Past, Present and Future of Spasmodic Dysphonia and the use of Botulinum toxin therapy

Transcription

1 Past, Present and Future of Spasmodic Dysphonia and the use of Botulinum toxin therapy ANDREW BLITZER, MD, DDS Professor of Clinical Otolaryngology Columbia University College Director, New York Center for Voice and Swallowing Disorders

2 Disclosures 1. Allergan, Inc research funding 2. Merz Pharm. research funding 3. Xomed/Medtronics royalties 4. Myotech-- royalties

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4 SD History TRAUBE (1871)- coined the term spastic dysphonia in a hysterical girl who was hoarse, with great strain, producing high pitch sounds SCHNITZLER (1875)- spastic aphonia ; phonic laryngeal spasm NOTHNAGEL (1881)- coordinated laryngeal spasm

5 SD History FRAENKEL (1887)- mogiphonia ; slowly developing disorder of the voice with increasing vocal fatigue; spastic constriction of the throat muscles and pain around the larynx; compared to mogigraphia or occupational writers cramp

6 SD History GOWERS (1893)- functional laryngeal spasm; the cords brought together too forcibly while speaking contrasted to phonic paralysis where the cords cannot be brought together while speaking

7 SD History GOWERS: The affliction has been compared to writer s cramp- a case reported by Gerhardt, in which the patient had suffered from writer s cramp, and at the age of 50, learned to play the flute; the act of blowing the flute brought on laryngeal spasm and an unintended voice (sound), accompanied by muscular contraction in the arm and at the corner of the mouth

8 SD History CRITCHLEY (1939)- described the voice pattern as a condition in which the patient sounds as though he were trying to talk wilst being choked

9 SD History BELLUSSI (1952)- stuttering with the vocal cords ARONSON (1973)-- described two types: adductor- strained-strangle hoarseness due to hyperadduction of the vocal folds abductor-intermittent breathy phonation or aphonia

10 SD History JACOMB and YANES(1979)- postulated that SD was a disorder of the extrapyramidal system based on the co-existance with other cranial dystonias and associated spastic dysphonia with Meige disease

11 DEDO, 1976, reported dramatic improvement of voice with anethestic block of the RLN and later by RLN section. ARONSON in 1983 reported 3 year results of RLN section where only 30% still had good voicing.

12 SD History ARONSON (1981)- SD has a tremor similar to that of ET Marsden (1982) reported SD, Meige and tortion dystonia as being one disorder BLITZER (1985)- SD not a spastic disease, but rather a laryngeal dystonia and EMG data similar to other dystonias

13 SD History Bielamowicz and Ludlow (2000) noted an improved signal in the contralateral thyroarytenoid muscle after treatment and hypothesized a central reduction in motor neuron activity due to changed sensimotor feedback.

14 Laryngeal Dystonia: classification Adductor- classical strain-strangle phonation punctuated by voicing arrests ( breaks or pauses ); involuntary cocontraction of the laryngeal muscles with hyperadduction of the vocal folds Abductor- whispering, weak, breathy voice, particularly at voice onset; involutary contraction of the posterior criocarytenoid muscles, resulting in inappropriate abduction of the vocal folds

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18 Laryngeal Dystonia: classification compensatory abductor - a patient with severe adductor dysphonia who compensates for adduction by whispering adductor respiratory dystonia- paradoxical adduction of the vocal folds on inspiration causing stridor Singer s Dystonia- hyperadduction for the task of singing

19 Spasmodic Dysphonia Cannito believes that all patients are mixed with an adductor or abductor predominence. The true mixed cases have equal symptoms of each. Cannito, MP, Johnson, P, Spastic Dysphonia: a continuum disorder J. Comm. Disord. 14: , 1981

20 Spasmodic Dysphonia : 1300 pts. 471 (63%) female 747 (82%) adductor 154 (17%) abductor 12 (1%) adductor breathing dystonia 12% had (+) family history

21 Spasmodic Dysphonia: Onset 82.4% remained focal 12.3% progressed to other cranial sites 5.3% progressed to extracranial sites

22 What Is Dystonia? A syndrome dominated by sustained muscle contractions frequently causing twisting and repetitive movements, or abnormal postures that may be sustained or intermittent. May involve any voluntary muscle. Because the movements and resulting postures are often unusual, and the condition is rare, it is one of the most frequently misdiagnosed neurological conditions.

23 Classification of Dystonia By Cause Primary Secondary Age at onset Childhood (< 26 yo) Adulthood Distribution Focal Segmental Generalized

24 Primary Idiopathic Dystonia Classification: by distribution Focal blepharospasm: forced involuntary eye closure oromandibular dystonia: face, jaw, tongue torticollis: neck writer s cramp: action induced dystonic contraction of arm muscles spasmodic dysphonia: vocal cords Segmental (cranial/axial/crural) Multifocal Generalized (ambulatory, non-ambulatory)

25 Prevalence of Dystonia Nutt: 1988 Torticollis 22,250 Oromandibular dystonia 17,750 Writers cramp 17,750 Spasmodic dysphonia 13,250 Generalized dystonia 8,750 Blepharospasm 4,500 Extrapolated from prevalence in Rochester, MN, based upon US population of 250 million

26 Primary or Secondary? 20% genetic linkage 20% seondary 60% primary idiopathic

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28 Therapy of Dystonia Clues when pathophysiology is unknown (1) Trial and error Treatment of other basal ganglia disorders Trihexyphenidyl, levodopa Treatment of spasticity Baclofen, intrathecal baclofen, tizanidine Suppress excitability in the CNS Benzodiazepines PET studies/biochemical studies Dopamine agonists

29 Therapy of Dystonia Surgical Intervention CNS: Thalamotomy/Pallidotomy/DBS Peripheral denervation, myectomy Peripheral tendon transfers Cervical stimulator Deep Brain Stimulation

30 Surgical Treatment of SD Dedo-(1976) RLN section Biller + Som (1983) RLN crush Netterville (1991) RLN avulsion Genack (1993) partial TA myectomy Berke (1999) RLN adductor denervationreinnervation Isshiki (2004) type 2 thyroplasty

31 Therapy of Dystonia Argument Against Surgery Complications Destructive surgery may block benefit from pharmacotherapy Hope: genetically - based site specific pharmacotherapy may be around the corner

32 Therapy of Dystonia Focal or Segmental Symptoms Primary therapy: usually local injections of botulinum toxin (BTX) Add pharmacotherapy as needed

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34 BoTX: General Considerations Common generic terminology BoTX BTX BT, BNT, BoNT, etc. Polypeptide (150 Kd) Eight distinct serotypes (A, B, C α, C β, D, E, F, G) Subtypes A1-A4; B1-2 Safe and effective for a variety of indications

35 Regulated Exocytosis Trends in Cell Biology, July 1997

36 Hypothetical Model of Synaptic Fusion Complex Vesicle VAMP SNAP-25 SYNTAXIN Plasma Membrane Sutton RB, Brunger AT, et al. Nature 1998;395:

37 History of Botox 1 st reported case of botulism was reported in 1810 by Justinus Kerner. He deduced that a toxin interrupted signal in motor nerves, spasring sensory nerves. He believed that it came from spoiled blood sausage ( Botulus ) He also thought that the sausage poisen could be used as therapy for conditions such as St.Vitus Dance (chorea), hyperhidrosis, and hypersalivation

38 History of Botox Belgian scientist Emile Pierre van Ermengen in 1895 identified the bacterium Bacillus botulinus, which was later names Chlostridium botulinum.

39 History of Botox In 1905, Tchitchikine found that C. botulinum produced a neurotoxin.

40 History of Botox During WWII Edward Schantz at Ft. Detrick, purified and crystallized the toxin as a biological weapon for the Dept. of Defense. Schantz continued his work with the U. of Wisconsin, and helped develop this agent as a therapeutic

41 Clinical Applications of Botulinum Toxin Focal Dystonia Blepharospasm (lid "apraxia") Oromandibular-facial-lingual dystonia Cervical dystonia (torticollis) Laryngeal dystonia (spasmodic dysphonia) Task-specific dystonia (occupational cramps) Other focal dystonias (idiopathic, secondary) Other Involuntary Movements Voice, head, and limb tremor Palatal myoclonus Hemifacial spasm Tics Other Inappropriate Contractions Strabismus, Nystagmus Myokymia, Bruxism (TMJ) Stuttering, Painful rigidity Muscle contraction & Migraine headaches Lumbosacral strain and back spasms Radiculopathy w/secondary muscle spasm Spasticity, Spastic bladder, Achalasia (esophageal) Pelvirectal spasms (anismus, vaginismus) Other spastic disorders Other Applications Protective ptosis, Essential hyperhidrosis Cosmetic (wrinkles, facial asymmetry) Bladder dysfunction, BPH, Debarking dogs...other

42 Spasmodic Dysphonia Adductor SD Bilateral BTX injections Unilateral BTX injections (more frequently) staggered bilateral injections more frequent mini dose BTX injections

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44 Spasmodic Dysphonia: BTX adductor breathing dystonia 12 patients treated dose to 3.75 U bilaterally average 55% improvement in breathing mean duration- 14 weeks

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46 Abductor SD PCA injection given percutaneously, posterior to the posterior thyroid lamina, through the inferior constrictor, and impaling the PCA over the cricoid PCA injection given percutaneously, through the cricothyroid membrane, through the rostrum of the cricoid and into the PCA

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48 Spasmodic Dysphonia: BTX abductor SD- (154 pts.) Unilateral PCA injection with 3.75 units After 2-3 weeks titrate U to 2.5U in the contralateral PCA 20% of patients need only unilateral dosing 12 patients had Type I thyroplasty + BTX 10 patients had Cricothyroid + PCA injected

49 Future Dystonia Treatment Therapy geared toward brain abnormalitytargeted specific drugs (eg. DRD) Phage interposition of gene deletion or removal of duplication Micro-electrode brain stimulation Stem cell implants in brain damaged areas

50 Future of Botulinum toxins Bioengineered, task specific toxins Recombinant Endopeptidases

51 Conclusion Spasmodic Dysphonia (Focal Laryngeal Dystonia) is a chronic disorder of the Central Nervous System for which there currently is no cure. Presently, the best therapy is aimed at controlling symptoms. Ultimately, there will be treatments available to modulate the CNS.