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, feque

ntly 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 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(> 20 yrs)

• most often sporadic, remain focal type(no progress to generalized type)

Classification by distributionFocal 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 bo

dy

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 Late-onset

< 15 yrs > 20 yrs

frequently onset in leg focal onset

commonly generalized remain focal

usually hereditary 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 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 P

he/Tyr profile

Juvenile PD DRD Childhood PTDonset age rare < 8 infancy to 12 uncommon < 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

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 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

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 toxinBlepharospasm

• 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 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

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)