Introduction to Movement Disorders Flashcards
which neurotransmitter is at the core of movement
dopamine
what are movement disorders sub-divided into
hypokinetic - too little movement
hyperkinetic - too much movement
what does multifocal degeneration often lead to
‘non-motor’ symptoms like in dementia, psychosis, sleep disorders and autonomic disorders
outline parkinsons disease epidmeiology
1 in 350 will get parkinsons
costing £2.9 billion pounds
outline the aetiology of parkinsons disease
hypokinetic neurodegenrative disease
cascade effect of dysfunctional proteins transferring onto neighbouring cells
alpha synuclein - begins in brain stem and substantia nigra, loss of core cells which project widely - mainly dopamine but also serotonin and adrenaline
outline the clinical presentation of parkinsons disease
varies depending on where disease begins e.g if in cortex causes cognitive problems like lewy body dementia, or if in brainstem causes autonomic dysfunction through, occipital area = visual problems
where does parkinsons manifest usually in the brain
parietal cortex - affects visuospatial functioning
how much of the substantia nigra can be lost before symptoms begin
90%
what is the main clinical feature of parkinsons
problem with initiating movement
what are the main structures of the basal ganglia relevant in parkinsons
striatum - caudate nucleus + putamen
lentiform nucleus - external globus pallidus and internal globus pallidus
outline the functional anatomy of the basal ganglia
four largely segregated parallel cortical loops
with some cross talk
link basal ganglia to the limbic system so movement selection is informed of emotional and motivational state to the frontal lobes involved in executive functioning and sensory cortex receiving proprioceptive feedback of motor activity
outline the direct pathway of movement in the basal ganglia
striatum to GPi directly
outline the indirect pathway of movement in the basal ganglia
striatum to Gpi indirectly via Gpe and STN (subthalamic nucleus)
outline direct pathway activation
GPi inhibition -> thalamic disinhibition -> cortical activation
outline indirect pathway activation
Gpi activation -> thalamic inhibition -> cortical inhibition
what are these basal ganglia loops sometimes compared to?
center surround phenomenon in the visual cortex - try to sharpen image and cant , same with sharpening movement
cant make movement precise
what does the direct pathway faciliate
it is the activation circuit, so faciliates the activation of desired movement pathways
what does the indirect pathway inhibit
it is the inhibitory circuit, inhibits activation of inappropriate/conflicting movement pathways
what does overactivity of the Gpi cause?
it’s preset mode is to inhibit, so it would be predicted to cause reduced activation of desired movements
BRADYKINESIA
what would underactivity of the GPi cause?
it’s preset mode is to inhibit so its predicted to cause excessive activation of undesired movement
CHOREA
what are the key features of parkinsonism
bradykinesia
associated with muscle ridgidity, asymmetric resting tremor, postural instability
what are some causes of parkinsonism
parkinsons disease
drugs (anti-dopaminergics)
cerebrovascular disease
structural lesions of basal ganglia
‘parkinsons plus’ syndromes (MSA, PSP, DLB)
outline the clinical signs of parkinsonism
tremor - rest tremor (rotary) or pill rolling (thumb and index)
bradykinesia = slow movement
problem with initiating movement -> basal ganglia doesnt allow initial release of movement
re-emerging tremor - they can extend hand with no tremor but complex after a while
outline the epidemiology of tremor
80% of patients experience tremor
most commonly affects hands and arms
may become severe with strong emotions
generally most severe when limb is at rest and improves with movement
outline postural instability
appendicular (limb related) symptoms
dont respond well to medication
balance excerises are key - yoga, pilates, kick boxing - need to build a reserve early on so less likely to reach critical threshold e.g build up reactive movement
physical exercise is. akey disease modifier - aerobic and strength training
outline dopaminergic fibres in bradykinesia in the basal ganglia
- dopaminergic fibres stimulate the direct pathway - D1 receptors
- dopaminergic fibres inhibit the indirect pathway - D2 receptors
outline the pathways through which reduced cortical activity results in bradykinesia
direct pathway (activating) becomes underactive -> overactive Gpi
indirect pathway (inhibitory) becomes overactive ->overactive Gpi
overactive Gpi (inhibitory) inhibits motor thalamus and cortex
= bradykinesia
why does giving dopamine drugs to parkinsonism patients not work?
as dopamine is involved in other things like vomiting response and peripheral gut movement - unwanted side effects and not desired ones
what is the first drug given to parkinsonism patients
LEVO-DOPA
can cross BBB
taken up into nigral nuerones
decarboxylated into dopamine
released into synaptic cleft
activates post striatal dopamine receptors
really effective - patients start to walk again as replacing lost dopamine in substantia nigra but DOSE is important
what is the problem with administering levo dopa
acts on circuit so if it is degenerating, no matter how much dopamine you give it wont work
what is the see saw effect in neurology
dopamine can override the circuits going through the basal ganglia/cortex, so side effects can be psychosis and cognitive effects as they use dopamine antagonist
what are some dopamine agonists
ropinirole
pramipexole
outline deep brain stimulation for treatment of parkinsonism
stimulation frequency and amplitude titrated against clinical imapairment
stimulating electrode blocks firing of neurons in its vicinity
DBS of the STN and GPi is a very effective treatment for advanced parkinsons disease
outline how deep brain stimulation works on the basal ganglia cortical circuit that causes bradykinesia
parkinsonism is caused by over-inhibition of motor thalamus
using DBS blocks output of STN or Gpi and reduces level of inhibition which improves bradykinesia
outline oscillatory activity in the basal ganglia of parkinsonism patients
excessive beta oscillations (10-30Hz) seen in PD patients measured by DBS electrode
drug induced improvement correlates with degree of synchronisation suppression
stimulation of STN at non-therapeutic 10-20Hz frequencies WORSENS bradykinesia
what does strong extensive synchronisation of beta band oscillations prevent
neurons coding information in time and space, both adjacent and spatially distributed neurons are locked into beta rhythm
oscillations cause disturbed cortical activation that degrades movement
what are problems with the standard model of the basal ganglia
direct and indirect pathways are far less distinct than originally believed - lot of COLLATERALISATION
- lesion of motor thalamus doesnt lead to parkinsonism
- lesion of Gpe predicted to cause chorea, but doesnt
- evidence shows basal ganglia could be more active during motor learning than motor activation
outline chorea
unpatterned, excessive movement
caused by dopamine
what is a myoclonus
sudden jerks of movement
e,g like when we are falling asleep
what is the prototypical form of chorea
huntingtons chorea
genetic condition excess of huntington gene leading to accumulation of huntington protein on caudate nucleus - results in chorea
anterior caudate nucleus function is thinking and behaviour so huntingtons patients usually demented
whats another way you can develop chorea?
sydenhams chorea
from streptococcus - different time course e.g someone has sore throat and then has abnormal movement
outline huntingtons disease
autosomal dominant neurodegenerative disorder
symptom onset is midle age
clinical features:
- chorea
- dementia
- anxiety and depression
outline the genetics of huntingtons disease
gene - Chr 4p
CAG (polyglutamine) repeat at N-terminus = explains 60% of onset age variability , more repeats = younger onset
<36 repeats = unaffected
> 40 = full penetrance
what is the aetiology of huntingtons disease
intranuclear inclusions
increased inclusion length promotes proteolysis and aggregation of huntington fragments
exceeds capacity of cell to clear via autphagy and proteasomes
inclusions are seen but small aggregates may be more pathological
outline the brain pathology of huntingtons disease
atrophy of striatum (caudate and putamen)
particularly affects spiny neurones projecting from putamen to GPe
outline the mechanism of chorea in the basal ganglia striatum circuit
degeneration of indirect pathway leads to disinhibition of motor thalamus and overactivation of inappropriate motor programs
what is dystonia
precision of movement is LOST
non-degenerative
just happens and manifests
= involuntary sustained muscle contractions leading to abnormal postures and repetitive movements
what are some examples of dystonia?
writing e.g writers cramp
spasmodic torticollis - neck muscles, cant move neck in one direction BUT if person touches face it gives sensory feedback, and forces basal ganglia to generate new circuit - neck moves head around
what are primary dystonias
genetic
young onset = generalised
late onset = usually focal
what are secondary dystonia
structural lesions
metabolic diseases
hereditary degenerative diseases
what % of dystonias are associated with degenerative diseases
25%
outline primary torsion dystonia
intially mapped to DYTI locus on Chr 8
gene codes for Torsin A - heat shock protein
only 30% penetrance
presents in childhood with lower limb dystonia
subsequent generalisation
what is the role of the basal ganglia in dystonia?
almost all lesions causing dystonia are in basal ganglia or thalamus
reduced functional activity and grey matter volume on MRI
neuronal activity in Gpi correlated with dystonic EMG activity
DBS of basal Gpi is an effective treatment
what is paired associative stimulation
pulses from median nerve stimulation timed to reach cortex 25ms before TMS pulse to thumb
after 90 pairs of pulses, cortical stimulation leads to enhanced thumb contractions
lasts for one hour and is specific to thumb
outline excessive neuroplasticity in dystonia patients
excessive plasticity could drive maladaptive reorganisation of cortical sensorimotor maps
so what is the mechanism of dystonia
excessive neuroplasticity :
- abnormal basal ganglia activity
- impaired surround inhibition
- dystonic movements
= supposedly
