Case 6 - Multiple sclerosis Flashcards
What are the 4 types of neurons?
Unipolar = sensory
Pseudounipolar = sensory
Bipolar = interneuron
Multipolar = interneuron or motor neuron
What is axonal transport?
Transport of proteins and polypeptides from soma to axonal end for secretion. Packaged into vesicles by golgi apparatus in the soma
What are the 2 types of axonal transport and what proteins do they use?
Anterograde transport - from soma to axonal end = uses kinesin
Retrograde transport - terminal sends signals to the soma = uses dyenin
What is the role of astrocytes?
- Supply metabolic fuel (as lactic acid) to neurons
- Synthesise NT
- Maintains K+ concentration
- Act as support cells, maintain the BBB
What are the 2 types of astrocytes and where are they primarily found?
Fibrous astrocyte = white matter
Protoplasmic astrocyte = grey matter
What is the role of microglial cells?
Proliferate following injury, act as scavengers and remove cellular debris. They are the resident macrophages = 1st line of immune defence in the CNS
What is the role of oligodendrocytes?
Synthesise myelin in the CNS
What is an electrotonic potential? Give an example of what can cause one
Non-propagated local current, resulting from a local change in ionic conductance.
Example = Amacrine cells in retina
What are relay nuclei? Give examples and where they are present
Integrate converging information, found in the CNS but predominantly in the thalamus. They include local interneurons and projection neurons
What is the composition of myelin?
Lipids: galactocerebroside
Glycoproteins: myelin basic protein, myelin oligodendrocyte protein, myelin associated glycoprotein
How do action potentials jump from node to node from myelinated neurons?
Small gaps between myelin sheath = Nodes of Ranvier, VG Na+ channels are only present here, so AP jump from node to node (‘saltatory conduction’)
By how much does myelination increase the speed of conduction of neurones?
Around 15x faster:
Unmyelinated conduction = 0.5-10 m/s
Myelinated conduction = 150 m/s
How does demyelination of neurons make people feel more tired?
Impairs signal conductance so it increases the energy cost of neurons = fatigue faster
Compare primary and secondary demyelination
Primary demyelination: myelin sheath is damaged or destroyed whilst axons remain intact
Secondary demyelination: myelin sheath is damaged as a result of primary axonal damage
Give an example of a demyelinating disease affecting the CNS and the PNS
CNS: multiple sclerosis, vitamin B12 deficiency
PNS: Guillian-Barre syndrome
What are the functions of the cerebellum?
Coordinates movement, planning and execution of movement, maintenance of posture, control of head and eye movement
It integrates sensory information about position of spinal cord, motor information from cortex and balance from vestibular organs
What are the functional divisions of the cerebellum and what are their roles?
Vestibulocerebellum: controls balance and eye movements (i.e. VOR)
Spinocerebellum: inc. vermis and intermediate zone, controls synergy of movement and receives proprioceptive information
Cerebrocerebellum: largest, involved in planning movements and motor learning
What are the inputs/ outputs of the functional divisions of the cerebellum?
Vestibulocerebellum: input= vestibular system, sends outputs to vestibular nuclei
Spinocerebellum: input= spinal cord (spinocerebellar tract), outputs= rubrospinal, vestibulospinal, reticulospinal
Cerebrocerebellum: input= cerebral cortex and pontine nuclei, ouput= thalamus and red nucleus
What is the pontine regulator of the cerebellum and lies in the centre? Give its role
Vermis: regulates posture and eye movements
What tracts transmit unconscious proprioceptive information to the cerebellum? Which transmit information from upper vs lower limbs?
Spinocerebellar tracts:
> Dorsal and ventral spinocerebellar = lower limbs
> Cuneocerebellar and rostral spinocerebellar = upper limbs
If a patient has difficulty carrying out skilled planned movements and motor learning, which part of the cerebellum is likely to be affected?
Cerebrocerebellum and spinocerebellum
What acronym can be used for manifestations of cerebellar dysfunction?
DANISH:
Dysdiadochokinesia (difficulty carrying out rapid, alternating movement)
Ataxia
Nystagmus
Intention tremor
Scanning speech (long pauses between words)
Hypotonia
How is the cerebellum connected to the brainstem?
Afferent and efferent connections run between the peduncles:
Superior peduncle = midbrain
Middle peduncle = pons
Inferior peduncle = medulla
What is multiple sclerosis?
Slow, progressive CNS disease, characterised by destruction of myelin sheath around axons in brain and spinal cord. Seems to be an immune attach against oligodendocytes
What are the 3 main areas of deficit in MS?
- Loss of sensations, i.e. touch and taste
- Motor coordination impairment, i.e. ataxia
- Vision impairment, i.e. involuntary eye movement
What is the pathophysiology of MS?
1- APC exposed to an antigen, then expresses it on its surface via MHC-2 complex (HLA)
2- APC presents antigen to Th cell = primed
3- Th cell proliferates after TCR recognises antigen, however due to similarity it also recognises myelin basic protein (molecular mimicry)
4- T cell enters circulation, passes BBB, basilar membrane and astrocytes - comes into contact w oligodendrocytes
5- T cell starts to adhere and interact with MBP, becoming activated and releases cytokines: IL-1, IL-6, TNF-a, which have effects:
> Increased self-adhesion molecules on BBB to facilitate immune cells entering
> Vasodilation to allow more blood cells to enter
> Increased capillary permeability = more WBCs can leak out
> Chemotaxis = attracts other lymphocytes
6- IFN-y released= activates macrophages = migrate to site
7- B-cells convert to plasma cells = produce ABs specific to myelin sheath/ oligodendrocytes
8- Macrophages undergo phagocytosis of oligodendrocytes/ myelin
9- Scar tissue forms on axons = plaque (sclera)
10- Plaque formation on multiple neurons = multiple sclerosis
11- T-regulatory cells release cytokines to decrease inflammation; IL-10, TGF-B = allows for minimal re-myelination (healing)
Does MS present with UMN or LMN signs? Give some examples of what may be seen upon physical exmination
UMN signs: increased tone (spasticity), hyperreflexia, presence of clonus, positive Babinski’s sign etc.
What visual defects can MS cause and why?
Causes defects as CN II is the only cranial nerve to have oligodendrocytes, so demyelination leads to optic neuritis:
- decreased visual acuity and blurred vision
- Colour vision abnormalities (affects rods)
- Pain on eye movement
- Marcus gunn pupils
What can damage to the medial longitudinal lemniscus in MS lead to?
Loses connections between cranial nerves III, IV, VI, so can result in bilateral internuclear ophthalmoplegia (nystagmus)
What is Uhthoff’s phenomenon? Why does it occur?
When neurological symptoms of MS flare up, i.e. when you’re dehydrated, unwell, stressed, tired, may re-experience symptoms of optic neuritis. It is reversible once the body cools down.
Thought to be due to increased temperature = decreases conductance along axon (and having demyelinated neurons worsens this)
What condition can be caused by demyelination of the corticobulbar tract? How might this present?
Pseudobulbar palsy - affects nuclei of CN V, VII, IX, X, XI, XII
- Decreased chewing, brisk/ hyperreflexive jaw reflex
- Absent facial expressions
- Dysphagia, dysphasia, hyperactive gag reflex
- Dysarthria (problem w speech articulation)
- Vertigo, slurred speech, ataxia, coordination
What can MS damage to the cortex and limbic system lead to?
Decreased memory
Depression
Sensory ataxia = loss of proprioception
What is Lhermitte’s phenomenon?
Flexing of the neck, which can cause shooting pain down the spine to the extremities. Caused by stretching demyelinated dorsal column of the cervical spinal cord
What type immune disorder is MS?
Type 4 hypersensitivity autoimmune disorder (cell-mediated)
What are some environmental causes of MS?
Viruses: Epstein Barre virus (EBV), human herpes virus 6 (HHV-6), hepatitis B
Bacterial infections
Low vitamin D levels in childhood = more common further from equator
Smoking
Conditions such as psoriasis, inflammatory bowel disease, Hashimoto’s, thyroiditis
What are some genetic causes of MS?
Gene HLA DR-2 present on chromosome 6; mutation may lead to a more exaggerated immune response to pathogens such as EBV and HHV-6
20-40x more likely if first degree relative
Females
Age 20-40 yrs
What is the epidemiology of MS?
- One of the most common neurological disorders: worldwide >2 million
- Onset in adults between 20-40 years
- More common in men than women (3.5 to 1); increased over past decades
- Prevalence rates higher further from the equator and in Northern parts of European countries (thought to relate to vitamin D within first 15y of life)
What 4 tests can be done to diagnose MS?
MRI of the brain and spinal cord, with and without contrast
Lumbar puncture
Visual evoked potentials
Neurological examination
How is MRI used to diagnose MS?
Look for lesions on:
- Periventricular white matter (first area to be affected)
- Brainstem
- Spinal cord
- Cerebellum
As lesions represent demyelination, inflammation, axonal loss, remyelination, gliosis or oedema
How are the two weighted MRI scans used for MS diagnosis when looking at new/ old lesions?
T1-weighted: contrast-enhanced, i.e. lesions appear dark (hypointense). This enhances acute (new) lesions
T2-weighted: lesions show as bright white (hyperintense). This enhances old plaques
How is a lumbar puncture used to diagnose MS?
- CSF protein and cell count usually normal
- CSF / serum glucose ratio : >0.4
Test for oligoclonal band patterns (increased IgG) on CSF and serum electrophoresis: bands absent in serum and bands present in CSF indicate primary CNS autoimmune disease (not specific to MS)
What type MS is lumbar puncture good for diagnosis of and why?
Primary progressive MS
As they have few lesions so hard to use MRI to diagnose it
How is visual evoked potentials used to diagnose MS?
As the optic nerve is first to be damaged, it tests how quick it is for a signal to pass to the brain, which is delayed in MS. Therefore MS patients would have a low conduction velocity result
What are some signs of MS that may be present with a full neuro exam?
Hyperactive reflexes and positive Babinski’s sign (and other UMN lesion signs)
Pale optic disc upon examination of retina with an ophthalmoscope