1. Dystonia Neurologist Dr. Park

2. 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

3. 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

4. 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

5. 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)

6. 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

7. 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

8. 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

9. 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

10. 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 20 yrs frequently onset in leg focal onset commonly generalized remain focal usually hereditary usually sporadic

11. 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

12. 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

13. Juvenile PD DRD Childhood PTD onset 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

14. 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

15. 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

16. 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

17. 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

18. 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)

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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)