Transcript Dystonia Neurologist Dr. Park

Dystonia
Neurologist Dr. Park
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
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 : writer’s cramp, musician’s 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
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
Classification by age at onset
* most important single factor a/w prognosis of primary dystonia
the 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(> 20 yrs)
• most often sporadic, remain focal type(no progress to generalized type)
Classification by distribution
Focal dystonia
• blepharospasm, torticollis, oromandibular dystonia, spastic dysphonia, writer’s
cramp, occupational cramp
Segmental dystonia
• dystonia in the two or more contiguous parts of body
• e.g. Cranial+brachial, cranial+axial, cranial+cervical(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
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
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),
Huntington’s chorea, MJD, DRPLA
• Autosomal recessive
* Wilson’s disease, Niemann-Pick, Metachromatic leukodystrophy,
Homocystinuria, Ataxia telangiectasia, Hallervorden-Spatz disease,
Hartnup’s disease, Gangliosidosis, DRD
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
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
< 15 yrs
frequently onset in leg
commonly generalized
usually hereditary
Late-onset
> 20 yrs
focal onset
remain focal
usually sporadic
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
• Symptoms
Blepharospasm: 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
Dopa-responsive dystonia(I)
• Onset : 5-6 years old, girls > 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 test
phenylalnine 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
Juvenile PD
onset age
gender
initial Sx
rare < 8
male predom.
foot dystonia/PD
diurnal
no
bradykinesia
present
Anti-Ch
yes
response
Dopa R
yes
Dopa
mod to high
dosage
“off”
fluctuation
dyskinesia
prominent
FluoroDopa decreased
PET
CIT SPECT decreased
Phe load test normal
Prognosis
progressive
DRD
Childhood PTD
infancy to 12
Female predom.
leg dystonia
gait disorder
sometimes
present
yes
uncommon < 6
Equal
arm or leg dystonia
yes
very low
no or mild
high
uncommon
uncommon
normal
unknown
unknown
normal
decreased
abnormal
plateaus
normal
normal
usually worsen
no
no
yes
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
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
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 types
rhythmic 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
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
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)
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
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
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(writer’s cramp)
• benztropine, trihexyphenidyl
• Botox
• occupational therapy
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
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
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(< 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
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)
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
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
Cervical dystonia(II)
• Muscles involved in cervical dystonia
Muscle
Flexion
longus coli
bi
SCM
bi
scalene
bi
levator
scapulae
trapezius
splenius
capitis
post. Paraspinalis
Rotation
Tilt
contra
ipsi
ipsi
ipsi
ipsi
ipsi
Extension
Shoulder elevation
ipsi
ipsi
ipsi
bi
bi
ipsi
bi
ipsi
Cervical dystonis(III)
• Number of injected sites per muscle
* SCM(2 sites), scapulae & trapezius(more sites)
• Doses for each muscle
Muscle
longus coli
SCM
scalene
lavator scapulae
trapezius
splenius capitis
post.paraspinalis
(semispinalis capitis
& longissimus capitis)
Range of doses(units)
20-50
40-75
40-60
50-100
80-120
80-200
40-100
Average dose(units)
25
50
50
50
100
150
80