Neuro 2 - motor control, movement disorders and stroke Flashcards
Cranial nerves
Most have both sensory and motor function
All, except I and II, have nuclei in brainstem
In brainstem, arranged in 3 motor and 3 sensory columns
Functionally specific, can have more than one function
Special somatic afferent (SSA) cranial nerves
Vision - optic
Auditory and vestibular - vestibulocochlear
Named cranial nerves
Olfactory Optic Occulomotor Trochlear Trigeminal Abducens Facial Vestibulocochlear Glossophrayngeal Vagus Accessory Hypoglossal
Special visceral afferent (SVA) cranial nerves
Taste - vagus, glossopharyngeal, facial
Olfaction - olfactory
General somatic afferent (GSA) cranial nerves
Skin, muscles, joints - vagus, glossopharyngeal, facial, trigeminal
General visceral afferent (GVA) cranial nerves
Viscera of head, thorax, abdomen - vagus, glossopharyngeal
General somatic efferent (GSE) cranial nerves
Tongue - hypoglossal
Eye muscles - abducens, trochlear, occulomotor
Special visceral efferent (SVE) cranial nerves
= Branchial motor (BM), skeletal muscle dervied from branchial arches
Mastication - trigeminal
Facial expression, middle ear - facial
Pharynx, larynx - glossopharyngeal, vagus
Sternocleidomastoid, trapezius - accessory
General visceral efferent (GVE) cranial nerves
Parasympathetic neurones for cranial, thoracic and abdominal viscera
Lacrimal and salivary glands (not parotid) - facial
Pupil constrictor, ciliary muscle - occulomotor
Parotid gland - glossopharyngeal
Heart, lungs, digestive tract - vagus
Optic nerve (II)
Associated only with special senses
- axons from ganglion cells in retina
- vision
If damage optic nerve, earlier, complete blindness in that eye
If damage optic tract (after chiasm), field vision loss - lose medial field in eye opposite, lose lateral field on this side
Vestibulocochlear nerve (VIII)
Associated only with special senses
- axons from spiral ganglion of cochlear and vestibular ganglion in inner ear
- hearing and position sense
Loss of vestibular inputs - ataxia, loss of balance, nystagmus
Loss of auditory inputs - loss of hearing on side of affected
Olfactory nerve (I)
Only special visceral afferent
- axons from olfactory mucosa
- olfaction
Damage -> anosmia
Occulomotor nerve (III)
Only motor function (GSE)
- somatomotor to all eye muscles except LR6SO4
- visceromotor, parasympathetic to smooth muscles in eye (ciliary and iris)
Damage -> inability to move eye in or up (down and out gaze), lateral strabismus of one eye (crossed eyes), ptosis
Trochlear nerve (IV)
Only motor function
GSE- somatomotor to superior oblique eye muscle
GVE - visceromotor to pupillary constrictor
Damage -> vertical diplopia (double vision), head tilt, hypertropia (maladjustment) of right eye when performing left gaze
Abducens nerve (VI)
Only motor function (GSE)
- somatomotor to lateral rectus eye muscle
Damage -> can’t look laterally, medial strabismus (crossed eyes)
Hypoglossal nerve (XII)
Only motor function (GSE)
- somatomotor to muscles of tongue, extrinsic (except palatoglossus) and intrinsic
Damage -> tongue deviates to side of lesion
Trigeminal nerve (V)
Sensory and motor pathways
SENSORY
Opthalmic - V1 - orbit to forehead
Maxillary - V2 - upper jaw to orbit
Mandibular - V3 - lower jaw
MOTOR
V3 only - muscles of mastication
Upper motor neurone lesion -> no deficit in jaw movement
Lower motor neurone lesion -> deviation of mandible to ipsilateral (weak) side
Facial nerve (VII)
Sensory and motor pathways
MOTOR (SVE)
- muscles of facial expression
- stapedius muscle (dampen sound in ear)
- part of digastric
VISCERAL SENSORY (SVA) - taste from anterior 2/3 tongue
GENERAL SOMATIC SENSORY FUNCTION (GSA)
- small region near external auditory meatus
PARASYMPATHETIC (GVE)
- secretory glands in head - lacrimation, nasal secretions, salivary glands
(Two Zebras Bit My Clavicle - temporal, zygomatic, buccal, mandibular, cervical)
Upper motor lesion -> bottom half of face (contralateral) can’t move, forehead sparing
Lower motor lesion -> whole half face (contralateral)
Vagus nerve (X)
Sensory and motor pathways
SENSORY
- viscerosensory from organs in thorax and abdomen
MOTOR
- innervation of some in pharynx and larynx
- parasympathetic to organs in thorax and abdomen
Accessory nerve (XI)
Sensory and motor pathways
Two motor components - cranial root to muscles in larynx and pharynx, spinal root to muscles in neck
Sensory info very small, about pain
Motor neurones in spinal cord
Spinal cord enlarged at levels where motor neurones for limbs are located - not uniform
Sensory input to dorsal horn, synapse through ventral horn -> motor
Position in ventral horn depends on type and location of muscle innervated - medial for trunk, lateral for limbs and distal muscles
Alpha motor neurone inputs
- lower motor neurone (as with gamma)
FROM:
- sensory input from muscles
- input from upper motor neurones to initiate and control voluntary movement
- interneurones (excitatory or inhibitory) to form circuits that produce coordinated movements
Types of somatic motor neurone
ALPHA
- large, multipolar neurones
- cell bodies in ventral horn of spinal cord, originate here
- terminate at NMJ or end plates
- innervate extrafusal muscle fibres, skeletal muscle
GAMMA
- smaller neurones
- cell bodies in ventral horn of spinal cord, originate here
- innervate specialised striated muscle fibres (intrafusal)
Motor unit
= alpha motor neurone + all innervated muscle fibres
One alpha motor neurone to several muscle fibres, each muscle fibre only one neurone
All alpha motor neurones innervating a muscle = motor neurone pool
Muscle spindles
Sensory neurones in muscle spindle encode info on muscle length - moitor extent of stretch and rate of change of length
Intrafusal fibres in parallel
Ia and II afferents
Lower motor neurones innervated by two different mechanisms
SUPRASPINAL MOTOR CIRCUITS
- volitional control over movement
SPINAL CORD REFLEX
- rapid, automatic, stereotyped response
- couples sensory input to motor output
Types of reflex
Monosynaptic - simplest, controls muscle length
Golgi tendon - controls muscle tension
Flexor/withdrawal reflex - rapidly remove limb from painful stimulus
Crossed extensor reflex - maintains body equilibrium
Monosynaptic reflex
Sensory receptor, sensory neurone, integrating centre (one synapse in ventral horn), motoneurone, effector muscle or gland
Still need antagonistic muscle pair to relax in response, otherwise muscles would snap - RECIPROCAL INNERVATION
Myotatic reflex
= stretch reflex, type of monosynaptic
Weight added to muscle Transient elongation of muscle Spindle stretched, neurones fire Alpha motor neurones fire Muscle contraction
To maintain tone, prevent muscular damage due to overlengthening
eg patellar tendon reflex
- if weak or absent, lower motor neurone lesion?
- if exaggerated, upper motor neurone lesion?
Gamma motor neurones
= fusimotor neurones
To adjust sensitivity of muscle spindles
When muscle contracts, spindle becomes slack, so no sensory info from spindle
Gamma motor neurone activation contracts muscle spindle fibres, so can now respond to eg changes in load weight
Golgi tendon
Skeletal muscle tendons contain mechanoreceptors
- golgi tendon organs
Ib sensory neurones in golgi tendon organ encodes info on muscle tension
Inhibit alpha neurones running to muscle of origin
Golgi tendon reflex
Muscle tension
Golgi tendon organ activated
Sensory Ib afferemt excoted
Spinal cord activates inhibitory interneurone to same muscle, and activates excitatory interneurone to antagonistic muscle
Motoneurone excited
Effector muscle relaxes, antagonistic muscle contracts
- protect muscle from producing too much tension and tearing or breaking tendons
- fine control of tension for grasping fragile objects
Felxor/withdrawal reflex
Nociceptor afferents excited
Spinal cord interneurones activate, excite flexor motoneurones
- rapidly withdraw body from painful stimulus
- needs synergy, muscles to work together to remove entire limb
Crossed extensor reflex
To maintain balance, eg after withdrawal reflex
- eg strengthen leg standing on, inhibit extensors in leg withdrawing
Central pattern generator
Neurones enable oscillations in movement - as one set neurones fire, others stop
To generate rhythmic motor activity
Convergence
Termination of several neurones onto one other neurone
- two nerves activated, subliminal fringes overlap = facilitation zone
- more motor neurones excited so bigger response, FACILITATION
(Repetitive stimulation of one nerve -> temporal summation)
Types of interneuron
INHIBITORY INTERNEURONE
- activated by primary afferent
- inhibit alpha motor neurone
- inhibit contraction of associated muscle
EXCITATORY INTERNEURONE
- activate gamma or alpha motor neurone
- synapse onto intrafusal muscle fibre to increase sensitivity of spindle
RENSHAW CELLS
- inhibitory interneurones
- activated by alpha motor neurones
- inhibits alpha motor neurones, negative feedback
- also inhibit interneurones and gamma motor neurone
- governors, prevent muscle damage from tetanus
Jendrassick manouvre - to condition reflex
Exaggerates lower limb tendon reflexes
- voluntary upper motor neurone innervation of arm overflows, to increase excitability of lower motor neurone pool in lower limbs
- > increased fusimotor drive
- > increased amplitude of reflex
- counteracts some normal descending inhibition from brain
- modulates interneuron excitability, so removes inhibitory action on late component of stretch reflex
Primary motor cortex - homunculus
Region where movement can be evoked with least amount of electrical stimulus
Pre-central gyrus, Brodmann’s area 4
(not 100% true, there are clusters, needed for coordination)
Supplementary motor area
= SMA
Medial surface of hemisphere, anterior to primary motor cortex
Medial part of Brodmann’s area 6
SMA PROPER - contains somatotopic map - contributes to corticospinal tract - interconnected to other motor areas PRE-SMA - not well connected to other motor areas - connected to pre-frontal cortex
- for more complex, purposeful movements, eg vocalisation and complex postural movements
(transforms kinematic to dynamic info)
Pre-motor area
Rostral to primary motor cortex
Two functionally distinct subdivisions - dorsal and ventral
- somatotopically organised
- preparation for movement
Cingulate motor area
In cingulate sulcus
- somatotopically organised
- preparation and execution of movements
Descending control of motor pathways
To innervate alpha, gamma motoneurones, and interneurones
Motor neurones topographically organised in ventral horn - flexors more posterior than extensors
- distal more lateral than proximal
Two major groups:
- Lateral pathways
- Medial pathways
Lateral pathways in descending control of motor
Controls both proximal and distal muscles
Responsible for most voluntary movements of arms and legs
- Lateral corticospinal tract
- Rubrospinal tract
Medial pathways in descending control of motor
Controls axial muscles (core)
Responsible for posture, balance, coarse control of axial and proximal muscles
- Vestibulospinal tracts (lateral and medial)
- Reticulospinal tracts (pontine and medullary)
- Tectospinal tract
- Anterior corticospinal tract
Lateral corticospinal tract
Main descending motor pathway
Motor cortex to spinal cord
- fibres form bulge on ventral surface of medulla, = pyramids
- fibres decussate at medulla-spinal cord junction - is the 90%
Innervate motor neurones in ventral horn of spinal cord
Controls muscles of distal limbs
Essential for fine movement of limbs
VOLUNTARY
Anterior corticospinal tract
Smaller than lateral pathway
Motor cortex to spinal cord
- is 10% of CST that doesn’t decussate in medulla, instead at spinal cord. Some still don’t decussate so are ipsilateral (minor) -> bilateral innervation for coordination
Controls muscles of trunk
Corticonuclear = corticobulbar tract
Motor cortex to brainstem nuclei
Voluntary motor functions of head, neck, face
CRANIAL NERVES
- most nuclei bilateral innervation from cortex except facial and hypoglossal
Rubrospinal tract
Small, role unimportant in humans Originates in red nucleus Decussates immediately (travels alongside lateral CST) Voluntary movements of upper limbs only
Vestibulospinal tract
Head orientation info received by vestibulocochlear nerve
So tract from vestibular nuclei -> motor control of neck, trunk and some leg muscles
Maintain upright posture and head stabilisation
Bilateral innervation of muscles
Tectospinal tract
Originates in superior colliculus in midbrain
Info from eyes and visual cortex
Innervate contralateral motor neurones controlling head position
Reticulospinal tract
Originates in reticulospinal formation in pons and medulla
Modulates voluntary movements, locomotion and posture, influences muscle tone
Ipsilateral innervation of motor neurones in spinal cord
Damage to descending motor pathways
- > immediate flaccidity of muscles on contralateral side, lose all reflex activity on that side
- most severe in arms and legs, trunk control usually preserved - as remaining brainstem pathways, bilateral projection of corticospinal pathway
- initially period of HYPOTONIA (= spinal shock)
Corticospinal tract impairment (lateral system)
Weakness of distal muscles (fingers)
Babinski sign (stroke sole of feet, instead of toes flexing they extend. normal in infants)
No spasticity, muscle tone may be decreased
Medial system interruption
Initial reduction in tone of postural muscles
Loss of righting reflex
Locomotor impairment, frequent falling
Lower motor neurone injury
Damage to alpha motor neurones innervating skeletal muscle
Effects limited to motor unit, so specific deficit
- muscle atrophy and weakness
- fasciculations, spontaneous action potentials
- fibrillation, twitching of individual muscle fibres
- decreased muscle tone (hypotonia) and reflexes (hyporeflexia)
Upper motor neurone injury
-> change in way system works, so planning affected as well as execution
Common, as large amount of cortex occupied by motor areas
If identify specific body regions affected, identify site of injury, as topographical arrangement
- increased muscle tone (spasticity), hyperactive stretch reflexes
- weakness, in distal muscles first
- pathological reflexes, eg Babinski sign
- reduced superficial reflexes
Lesion dividing spinal cord from CNS
Flaccid paralysis, loss of both voluntary and muscle tone
Lesion dividing upper and lower brainstem
Decerebrate posture:
Arms adducted and extended, wrists pronated, legs fully extended with plantar flexion of feet
Lesion dividing cerebrum from upper brainstem
Decorticate posture:
Arms abducted and flexed, wrists and fingers flexed on chest, legs stiffly extended and internally rotated, plantar flexion of feet
Cerebellum - inc deep nuclei
Hindbrain
Neuronal machine
White matter mainly, thin outer layer of densely folded grey matter
Most regular anatomy in brain:
4 deep (intracerebellar) nuclei on each side
- Dentate - don’t
- Emboliform - eat
- Globose - greasy
- Fastigal - food
Info from cerebellar cortex to deep nuclei, then exits cerebellum
Spinal cord inputs into cerebellum
Detailed, external proprioceptive information:
- dorsal spino-cerebellar tract - inferior peduncle - lower limb
- cuneo-cerebellar tract - inferior peduncle - upper limb
Integrated, internal proprioceptive information:
- ventral spino-cerebellar tract - superior peduncle - lower limb
- rostral spino-cerebellar tract - inferior peduncle - upper limb
-> unconscious proprioception, mainly pass ipsilateral to anterior lobe and vermis, straight to cerebellum not higher centres
Non-spinal cord inputs to cerebellum
Cerebral cortex -> cerebellar cortex
Vestibular nuclei (ipsilateral) -> floculonodular node
Reticular formation (ipsilateral) -> cerebellar cortex
Inferior olivary nucleus (contralateral) -> cerebellar cortex
- all sources of cerebellar input and all targets of its output go to inferior olivary nucleus
Purkinje cells
Large neurones in cortex of cerebellum
- triangular cell body
- numerous branching dendrites
- single long axon
Release GABA to regulate and coordinate motor movements
Cerebellar cortex layer
Outer synaptic layer - molecular layer
Immediate discharge layer - purkinje layer
Inner receptive layer - granular layer
Cerebellar inputs
Two types of input:
CLIMBING FIBRES - wrap around dendritic tree of purkinje cells
- from inferior olivary nucleus
- end on purkinje cells
- non-movement related
- somatosensory, visual, and cerebral cortical info
MOSSY FIBRES
- from all other afferents - nuclei in spinal cord and brainstem
- end on granule cells
- movement-related behaviour
- sensory info from periphery, info from cortex
Cerebellar function
Balance, posture, muscle tone, limb movements
- skilled voluntary movement planning (ipsilateral)
SUBCONSCIOUS
Relays info between body muscles and areas of cerebral cortex involved in motor control
Cerebellar outputs
Lateral hemispheric cortex
- pre-programming movements
- cerebrocerebellum
Paravermal cortex and Vermis
- motor excution
- spinocerebellum
Flocculo-nodular lobe
- vestibulocerebellum
- control of posture, balance, eye movement and coordination
Cerebellar damage signs
IPSILATERAL (as double crosses) Danish P: - dysdiadochokinesis - ataxia - nystagmus - intention tremor - slurred speech - hypotonia - past pointing
eg excessive alcohol abuse -> permanent slurred speech, loss of balance or coordination
Basal nuclei
= basal ganglia
Subcortical, base of brain, collection of neuronal cell bodies
Includes:
- caudate nucleus
- putamen
- globus pallidus - external and internal segment
- subthalamic nucleus
- substantia nigra - pars compacta and pars reticulata
- nucleus accumbens
Components of basal nuclei - striatum
= caudate nucleus + putamen
Input region of basal nuclei
Separated by internal capsule
Components of basal nuclei - lentiform nucleus
= putamen + globus pallidus
Components of basal nuclei - internal segment of globus pallidus and pars reticulata of substantia nigra
Output region of basal nuclei
Project to thalamus
Components of basal nuclei - pars compacta of substantia nigra
Dopamine-containing neurones
Project to striatum
Components of basal nuclei - nucleus accumbens
Forms part of ventral striatum
Involved in motivation and reward
Function of basal nuclei
Initiation and control of voluntary movements
+ eye movements
+ learning routine behaviour
+ emotional and motivational behavioural responses
Basal nuclei motor loop
Excitatory connection from cortex to putamen
Cortical activation -> excitation of putamen -> inhibit globus pallidus -> release ventral lateral nucleus from inhibition
-> modulates activity in SMA (supplementary motor area)
Direct pathway through basal ganglia
Cerebral cortex: excitatory glutamate -> striatum
Tonically active substantia nigra pars compacta: excitatory dopamine -> striatum
Striatum: inhibitory GABA -> INTERNAL globus pallidus
Internal globus pallidus: inhibitory GABA -> thalamus
Thalamus: excitatory glutamate -> motor cortex, and project to all other cortex
OVERALL
- activation of thalamus to activate motor cortex, allowing voluntary movements
Indirect pathway through basal ganglia
Cerebral cortex: excitatory glutamate -> striatum
Tonically active substantia nigra pars compacta: excitatory dopamine -> striatum
Striatum: inhibitory GABA -> EXTERNAL globus pallidus
External globus pallidus: inhibitory GABA -> subthalamic nucleus
Subthalamic nucleus: excitatory glutamate -> internal globus pallidus
Internal globus pallidus: MORE inhibitory GABA -> thalamus
Thalamus: LESS excitatory glutamate -> motor cortex, and project to all other cortex
Key diff is goes via external globus pallidus and subthalamic nucleus, so inhibition to thalamus
OVERALL
- inhibition of unwanted movement, reduced output to motor cortex
Huntingdon’s disease
Autosomal dominant neurodegenerative
Loss of striatal neurones, lose inhibitory influence on thalamus
-> loss of cortical neurones
- hyperkinesia, dyskinesia
- chorea
- dementia
- changes in mood and personality
- > death
Ballism
Ballistic movements - violent, flinging movements of extremities
Typically by damage to subthalamic nucleus, may be stroke
(subthalamic nucleus is excitatory to internal globus pallidus, hence suppresses movement)
Often hemiballism, only one side
Other basal nuclei loops
Occulomotor loop - control gaze
Prefrontal and orbitofrontal loops - cognition
Limbic loop - emotional and visceral functions
Aetiology of Parkinson’s disease
Genetics - sometimes inheritable, 12 different genes can cause, number of different hits - 10% causes, often when younger onset
Toxins - can be drug induced
Mitochondrial dysfunction - esp in dopamine neurones
Abnormal protein aggregation (Lewy bodies)
-> death of neurones in substantia nigra -> dopamine depletion in striatum
(caffeine and nictotine limit neurodegeneration??)
Cardinal features of Parkinson’s disease
TREMOR
- 2/3 have
- asymmetric (as 2 nigra-striatal pathways), slow frequency, rhythmic, at rest
- mainly in limbs, not head
RIGIDITY
- hypertonic limbs, uniform increase in tone
- not spasticity
BRADYKINESIA
- decreased frequency and amplitude of movement
- reduced facial expression, gait freezing when environment challenges, micrographia (small writing), fine finger movement hard
POSTURAL INSTABILITY
- reduced postural reflexes, so can’t correct when knocked off balance
- need to attend to gait, can’t walk and talk
OVERALL:
- as is loss of dopamine neurones in substantia nigra pars compacta, damage to indirect pathway so -> can’t prevent unwanted movement, damage to direct pathway so -> can’t initiate voluntary movement
Pathology and progression of Parkinson’s
Degeneration of dopamine neurones, substantia nigra becomes pale
Also loss in putamen and caudate nucleus, that also use dopamine as neurotransmitter
As substantia nigra reduces, brain compensates until reach threshold for clinical expression, only symptoms at 70% loss of cells (problem for early treatment)
Then rapid degeneration
- live around 25 years post diagnosis, slow degeneration
Non-motor complications of Parkinson’s
Dementia
Depression - basal ganglia also for cognition and mood, also lose NA neurones and serotonin
Anxiety
Sleep disturbance
Drowsiness
Restlessness
Impulse control problems - basal ganglia also for pleasure and reward
Autonomic disturbances in Parkinson’s
Dysphagia Drooling Bladder dysfunction Constipation Weight loss Postural hypotension Pain
Treatment options for Parksinson’s
PREVENTATIVE - none, causal factors unclear SYMPTOMATIC - pharmacological - deep brain stimulation (surgical) NON-MOTOR MANAGEMENT - cognitive therapy - speech therapy - physiotherapy - dietician - psychologist RESTORATIVE - experimental - stem cell transplant - gene therapy - neurotrophic factors - to support surviving cells
Drug classes to treat Parkinson’s symptoms
Dopaminergic agents - Levodopa, dopamine receptor agonists
COMT (catechol-O-methyl transferase) inhibitors
MAO-B (monoamine oxidase) inhibitors
Anticholinergics
Amantadine
Memantine
Parkinson’s drugs - Levodopa
= L-dopa
Effective to relieve motor symptoms, boost remaining cells function
Requires active transport across gut-blood BB barrier - is partly converted to dopamine in blood, bad as -> GI side effects
Need to give in high doses
Give with decarboxylase inhibitor to limit peripheral conversion to dopamine
Fast onset -> on, but also fast -> off
Side effects -> dyskinesias
- excessive dopaminergic stimulation, at peak dose -> ballistic movement
Initially will increase survival rate, but won’t work forever
Parkinson’s drugs - direct dopamine receptor agonists
GOOD
- longer half life than L-dopa
- mono or adjunct therapy
- delay/reduce dyskinesias
- neuroprotective???
BAD
- nausea, vomiting - direct action on peripheral dopamine receptors
- dizziness, postural hypotension, headache, drowsiness
- dyskinesias
- confusion, hallucinations, paranoia
- pulmonary and retroperitoneal fibrosis, pleural effusion and thickening
Parkinson’s drugs - inhibitors of dopamine metabolism
MAO-B (monoamine oxidase) inhibitors
or
COMT (catechol-O-methyl transferase) inhibitors
Parkinson’s drugs - MAO-B (monoamine oxidase) inhibitors
Selegiline
- inhibits dopamine metabolism in brain, so dopamine is not broken down in synapse, instead repackaged to vesicles and recycled
- neuroprotective???
- given as patch, so constant concentration
Rare side effects, need low tyramine diet, not with antidepressants
Parkinson’s drugs - Anticholinergics
Works as dopaminergic depletion -> cholinergic overactivity to compensate
Effective for tremor, and ~rigidity
Side effects - dry mouth, sedation, confusion, constipation
eg Trihexyphenidyl, Benztropine, Ethopropazine
Parkinson’s drugs - Amantadine
Antiviral agent
Effective for tremor, bradykinesia, rigidity, dyskinesias
Exact mechanism unclear
Side effects - autonomic, psychiatric
Parkinson’s drugs - Memantine
NMDA receptor antagonist
Mechanism unclear
Parkinson’s treatment - deep brain stimulation
Surgery - electrode implanted to motor output regions, connected to pacemaker in chest
Invasive and risky, only after drugs no longer effective
Very effective to control motor symptoms
Parkinson’s treatment - restorative factors?
Stem cell transplant?
Gene therapy - neurotrophins?
Huntingdon’s disease genetics
Autosomal dominant
Polyglutamine expansion repeat on Huntingtin (Htt) gene
- random mutation replicates multiples of GGGGG etc
-> incorrect protein folding
-> oligomers, sticky, as micro-aggregation
-> insoluble so precipitate as solids in cell
-> disrupts cell working, toxic effects on function
More repeats, earlier onset, worse effects
Treatment of Huntingdon’s disease
Hugely varied symptoms, so need many different treatments
In gene therapy, could inhibit RNA, aggregation, encourage autophagy etc
- but can’t lose Huntingtin, has useful function!
Myelination
MYELIN
- lipid rich
- spiral wrapping of glial plasma membrane extensions around neurones
NODES OF RANVIER
- periodic gaps in sheath to allow saltatory conduction
- > faster speed of conduction
- > cool neurones
- > structural support for neurones
Demyelination vs dysmyelination vs axonal degeneration
Demyelination = loss of myelin, with relative preservation of axons. Can be in PNS or CNS.
Dysmyelination = failure to form normal myelin
Axonal degeneration as primary process -> secondary degeneration of myelin. Would get decreased amplitude.
Immune-mediated PNS demyelination
ACUTE Guillain Barre Syndrome - can be post infection - distal then proximal - weakness and paraethesia, esp in neck - early loss of reflexes -> resp failure, autonomic dysfunction
CHRONIC
Chronic immune demyelinating polyneuropathy
Other causes of PNS demyelination
Compression
- often transient and minor
- carpal tunnel syndrome, radial neuropathy etc
Hereditary
- Charcot Marie Tooth disease
Toxic-metabolic
- lead, leprosy, diptheria
As PNS recovers, -> ‘onion bulb’ formation, layering of myelin formation and destruction
Immune-mediated CNS demyelination
Multiple sclerosis
Acute disseminated inflammatory demyelination
Acute haemorrhagic leucoencephalitis
Neuromyelitis optica
Acute disseminated inflammatory demyelination
= ADEM Monophasic illness Post-infection More children than adults get -> fever, drowsiness, fits, coma, meningism
Can be fatal, rare so not well understood
Neuromyelitis optica
Inflammation affecting spinal cord mainly, and optic nerve
NMO-IgG antibody to diagnose
Longitudinally extensive cord lesions, across more than 3 vertebral segments
-> Optic neuritis
Treatment responsive to immunosuppression
Central pontine myelinolysis
Often after rapid correction of sodium (fast infusion following hyponatraemia)
Progressive multifocal leucoencephalopathy
JC virus causes - immunocompetent should resist
Can be asymptomatic
Impaired immunity can reactivate
Can’t treat, need immune system to
Aetiology of multiple sclerosis
UNKNOWN
Genetic susceptibility and environment interplay
- 10x increased risk in 1st degree relatives
- 3x more in women
Environmental triggers:
- multiple infectious agents - antigens on virus similar to myelin?
- aberrant response to infection - Epstein-Barr and glandular fever link
- low sunlight
- vitamin D deficiency (immune regulator)
- smoking
-> onset in 20s-30s usually
Lesions in multiple sclerosis
‘Demyelinating lesions disseminated in time and space’
- different parts of NS at different times
- need multiple episodes of neurological dysfunction for 24hours + for diagnosis
Perivenular or periventricular distribution (loss of white matter mainly)
- > axonal loss (probably secondary)
- > inflammation
Diagnosing MS
Presentation:
- weakness in limb(s)
- optic neuritis
- paraesthesiae
- diplopia
- urinary symptoms
History:
- onset over days
- fatigue
- family history
- worse in heat - Uhtoff’s phenomenon
- shock down spine when bend neck forward - Lhermitte’s phenomenon
Examination:
- may be no signs
- or signs of multifocal CNS disease
MRI - white matter lesions
CSF - oligoclonal bands, antibodies, suspicious if not also in blood as implies local process
Clinically isolated syndrome - first episode of MS?
If normal MRI, very low likelihood of MS
If white matter lesions, 50% MS at 2 years, 80% at 20 years
Phases of MS
70%
Relapsing-remitting initially, then secondary progressive
- once secondary progressive, neurodegenerative, no treatment
10%
Benign relapsing-remitting
- good treatments, autoimmune
20%
Primary progressive
MS presentation - optic neuritis
45yrs + usually
Onset 1-2 weeks
Spontaneous improvement, 1/3 recur in 5-10 years
Future MS risk
Peri-ocular pain, worse in heat
Visual field defect
Extent of recovery influenced by severity of visual loss
Steroids improve short term recovery, not long term
Treatment only for - monocular vision, severe bilateral loss, require rapid recovery (occupation)
Factors for rapid progression of MS
- male (though more common in females)
- older age onset
- primary progressive type MS (PPMS)
- brainstem/cerebellar presentation
- change in MRI lesion load
- more attacks in first year, short gap between first two episodes
MS drugs - steroids
1st line, corticosteroids
- only in very severe symptoms - need high doses to penetrate NS so side effects bad
- no more than 3x per year
- shorten relapse duration, no effect on extent of functional recovery
MS drugs - interferons and glatiramer
Reduce relapses by 1/3
No reduction in disability progression - but may delay time to progress to secondary progressive?
Very expensive! So only give if:
- still ambulant
- 2 relapses in 2 years
- 1 disabling relapse
- MRI evidence of new or enhancing lesions after 1 year
Used less now, not that effective
MS drugs - fingolimod
Tablet
Sphingosine-1-phosphate receptor inhibitor
- inhibits trafficking of inflammatory cells
BUT risky - CVS, respiratory issues
60% reduction in relapse rate
MS drugs - dimethylfumarate
Most common, tablet
Transcription factor - anti-inflammatory and lowers oxidative stress
Safe
50% reduction in relapse rate
MS drugs - teriflunomide
Tablet Anti-inflammatory immunosuppressant 30% reduction in relapse rate Risky - hepatotoxic and teratogenicity --> rarely used, last line
MS drugs - natalizumab
Monoclonal antibody therapy
Monthly infusion
2/3 relapse reduction rate at one year
Risky, only for severe relapse-remitting disease
MS drugs - alemtuzumab
Monoclonal antibody therapy
Reduces relapse by 75%
Decreased disability over three years by 71%
Side effects - increased incidence of other autoimmune diseases
MS drugs - neuroprotection
No licensed drugs currently
To slow progression
Symptoms of MS
Bowel + bladder dysfunction Spasticity Mood Erectile dysfunction Tremor Pain Fatigue Vision Cognition Mobility Speech + swallow - drugs available to help relieve these symptoms
Cerebral arteries supply
Anterior -> motor + sensory cortex of lower limb
Middle -> motor + sensory cortex of upper limb and face, and auditory cortex
Posterior -> visual cortex
Posterior inferior cerebellar artery -> lateral medulla
Watershed infarcts
Where territories supplied by different vessels overlap
If perfusion pressure is low, terminal branches of major arteries have insufficient supply
FAST
Face
Arms
Speech
Time
Middle cerebral artery syndrome
MCA most common site for ischaemic stroke
- as is main branch of internal carotid, so blood straight from body, bringing clots etc
- > contralateral hemiparesis, hemisensory loss from face, upper and lower extremities
Cerebral aneurysm
Weakness in wall of cerebral artery or vein
Dilation/ballooning of vessel
- may cause no symptoms until bursts, -> haemmorhage
- if large, may cause symptoms as press on associated brain structures
Clipping treatment - major surgery - to prevent burst or after to stop bleeding
Coil procedure - less major - wire passed up and coiled into aneurysm to block, preventative
Cerebral blood flow
50ml/min/100g brain weight
15% cardiac output
Kept constant
CBF = cerebral perfusion pressure / cerebral vascular resistance (CPP = MAP - ICP, typically 70-90mmHg)
Autoregulation of cerebral blood flow
Even over large fluctuations in MAP, CBF kept in tight limits
Below limits - CBF lower - ischaemic damage
Above limits - ICP higher - oedema, crushing of brain tissue, shifting of brain structures, restriction of blood flow, herniation
By neural, metabolic, myogenic control - work together to maintain CBF - flow adjusted rapidly at microvascular level
Neural control of CBF
1 - sympathetic neurones from superior cervical ganglion
- travel with internal carotid and vertebral arteries into skull
- release NA -> vasoconstriction
2 - parasympathetic neurones from branches facial nerve
- release ACh -> modest vasodilation
3 - sensory nerve fibres on blood vessels
- release vasodilatory substances
(overall weak control)
Metabolic control of CBF
Local increase in brain metabolism - lower pO₂, raise pCO₂, lower pH
-> vasodilation of vascular smooth muscle
Increase pCO₂ of arterial blood, CO₂ crosses BBB, lower pH
-> vasodilation of vascular smooth muscle
Hypoxia/seizures increase [K⁺]
-> vasodilation
Reduced O₂ supply, or increased O₂ demand causes rapid adenosine formation
-> potent vasodilator
Myogenic control of CBF
Stress sensing mechanism
Pressure increases diameter of vessels
-> vasoconstriction
Functional MRI scan
fMRI Fast (5s) For vascular markers eg gadolinium Changes in blood flow alter signal Oxy- and deoxyhameoglobin give different signals
Positron emission tomography
PET
Radioactive solutions into body
Positron emitting isotopes used as markers of blood flow
Linked to deoxyglucose, and receptor ligands
-> activity maps, not images
Stroke definition
Acute (rapid onset) focal injury
- of central nervous system
- due to vascular cause
eg cerebral infarction, intracerebral haemorrhage, subarachnoid haemorrhage
Affects brain or (rarely) spinal cord
Types of stroke
75% - cerebral infarction
20% - intracerebral haemorrhage
5% - subarachnoid haemorrhage
(blood white on CT, darker patches are infarction, white is haemorrhage. Infarct bright on MRI!!)
Burden of stroke
Second most common cause of death worldwide (after ischaemic heart disease)
Commonest cause of disability
5% NHS resources
- deprived areas more risk, more death
- racial differences, afro-caribbeans and south asians higher risk - higher bp, diabetes, high cholesterol, sickle cell disease
20% strokes fatal
50% -> permanent disability
Causes of ischaemic stroke (cerebral infarction)
ATHEROSCLEROSIS - form esp in turbulent blood flow, clots group and travel to brain from here
CARDIAC DISEASE - atrial fibrillation mainly, or ventricular aneurysm- blood sits for longer, so clots
- patent foramen ovale - blood can flow from right heart (maybe DVT in leg) to left heart, clot to brain
- infective endocarditis or tumours can throw clots
‘SMALL VESSEL DISEASE’ - thickening of small blood vessels in brain, shrink until they block (or become more fragile and bleed, -> haemorrhage)
ARTERIAL DISSECTION - blood gets into wall of vessel
- haemorrhage into vessel -> occlusion, or intimal tear
ABNORMAL BLOOD CLOTTING - anti-phospholipid syndrome (antibodies increase clotting)
- malignancy, due to systemic inflammation
- polycythaemia, Hb levels too high, sticky blood
ALSO many other causes - drugs, vasculitis, infection, inherited, metabolic
Risk factors for atherosclerosis
Hypertension Hypercholesterolaemia Diabetes Smoking Excess alcohol Stress Male gender Family history
Causes of intracerebral haemorrhage
Hypertension
Cerebral amyloid angiopathy - amyloid deposition in vessels, only in age really
Abnormal blood vessels
Dural venous sinus thrombosis
Intracranial neoplasm (tumours, some prone to bleed)
Coagulopathy - clotting problems
Ischaemic stroke -> secondary haemorrhage
Clinical features of stroke
Sudden onset - not even seconds, instant
‘Negative’ symptoms - lost something not gained, eg lost sensation not started tingling, weakness not twitching
- explained by single lesion
- explained by blockage of artery (ischaemic)
All usually, doesn’t always follow rules
Vascular territories of brain
Cerebral arteries have zones
ACA - medial strips, inside of medial surface
MCA - most of brain, temporal lobe and most of lateral surface
PCA - occipital lobe, stretch to bottom of temporal
Anterior circulation from internal carotid, splits to MCA and ACA
Posterior circulation in vertebro-basilar
-> so different arteries blocked, different functions of the brain, different presentations
Stroke syndromes
TACS - total anterior cerebral PACS - partial anterior cerebral POCS - posterior cerebral LACS - lacunar (ischaemic only)
MANY stroke mimics!
Total anterior circulation stroke
Need all three of:
- hemiparesis
- hemianopia (loss of vision)
- higher cortical function eg dysphagia, neglect/inattention - unable to attend to opposite side of body
Partial anterior circulation stroke
Occlusion of MCA branch or ACA Need two of: - hemiparesis - usually face + arm, or leg - hemianopia (vision loss) - higher cortical function OR - isolated higher cortical function
Lacunar stroke
Mostly in lenticulostriate arteries, off MCA - no other arteries supply area, these are end arteries
- > recognised syndromes:
- pure hemiparesis
- hemisensory loss
- dysarthia (clumsy hand)
- ataxic hemiparesis
Posterior circulation stroke
- > recognised syndromes:
- isolated hemianopia (vision loss)
- cerebellum
- brainstem
Principles of stroke treatment
Hyperacute - protect penumbra (=tissue at risk), need to get clot out to protect and limit cell death (ischaemic core is already irreversibly dead)
Prevention of complications
Secondary prevention (identify cause)
Rehabiliatation and recovery
Thrombolysis
Tissue plasminogen activator (tPA) given
-> activate plasmin, to digest clots
Needs treatment within 4.5 hours Will reduce future deficit MAY reduce mortality if very early (does increase haemorrhage risk in first 7 days) - doesn't dissolve big clots well
Thrombectomy
Insert wire mesh - stent retrievers
Then pull back out, remove clot
Useful for big clots, improves IV access to middle of clot
Can treat slightly later - 6 hours - so time to assess usefulness with brain imaging
Immediate care after stroke
Only have 24 hour window as long as penumbra persists
Thrombolysis/thrombectomy Avoid hyperglycaemia Control temperature in fever Oxygen Hydration Early nutrition
Early secondary prevention
Anti-thrombotics - balance risk (as may bleed after stroke)
- anti-platelets - aspirin, clopidogrel
- anticoagulants
Causes of ischaemic stroke
50% - arterial atherothromboembolism
25% - intracranial small vessel disease
20% - embolism from heart
Need to know (imaging) for secondary prevention
Secondary prevention
Lower bp (as long as not hypotensive)
Lipid lowering - no threshold for treatment, need to lower LDL levels, eg statins
Anti-thrombotics - anti-platelets - aspirin, clopidogrel
- anticoagulants - esp if atrial fibrillation
Carotid endarterectomy - need to remove atherosclerotic plaque
Carotid surgery within 48 hours! Sooner the better as long as stable.
International classification of Functioning, Disability and health
ICF
To ‘mainstream’ experience of disability - everyone will be disabled at some point
Shift focus from cause to impact
Focus on what you can do, not what you can
Stroke is more than a disease, people not patients
More to life than ADL, even if you’re 90!
Impairments after stroke
Motor function - weakness, incoordination
Sensory function - vision, hearing, numbness, pain
Communication - dysarthia (speech), dysphasia (language), dyslexia, dysgraphia (writing)
Swallowing
Cognitive function - motor planning, attention, memory
Emotional function
Fatigue
Bladder and bowel function
Sexual function
Pain - central or musculoskeletal
- often ignored, need to consider all aspects if working to ICF
Emotional consequences of stroke
1/3 have depression
1/4 have anxiety
1/5 have insomnia
1/5 have emotionalism
+ fatigue, lack confidence, fear of second stroke, social isolation
2/3 can’t return to work, decrease in income
+ impact for carers and families
Stroke rehabilitation
Brain recovery, + bodily maintenance (nutrition, CVS exercise, reconditioning)
- repetitive practice
- build up in difficulty
- targeted activities
- break activities into components
- compensation and recovery need to be balanced
Gradual management of expectations, goal setting short and long term
Better in specific stroke rehabilitation units! Coordinate multi-disciplinary team, need stroke specialist team
Early supported discharge teams
Same kind of high intensity care as in hospital, but in home environment
- therapists better understand goals and limitations to patient
- > improved otucomes
Determinants of rehab effectiveness
Younger age better
Pre-treatment disability
Cognitive impairment
Physiotherapy following stroke
Return motor function to normal, or find ways to compensate for it
Increase strength
Improve CVS fitness
Prevent deconditioning
Improve spasticity - drugs, passive movement, splinting, botulinum toxin
(exercise also helps with mood, improves neurogenesis)
Other therapies following stroke
Need to practice:
- swallowing (modified diet)
- communication, esp with family/friends
- arrange for vision/hearing loss help
- emotional consequences discussed
NEED at least one month off driving, never if visual loss.
