1

Update on Dystonia,

Chorea, and Tics

Joseph Jankovic, MD Professor of Neurology, Distinguished Chair in Movement Disorders,

Director, Parkinson's Disease Center and Movement Disorders Clinic,

Department of Neurology, Baylor College of Medicine, Houston, Texas

Phenomenology and classification of dystonia: A consensus update.

Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK.

Mov Disord 2013;28:863-73

• Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.

• Dystonic movements are typically patterned and twisting. • Dystonia is often initiated or worsened by voluntary action

and associated with overflow muscle activation. • Some forms of dystonia, such as blepharospasm and

laryngeal dystonia, are not associated with postures, but are characterized by focal involuntary contractions that interfere with physiological opening or closing of the eyelids or the larynx.

• Dystonia is classified along two axes: 1. Clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features)

2. Etiology, which includes nervous system pathology and inheritance.

The prevalence of primary dystonia: A systematic review and meta‐analysis

Steeves et al. Mov Disord 2012;27:1789-96

Genetic Classification of Dystonias Primary Dystonias

Classification

Chromosome Gene mutation Gene product

Pattern of inheritance

Onset

Distribution, additional features

Origin

Comment

DYT1 9q34, GAG deletion,

TOR1A/TorsinA

AD C Distal limbs, generalized Penetrance: 30% AJ, 70% NJ

DYT2 NM AR Spanish gypsies, Iranian Jews

DYT6 8q21-22

THAP1 AD A, C Cervical, cranial, brachial German-American

Mennonite-Amish

DYT7 18p AD A Cervical, cranial, spasmodic dysphonia, hand tremor German

DYT13 1p36.13-32 AD A, C Cranial-cervical and upper limb Italian

DYT17 20p11.22-q13.12 AR C Cervical dystonia, dysphonia, segmental, generalized Lebanese

DYT21 2q14.3-q21.3 AD A Late-onset Sweden

DYT23 9q34.11,CIZ1 AD A Cervical Caucasians

DYT24 3, ANO3 AD A Cranial-cervical-laryngeal, tremor, myoclonus European

DYT25 18p, GNAL AD A Cervical>cranial>arm European

A = adult onset; AJ = Ashkenazi Jewish; AD = autosomal dominant; AR = autosomal recessive; C = childhood onset; NJ = Non-Jewish; NM = not mapped yet

Genetic Classification of Dystonias Dystonia Plus Syndromes

Classification

Chromosome Gene mutation Gene product

Pattern of inheritance

Onset

Distribution, additional features

Origin

Comment

DYT3 Xq TAF1

XR A Parkinsonism Filipinos (Lubag) mosaic striatal

gliosis

DYT4 19p13.3-p13.2 TUBB4 (β-tubulin 4a)

AD C,A Whispering dysphonia,

cranial, cervical, limb, facial atrophy, ptosis, edentulous

Australian

DYT5a

14q22.1

GCH1/GTP cyclohydrolase I

AD

C Gait disorder, parkinsonism, myoclonus, spasticity

Dopa-responsive dystonia, diurnal

fluctuation

DYT5b 11p15.5 tyrosine hydroxylase

AR C Gait disorder, parkinsonism,

myoclonus, spasticity Dopa-responsive dystonia, diurnal

fluctuation

DYT11 7q21-31 SGCE

ε-sarcoglycan AD C Myoclonus, behavioral and

psychiatric problems Alcohol-responsive

DYT12 19q12-13.2

ATP1A3 Na/K-ATPase α3

subunit

AD A, C Cranial, upper limbs,

parkinsonism, depression, seizures

Rapid-onset, triggered by stress

DYT15 18p11 AD C Myoclonus Canadian

DYT16

2q31.2 PRKRA

protein kinase, interferon-inducible

double-stranded RNA-dependent

activator

AR C Dystonia, axial,

oromandibular, laryngeal, parkinsonism

Brazilian, German

2

Paroxysmal Dyskinesias

PKD DYT10/19

PNKD DYT8/20

PED DYT9/18

16p11.2-q12.1 (IC)

proline-rich transmembrane protein 2 gene (PRRT2)

Infantile convulsions, migraine, episodic ataxia

Anticonvulsants

2q33-35 (PNKD)

10q22

(α-subunit of a Ca-sensitive K channel, KCNMA1)

Clonazepam

16p12-q12 (ICCA)

1p35-p31

glucose transporter type 1 (GLUT1) (SLC2A1)

Anticonvulsants, levodopa, BoNT

The genetics of dystonia: new twists in an old tale. Charlesworth et al. Brain 2013;136:2017-37

• In the past few years, with the advent of new sequencing

technologies, there has been a step change in the pace of

discovery in the field of dystonia genetics.

• In just over a year, four new genes have been shown to

cause primary dystonia (CIZ1, ANO3, TUBB4A and GNAL)

• PRRT2 has been identified as the cause of paroxysmal

kinesigenic dystonia

• Other genes, such as SLC30A10 and ATP1A3, have been

linked to more complicated forms of dystonia or new

phenotypes.

A workable strategy for identifying the likely genetic basis for some of the major forms of dystonia

Charlesworth et al. Brain 2013;136:2017-37

Genetics and Pathophysiology of Neurodegeneration with

Brain Iron Accumulation (NBIA) Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP.

Curr Neuropharmacol 2013;11:59-79

Condition (Acronym) Synonym Gene Chromosomal

position

PKAN NBIA1 PANK2 20p13

PLAN NBIA2, PARK14 PLA2G6 22q12

FAHN SPG35 FA2H 16q23

MPAN -- C19orf12 19q12

Kufor-Rakeb disease PARK9 ATP13A2 1p36

Aceruloplasminemia -- CP 3q23

Neuroferritinopathy -- FTL 19q13

BPAN (SENDA)

-- n.k. n.k.

Idiopathic late-onset

cases

-- Probably

heterogene

ous

Probably

heterogeneous

Distinguishing features in different types of NBIA. aCP = aceruloplasminemia; BPAN = beta-propeller protein-associated neurodegeneration;

FAHN = fatty acid hydroxylase-associated neurodegeneration; INAD = infantile neuroaxonal

dystrophy; KRD = Kufor-Rakeb disease; MPAN = mitochondrial membrane protein-associated

neurodegeneration; PKAN = pantothenate kinase associated neurodegeneration; WSS =

Woodhouse-Sakati syndrome.

Horvath. Brain 2013;136:1687-91

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation.

McNeill et al. Neurology 2008;70:1614-9

PKAN

17 y/o

Infantile

Neuroaxonal

Dystrophy

9 y/o

Neuro-

ferritinopathy

69 y/o

Acerulo-

plasminemia

55 y/o

T2* MRI Scan

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PKAN

17 y/o

Infantile

Neuroaxonal

Dystrophy

9 y/o

Neuro-

ferritinopathy

69 y/o

Acerulo-

plasminemia

55 y/o

Fast Spin Echo (FSE)

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation.

McNeill et al. Neurology 2008;70:1614-9

Levodopa

Anticholinergics

Tetrabenazine

Benzodiazepines

Selective

Peripheral

Denervation

Myectomy Pallidotomy

Deep Brain Stimulation

(Globus Pallidus)

Central

Surgeries

Peripheral

Surgeries

Botulinum

Toxin B

Botulinum

Toxin A

Physical and Occupational Therapy

Constraint Induced Therapy, rTMS

Dystonia

Oral Medications

Chemodenervation Surgical Therapies

Other Modalities

Jankovic J. Lancet Neurol 2009;8:844-56

Baclofen Oral, IT

Mov Disord 2013;28:1001-12

Huntington Disease

Movement Disorders

Behavioral Symptoms

Cognitive Decline

First Symptoms of Huntington Disease

Chorea 877 28

Trouble walking 262 9

Unsteadiness/imbalance 260 8

Difficult to get along with 167 5

Depression 165 5

Clumsiness 154 5

Speech difficulty 149 5

Memory loss 93 3

Trouble holding an object 62 2

Lack of motivation 53 2

Suspicions/paranoia 48 2

Intellectual decline 44 1

Changes in sleep 30 1

Hallucinations 23 1

Weight loss 20 0.6

Sexual problems 7 0.2

Other mental 363 12

Other physical 297 10

% of observed

Symptom # of Pts. * symptoms **

*Number of patients from a total of 1,901 with initial symptom information.

**Percent of all observed symptoms from a total of 3,086. Patients could report up to three initial symptoms.

Foroud et al. JNNP 1999;66:52-56 Ross and Tabrizi. Lancet Neurol 2011;10:83-98

Progression of Huntington Disease

4

Birth 10 20 30 40 50 60 70 0

Juvenile/adolescent onset

Early onset

Mid-life onset

Late onset

Clinical onset

Dis

ease

pro

gre

ssio

n

Age

Age-dependent Progression of HD

Birth 10 20 30 40 50 60 70

Age

Huntington Disease

5 – 15 years 15 – 30 years Duration

Dementia, dysarthria, abnormal eye movements, tremor, seizures, ataxia, myoclonus

Dementia, dysarthria,

abnormal eye

movements, dystonia,

rigidity

Late features

Personality changes,

rigidity, bradykinesia,

dystonia

Chorea, personality

changes

Initial features

AD (from the father) AD Inheritance

< 15 35 – 55 Age at onset

Juvenile onset Adult onset

CAG Repeats 37 – 50 >50

Normal HD Harris et al. Ann Neurol 1992;31:69-75

Normal HD

Atrophy: Putamen > Caudate

Medium-Sized Spiny Neuron

Projecting neurons

Interneurons (spared)

1

1

SNc SNr

GPe

GPi

2

3 GABA

Tachykinin

GABA

Substance P

GABA

Tachykinin

Ach, Somatostatin

• <40% loss of neurons in SN

• Neuronal intranuclear inclusions formed by

aggregation of the N-terminal huntingtin fragments

GABA

Enkephalin

STRIATUM

Pathology of Huntington Disease

(CAG)n

27-35 CAG repeats - “intermediate”

26 CAG repeats – “normal allele”

40 CAG repeats – “inevitable” HD

> ~70 - juvenile onset HD

n

70

27

40

exon

tel

~210 Kb

cen

1 2 67 Encodes a 348 kD, 3,144 AA protein, “huntingtin“, Htt

In HD the polyglutamine segment near the NH2 is elongated

Huntingtin Gene Htt (IT15) – 4p16.3

36-39 CAG repeats - “reduced penetrance” 36

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Genetic Diagnostic Testing Autopsy-Proven Huntington Disease with 29 Trinucleotide Repeats

Kenney C, Powell S, Jankovic J. Mov Disord 2007;22:127-30

• 65 y/o man with a 5-year history of cognitive decline, chorea, inability to sustain tongue protrusion, gait and balance problems, MMSE 27/30

• 29/20 CAG repeats

• Additional studies were normal including CK, anti-cardiolipin Ab, ESR, thyroid function, blood smear for acanthocytes, and DNA analysis for dentatorubral-pallido-luysian atrophy

• Patient died after a fall during which he suffered SAH

• Autopsy: acute SAH in the right Sylvian fissure; thinning of the cortical ribbon, moderate gliosis and neuronal loss in the caudate and putamen, ubiquitin-positive neuronal intranuclear inclusions in the cortical and other areas

• Patient’s father, who died at age 79, had cognitive decline and involuntary movements. No other FHx of neurologic disorders

• The patient’s “asymptomatic”, 38 y/o, son has 32/19 CAG repeats

Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS.

Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, Young AB,

Shoulson I. Neurology 2013;80:2022-7

• The Prospective Huntington At Risk Observational Study (PHAROS)

enrolled adults at risk for HD, assessed every 9 months with the

UHDRS by investigators unaware of participants' gene status.

• 50 (5.1%) of the 983 participants had an intermediate allele (IA) (27-35

CAG repeats).

• The IA subjects were significantly worse on apathy and suicidal

ideation and on 5 of the 9 other behavioral items and on total behavior

scores than controls and expanded participants.

• CONCLUSIONS: In a cohort at risk for HD, the IA was associated with

significant behavioral abnormalities but normal motor and cognition.

This behavioral phenotype may represent a prodromal stage of HD,

with the potential for subsequent clinical manifestations, or be part of a

distinct phenotype conferred by pathology independent of the CAG

expansion length.

Mov Disord 2012;27:1714-7

A Randomized, Double-Blind, Placebo-Controlled Trial of Tetrabenazine as Antichorea Therapy in

Huntington’s Disease (TETRA-HD)

• N = 84 HD subjects randomized, 16 centers

• Tetrabenazine (n = 54) or placebo (n = 30)

• Dosage increased over 7 weeks up to 8 tablets (100 mg) daily, until the desired antichoreic effect or intolerable side effects occurred

• During the last 5 weeks of the study, the dosage remained constant (unless reduced because of intolerable adverse effects)

• Primary outcome: change from baseline in UHDRS chorea score

• Secondary outcomes: CGI, the UHDRS total motor score, functional scales, gait score, tolerability, and safety

Huntington Study Group. Mov Disord 2006;11:136-142

Mean Change in UHDRS Total Maximal Chorea Score (Primary Study Endpoint: From Baseline to Week 12)

TETRA-HD

ANCOVA=analysis of covariance; ITT-LOC=intent-to-treat analysis.

There was blinded washout of study drug at week 12. Change favors tetrabenazine

(P=0.0001; ANCOVA, ITT-LOC). Chorea Scale range: 0 to 28

Week

Ch

ore

a

-2 0 2 4 6 8 10 12 14 16

-6

-5

-4

-3

-2

-1

0

1

Placebo

Tetrabenazine

N = 84 (TBZ = 54, placebo = 30)

Mean score decline (UHDRS units): 5.0 (TBZ) vs 1.5 (placebo) (p < 0.0001)

Huntington Study Group. Mov Disord 2006;11:136-142

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Expert Opinion on Orphan Drugs 2013

• Tetrabenazine (TBZ) is a centrally-acting, dopamine depleting drug that has

been used for treatment of hyperkinetic movement disorders but was not

commercially available in the United States until 2008, when the Food and Drug

Administration (FDA) approved TBZ for the management of chorea associated

with Huntington’s disease (HD) under an orphan drug designation.

• While sedation, insomnia, mood changes, parkinsonism, and restlessness may

occur, these adverse effects can be managed effectively with appropriate

titration and monitoring. A black box warning against depression and

suicidality warrants careful patient selection, close monitoring and judicious

use of antidepressants.

• TBZ possesses a unique mechanism of action as a presynaptic dopamine

depletor that offers possible advantages over dopamine receptor blocking

drugs.

• TBZ has a strong potential for application in other hyperkinetic movement

disorders, particularly tardive dyskinesia and Tourette syndrome, but

randomized, controlled clinical trials are lacking.

Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 2009;8:844-56

Experimental Therapeutics • Pridopidine (ACR16; Huntexil,

“dopaminergic stabilizer”)

(MermaiHD and HART trials)

• Ethyl-EPA (Miraxion)

• Latrepirdine (Dimebon)

(DIMOND and HORIZON trials)

• Creatine, CoQ10, Lithium

• Selististat (sirtuin deacetylase),

• Histone deacetylase inhibitors

(HDACi 4b)

• Phosphodiesterase PDE10A

inhibitors (TP-10)

• PBT2

• Ganglioside GM1

• Rhes inhibitors

• Neurturin

• Anti-htt Ab (intrabody)

• Small interfering (si) RNA

• Antisense oligonucleotides

• Cell replacement (fetal cells,

embryonic stem cells or

induced pluripotent cells)

Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 2009;8:844-56

N Engl J Med 2012;367:1753-4 Phenocopies of HD

• HDL1 – AD, seizures (prion protein, PRNP; 20p12)

• HDL2 – AD, no seizures (junctophilin, JPH3; 16q24.3)

• HDL3 – AR (4p16.3)

• DRPLA – AD (c-Jun NH-terminal kinase, JNK, 12p)

• Neuroacanthocytosis – AR (VPS13A, 9q21)

• McLeod syndrome – X-linked (HK, Xp21)

• Mitochondrial encephalomyopathies

• Benign hereditary chorea (NKX2-1/TITF-1, 14q13.1-q21.1)

• Ataxia-Chorea:

• SCA1(ataxin-1, CAG expansion, 6p23)

• SCA2 (ataxin-2, CAG expansion, 12q24.1)

• SCA17 (TATA-Box binding protein, CAG expansion, 6q27)

• Friedreich’s ataxia (frataxin, GAA expansion, 9p13)

• Ataxia telangiectasia (protein kinase PI-3, ATM gene, 11q22)

• Neurodegeneration with brain iron accumulation (NBIA)

• Psychogenic chorea

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ADHD

Tics

OCD

Behavioral problems poor impulse control, self-injurious behavior,

and other behavioral problems

TS

PLUS

Jankovic. Tourette's Syndrome. N Engl J Med 2001;345:1184-92

Tic Characteristics • Simple or complex movements (motor) or sounds (phonic)

• Jerk-like (clonic), dystonic, tonic, or blocking

• Premonitory feelings or sensations

• Intermittent

• Repetitive (stereotypic)

• Temporary suppressibility

• Suggestibility

• Increase with stress

• Increase during relaxation after stress

• Decrease with distraction and with concentration

• Waxing and waning, transient remissions

• Persist during sleep

Malignant Tourette Syndrome Cheung MC, Shahed J, Jankovic J. Mov Disord 2007;22:1743-50

• Malignant TS defined as ≥ 2 emergency room visits or ≥ 1

hospitalizations for TS symptoms or its associated

behavioral co-morbidities

• Of 332 TS patients evaluated during the three-year period,

17 (5.1%) met criteria for malignant TS

• Compared to patients with non-malignant TS, those with

malignant TS were significantly more likely to have a

personal history of obsessive compulsive

behavior/disorder, complex phonic tics, coprolalia,

copropraxia, self-injurious behavior, mood disorder,

suicidal ideation, and poor response to medications

In one patient with a “whiplash” tic causing compressive cervical myelopathy, we were able to reverse the neurological deficit with botulinum toxin injections into the cervical muscles. This treatment modality can be particularly effective and even life-saving in patients with tics manifested by severe, repetitive, neck extension. Such tics, if left untreated could results in secondary compressive myelopathy and quadraparesis.

Malignant Tourette Syndrome Cheung MC, Shahed J, Jankovic J. Mov Disord 2007;22:1743-50

Krauss JK, Jankovic J. Severe motor tics causing cervical myelopathy in Tourette’s syndrome. Mov Disord 1996;11:563-6

Age When Tic and OCD Symptoms Are at Their Worst

(N = 46)

(N = 19)

Bloch et al. Arch Pediatr Adolesc Med 2006;160:65-9

46 children with TS

Structured interview

at a mean age of 11.4

years and again

at 19.0 years

Tic and OCD Severity at Initial Assessment in Childhood (time 1) and Follow-up in Early Adulthood (time 2)

Tic Severity (N = 46) measured by the Yale Global Tic Severity Scale (YGTSS),

OCD (N = 19) by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS)

1/3 → remission IQ → OCD

Bloch et al. Arch Pediatr Adolesc Med 2006;160:65-9

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• We reviewed medical records of all new TS patients, ≥ 19 y/o on

initial evaluation, referred to our Movement Disorders Clinic over the

past 5 years, and compared them with 100 TS patients ≤18 y/o

• The mean age of 43 adult TS patients was 58.8 ± 6.7 years; the

mean age at initial visit of children with TS was 12.9 ±2.0 years

• Of the adult TS patients, 35 (81.4%) had a history of tics with onset

before age 18 (mean age at onset 8.5 ± 3.4 years); 8 (18.6%) reported

first occurrence of tics after age 18 (mean age at onset 37.8 ± 13.2

years); only 2 (4.7%) patients reported tic onset after age 50

• Conclusion: Adult TS largely represents re-emergence or

exacerbation of childhood-onset TS. During the course of TS,

phonic and complex motor tics, self-injurious behaviors, and ADHD

tend to improve, but facial, neck and trunk tics dominate the adult

TS phenotype.

Tourette Syndrome in Adults Jankovic J, Gelineau-Kattner R, Davidson A. Mov Disord 2010;25:2171-5

Widespread abnormality of the GABA-ergic system in Tourette syndrome.

Lerner et al. Brain 2012;135:1926-36

Decreased binding of [11C]flumazenil: bilateral ventral striatum (VS), bilateral thalamus (Th), right insula (Ins) and bilateral amygdala (Amg)

Increased binding of [11C]flumazenil: bilateral SN, left periaqueductal grey (PAG), right posterior cingulate cortex (PCC) (Cing) and bilateral cerebellum, dentate

nuclei (CB).

The bereitschaftspotential in jerky movement disorders.

van der Salm et al. J Neurol Neurosurg Psychiatry 2012;83:1162-7

6/14 TS patients had a BP prior to tics, two of which

were late BPs

TOURETTE SYNDROME Therapeutic Strategies

TICS

First Line Guanfacine

Tetrabenazine

Second Line

Fluphenazine, Risperidone Atypical Antipsychotics

Clonazepam Topiramate

BotulinumToxin Habit Reversal

Third Line Deep Brain Stimulation

OCD

First Line Cognitive Behavioral

Therapy

SSRI’s

Second Line Atypical Antipsychotics

ADHD

First Line Behavioral Therapy

Guanfacine

Second Line Clonidine

Methylphenidate

Other CNS stimulants

Atomoxetine

Third Line Deep Brain Stimulation

Jankovic, Kurlan.

Mov Disord 2011;26:1149-56

Deep Brain Stimulation for TS – Target Selection Viswanathan A, Jimenez-Shahed J, Baizabal-Carvallo F. Jankovic J.

Stereotact Funct Neurosurg 2012;90:213-24

Bilateral GPi DBS in TS Baylor College of Medicine

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Parkinson’s Disease Center and Movement Disorders Clinic

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