CNS Week 3 Movement Disorders Flashcards
What type of disease is huntingtons
An inherited neurological disorder
The gene was the first to be discovered on chromosome 4
Autosomal dominant inheritance with full penetration with expansion in the disease range (if you live long enough you will get huntingtons)
Is a trinucleotide repeat disorder - repeating CAG
What is the biological effect of huntington gene
HD gene codes for the huntingtin protein (HTT)
Well preserved function present in almost all livng things (absence of HTT causes embryonic death)
Mutated HTT has a gain of function effect as it is toxic to certain cell types especially in the brain
Effect of HTT protein on the brain
HTT is neurotoxic
Kills cells in different ways (striatum affected first)
Also widespreaf cell death throughout the brain
Age of onset of huntingtons disease
Typically between 30-50
However now recognised it can occur at any age
What causes the age at which huntingtons occurs
50% of age of onset relates to CAG repeat number
The other 50% relates to other genetic factors and potentially environmental factors
Life expectancy after diagnosis of huntingtons
20 years
Clinical features of huntingtons
Neurological- chorea (extra uncontrolled movements), dystonia, dysarthria, dysphagia
Cognitive- progressive dementia of frontal lobe type, loss of empathy, lack of insight, loss of verbal fluency, loss of ability to sequence
Psychiatric features- depression, anxiety, psychosis
Non neurological features- high metabolic rate and weight loss
Diagnosis of huntingtons if asymptomatic
A positive gene does not designate onset of the disease but only a pre symptomatic carrier status
Diagnosis of huntingtons disease
Relies on presence of a movement disorder in conjunction with a positive gene test
There may be psychiatric prodrome, but diagnosis cannot rest on this as this is common in those with positive predictive test
Early clinical features of huntingtons
Chorea
Psychiatric features
Frontal lobe features
Mid disease features of huntingtons
Marked chorea, dystonia, falls, declining mobility, frontal lobe dementia and loss of verbal fluency, swallowing difficulties, behavioural issues and psychiatric features
Late features of huntingtons disease
Anarthric, severe swallowing problems, immobile weight loss
Social aspects of huntingtons disease
DVLA notifiable condition - usually cant drive for ling
Usually fail to continue to work beyond early stages related to chorea but also frontal lobe features
Very high levels of career strain
Family dynamic- people are aware their children are at risk
Treatment of huntingtons
No treatment which stops the cell death of brain cells
Chorea- responds to dopamine blocking drugs
Psychiatric medications - neuroleptics, antidepressants
Disadvantages of huntington medication
Can cause side effects as it is long term which can be difficult to distinguish from symptoms of huntingtons itself
Non medical treatment of huntingtons
Annual speech and swallowing assesments
Regular weight checks, fortified diet supplements
Social care aspects to support family
CPN may be needed for significant psychiatric issues
How is pre symptomatic testing in huntingtons carried out
Possible to test asymptomatic carriers ages >18
Through genetic counselling service
High levels of morbidity in those who test gene positive - high levels of depression
Methods of IVF whihc allow pretty good guarantee of unaffected child without the need for test
What is huntingtons disease
An autosomal dominant inherited genetic condiiton causing a slowly progressive disease with a movement disorder, frontal lobe dementia and psychiatric problems
How many protein coding genes are there in humans
20,000
What is autosomal dominant inheritance
One parent is affected with a disease due to a mutation in the relevant gene. As it is dominant he only needs one copy of the gene for it to be present and there is a 50% chance of his offspring inheriting it
What is autosomal recessive inheritance
Both copies of the gene need to be mutated to have the disease eg 2 parents that are both carriers so have one copy of the gene
25% chance of offspring having the disease, 50% of them being carriers and 25% chance of being unaffected
What are triplet repeats
Repetitive sequences common in the genome eg CAG Often polymorphic (length varies) Changes in length can impact gene function
What do longer triplet repeat sequences lead to
Longer repeats = more severe disease phenotype
Several severe neuromuscular and neurodegenerative disorders associated with changes in repeat length
Huntington disease allele repeat sizes
Normal <27 Intermediate 27-35 Range of partial penetrance 36-39 Classic HD 40-65 Juvenile HD >65 (can be up to 250 repeats)
What is type 1 myotinic dystrophy
Myotonic myopathy with associated abnormalities in other organs:
Myotonia: difficulty in relaxing clenched hands
Muscular dystrophy
Cataracts
Testicular atrophy
Frontal balding
Cardiac conduction defects
Triplet repeat causing myotonic dystrophy type 1
Expansion of a CTG nucleotide repeat in the 3’ UTR of the DMPK gene
DMPK is expressed mainly in muscles and CNS
CTG repeats are transcribed into mRNA but not translated into protein
Myotonic dystrophy type 1 allele repeat sizes
5-35 stable (no DM)
36-50 may be unstable (no DM)
51-150 unstable (no, minimal or classical DM)
>150 unstable (classical, juvenile or congenital DM)
What is the location of the CAG expansion that causes huntingtons
CAG expansion in exon 1 of the HTT gene
What is the location of the CTG expansion that causes myotonic dystrophy
CTG expansion in the 3’UTR (non coding region) of the DMPK gene (gain of fucntion)
Describe triplet repeat instability
Repeats can expand due to errors in DNA replication and repair - account for normal variation in repeat length
Beyond a certain size, repeats become unstable and more likely to expand
Full expansion mutations can be inherited from unaffected parents with an intermediate or premutation allele
What is repeat anticipation
Repeat instability means repeats can expand in subsequent generations
An intermediate repeat or a small expansion can increase in size in subsequent generations
Results in a more severe phenotype in child than in the parent
Parent of origin within myotonic dystrophy
Maternal transmission
Large expansions in the CTG repeat occur almost exclusively on maternal transmission
Female carriers of unstable repeat sizes >46 CTGs more likely to have children with larger expansions
(Expansion occurs in the oocyte)
Parent of origin in huntingtons disease
Large expansions in the CAG repeat occur almost exclusively on paternal transmission
Male carriers of unstable repeat sizes (>27 CAGs) are more likely to have children with larger expansions
(Expansion occurs during spermatogenesis)
What is the polymerase chain reaction used for
Method to amplify DNA
Uses DNA template strand eg genomic DNA extracted from patient blood sample
Requires primers - short stretches of DNA that are complimentary to the sequence being amplified
How can PCR be used to detect triplet repeat expansions
Primers flanking (either side) of the CAG repeat region
2 primer pairs used
HD1 + HD3
And HD2 + HD5
Describe the PCR reaction using the HD1 and HD3 pair
Amplification across the CAG repeat
HD1 primer is fluorescently labelled
PCR fragment sizes can be detected by capillary electrophoresis
Samples with known allele sizes included as controls
What does it mean if the HD1 +HD3 PCR testing is positive
Single allele detected so patient may be homozygous for this repeat size
Patient may have an expansion that is not detectable by this method
Define genetic counselling
The process by which patients or relatives at risk of a disorder that may be hereditary are advised of the consequences of the disorder, the probability of developing or transmitting it and the ways this may be prevented, avoided or ameliorated
Aims of genetic counselling
Understand the clinical features of a condition and its management
Understand the inheritance of the disorder
Understand the options for managing the risks
Make the best possible non judgemental adjustment to the disorder
What are the core principles in genetic counselling
Autonomy of the individual or couple
Patients right to full and complete information in a form they understand
Preservation of confidentiality (even when seeing members of the same family)
Aimed at facilitative decision making with time to explore all options
What is autosomal dominant
Heterozygotes with one copy of the abnormal gene are affected
What is autosomal recessive
Homozygotes with 2 copies of the abnormal gene are affected
What is X linked recessive
Males with one copy of the abnormal gene on the X chromosome are affected
What is penetrance
Can be complete or incomplete
The proportion of individuals with the gene who are affected often dependent on age of assessment eg if you have huntingtons and live long enough it will be expressed
What is variable expressivity
Variation in expression
The degree to which a disorder is expressed in an individual - different complications are common in autosomal dominant conditions
What is reduced penetrance
Common in cancer predisposition syndromes
Not everyone who inherits the mutation develops cancer in their lifetime
Benefits of predictive tests
Reduce uncertainty
Screening / surgery / treatment to reduce the risk of the conditon
Pregnancy options
Plan life eg career
Information for relatives
Problems with predictive tests
Further uncertainty
Financial implications eg insurance and mortgages
May restrict career choices eg army
Survivor guilt
Information about relatives risk
Clinical features of huntington disease
Movement disorder - involuntary movements, abnormal gait, psychiatric disturbances, personality changes, depression, apathy, aggression, cognitve decline (early onset dementia)
Symptoms of migraines
Severe throbbing headache, unilateral at first but may spread to the opposite side Sonophobia Photophobia Pallor Perspiration Vomitting
Symptoms of a stroke
Motor and sensory deficits in face (cranial nerves V and VII); unilateral, bilateral or alternating V and VII
Abnormal eye movements
Dysphagia (cranial nerve X)
Vertigo, atiaxia, motor and sensory deficits which may be unilateral or alternating
Headache
Vomitting
Altered consciousness
What are the 3 phases of an epileptic seizure
Tonic phase: epileptic cry, incontinence, cyanosis, generalised stiffening of body and limbs
Clonic phase: incontinence, cyanosis, clonic jerks of limbs, body and head, salivary frothing, eye blinking
Postictal stupor: drowsy, sleepy, confused, limbs and body limp, salivary drooling, unresponsive
What is parkinsons disease chemically
Lack of dopamine in the substantia nigra
Stages of parkinsons disease
Stage 1: unilateral involvement, blank facies, affected arm in semiflexed position with tremor; patient leans to unaffected side
Stage 2: bilateral involvement with early postural changes; slow shuffling gait with decreased excursion of legs
Stage 3: pronounced gait disturbances and moderate generalised disability: postural instability with tendency to fall
Stage 4: significant disability; limited ambulation with assistance
Stage 5: complete invalidism; confined to bed or chair cannot stand or walk eevn with assistance
What is bradykinesia
Slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive actions (symptom of parkinsons)
What is multiple sclerosis
A chronic condition with low incidence but high prevalence
Dissemination of CNS inflammatory demyelinating lesiosn in space and time
No cure but treatments are available
What is myasthenia gravis
An autoimmune disorder of the neuromuscular junction
Fluctuating skeletal muscle weakness
Typically presenting with ptosis, diplopia or bulbar symptoms
Myasthenic crisis is a medical emergency characterised by neuromuscular respiratory failure
Spontaneous or precipitated by infection, surgery or medication
Requires early diagnosis and respiratory monitoring
What is guillain barre syndrome
Acute immune mediated polyneuropathy
- progressive muscle weakness
- reduced or absent tendon reflexes
- from mild weakness to complete paralysis of limb, facial, respiratory and bulbar muscles
- autonomic nervous system dysfunction
What is a DALY
Disability adjusted life years
One year lost due to ill health, disability or early death
Role of the motor cortex
Integrates information and produces motor signals
Role of the basal ganglia
Receives sensory and motor cortical informatino and helps plan movement by feeding back to the cortex via the thalamus (initiates voluntary movement)
Prevents unwanted movement, is involved in learning movement and associated reward
Role of the cerebellum
Receives infromation from the body and assists with dynamic coordination of movement balance and posture
What is the basal ganglia
A group of sub cortical grey matter structures that are part of the extra pyramidal motor systems
Does not initiate movement but helps plan movement by integrating cortical input and feeding back to the cortex via the thalamus through a direct and indirect pathway
What can injury to or CNS dysfunction of the basal ganglia cause
Abnormal involuntary movements (dyskinesias)
Slowed voluntary movement (bradykinesia)
Ridged postures (dystonia)
Struggle to move (akinesia)
What structures make up the basal ganglia
Caudate nucleus Putamen Globus pallidus Subthalamic nucleus Substantia nigra
What are the 2 parts of the substantia nigra
Pars reticulata (SNr)
Pars compacta (SNc)
Dark cells in the midbrain
What do the caudate nucelus and putamen make up
Neostriatum
2 parts of the globus pallidus
Internal (Gpi)
External (Gpe)
Major inputs of the basal ganglia
Cerebral cortex (corticostriate) Thalamus (thalamostriate) Brain stem (SNc- nigtostriate)
Maojr outputs of the basal ganglia
Thalamic nuclei
The cortex (via thalamus)
And brain stem
What are the striatal afferents
Corticostriatal (glutamatergic)
Thalamostriatal (glutamatergic)
Nigrostriatal (dopaminergic)
Where do the striatal afferents synapse
They synapse onto the medium spiny neurons (90% of cells in the striatum- GABAergic)
What are the striatal efferents
Medium spiny neurons
Striatopallidal (GABAergic)
- direct and indirect
Striatonigral (GABAergic)
What type of neurotransmitters are glutamate and dopamine
Glutamate - excitatory
Dopamine - excitatory or inhibitory depending on which receptor its binded to
What is the globus pallidus
- internal (GPi) and external (GPe) segments
- input to both GABAergic projection neurons
- output from both GABAergic
What is the major output structure of the basal ganglia
GPi
What is the direct pathway of movement
Cerebral cortex releases glutamate which is absorbed by the striatum and activity increases
More GABA is released to the internal globus pallidus
Activity decreases in the global pallidus internal
Activity of the thalamus is increased due to reduced tonic level of activity
More glutamate is released and movement is turned on
Role of dopamine in the direct pathway of movement
Dopamine released from the substantia nigra pars reticulata onto dopamine 1 receptor. This switches the neurons on and reduces movement
What is the indirect pathway of movement
Glutamate released by the cerebral cortex into the striatum. Striatum is excited so more GABA is released and absorbed into the globus pallidus external (activity reduces)
Less GABA is released so there is less inhibition of the substantia nigra
More glutamate is released to the globus pallidus internal
More GABA is released and inhibits the thalamus and turns movement off
Role of dopamine in the indirect pathway
Inhibits neuroon (switches off the indirect pathway)
What are the symptoms of the disruptions of the basal ganglia
Slowness of voluntary movement / postural reflexes (bradykinesia)
Muscular rigidity
Lack of movement (akinesia)
Abnormal involuntaty movements (dyskinesia)
What is the role of the basal ganglia
Facilitate context appropriate voluntary behaviour and movement
Inhibit inappropriate involuntary movement
Pathology of huntingtons disease
10-20% reduction in brain weight (atrophy)
Decreased striatal volume and cell death
Loss of GABA containing medium spiny neurons in the striatum
1st: enkephalin containing MSN
Later stage: substance P containing
Cholinergic interneurons of the striatum are spared
Decreased cortical volume and cell death
Symptoms of parkinsons disease
Tremor Bradykinesia Rigidity Mask like expression Postural instability Microphagia (small writing) Shuffling gait
Later:
Depression
Dementia
Endocrine dysfunction (constipation)
What are lewy bodies
Inclusions in neurones with core of a-synuclein
(Aggregate to form fibrils and may contribute to dementia seen in 50% of parkinson patients
Causes of PD
- Oxidative stress
- 15% of patients have a first degree relative with PD
- genetic causal factors - familial PD is rare
- PARK1 or SNCA gene codes a-synuclein ; autosomal dominant early onset PD with lewy bodies and marked rigidity
- PINK1 and PARK7 gene mutations also cause autosomal recessive forms of PD
- drug induced neurodegeneration - MPTP (environmental toxin) synthetic heroin causes immediate parkinsonism when injected
Diagnosis of parkinsons disease using PET scan
Used to visualise and quantify dopaminergic neurones using radioactive ligands which bind to dopamine transporter proteins
Role of dopamine in parkinsons disease
As there is less dopamine being released from the substantia nigra the direct pathway is less stimulated so results in reduced movement
What is the first line treatment of parkinsons disease
Levodopa (L dopa)
A precursor of dopamine
L dopa with peripheral DOPA decarboxylase inhibitor
Why cant you use dopamine to treat parkinsons disease
Because it does not cross the blood brain barrier
Unwanted effects of levodopa
Development of dyskinetic movements due to fluctuations of dopamine throughout the day
Rapid fluctuation in clinical state
Nausea and anorexia
Hypotension
Psychotic effects
Surgical treatment for parkinsons disease
Implantation of deep brain stimulation
Or surgery to implant a tube into the small intestine that releases levodopa
Benefits and risks of levodopa
More improvement in motor symptoms
More improvement in activities of daily living
More motor complications
Fewer adverse events
Benefits and risks of dopamine agonists for treating PD
Less improvement in motor symptoms
Less improvement in activities of daily living
Fewer motor complications
More specified adverse events
Benefits and risks of monoamine oxidase B inhibitors for treating PD
Less improvement in motor symptoms
Less improvement in activities of daily living
Fewer motor complications
Fewer specified adverse events
Neuropathology of parkinsons disease
Loss of the substantia nigra pars
Alters balance of basal ganglia circuitry to lack of movement
Key features of executive dysfunction
Normal speech and perception
IQ may be normal
Loss of goal oriented behaviour
Stimulus driven behaviour (eg it is normal to put glasses on your head so a patient will put glasses on even if the context is inappropriate
Deficit in apathy (unable to correct mistakes)
Socially inappropriate behaviour
What can cause executive dysfunction
Unilateral frontal damage (caused by head injury), degenerative disease, stroke, surgery
Subcortical and cortical damage
When is executive function required
When the situationr requires a response that competes with a strong habitual response
A novel solution is required or the task is not well learnt (no memories / habit to draw on)
The situation requires error correction or troubleshooting
Define executive function
A description of psychological processes that underlie flexible goal directed behaviour
Purpose of the wisconsin card sorting test
Measures the ability to learn concepts and considered a good measure of frontal lobe functioning
What is a TIA
Transient ischaemic attack -
Symptoms only one hour means more at risk of stroke
Define stroke
Acute onset of neurological deficits (lasting for more than 24 hours) due to a disturbance in blood supply to the brain
Approx 15million people suffer strokes each year
1/3 die, 1/3 left disabled
Non modifiable stroke risk factors
Age (avg between 68-73) Atrial fibrillation (2-6 x ) Gender (females less likely pre menopause but more severe) Ethnicity Family history
Modifiable stroke risk factors
Hypertension Diabetes (6 x inc risk) Hyperlipidaemia (high cholesterol) Smoking Obestiy Carotid artery disease Atherosclerosis
What are the 2 different types of strokes
Ischaemic (85%): blocked blood vessels
Haemorrhagic (15%): ruptured blood vessels
What are the different types of ischaemic strokes
Thrombotic (55%): build up of plaque in the cerebral vessel
(Lacunar occlusion or large vesse occlusion)
Embolic (30%): travelling clot or plaque lodged in major cerebral vessel
(Large vessel occlusion)
Haemorrhage Stroke symptoms
thunderclap headache, seizures, nausea, unilateral weakness (common in all types of stroke)
Anterior circulation stroke symptoms
Hemiplegia / paresis Hemisensory loss Hemianopia Dysphasia Aphasia (Motor and sensory deficits in the opposite side of the body to where the stroke has occured)
Posterior circulation stroke symptoms
Dizziness
Unilateral limb weakness (can be bilateral)
Ataxia (broken down coordination - damage to the cerebellum)
Dysarthria (speech, hard to express self)
Harder to diagnose due to more generalised symptoms
Non specific stroke symptoms
Confusion Drowsiness Dizziness Nausea Double vision Incontinence
What is a lacunar infarction
Commonly occuring in brainstem, thalamus, basal ganglia
Small strategic strokes in penetrating arteries that feed sub cortical structures
80% clinically silent
Motor hemiplegia syndrome - infarction in the posterior limb of the internal capsule, basal ganglia or pons
Which artery is most comminly affected by strokes
Middle cerebral artery
Symptoms of stroke in the middle cerebral artery
Hemiplegia, hemisensory loss, dysphagia
How is a stroke identified
Neurological examination followed by urgent referral for neuroimaging
Via CT which can detect haemorrhage but is less effective at detecting acute ischaemic stroke
What on a CT scan indicates a stroke has occurred
Lack of putamen
Haemorrhage stroke mortality / outcome
45% mortality
30% vasospasm: likely to have ischaemic stroke in the next 7-14 days
Haemorrhage stroke treatment
Pain management and surgery to repair the bleed with clipping or coiling (microclip over the base of the rupture)
May include lowering blood pressure with labetalol or glycerol trinitrate
Treatment of ischemic strokes
Thrombolysis with altepase (tissue plasminogen activator).within 3 hours
Thrombectomy with retriever devices within 6hrs (physical removal of clot. Used when TPA is contraindicated or failed)
What is the penumbra
The area surrounding an ischemic event such as thrombotic or embolic stroke
The area that is at risk of progressing to infarction but is still salvageable if reperfused (located around the infarct core)
Why is time crucial in stroke treatment
Becuase the core tissue starts to expand into the penumbra at 12-22 ml/100g/min
What do the core and the penumbra represent
Core represents irreversibly damaged tissue
Penumbra represents potentially salvageable tissue
Order of events that are likely to occur after a stroke
1) failure of ion pumps, cell depolarisation and swelling
2) excessive glutamate release
3) peri infarct depolarisations
4) inflammatory cells infiltrate the brain
5) apoptosis
What is vascular cognitive impairment
A heterogeneous group of cognitive phenotypes (mild to severe) that are presumed to share a vascular origin
What cerebrovascular pathologies associated with vascular cognitive impairment can be visualised with neuroimaging
White matter change
Lacunar infarction
Microbleeds
Enlarged perivascular spaces
Cerebral amyloid angiopathy
What happens to nerves in MS
The myelin sheath which is a protective membrane that wraps around the axon of a nerve cell is destroyed with inflammation and scarring
Cause of right leg numbness
Lesion in the left side of the brain (Sensory cortex)
Describe inflammatory neurodegeneration in MS
Immune mediated pathogenesis is thought to drive neurodegeneration
Early relapsing remitting pahse is more susceptible to treatment
Both inflammation and neurodegeneration are involved throughout the disease course
Describe the immunopathology of MS
Inflammation is present at all stages of MS, from acute disease through to later chronic disease
Neurodegenerative damage has been correlated with immune mechansims
Brain reserve and repair mechanisms are important in compensating for CNS damage
Role of T cells and B cells in MS
T cells have been viewed at the centre of MS immunopathology
But B cells also have multiple functions that may contribute to MS pathogenesis in addition to their capacity to differentiate into antibody secreting cells
Clinical features suggestive of MS
Onset between 15-50 Blurred or double vision Lhermitte’s sign Fatigue Heat sensitivity Bladder symptoms Cognitive or affective changes
Central symptoms of MS
Fatigue Cognitive impairment Depression Anxiety Unstable mood
Visual symptoms of MS
Nystagmus
Optic neuritis
Diplopia
Musculoskeletal symptoms of MS
Weakness
Spasms
Ataxia
Sensation symptoms of MS
Pain
Hypoesthesias
Paraesthesias
Bowel symptoms of MS
Incontinece
Diarrhoea or constipation
Urinary symptoms of MS
Incontinence
Frequent or retention
Which neurotransmitters are affected to cuase jerky movements of arms and legs (huntingtons disease)
ACh and GABA
