Dystonia and Tourette Syndrome Flashcards
Dystonia
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
Dystonia disorders
Group of disorders with very different etiology and pathophysiology
Classifications of dystonia
- generalized (whole body)
- segmental or focal (including torticollis,
blepharospasm, Writer’s cramp)
Dystonia triggers and length
- Continuous, episodic or fluctuating
- Triggered by specific acts (i.e. playing piano or writing) or by voluntary movements
- Exacerbated by stress and fatigue
Examples of focal dystonia
- 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.
Primary dystonia
occurs as an isolated sign in the absence of an identifiable neuropathological lesion or exogenous cause
Secondary dystonia
result from a lesion to the motor system
(mainly putamen or globus pallidum), and is typically accompanied by additional neurological signs
Primary dystonia is a _____, charcaterized by abnormal activity in multiple regions involved in ___ control and _____ including…
motor circuit disorder; motor control and sensorimotor integration
including spinal cord, brainstem, cerebellum, basal ganglia and
cerebral cortex
Pathophysiology of dystonia
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
Pathophysiology Task-specific dystonia
Specific motor programs may be disrupted causing task-specific dystonia
ex. writing or piano playing
Causes of sporadic dystonia
- 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
Genetic mutations associated with dystonia
- TORSIN A gene mutation
- missense mutations in D2 receptor gene
- L-DOPA responsive dystonia
TORSIN A gene mutation
- 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
L-Dopa-responsive dystonia (Segawa syndrome)
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
GTP-cyclohydrolase 1 (GCH1)
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)
L-dopa treatment for dystonia
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)
Targets of drugs for dystonia
Basal ganglia (l-dopa) Spinal cord and neuromuscular junctions (baclofen, benzo, botulinum toxin and anticolinergics)
Drugs that target the Spinal cord and neuromuscular junctions
AT neuromuscular junction - Botulinum toxin - anticholinergic (trihexyphenidyl) AT SC - baclofen - benzos (clonazepan)
Baclofen
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
Benzodiazepines
GABA-A receptor agonists
ex. clonazepan
- less effective than baclofen and anticholinergics and produces sedation.
Anticholinergic drugs
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
Botulinum toxin
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
How long does Botulinum toxin work
Clinical effects are seen within one week and last for 3-4 months.
Treatments of choice
- in kids: l-dopa (1st), anti-cholinergics (2)
- In adults: Anticholinergics (1st)
- for focal dystonia (ex. blepharospasm, oromandibular and cervical dystonia) –Botulinum toxin preferred
How Botulinum toxin work
Toxin is recognized and enodcytosed –> light chain of toxin cleaves specific SNARES (incl. SNAP-25, VAMP, Syntaxin) –> prevents synaptic fusion of vesicles to membrane
Tic
jerklike, coordinated stereotyped movements
Suppression of tics
Most tics can be suppressed for short periods, but this causes anxiety
Tourette’s syndrome (TS) definition
is a complex neurobehavioral disorder with
familial transmission–primarily motor, focal, phonic tics + OCD/ADHD
Tourette’s syndrome (TS) charcaterized by
- 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
TS pathophysiology
- 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
TS as a developmental disorder
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
TS affects __% of the population
1% but likely higher
People suppress it etc.
TS shares genetic susceptibility with ____
ASD and SCZ
Treatment of motor symptoms in TS
- Antipsychotic drugs
- Botulinum toxin focal injections
- SSRIs
Antipsychotic drugs in TS
D2 antagonists, e.g. haloperidol
are the most effective pharmacotherapy for TS
SSRIs in TS
ex. clomipramine, fluoxetine, sertraline
are effective in some individuals to treat obsessive-compulsive symptoms
Botulinum toxin in TS
Focal injections, often into face
used to prevent tics by preventing muscle movement
