Dystonia Neurologist Dr. Park

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DystoniaNeurologist Dr. Park
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Definition of dystonia

• Oppenheim(1911) dystonia musculorum
  deformans, a syndrome in children with twisted
  posture, muscle spasms, bizarre walking
  progression of symtom, leading to sustained fixed
  postural deformity
• Flatau Sterling(1911) inherited disease
  progressive torsion spasm
• Derek Denny-Brown(1964) a fixed or relatively
  fixed attitude.
• Fahn et al(1987) a syndrome of sustained muscle
  contractions, fequently causing twisting
  repetitive movements, or abnormal postures

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Features of dystonic movements(I)

• Speed from slow to rapid, more often the
  latter myoclonic dystonia so fast,
  prolonged EMG burst on EMG myoclonus short
  duration burst on EMG
• Aggravated by voluntary movement, stress,
  emotional upset, fatigue Action dystonia
  dystonic movement with voluntary movement
  Task specific dystonia writers cramp,
  musicians cramp, chewing,
• 
  speaking
• paradoxical dystonia for dystonia at
  rest to be improved by active
• 
  movement mistake as akathisia
• Relieved by relaxation, hypnosis sleep
  diminished by tactile or proprioceptive sensory
  trick - a hand on the chin or side of face
  in torticollis - touching the lips or placing
  an object in the mouth in oro-lingual dystonia

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Features of dystonic movements(II)

• Spreading to contiguous body parts the younger,
  the more likely
• Pain uncommon except cervical dystonia 75
  of Pts of cervical dystonia
• Dystonic storms a crisis of sudden marked
  increase in severity
  rhabdomyolysis myoglobinuria

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Classification by age at onset

• most important single factor a/w prognosis of
  primary dystoniathe younger age at onset, the
  more severe the more spread
• Childhood-onset(0-12 yrs)
• most often hereditary probably autosomal
  dominant with incomplete penetrance
• progress to generalized type
• Adolescent-onset(13-20 yrs)
• Adult-onset(gt 20 yrs)
• most often sporadic, remain focal type(no
  progress to generalized type)

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Classification by distribution

• Focal dystonia
• blepharospasm, torticollis, oromandibular
  dystonia, spastic dysphonia, writers cramp,
  occupational cramp
• Segmental dystonia
• dystonia in the two or more contiguous parts of
  body
• e.g. Cranialbrachial, cranialaxial,
  cranialcervical(Meige syndrome)
• Generalized dystonia
• Involves several body areas on both sides of the
  body
• a combination of leg involvement plus involvement
  of any other area of the body
• Multifocal dystonia
• two or more noncontiguous parts of the body
• Hemidystonia
• affect one-half of the body
• symptomatic rather than primary

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Classification by etiology(I)

• Primary dystonia(ITD, dystonia musculorum
  deformans)
• no known underlying brain lesion
• hereditary idiopathic form
• the only neurologic abnormalities dystonia
• Secondary dystonia
• CP, delayed-onset dystonia, encephalitis, CJD,
  SSPE, HIV infection
• head trauma, primary antiphospholipid syndrome,
  AVM, hypoxis, stroke
• brain tumor, MS, CPM, spinal cord injury,
  psychogenic
• Drug-induced levodopa, ergotamine, AED,
  dopamine D2 Rc blocking agent(butyrophenone,
  phenothiazine, tetrobenazine)
• toxin(Mn, CO, carbon disulfide, cyanide,
  disulfiram), hypoparathyroidism

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Classification by etiology(II)

• Dystonia-plus syndrome
• dystonia a/w parkinsonism or myoclonus without
  known neurodegeneration
• DRD myoclonic dystonia(neurochemical disorder)
• Heredodegenerative disease
• X-linked recessive Lubag DYT3 gene(Xq 13),
  filipino male, young adult onset, cranial
• dystonia, parkinsonism
• Autosomal dominant Rapid-onset
  dystonia-parkinsonism(RDP) adolescent adult
  onset Juvenile parkinsonism(Early-onset
  parkinsonism with dystonia),
• Huntingtons chorea, MJD, DRPLA
• Autosomal recessive Wilsons disease,
  Niemann-Pick, Metachromatic leukodystrophy,
  Homocystinuria, Ataxia telangiectasia,
  Hallervorden-Spatz disease, Hartnups disease,
  Gangliosidosis, DRD

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Dystonia-Parkinsonism

• Long-term S/E of Levodopa
• Hemiparkinsonism-hemiatrophy syndrome
• Lubag
• Juvenile parkinsonism
• DRD
• Corticobasal ganglionic degeneration(CBD)
• Multiple system atrophy(MSA)
• Progressive supranuclear palsy(PSP)
• Neuroacanthocytosis
• CO poisoning

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Idiopathic torsion dystonia(I)

• Dystonia without any other abnormal involuntary
  movement
• usually starts in childhood in limbs
• autosomal dominant with reduced penetrance(30-40
  )
• Gene DYT1, chromosome 9q34in non-jewish
  Ashkenazi Jewish
• Late-onset, cervical cranial-cervical onset
  genetic heterogeneity
• Early-onset
  Late-onset
• lt 15 yrs
  gt 20 yrs
• frequently onset in leg
  focal onset
• commonly generalized
  remain focal
• usually hereditary
  usually sporadic

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Idiopathic torsion dystonia(II) (adult type)

• Onset in 4th to 6th decades
• foci in the axial skeletal muscles(cranium and
  neck)
• rarely generalized
• insidious onset , gradual progression in the
  first few years
• SymptomsBlepharospasm rapid blinking of the
  eyelids
• Torticollis (wryneck) turning of the head
  to one side(sternocleidomastoid and
• 
  trapezius)
• Spasmodic dysphonia strained or breathy
  speech
• Oromandibular dystonia involuntary jaw
  opening/closing and tongue
• 
  movement
• "Writers Cramp" a dystonia affecting the
  hand and arm muscles, usually
• occurring with
  intended movement

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Dopa-responsive dystonia(I)

• Onset 5-6 years old, girls gt boys
• autosomal dominant inheritance with reduced
  penetrance
• Chromosome 14, point mutation in the gene for
  GTP(guanosine triphosphate) cyclohydrolase I
  rate limiting enzyme in formation of
  tetrahydrobioptern, cofactor of
• tyrosine hydroxylase phenylalanine
  hydroxylase
• focal dystonia, typically dystonia of lower limbs
  affecting gait
• diurnal variation no symptom in morning, worse
  at night worsen after exertion
• may develop concurrent parkinsonism
• markedly improve with low dose levodopa no
  adverse effects of response fluctuation despite
  long use
• Phenylalanine loading testphenylalnine
  ingestion(100mg/kg) ? sampling 1ml plasma 0, 1,
  2, 4, 6 hours later ? Phenylalanine levels peak
  at 2 hrs and are markedly elevated at 4 and 6 hrs
  compared to controls. Tyrosine levels do not
  increase at all ? increased Plasma Phe/Tyr
  profile

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• Juvenile PD
  DRD Childhood
  PTD
• onset age rare lt 8
  infancy to 12
  uncommon lt 6
• gender male predom.
  Female predom. Equal
• initial Sx foot dystonia/PD
  leg dystonia arm or
  leg dystonia
• 
  gait disorder
• diurnal no
  sometimes
  no
• bradykinesia present
  present no
• Anti-Ch yes
  yes
  yes
• response
• Dopa R yes
  yes
  no or mild
• Dopa mod to high
  very low high
• dosage
• off fluctuation
  uncommon
  unknown
• dyskinesia prominent
  uncommon unknown
• FluoroDopa decreased
  normal normal
• PET
• ?CIT SPECT decreased
  decreased normal
• Phe load test normal
  abnormal normal
• Prognosis progressive
  plateaus
  usually worsen

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Rapid-onset dystonia- parkinsonism(RDP)

• Autosomal dominant inheritance
• adolescent adult onset
• Clinical features sudden onset of dysarthria,
  dysphagia, severe dystonic spasm,
• bradykinesia postural instability over
  hours
• progress to generalized over hours to a
  few weeks
• normal cranial imaging
• involvement of dopaminergic system low CSF HVA
  concentration

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Myoclonic dystonia

• Autosomal dominant inheritance with reduced
  penetrance
• Rare varient of dystonia-plus syndrome
• dystonia myoclonus, predominantly in arms
  axial muscles
• onset adolescent or early adult
• extremely sensitive to alcohol

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Psychogenic dystonia(I)

• Clues relating to the movements
• abrup onset
• inconsistent movement
• incongruous movement(not fit with recognized
  pattern or normal physiological pattern)
• presence of additional typesrhythmic shaking,
  bizarre gait, excessive startle, deliberate
  slowness carrying out requested voluntary
  movement
• spantaneous remission
• disappear with distraction
• response to placebo
• dystonia beginning as a fixed posture
• presence as a paroxysmal disorder

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Psychogenic dystonia(II)

• Clues relating to the other medical observation
• false weakness
• false sensory complaints
• multiple somatization
• self-inflicted injury
• obvious psychiatric disturbance
• employed in the health profession or in insurance
  claims
• presence of secondary gain
• litigation or compensation pending

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Treatment of dystonia(I)

• Physical supportive therapy
• physical therapy brace improve posture
  prevent contracture
• 
  a substitute for a sensory trick
• muscle relaxation technique sensory feedback
  therapy adjunct
• Dopaminergic therapy
• in DRD, small dose of levodopa(100mgof levodopa
  with 25mg of decarboxylase inhibitor) also
  improve with anticholinergic carbamazepine
• in Pts with idiopathic or other types of dystonia
  rarely improved with dopaminergic therapy
• Antidopaminergic therapy
• usually limited(Jankovic, 1995)
• Tardive dystonia tetrabenazine, Risperidone(D2
  dopamine Rc blocking with high affinity for 5HT2
  Rc), Clozapine(D4 Rc blocking , relatively low
  affinity for D2 Rc, high affinity for 5-HT2A Rc)

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Treatment of dystonia(II)

• Anticholinergic therapy
• Trihexyphenidyl
• generalized segmental dystonia(Jabbari,
  1989)
• short duration before onset of therapy
  favorable response
• start with 2 mg ? slowly increase up to
  12 mg/D over next 4 weeks
• ? switch to SR preparation
• S/E dose-related drowsiness, confusion,
  memory difficulty, hallucination
• Other pharmacologic therapy
• Benzodiazepine(clonazepam or lorazepam)
  additional effect in case of unsatisfactory
  anticholinergic response clonazepam useful
  for blepharospasm with myoclonic dystonia
• Baclofen helpful for oromandibular dystonia
  intrathecal baclofen more effective in dystonia
  with spasticity or pain

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Treatment of dystonia(III)

• Peripheral deafferentiation somatosensory input
  in the pathogenesis of dystonia 5-10 ml of 0.5
  lidocaine
• Kinesigenic paroxysmal dystonia
  AED(carbamazepine, phenytoin)
• non-kinesigenic paroxysmal dystonia clonazepam,
  acetazolamide

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Treatment of dystonia(IV)

• Blepharospasm
  
• clonazepam, lorazepam
• Botox
• trihexyphenidyl
• orbicularis oculi myectomy
• Oromandibular dystonia
• baclofen
• trihexyphenidyl
• Botox
• Spasmodic dysphonia
• Botox

• Cervical
• trihexyphenidyl
• diazepam, lorazepam, clonazepam
• Botox
• tetrabenazine
• carbamazepine
• baclofen
• Task-specific dystonia(writers cramp)
• benztropine, trihexyphenidyl
• Botox
• occupational therapy

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Treatment of dystonia(V)

• Segmental generalized dystonia
• levodopa(in child-young adults)
• trihexyphenidyl, benztropine
• diazepam, lorazepam, clonazepam
• baclofen
• carbamazepine
• tetrabenazine(with lithium)
• triple therapy tetrabenazine, fluphenazine,
  trihexyphenidyl
• intrathecal baclofen infusion
• thalamotomy

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Botulium 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

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Botulium 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(lt 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

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Botulium toxin(III)

• Dilution of Botox
• with 0.9 Sodium Chloride Injection, store in a
  refrigerator
• 100 U/vial
• added dilutent
  Resulting dose Units per 0.1 mL
• 1.0 mL
  10 U
• 2.0 mL
  5 U
• 4.0 mL
  2.5 U
• 8.0 mL
  1.25 U
• Antibody against Botox
• 4.3 - 10.5
• For long term response minimal effective dose
  maximize treatment interval( at least 1 month)
  minimize protein expose(less boosters)

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Botulium toxin

• Blepharospasm
• moderate or marked improvement in 94
• average improvement latency 4.2 days,
• average duration of maximum benefit 12.4 wks
• Injection
• orbicularis oculi, avoid inf. Med.
  Part(lacrimal duct) central upper
• lid(levator palpebra)
• pretarsal rather than preseptal portion of
  orbicularis oculi
• 5 U in each site in the upper lid 5 U in the
  lower lid laterally only hemifacial spasm
  older people less

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• 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
• Writers 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

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• 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

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• Cervical dystonia(II)
• Muscles involved in cervical dystonia
• Muscle Flexion Rotation
  Tilt Extension Shoulder elevation
  
• longus coli bi
• SCM bi contra
  ipsi
• scalene bi
  ipsi
• levator
  ipsi
  ipsi
• scapulae
• trapezius ipsi
  ipsi bi ipsi
• splenius ipsi
  ipsi bi
• capitis
• post. Paraspinalis
  ipsi bi

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• Cervical dystonis(III)
• Number of injected sites per muscle SCM(2
  sites), scapulae trapezius(more sites)
• Doses for each muscle
• Muscle Range of
  doses(units) Average dose(units)
• longus coli 20-50
  25
• SCM 40-75
  50
• scalene 40-60
  50
• lavator scapulae 50-100
  50
• trapezius 80-120
  100
• splenius capitis 80-200
  150
• post.paraspinalis 40-100
  80
• (semispinalis capitis
• longissimus capitis)