שימוש בבוטולינום טוקסין בנוירולוגיה כללית

ד"ר מ. אנקה-הרשקוביץ

מנהלת מרפאה להפרעות תנועה

מרפאה נוירולוגית

בית חולים ע"ש אדית וולפסון

Treatment of spasticity with botulinum toxin

Spasticity - an abnormal increase in muscle contraction caused by damage to central motor pathways that control voluntary movement.

*Spasticity manifests as an increase in stretch reflexes, producing tendon jerks and resistance appearing as muscle tone.

*Causes of spasticity: demyelination from multiple sclerosis, congenital damage from diseases such as cerebral palsy, trauma to the brain or spinal cord, hemorrhage or infarction, and other pathologic conditions that interrupt neural pathways.

*Effects of spasticity range from mild muscle stiffness to severe, painful muscle contractures and repetitive spasms that reduce mobility and substantially impede normal activities of daily living.

Botulinum toxin therapy reduces spasticity and pain associated with several disorders.

Local treatment with botulinum toxins can be used as adjunctive therapy, along with oral

antispasticity medications, or alone to provide localized decrease in symptoms of spasticity and pain.

Botulinum toxin therapy may be particularly useful for patients with spasticity due to stroke, whose treatment can be tailored based on recovery of function over time.

CNS Drugs. 2003;17(15):1093-107.:Poststroke motor dysfunction and spasticity: novel pharmacological and physical treatment strategies.

Hesse S, Werner C. //Department of Neurological Rehabilitation, Klinik Berlin, Germany.

Following stroke, approximately 90% of patients experience persistent neurological motor deficits that lead to disability and handicap. Both pharmacological and physical treatment strategies for motor rehabilitation may be considered. Botulinum toxin A has proven effective and well tolerated in several placebo-controlled trials for the treatment of focal upper and lower limb spasticity, although it has not been shown to improve motor function.

The focal injection of botulinum toxin A inhibits the release of acetylcholine into the synaptic cleft, resulting in a reversible paresis of the muscles relevant for the spastic deformity. Other drugs, such as benzodiazepines, antiepileptic drugs and antipsychotics, may have detrimental effects on motor function and should be avoided, if possible.

&J Neurol. 2004 Feb;251(2):189-96. :Botulinum toxin in post-stroke patients: stiffness modifications and clinical implications.

Miscio G, Del Conte C, Pianca D, Pisano F.//Department of Neurology, Oggebbio (VB), Italy.

Eighteen consecutive chronic post-stroke spastic patients were injected Botulinum toxin A in the forearm flexor spastic muscles. Hand function for selected tasks improved in 50% of patients

BT can be considered a valid therapeutic tool in all spastic patients, because of immediate advantages: reduction of muscle hypertonia, pain relief, improvement in selected motor performances.

Ann Readapt Med Phys. 2003 Jul;46(6):299-302.

[Multiple sclerosis and botulinum toxin]

Lamotte D, Thoumie P//.Service de reeducation neuro-orthopedique, hopital Rothschild, 33, Paris, France.

The aim of this work was to collect litterature datas to have an indication of botulinum toxin in multiple sclerosis disease. METHOD: The international literature relating the years 1982-2002 was carried out with the Medline data bank. The article presenting of the controlled studies were mainly retained. RESULTS: Thirty-seven articles were indexed, 6 were retained according to our criteria. The selected articles show mainly a use of botulinum toxin in the spasticity. The principal criteria of evaluation were the muscular tone, the spasms, the pain, the or passive amplitude of joint.Two articles report the effectiveness of toxin injection in acquired nystagmus and the paralysis of a vocal fold. DISCUSSION: This review shows that the principal indication of toxin in multiple sclerosis is spasticity with a good effectiveness of the treatment.

CONCLUSION: Botulinum toxin has an indication in the treatment of spasticity of patients with multiple sclerosis. However more studies are necessary with more sits of injection to fix the good indications.

Sialorrhea and botulinum toxinBT blocks all cholinergic transmission, including the autonomous nervous system, it is plausible to expect a reduction in sweating and salivation on local injection of the product.

The first publications indicated such efficiency without serious side effects. For sialorrhea and the drooling in certain chronical neurological diseases, BT seems to have very promising effects. However, it has not been precisely determined whether to inject the parotid gland, the submandibular gland, or both. Botulinum toxin may be an effective and safe treatment of parkinsonian sialorrhea.

Mov Disord. 2004 Mar;19 Suppl 8:S137-41

Botulinum toxin treatment of secretory disorders.Naumann M, Jost W.//Department of Neurology, Wurzburg, Germany

Botulinum neurotoxin serotype A (BT) has revolutionised the treatment of a variety of autonomic hypersecretory disorders.

We need further formal clinical trials to evaluate risks and benefits of BT for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar amyotrophic lateral sclerosis. BT injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this disabling condition.

Hyperhydrosis

Hyperhidrosis

Clinical Range of Primary HeadachesClinical Range of Primary Headaches

Binder et al (Abs) Binder et al (Abs)

Mauskop and Basdeo Mauskop and Basdeo

Smuts et al (suppl)Smuts et al (suppl)

Relja and Korsic (Abs)Relja and Korsic (Abs) Relja et al (Abs)Relja et al (Abs)

Binder et alBrin et al (Abs)

Binder et alBrin et al (Abs)

Smuts and Barnard Smuts and Barnard

19981998 19991999 20002000 20012001

Klapper and Klapper Klapper and Klapper

WheelerWheeler

Rollnik et al Rollnik et al

Carruthers et alCarruthers et al PortaPorta

Schulte-Mattler Schulte-Mattler

Freund and Schwartz Freund and Schwartz

Silberstein et alSilberstein et al

Botulinum Toxin Type A for Headache: An Evolving Clinical ExperienceBotulinum Toxin Type A for Headache: An Evolving Clinical Experience

MIGRAINEMIGRAINE

TENSION/OTHERTENSION/OTHER

Abs = abstractBold = double-blind placebo-controlled

Botulinum Toxin Type A: Migraine HeadacheBotulinum Toxin Type A: Migraine Headache

Binder WJ, et al. Otolaryngol Head Neck Surg. 2000;123:669-676.Binder WJ, et al. Otolaryngol Head Neck Surg. 2000;123:669-676.

CompleteresponseCompleteresponse

PartialresponsePartial

responseNo

responseNo

response

% o

f sub

ject

s%

of s

ubje

cts

00

1010

2020

3030

4040

5050

6060

7070Low baseline frequency (n=43)Low baseline frequency (n=43)

High baseline frequency (n=34)High baseline frequency (n=34)

0

2

4

6

8

1 0

1 2

-1 1 2 3M o n th

N u m b e r o f h e a d a c h e - f re e

d a y s /m o n th /p a t ie n t

P la c e b o

B o t u l in u m to x in t y p e A

B o t u l i n u m T o x i n T y p e A : C h r o n i c T e n s i o n -T y p e H e a d a c h eB o t u l i n u m T o x i n T y p e A : C h r o n i c T e n s i o n -T y p e H e a d a c h e

A d a p te d f r o m S m u ts J A , e t a l. E u r J N e u r o l. 1 9 9 9 ;6 ( s u p p l) :S 9 9 - S 1 0 2 .A d a p te d f r o m S m u ts J A , e t a l. E u r J N e u r o l. 1 9 9 9 ;6 ( s u p p l) :S 9 9 - S 1 0 2 .

In j .

Summary of All Studies:Botulinum Toxin Type A in Headache

Summary of All Studies:Botulinum Toxin Type A in Headache• No reported treatment-related serious adverse

events– Few adverse events overall

• Reduced frequency and severity of episodic and chronic migraine and chronic tension-type headaches

• Generally, findings of decreased headache frequency with botulinum toxin type A compare to other preventive headache medications

• No reported treatment-related serious adverse events– Few adverse events overall

• Reduced frequency and severity of episodic and chronic migraine and chronic tension-type headaches

• Generally, findings of decreased headache frequency with botulinum toxin type A compare to other preventive headache medications

Botulinum Toxin Type A:Hypothesis of ActionBotulinum Toxin Type A:Hypothesis of Action

• Muscle– Alpha motor neuron inhibition– Gamma motor neuron inhibition

• Ia afferent reduction

• Nociceptors/pain pathway– C and A delta fibers (group III and IV)– Mechano- and chemonociceptors– Substance P, CGRP, glutamate release

• Muscle– Alpha motor neuron inhibition– Gamma motor neuron inhibition

• Ia afferent reduction

• Nociceptors/pain pathway– C and A delta fibers (group III and IV)– Mechano- and chemonociceptors– Substance P, CGRP, glutamate release

CGRP = calcitonin gene-related peptide

Aoki KR. J Neurol. 2001;248(suppl):3-10.

CGRP = calcitonin gene-related peptide

Aoki KR. J Neurol. 2001;248(suppl):3-10.

Reproduced with permission from: Silberstein SD, et al. Headache in Clinical Practice.Isis Medical Media; 1998:41-55.

Neurogenic InflammationNeurogenic Inflammation

CGRP

Substance P

5-HT1 Receptor

Neurokinin A

Postsynaptic Receptor

Axon Terminal

Other?

Possible Candidates for Injectable Therapy Possible Candidates for Injectable Therapy

• Disabling primary headaches

– Frequent migraine

– Chronic migraine

– Chronic tension-type headache

– Medication overuse (“drug-induced”) headache

• Patients with jaw or neck muscle spasm

• Acute meds contraindicated

• Patients with compliance problems

• Patients refractory to routine treatment

• Disabling primary headaches

– Frequent migraine

– Chronic migraine

– Chronic tension-type headache

– Medication overuse (“drug-induced”) headache

• Patients with jaw or neck muscle spasm

• Acute meds contraindicated

• Patients with compliance problems

• Patients refractory to routine treatment

Injection Site: Glabellar and Frontal RegionsInjection Site: Glabellar and Frontal Regions

Frontalis muscle

Procerusmuscle

Corrugatormuscle

Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ. 1997.Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ. 1997.

XX X

XX

XXX

Injection Site: Suboccipital RegionInjection Site: Suboccipital Region

Trapeziusmuscle

Adapted with permission from: Netter FH. Atlas of Human Anatomy. Icon Learning Systems; Teterboro, NJ. 1997.

X

X

Splenius capitismuscleX

Patient ManagementPatient Management

• Expectations– May take several treatments to achieve maximal effect

– Response to injection may change over time

• Rare adverse events– Headache

– Rash, itching

– Flu-like symptoms

– Ptosis: brow, eyelid

• Expectations– May take several treatments to achieve maximal effect

– Response to injection may change over time

• Rare adverse events– Headache

– Rash, itching

– Flu-like symptoms

– Ptosis: brow, eyelid

“Regarding every disease now incurable we may entertain the hope that our powerlessness may not be permanent, and that we, or those who come after us , may be able to speak in very different terms “

W.R.Gowers , 1879