EXTRAPYRAMIDAL DISORDERS Flashcards
Function of the basal ganglia?
It’s like a collection of brakes or accelerators
To fine-tune voluntary movements
It recieves impulses fron the cerebral cortex, processes them and adjusts them and then covey this infromation to the thalamus and then back to the cortex
Ultimately the fine-tuned movement instruction is sent to skeletal muscles via the spinal cord
Also involves in planning, modulation of movements, memory, eye movements, reward processing and motivation
Components of the basal ganglia?
Caudate nucleus
Putamen
Nucleus accumbens and olfactory tubercle
Globus pallidus
Subthalamic nucleus
Substantia nigra
Which part of the striatum is part of the basal ganglia?
The dorsal striatum
What are the 2 components of the striatum?
The caudate nucleus and the putamen
What forms the corpus striatum?
The striatum and the globus pallidus
Input nuclei of the basal ganglia?
The striatum and the caudate nucleus
What is the nucleus accumbens?
The most cranial aspect of the striatum where the caudate nucleus and the putamen join together
Function of striatum?
It recieve excitatory glutamatergic inputs from the cerebral cortex.
The synapsing pattern reflects topography of the cortex e.g. caudal parts of the cortex project to the caudal part of the brain the striatum
Structure of the caudate nucleus?
Consists of a head, tail and the body
Terminates by connecting with the amygdala at the tail of the caudate nucleus
Function of the caudate nucleus?
Integrates sensory information about the spatial position of the body and according to that sends infromation about necessary fine tunes of motor response to that stimuli to the thalamus
Also contributes to body & limb posture and speed &accurary of directed movements
Intrinsic nuclei of the basal ganglia?
External globus pallidus
Subthalamic nuclei
Pars compacta of the substantia nigra
Output nuclei of the basal ganglia?
Internal globus pallidus
Pars reticulata of the substantia nigra
Function of putamen?
To regulate motor functions and influence various types of learning
It uses dopamine
What are the 2 divisions of the globus pallidus?
The internal globus pallidus and the external globus pallidus
What are the 2 components of the substantia nigra?
The pars compacta and the pars reticulata
Function of the substantia nigra pars compacta?
Output to the basal ganglia circuit, supplying the striatum with dopamine through specific D1 and D2 neurones within the nigrostriatal pathways
Function of the substantia nigra pars reticulata?
Serves as input - conveys signals from the basal ganglia to the thalamus
Why does the substantia nigra have a dark appearance?
Due to the neuromelanin present in the cells in the pars compacta
Arterial supply to the basal ganglia?
Middle cerebral artery - main aretry is the lenticulostriate artery
Direct pathway of basal ganglia structure
Glutamate neurones project from the thalamus to motor regions of cerebral cortex = excitatory = stimulates movement
Neurones from the globus pallidus internal and substantia nigra pars reticulata project to the thalamus and release GABA = inhibition = suppression of movement to prevent unwanted movements from occurring
Infromation from movement is sent from cortex to striatum via the corticostriatal pathway. Glutamate nuyerones excite neurons on the striatum. Activated stiatam neurones release GABA in the globus pallidus internal and substantia nigra pars reticulata = inhibition of these regions = stops inhibition of neurones in the thalamus which are involved in movement = movement can occur!
Neurones from the substantia nigra pars compacta travel to the striatum via the nigrostriatal pathway and release dopamine in the striatum = facilitates activity in direct pathway
Indirect pathway of the basal ganglia structure
GABA neurones project from globus pallidus external to the Subthalamic nucleus = inhibition on glutamate neurones in Subthalamic nucleus
Signals from cerebral cortex causes activation of GABA neurones in the striatum which projects to the globus pallidus external and inhibits thr activity of neurones there. This prevents globus pallidus external neurones from inhibiting the neurones in the Subthalamic nucleus
Projections from the cortex activate the Subthalamic nucleus neurones and stimulate GABA neurones in the globus pallidus internal and substantia nigra pars reticulata = project to the thalamus = inhibits thalamic neurones that travel the motor regions of the cerebral cortex to stimulate movement = therefore inhibits movement
This antagonises the activity of the direct pathway and acts to keep unwanted movements from occurring
Neurones from the substantia nigra pars compacta travel to the striatum via the nigrostriatal pathway. These can modulate the activity of the indirect pathway through dopamine release in the striatum = inhibition of activity in indirect pathway = facilitation of movement
What broadly causes movement disrders?
Disturbance of the cerebellum and extrapyramidal system e.g. basal ganglia, thalamus, Subthalamic nuclei and red nucleus
Positive symptoms of movement disorders?
Chorea
Athetosis
Ballismus
Dystonia
Tremor
Rigidity
(Due to disinhibition of undamaged parts of the motor system)
Negative symptoms of movement disorders?
Hypokinesia and bradykinesia
What is a tremor?
An involuntary, regular, rhythmic, oscillatory movement produced by alternating or irregularly synchronous contractions of antagonistic muscles
Types of tremor?
Physiological
Exaggerated physiological e.g. thyrotoxicosis or anxiety
Essential tremor
Dystonic tremor
Cerebellar tremor
Parkinsonian tremor
Functional tremor
What is an essential tremor?
An autosomal dominant condition that affects both upper limbs usually
There is often a strong FHx
Features of an essential tremor?
It’s a postural tremor i.e. worse if arms are outstretched
Improved by alcohol and rest
It’s the most common cause of titubation (a head tremor)
Why does alcohol improve an essential tremor?
Alcohol enhances GABA which is inhibitors and dampens the excessive firing of neurones
Management of essential tremor?
Propranolol first line
What is titubation?
Head tremor
Type of tremor seen in parkinsonism?
Resting, pill-rolling tremor
Causes of tremor?
Parkinsonism
Essential tremor
Anxiety
Thyrotoxicosis
Hepatic encephalopathy
CO retention
Cerebellar disease
Drug withdrawal e.g. alcohol or opiates
What type of tremor does cerebellar disease cause/
An intention tremor
What is an intention tremor?
Involuntary, thyroid muscle contractions that occur during purposeful, voluntary movement e.g. reaching for something
Most commonly affects the upper limbs
What is myoclonus?
A brief, involuntary, shock-like contraction of a group of muscles; Irregular in rhythm and amplitude, asynchronous and asyemmetrical
Can cause whole body to jerk or just an area
Caused by abnormal discharges in the CNS of motor neurones or interneurones
What is chorea?
“To dance”
Brief, semi-directed, irregular movements that are not repetitive or rhythmic, but appear to flow from one muscle to the next
What is hemiballismus?
Unilateral - affects ipsilateral arm & leg
Intermittent, sudden involuntary large movements
What is athetosis?
Slow, involuntary, convoluted, writhing movements of hands and feet
Slow, sinuous movements that flow into 1 another
What is dystonia?
Sustained muscle contractions causing abnormal, often repetitive movements or postures
Movements are typically twisting, patterned or tremulous
It can be focal, segmental or generalised
Tremor is often a feature
Often worsened by voluntary movements
Where is the lesion likely in a patient with athetosis?
In the lentiform nucleus in the basal ganglia
Where is the lesion likely in a patient with chorea?
Caudate nucleus
Causes of chorea?
Inherited e.g. huntingtons, Wilson’s
Sydenhams (as a consequence of rheumatic fever)
Hormonal and endocrine - typically oestrogen-related e.g. in pregnancy or SE of contraceptive pill
Degenerative
Drugs e.g. phenytoin, neuroleptics
Structural - stroke, tumours, trauma
SLE
Polycythemia vera
Causes of athetosis?
Birth hypoxia or kernicterus
Hepatic encephalopathy
All other causes same as chorea:
Inherited e.g. huntingtons, Wilson’s
Sydenhams (as a consequence of rheumatic fever)
Hormonal and endocrine - typically oestrogen-related e.g. in pregnancy or SE of contraceptive pill
Degenerative
Drugs e.g. phenytoin, neuroleptics
Structural - stroke, tumours, trauma
SLE
Polycythemia vera
Where is the lesion likely to be in a patient who has hemiballismus?
Subthalamic nuclei
What is considered the commonest form of tremor?
Dystonic tremor
Causes of dystonia?
Genetics
Drug-induced e.g. parkinsonian medications and neuroleptics
Related to trauma
Idiopathic
What is parkinsonism?
An umbrella term for the clinical syndrome involving bradykinesia plus at least one of tremor, rigidity or postural instability
Causes of parkinsonisms?
Parkinson’s disease
Drug induced e.g. antipsychotics and metoclopramide
Degenerative: Progressive supranuclear palsy, Multiple system atrophy
Metabolic: Wilsons disease
Infection: Post-encephalitis, prion disease e.g. cruz-felt Jakob disease
Dementia pugilistica
Toxins e.g. CO, MPTP, mercury
What is dementia pugilistica?
A form of chronic traumatic encephalopathy
Caused by chronic head trauma
Commonly seen in boxing
Red flags to diagnosing parkinsonsism and a cause that is not parkinsons disease?
Recent use of dopamine blocking drugs
Lack of the typical tremor (resting pill-rolling)
Symmetrical signs (parkinsons is usually asymmetrical i.e. affects 1 side more than the other)
Early cognitive dysfunction
Early balance disturbances eg. In PSNP where people tend to fall backwards
Significant and early autonomic dysfunction e.g. MSA
Poor response to usual parkinsons medications
Dementia with Parkinson’s vs dementia with Lewy body?
The only real difference is that in Lewy body dementia, the dementia occurs first before the motor symptoms (may also have recurrent visual hallucinations & act out dreams)
In parkinsons, the motor symptoms occur first and then dementia follows
What is parkinsons disease?
A chronic, progressive neurodegenerative condition resulting from the loss of the dopamine-containing cells of the substantia nigra
The dopamine deficiency within the basal ganglia leads to a movement disorder with classical parkinsonian motor symptoms
How much dopaminergic cell activity must be lost for parkinsons disease to be clinically apparent?
At least 50%
Cause of parkinsons?
Dopamine denervation due to Lewy body deposition and cell death in the substantia nigra
A large number of extra-nigral and non-dopaminergic brain regions are also affected
Minority of people have a FHx - associated with early-onset i..e <40
Most common cause of parkinsonisms?
Parkinson’s disease
Epidemiology of parkinsons disease?
Common
Mean age of diagnosis is 65
Increases with age - nearly 2% of over 80s
Prevalence higher in men
Lifetime risk is 2.7%
Complications of parkinsons disease?
Motor complications e.g. deteriorating function, dyskinesia, falls, NMS
Mental health problems
Autonomic dysfunction e.g. orthostatic hypotension, syncope, excessive salivation, sweating, bladder and bowel problems, sexual problems
Sleep disturbances
Symptomatic progression of parkinsons disease?
In early disease the motor symptoms are usually unilateral
It’s progressive so by later disease its usually bilateral
Symptoms of Parkinson’s disease?
Resting tremor
Gradual onset progressive bradykinesia
Rigidity
Others:
Postural instability
Gait disorders - shuffling, festination or freezing
Mental health problems - usually depression + insomnia + Cognitive impairment
Anosmia
Hypomima - reduced facial expression
Sleep disturbance
Fatigue
Autonomic dysfunction e.g. postural hypotension, hyperhidrosis
Dysphagia
Drooling
Blurred vision and eye opening ataxia
Constipation & urinary incontinence
Describe the bradykinesia seen in parkinsons disease?
Slowness in initiation of voluntary movement with progressive reduction in speed and amplitude of sustained repetitive actions e.g. finger tapping
Poverty of movement can also be seen - sometimes referred to as hypokinesia
How can hypokinesia present in parkinsons disease?
Reduced or flat facial expression
Reduced blinking
Difficulty with fine movements e.g. handwriting, buttoning clothes
Slow, short shuffling gait with reduced arm swinging
Freezing gait
Type of rigidity seen in parkinsons disease?
Lead-pipe rigidity or cogwheel rigidity
What is lead-pipe rigidity?
Constant resistance felt when a limb is passively flexed in the presence of increased tone without tremor
What is cogwheel rigidity?
Cogwheel rigidity refers to resistance that stops and starts as the limb is moved through its range of motion. Like going through the cogs!! This is with a tremor
When does the resting tremor in Parkinson’s disease typically improve?
On moving, with mental concentration and during sleep
What is a pill-rolling tremor?
Simultaneous rubbing movements of the thumb and index fingers against each other e.g. appears they are rolling a small object between their fingers
Drug causes of parkinsonisms?
Antipsychotics - usually first-generation e.g. haloperidol
Anti-emetics e.g. prochlorperazine and metoclopramide
More rarely:
Antidepressants e.g. SSRIs
CCB
Cinnarizine
Amiodarone
Lithium
Cholinesterase inhibitors e.g. donepezil
Sodium valproate
Methyldopa
Pethidine
What typically worsens the resting tremor seen in parkinsons?
Stress or being tired
How can drug-induced Parkinsonism present differently to parkinsons disease?
Motor symptoms have a rapid onset and are bilateral
Rigidity and resting tremor are uncommon
What can you do if you have difficulty differentiating between an essential tremor and Parkinson’s disease?
123I‑FP‑CIT single photon emission computed tomography (SPECT).
A type of functional Neuroimaging that can assess dopamine levels
What are the 2 types of multiple system atrophy?
MSA-P - predominant parkinsonian features
MSA-C - predominant cerebellar features
Features of multiple system atrophy?
parkinsonism
autonomic disturbance - erectile dysfunction, postural hypotension and atonic bladder, urinary retention
cerebellar signs - ataxia
What is multiple system atrophy?
A rare, neurodegenrative disorder characterised by autonomic dysfunction, Parkinsonisms and ataxia
Usually affects ~55
Its caused by progressive degeneration of neurones in the basal ganglia, inferior oligarch nucleus and cerebellum
What is progressive supranuclear palsy?
Aka Steele-Richardson-olszewski syndrome
It’s a ‘Parkinson Plus’ syndrome
A late-onset (~63) neurodegenerative disease involving gradual deterioration and death of specific volumes of the brain
Involves accumulation of tau protein in the brain
Features of progressive supranuclear palsy?
Postural instability and falls - tend to have a stiff, broad-based gait. Particularly falls backwards
Impairment of vertical gaze e..g difficulty reading or ascending stairs
Parkinsonism with bradykinesia being prominent - symmetrical
Cognitive impairment - mostly frontal love dysfunction
pathophysiology of drug-induced parkinsonism
Medications which reduce dopamine levels from the basal ganglia = brain cannot transmit signals to correctly coordinate movement
Advice about driving for patients with parkinsons?
DVLA days that group 1 and 2 may drive as long as safe vehicle control is maintained at all times
First line medical treatment for parkinsons disease if motor symptoms are affecting the patient’s quality of life?
Levodopa
First line medical treatment for parkinsons if motor symptoms are not affecting the patient’s quality of life?
Oral MAO-B inhibitors OR levodopa OR oral/transdermal dopamine agonists
Examples of oral MAO-B inhibitors?
Selegiline, rasagiline or safinamide
Examples of oral dopamine agonists that can be used for parkinsons disease?
Pramipexole or ropinirole
Example of transdermal dopamine agonist that can be used for parkinsons?
Rotigotine
Levodopa vs MAO-B inhibitors vs dopamine agonists for Tx of parkinsons?
Levodopa typically provides more improvement in motor symptoms and daily functioning, fewer adverse effects but may cause more motor complications
Oral MAO-B usually provide less improvement in motor symptoms and daily functioning, fewer motor complications and fewer adverse effects
Dopamine agonists provide less improvement in motor symptoms and daily functioning, fewer motor complications but more adverse effects e.g. excessive sleepiness, hallucinations and impulse control disorders
Specific adverse efefcts of dopamine agonists for parkinsons disease?
Excessive sleepiness
Hallucinations
Impulse control disorders
What are impulse control disorders?
A group of behaviour disorders characterised by impulsivity
E.g. failure to resist an urge or temptation or having an inability to not speak on a thought
E.,g. Gambling or hypersexuality
What can be used to manage parkinsons when pt have developed dyskinesia or motor fluctuations despite optimal levodopa therapy?
Additional of a dopamine agonist, MAO-B inhibitor or a COMT inhibitor as an adjunct
What are COMT inhibitors and give 2 examples?
Oral Catechol-O-methyl transferase inhibitors
Entacapone or opicapone
Who are impulse control disorders most common in?
Can occur with any dopaminergic therapy
More common with:
Dopamine agonist therapy - this doubles the risk!
History of previous impulse behaviours
History of alcohol consumption or smoking
How can we medically manage drooling of saliva in Parkinson’s disease?
Glycopyrronium bromide
Non motor sympotms of parkinsons?
Constipation
N&V
Pain
Sleep disturbance and daytime sleepiness
Depression and anxiety
Dementia and cognitive impairment
Impulse control disorders and psychotic symptoms
Orthostatic hypotension
Speech and swallowing problems & weight loss
Excessive salivation and sweating
Bladder and sexual problems
How is levodopa given for management of parkinsons motor symptoms?
Nearly always given combined with a decarboxylase inhibitor e.g. carbidopa
This prevents the peripheral metabolism of levodopa to dopamine outside of the brain as decarboxylase is the enzyme for this = reduces the SE
Common adverse efefcts of levodopa
Major: with years of use there is motor fluctuation and dyskinesias
Dry mouth
Anorexia
Palpitations
Postural hypotension
Psychosis
End of dose wearing off : symptoms worsen towards end of dosage interval
On-off phenomenon: large variations in motor performance
Dyskinesias at peak dose
What are dyskinesias?
Involuntary, erratic movement disorders e.g. dystonia, chorea, athetosis
What is important information to give patients about stopping levodopa?
It’s important not to acutely stop levodopa as this can cause acute dystonia
How do MAO-B inhibitors work to manage Parkinson’s?
They inhibit the breakdown of dopamine secreted by dopaminergic neurons in the substantia nigra
Moa of COMT inhibitors for parkinsons?
COMT is an enzyme involved in the breakdown of dopamine so it can be used as an adjunct to levodopa to improve dopaminergic activity in the substantia nigra
Why do we often delay treatment for parkinsons?
Treatment does not alter the natural history of parkinsons
It avoids the complications of drugs
We can introduce the drugs according to the patient’s biological age and functional requirements
Why is there an argument for not using Anticholinergics for managing parkinsons?
They possibly cause cognitive slowing and confusion
They can cause bladder and bowel dysfunction
They must be used with care, especially in the elderly!
Why do you have to be cautious about using MAO-B inhibitors in patients with postural hypotension?
As it can increase the risk of cardiac arrhythmias and death
2 classes of dopamine agonists?
Ergot based and non-ergot based
What can ergot-based dopamine agonists cause as complications?
Impulse disorders
Organ fibrosis e.g. retroperitoneal and lung fibrosis
What is the duodopa gel?
A combination of levodopa and carbidopa that is administered as a continous infusion via percutaneous jejunostomy tube
Very expensive!
How can we manage the wearing off symtpms, and peak/end of dose dyskinesia and dystonia caused by levodopa therapy?
Smaller doses more often
Use in conjunction with other classes of medication to limit total amoutn of levodopa
Main side efefcts of COMT inhibitors?
Severe diarrhoea especially with entacapone
Can worsen dyskinesia
What is hedonistic homeostatic dysregulation?
Neuropsychological behaviour disorder associated with substance misuse and addiction
How common is cognitive impairment in parkinsons disease?
At least 50% of sufferers have some cognitive impairment within5. Years
Management of cognitive impairment in parkinsons?
Atypical antipsychotics (note you can’t use typical antipsychotics as they are dopamine blocking so worsen motor symptoms)
Cholinesterase inhibitors
Memantine if cardiac arrhythmia or mod-sev dementia
Why can parkinsons disease cause hypersalivation and drool?
As there can be reduced automatic actions e,g. Swallowing
This creates an inability to manage the flow of saliva
Sleep disorders common in parkinsons?
Fragmented sleep
Vivid & disturbing dreams
REM sleep behaviour disorder
Restless limbs and akathisia
Daytime hypersomnolence
Obstructive sleep apnoea
Pains nd bladder dysfunction as well as problematic parkinsons Sx can keep pt up
Red flags suggesting its not parkinsons?
Early balance problems
Symmetrical signs
Opthalmoparesis
Associated pyramidal and cerebellar signs
Absence of resting tremor
Early onset of dementia
Profound autonomic dysfunction
Rapid disease progression
Poor response to levodopa
What is a DaTSCAN?
A brain scan to diagnose parkinsons disease and differentiate parkinsons syndromes with other diseasese e.g. dementia
surgical options for management parkinsons
Thalamotomy - surgical destruction of thalamus. Best for drug-resistant tremor
Pallidotomy - surgical destruction of the globus pallidus
Deep brain stimulation
Cell transplants
What is deep brain stimulation?
A surgical procedure that implants a neurostimulator and electrodes which send electrical impulses to specified targets in the brain responsible for movement control
Can help with parkinsons, essential tremor, dystonia and some neuropsychiatric conditions too
What is cell transplant for parkinsons disease?
The transplantation product is generated from embryonic stem cells and functions to replace the dopamine nerve cells which are lost in the parkinsonian brain
A new treatment that is still under research process
MDT for parkinsons disease?
Specialist nurses
PT
OT
Speech therapy
Support groups
Dieticians
Social services
Continence advisors
Psychiatric
What is Braak’s hypothesis?
That sporadic parkinsons disease is caused by a pathogen that enters the body via the nasal cavity and subsequently is swallowed and reaches the gut, initiating lewy pathological in the nose and digestive tract
2 enzymes involved in breaking down dopamine?
MAO
COMT
What is Parkinson’s UK?
A charity that funds research to find a cure and help ensure everyone understands the real impact of parkinsons
What is Parkinson’s Europe?
A charity that works with and campaign with people with parkinsons
They advocate, raise awareness and work with other global parkinsons organisations to provide current info, share good practices and highlight research
What is Huntington’s disease?
An autosomal dominant genetic condition that causes progressive neurological dysfunction
It’s progressive and incurable.
Prognosis of Huntington’s disease?
Typically results in death 20 years after initial symptoms develop
Genetics of Huntington’s disease?
Autosomal dominant
A trinucletodie repeat disorder: repeat exapansion of CAG (this means anticipation may be seen)
Due to a defect in huntingtin gene on chromosome 4 which codes for huntingtin protein
What is anticipation?
A feature of trinucletodie repeat disorders where successive generations have more repeats in the gene resulting in earlier age of onset and increased disease severity
Pathophysiology of Huntington’s disease?
Genetic mutation results in degeneration of cholinergic and GABAergic neurons in the striatum of the basal ganglia
What age does Huntington’s disease occur?
After 35 years of age
Usually 30-50
Presentation of Huntington’s disease?
Chorea
Dystonia
Saccadic eye movements
Personality changes e.g. irritability, apathy, depression
Intellectual impairment
Dysphagia
Rigidity vs spasticity cause?
Rigidity - extrapyramidal disorders
Spasticity - UMN lesion
Diagnosis of Huntington’s disease?
Genetic testing
Management of Huntington’s disease?
Genetic counselling
Physiotherapy to improve mobility, maintain joint function and prevent contractures
SALT
Tetrabenazine for chorea
Manage mental health conditions
Advanced directives and end-of-life care
What typically causes death in Huntington’s disease?
Aspiration pneumonia
(Note suicide is also a common cause)
Pathophysiology of parkinsons disease?
Progressive degeneration of dopaminergic neurones within the pars compacta of the substantia nigra in the midbrain for many reasons (not really known)
Lewy bodies (eosinophilic intraneuronal inclusions) are found in the surviving neurones
Nigral cells projecting to the striatum in the nigrostriatal pathway are mostly affected = loss of dopamine in striatum = movement is not smooth, coordinated or controlled
What are Parkinson plus syndromes?
Other forms of parkinsonism that have clinical features that are not typical of parkinsons disease
Progressive supranuclear palsy, multi system atrophy and corticobasal degeneration
What is corticobasal degeneration?
A rare disorder characterised by strikingly unilateral involvement with rigidity and dystonia in arms. Can also cause an “alien” arm, tremors, ataxia, slow slurred speech, dementia, difficult swallowing
Areas of the brain die and shrink
Which dopamine receptors are excitatory and which are inhibitory?
Excitatory - D1-class receptors
Inhibitory - D2-class receptors
Risk factors for parkinsons disease?
FHx
Genetics
Pesticides
Protective factors for parkinsons disease?
Smoking
Coffee
Vigorous exercise
Nicotine
Use of NSAIDs
Omega 3 fatty acids
why shouldn’t parkinsons medications be stopped abruptly?
Can cause dopamine agonist withdrawal syndrome
May also cause acute dystonia
Symptoms of dopamine agonist withdrawal syndrome?
Anxiety and panic attacks
Dysphoria - sense of unease due to a mismatch between biological sex and gender
Depression
Agitation
Irritability
Suicidal ideation
Fatigue
Orthostatic hypotension
N&V
Diaphoresis
Generalised pain
Drug cravings
