Dystonia and Tourette Syndrome

Question 1

Dystonia

Answer 1

Involuntary, sustained, patterned and repetitive co-contraction of agonist and antagonist muscles, causing twisting movements or abnormal posture
- antag and agonist muscles contract at same time

Question 2

Dystonia disorders

Answer 2

Group of disorders with very different etiology and pathophysiology

Question 3

Classifications of dystonia

Answer 3

• generalized (whole body)
• segmental or focal (including torticollis,
  blepharospasm, Writer’s cramp)

Question 4

Dystonia triggers and length

Answer 4

• Continuous, episodic or fluctuating
• Triggered by specific acts (i.e. playing piano or writing) or by voluntary movements
• Exacerbated by stress and fatigue

Question 5

Examples of focal dystonia

Answer 5

• Writer’s cramp. Abnormal clenching of
  fingers occurs selectively during writing;
  the patient is otherwise normal.
• Dystonia of arm, neck and face,
  exacerbated during writing. Patient first
  developed writer’s cramp, but subsequently developed dystonia of the neck (torticollis) and face.
• Involuntary dystonic flexion of trunk
  and extension of neck (retrocollis) during
  gait.

Question 6

Primary dystonia

Answer 6

occurs as an isolated sign in the absence of an identifiable neuropathological lesion or exogenous cause

Question 7

Secondary dystonia

Answer 7

result from a lesion to the motor system

(mainly putamen or globus pallidum), and is typically accompanied by additional neurological signs

Question 8

Primary dystonia is a _____, charcaterized by abnormal activity in multiple regions involved in ___ control and _____ including…

Answer 8

motor circuit disorder; motor control and sensorimotor integration
including spinal cord, brainstem, cerebellum, basal ganglia and
cerebral cortex

Question 9

Pathophysiology of dystonia

Answer 9

Overall dystonia is considered the result of deficient inhibition in cortical and subcortical areas –> Abnormal synchronization of presynaptic inputs to agonist and antagonist motor neuron pools

Question 10

Pathophysiology Task-specific dystonia

Answer 10

Specific motor programs may be disrupted causing task-specific dystonia
ex. writing or piano playing

Question 11

Causes of sporadic dystonia

Answer 11

• Antipsychotic treatments causing D2 receptor blockade
• When unilateral it can be due to tumors, stroke or trauma
• Peripheral trauma or muscle overuse determining topographic reorganization and abnormal plasticity of the somatosensory
  cortex.
• Genetic mutations

Question 12

Genetic mutations associated with dystonia

Answer 12

• TORSIN A gene mutation
• missense mutations in D2 receptor gene
• L-DOPA responsive dystonia

Question 13

TORSIN A gene mutation

Answer 13

• Torsin A is an ER chaperone enriched in dopaminergic neurons
• involved in proper intracellular trafficking of Na+-K+ ATPase and GTP cyclohydrolase 1
  i. e. it is normally involved in trafiicking of membrane proteins –> mutations affect that

Question 14

L-Dopa-responsive dystonia (Segawa syndrome)

Answer 14

mutation in the GTP-cyclohydrolase 1 (GCH1) gene, which catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase (prevents DA production) lack of dopamine

Question 15

GTP-cyclohydrolase 1 (GCH1)

Answer 15

implicated in 2 genetic causes for dystonia (L-dopa responsive dystonia and Torsin A mutations)
Is a gene that forms the enzyme GTP-cyclohydrolase 1 (GCH1) which is an early enzyme in the formation of DA (the step from GTP to dihydronepoterin)

Question 16

L-dopa treatment for dystonia

Answer 16

L-dopa in dopa-responsive dystonia and other forms of earlyonset dystonia. 
Small doses (much lower doses than used in PD) may provide complete relief from symptoms (complete remission)

Question 17

Targets of drugs for dystonia

Answer 17

Basal ganglia (l-dopa)
Spinal cord and neuromuscular junctions (baclofen, benzo, botulinum toxin and anticolinergics)

Question 18

Drugs that target the Spinal cord and neuromuscular junctions

Answer 18

AT neuromuscular junction
- Botulinum toxin
- anticholinergic (trihexyphenidyl)
AT SC
- baclofen
- benzos (clonazepan)

Question 19

Baclofen

Answer 19

Derivative of GABA, works as a presynaptic GABA-B receptor agonist, producing
neuronal hyperpolarization
and pre-synaptic inhibition.
- Primarily used to treat spasticity.
- can’t cross the BBB so administered intrathecally in cases of severe dystonia

Question 20

Benzodiazepines

Answer 20

GABA-A receptor agonists

ex. clonazepan
- less effective than baclofen and anticholinergics and produces sedation.

Question 21

Anticholinergic drugs

Answer 21

ex. trihexyphenidyl = muscarinic acetylcholine receptor antagonist
- first choice for adults
- second for children after L-dopa
- Side effects include memory loss, confusion, hallucinations, sedation.
- Therapeutic response to anticholinergic therapy wanes over time

Question 22

Botulinum toxin

Answer 22

the treatment of choice for focal dystonia such as blepharospasm, oromandibular and cervical dystonia.
- Inhibits acetylcholine exocytosis at the
neromuscular junction (chemical
denervation)
- Injected directly into the dystonic muscles.
- Botulinum toxin resistance may arise due to
antibody development

Question 23

How long does Botulinum toxin work

Answer 23

Clinical effects are seen within one week and last for 3-4 months.

Question 24

Treatments of choice

Answer 24

• in kids: l-dopa (1st), anti-cholinergics (2)
• In adults: Anticholinergics (1st)
• for focal dystonia (ex. blepharospasm, oromandibular and cervical dystonia) –Botulinum toxin preferred

Question 25

How Botulinum toxin work

Answer 25

Toxin is recognized and enodcytosed –> light chain of toxin cleaves specific SNARES (incl. SNAP-25, VAMP, Syntaxin) –> prevents synaptic fusion of vesicles to membrane

Question 26

Tic

Answer 26

jerklike, coordinated stereotyped movements

Question 27

Suppression of tics

Answer 27

Most tics can be suppressed for short periods, but this causes anxiety

Question 28

Tourette’s syndrome (TS) definition

Answer 28

is a complex neurobehavioral disorder with

familial transmission–primarily motor, focal, phonic tics + OCD/ADHD

Question 29

Tourette’s syndrome (TS) charcaterized by

Answer 29

• motor, vocal or phonic tics
• OCD (“cognitive tics”), including self-injurious behaviour
• attention deficit-hyperactivity disorder (ADHD)
• coprolalia (shouting obscenities) in less than 50% of patients
• poor impulse control

Question 30

TS pathophysiology

Answer 30

• Involving dysfunction in several brain areas (frontal cortex, limbic system, thalamus, striatum etc)
• Reduced caudate volume in some patients.
• Reduced metabolic activity in striatum and thalamus consistent with a reduction in
  the indirect pathway

Question 31

TS as a developmental disorder

Answer 31

It may represent a developmental disorder resulting in dopaminergic hyper-innervation of the ventral striatum and associated limbic
system.
Also, number and distribution of interneurons might be affected

Question 32

TS affects __% of the population

Answer 32

1% but likely higher

People suppress it etc.

Question 33

TS shares genetic susceptibility with ____

Answer 33

ASD and SCZ

Question 34

Treatment of motor symptoms in TS

Answer 34

• Antipsychotic drugs
• Botulinum toxin focal injections
• SSRIs

Question 35

Antipsychotic drugs in TS

Answer 35

D2 antagonists, e.g. haloperidol

are the most effective pharmacotherapy for TS

Question 36

SSRIs in TS

Answer 36

ex. clomipramine, fluoxetine, sertraline

are effective in some individuals to treat obsessive-compulsive symptoms

Question 37

Botulinum toxin in TS

Answer 37

Focal injections, often into face

used to prevent tics by preventing muscle movement