Basal ganglia and movement disorders Flashcards
Main functions of basal ganglia
modulation of voluntary motor activity
balance of inhibitory/excitatory pathways, gives input to thalamus and from there to cortex
activity encodes for:
- decision to move
- direction/amplitude of movement
- motor expression of emotions
- making movemetns and behaviour more efficient (proceduralization)
circuits in basal ganglia
motor: controls body/eye movements
associative: higher level cognitive function
limbic: emotional/motivational processing
Thalamus main role
under chronic inhibition when we are not moving
want to move –> balance of inhibitory and excitatory circuits –> measured input to motor cortex, and measured movement
Release-inhibition model (Direct)
release tonic inhibition of thalamus –> increased excitation of motor cortex –> increased motor output
Release-inhibition model (Indirect)
inhibits output from thalamus –> decreased excitation of motor cortex –> reduced motor output
Function of direct/indirect pathways
happening simultaneously –> fine balance
Target-oriented, efficient movements are facilitated (direct)
superfluos competing movements are inhibited (indirect)
streamline movement –> target-oriented, efficient
Lesions to the Basal Ganglia
Parkinson’s: inhibition of motor output
Ballism/Huntington’s: excessive motor output
Ballism
hyperkinetic
large amplitude, non-rhythmic, sudden uncontrolled flinging movements of extremities
usually only occurs on one side (hemiballism)
underlying cause –> lesion/stroke of contralateral subthalamic nucleus
LOSS of indirect pathway –> no more suppression of superfluos movement
Huntington’s disease
hyperkinetic
deficits in cognition, behaviour and a characteristic hyperkinetic disorder
Brief, irregular unpredictable movements that move randomly from one part of body to another (Chorea)
Degeneration of striatum (caudate/putamen)
- damage to striatum: effects on both direct and indirect pathways
- direct pathway: loss of target-oriented, efficient movemetns
- indirect: subthalamus remains inhibited; no control over superfluous competing movements
CAG repeats on chromosome 4 –> abnormal amount of huntingtin
Parkinson’s disease
degeneration of dopaminergic neurons of substantia nigra
Direct: less inhibition of tonic inhibition of thalamus –> target oriented and efficient movements not facilitated
Indirect: GPe is inhibited, less inhibitory input to STN, more excitatoyr input to GPi, more inhibition of thalamus
Hypo/akinesia
Loss of facial expression - hypomimia
PD treatment options
L-Dopa
deep brain stimulation of subthalamic nucleus, restores tonic firing pattern from STN to GPi –> less inhibition of the thalamus
Motor circuit of basal ganglia fxn
motor performance and regulation of eye movemetns
both direct/indirect
measured and coordinated motor performance
regulation of gaze and orientation of eyes, amplitude of saccades
Associative circuit of basal ganglia fxn
participates in planning complex motor activity
when a novel task has been practiced/well-learned, activity in associative circuit decreases and motor circuit becomes more active
Limbic circuit of basal ganglia fxn
motor expression of emotion
postures, gestures and facial expresion related to emotion
rich in dopaminergic neurons - mask face in PD
Classification of movement disorders
Pyramidal syndromes
Basal ganglia disorders
Cerebellar disorders
Basal ganglia disorders
Parnkinsonian syndromes
Dyskinesias
Stereotyped movements
Cerebellar disorder characteristic
ataxia
Parkinsonian syndrome characteristics
akinesia
rigidity
Dyskinesias characteristics
chorea dystonia myoclonus tics tremor
Pyramidal symptoms
spasticity - velocity/direction dependent
weakness
paralysis
UMN (CST, corticobulbar)
extrapyramidal symptoms
rigidity
no overt weakness
insufficient/excessive/abnormal movements
“basal ganglia”
Basal ganglia lesion symptoms
no weakness no paralysis slowed movement/involuntary movement rigidity, not velocity dependent constant resistance throughout range of movement normal muscle tone normal reflexes
Basal ganglia structures
caudate-putamen (neostriatum)
Globus pallidus (external/internal)
substantia nigra (source of dopamine), pars reticulata, pars compacta
subthalamic nucleus
General approach to movement disorders
Identify pattern of abnormal movement
find out underlying cause, if any
treat underlying cause/give symptomatic therapy
Tremor
regular
repetitive
sinusoidal cycles
alternating contractions of antagonistic pairs of muscles
Clinical assessment of tremor
Topography - place
Activation condition (rest, posture, non-goal/goal-directed movements)
Frequency of tremor (Low 7)
Common causes of tremor
Enhanced physiological tremor - drugs, anxiety, hyperthyroidism
Essential tremor
Parkinson’s disease
Cerebellar disease
Anxiety and tremor
movement stretches agonist and causes an afferent volley eliciting reflexes in antagonistic extensors
when reflex gains and conduction times are appropriate, an oscillation will result
Adrenaline/thyroid hormoens sensitize muscle spindles –> stronger afferent volley, increases tremor amplitude
Activation condition of tremor
Intention - cerebellar
Postural - essential
Rest - Parkinson’s disease
Essential tremor core criteria
Bilateral action tremor of hands and forearms (but no rest tremor)
absence of other neurological signs except cogwheeling
ma have isolated head tremor with no abnormal posture
shouldn’t have slow movements
most common movement disorder
Essential tremor red flags
unilateral/focal/leg tremor gait disturbance rigidity bradykinesia rest tremor sudden/rapid onset current drug treatment that might cause/worsen tremor isolated head tremor with abnormal posture (head tilt/turning)
Essential tremor treatment first line
Propranolol
CI: cardiac, pulmonary, DM
Primidone: preferentially for patients >60
2nd line treatments for essential tremor
Gabapentin - conflicting results
Clonazepam - for predominant kinetic tremor
Topiramate - may work with as little as 50 mg/day
3rd line treatments for essential tremor
Clozapine - usually better for PD
Olanzapine - single open label trial
Last resort treatment for essential tremor
surgery
VIM thalamus stimulation
Essential tremor vs Parkinson’s disease
Tremor:
- Archimides’ spiral poor
- cogwheeling
- head/voice may be affected
- relatively symmetric
- writing large, tremulous
- typically better while walking
- often improves with alcohol
Parkinson’s disease features
TRAP Tremor: resting Rigidity Akinesia/bradykinesia Postural instability: relatively late presentation Masked face Micrographia
Pathology of Parkinson’s disease
loss of dopaminergic cells in substantia nigra (PET scan)
causes: genetics? toxins?
Genetic factors of Parkinson’s disease
increased risk in primary relatives twin studies - low concordance Recently many genes implicated in rare cases of PD that are strongly familial - alpha-synuclein - Parkin - LRRK2
Environmental factors of Parkinson’s disease
increased risk in people growing up in rural areas Toxins: - MPTP - Hydrocarbons - Manganese - methanol -cyanide - carbon disulfide - lacquer thinner - thiocarbamate - N-hexane - organochloride
Parkinson’s disease protective agents
Coffee
smoking
Early signs of PD
Anosmia Depression, anxiety REM sleep disorder masked faces micrographia stiffness, neck pain constipation - risk increased if
Early motor symptoms of PD
symptoms most predictive of PD (rather than atypical Parkinsonism)
Asymmetric onset of tremor/rigidity/bradykinesia
L-dopa responsiveness
note: 30% of PD patients do not have tremor
Parkinson’s plus/Parkinsonism
doesn't respond significantly to medications symptomatic treatment only Multiple infarcts --> vascular Parkinsonism Progressive supranuclear palsy (PSP) Multisystem atrophy: - striatonigral degeneration - shy-Drager - Olivopontocerebellar atrophy
Impulse control disorders in Parkinson’s
6-18% of PD subjects on dopamine agonists develop ICD
Pathological gambling
hypersexuality
compulsive shopping, eating
Levodopa
Levodopa therapy
prolongs survival
BUT problems of long-term complications, e.g. dyskinesia
disease progression and levodopa effectiveness
- symptoms and side effects occur as levodopa therapeutic window diminishes
GI problems: use carbidopa - prevents levodopa conversion to dopamine in gut to reduce GI symptoms; also doesn’t cross BBB, so only acts on gut
Surgical treatment of PD
Stereotaxic surgery: DBS, pallidotomy
Repalcement: fetal cell transplant, genetic engineered cell lines, human retinal cells
Supportive treatment of PD
physio
rehab
occupational modification
support groups
Chorea
irregular non-repetitive non-purposeful unpredictable smooth, flowing, fast/slow not suppressible
Causes of chorea
Huntington's disease Drugs - levodopa, neuroleptic drugs Infections Thyrotoxicosis Pregnancy
Huntington’s disease treatment
Chorea: anti-dopaminergic drugs - dopamine depleting agents preferred over dopamine receptor blockers
Dementia: no treatment
Counselling
Tic
irregular non-purposeful predictable in pattern but not in time stereotypic suppressible
Tourette’s syndrome
multiple tics
childhood onset
persistent for > 1 year
Coprolalia (involuntary swearing)
Tourette’s treatment
Anti-dopaminergic drugs
Dopamine depleting agents preferred > dopamine receptor blockers
Ballism
irregular non-repetitive non-purposeful unpredictable violent, proximal not suppressible Normally associated with damage to subthalamic nucleus
Causes/treatment for ballism
cerebrovascular (hemiballismus) infections tumors sedation develops into chorea - treatment with dopamine blocking agents
Dystonia
involuntary msucle contractions co-contraction of antagonists abnormal postures may be worse with specific actions disappears during sleep Classified by etiology, age of onset, anatomical
Dystonia - rule out
drug DOPA-responsive WIlson's Huntington's Structural lesions of the basal ganglia
Generalized dystonia
normal birth history, milestones autosomal dominant childhood onset starts in lower limbs, spread upwards also know as idiopathic torsion dystonia
Focal dystonia
eyelids face jaws neck voice upper limbs task-specific dystonia lower limb dystonia truncal dystonia
Task-specific dystonia
writer’s, musician’s, painter’s, golfer’s, dartsman’s, trapshooter’s cramps
Dystonia treatment of primary cause
treat primary cause if any
discontinue drugs if possible
DOPA for DOPA-responsive dystonia
Reduce copper if WIlson’s disease
Dystonia symptomatic treatment
Medications - usually don’t work very well
- anticholinergic, dopaminergic, anti-dopaminergic
- GAGA-ergic
- anticonvulsants
-baclofen
Botox: mainly focal
- blepharospasm, oromandibular, cervical, others
Surgical treatment of dystonia
myectomy
tenotomy
thalamotomy
?? DBS
Myoclonus
shock-like movements caused by sudden muscle contraction (positive myoclonus) or by muscle relaxation (negative myoclonus)
Asterexis is a type of negative myoclonus
Drug-induced movement disorders
Acute dystonic reactions Parkinsonism Akathisia Neuroleptic malignant syndrome Tardive dyskinesias
Acute dystonic reactions
within 96 hours of therapy
oculogyric crisis
seen in 2.3-21%, usually young males
mechanism unknown - related to greater activation of unblocked D1 receptors??
Effectively controlled by anticholinergics
Drug-induced Parkinsonism
Dopamine receptor blocking agents neuroleptics antiemetics (metoclopramide) Ca channel blockers (flunarizine) antihypertensives
Drug-induced akathisia
inability to remain seated
often seen with neuroleptic use
sensation of inner restlessness, dysphoria, anxiety
compulsion to move legs - walking on spot
may be associated with Parkinson’s disease
usually 1 hour after administration, but may be several weeks later
Neuroleptic malignant syndrome
uncommon, but canbe fatal
agitation, lethargy, confusion, delirium, stupor, coma
hyperthermia, tachypnea, BP changes
rigidity, akinesia, tremor, dystonia, chorea
seizures
elevated CK
myoglobinuria
may occur with first exposure to neuroleptics, or when re-instituting therapy after a long period of time
acute withdrawal of dopaminergic drugs
general supportive measures - management of hyperthermia, adequate hydration, dopamine agonists
Tardive syndrome
abnormal involuntary movement
exposure to causative agent within 6 mo of onset
persistence for at least 1 mo after stopping
minimum 3 mo exposure
Tardive dyskinesia: can get almost any movemetn disorder as a tardive phenomenom:
- dyskinesia
- dystonia
- tic
- akathisia
- tremor
- myoclonus
Treatment summary of movement disorders
tremor - PD: levodopa, dopamine agonists
Essential tremor - beta blockers, anticonvulsants
Chorea, tics, ballism: tetrabenazine (dopamine depleting agent)
dystonia: anticholinergics, botox
Braak hypothesis
Parkinson's disease selective neuronal death in brainstem caudo-rostrally progressive pattern 1, 2) autonomic/olfactory disturbances 3,4) sleep and motor 5, 6)emotional and cognitive disturbances
