiration

• injection : posterior cricoarytenoid muscle, posterior to thyroid lamina

Writer’s cramp

• average latency : 5.6 days, average duration : 9.2 wks

• Injection : belly of the most active muscle in EMG study* wrist flexor or extensor

Cervical dystonia(I)

• goal of therapy* improve abnormal posture & neck pain* prevent secondary complication(contracture, cervical radiculopathy, cervical myelopathy)

• average improvement : 1 week, average duration : 3-4 months

• adverse effect : dysphagia(14 %), neck weakness, nausea

• Favorable response* proper selection of involved muscle* appropriate dosage* short-duration dystonia

• Examination of the Pts with cervical dystonia * allow head to draw into the maximal abnormal posture without resisting* examine while standing, walking, sitting & writing* passively move the head* palpate contracting muscle* EMG