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
What is McDonald’s criteria for diagnosis of MS?
States that MS disseminates in time in space, i.e. has to have 2 or more different relapses at 2 different time points:
> Disseminates in space= based on MRI with lesions present in distinct locations of CNS, indicating a multifocal CNS process
> Disseminates in time= development of new CNS lesions over time or positive oligoclonal bands
What is ‘clinically isolated syndrome’?
The first episode of demyelination and accompanying signs/ symptoms. You cannot diagnose MS from this as it hasn’t disseminated in time and space. Some people may never have another episode
What is benign MS and what proportion of MS patients have this?
Very short episodes of mild symptoms, then return to normal between attacks
10-20% of MS patients
What is relapsing-remitting vs relapse-persisting MS? What proportion of MS patients have this?
Unpredictable attacks (relapses) lasting >24 hours with periods of remission/ improvement for months-years. Relapsing-remitting is where the remission returns to normal levels, but relapse-permitting is where remission never returns to normal (gradually worsens).
85-90% of MS patients
What is secondary progressive MS? What proportion of MS patients have this?
Relapses alternating with remission, followed by gradual progression of the disease. The gradient of progression can vary between individuals and may include severe symptoms.
After around 20 years, 50% of patients with relapsing-remitting MS will develop SPMS
What is primary progressive MS? What proportion of MS patients have this?
Disease progresses gradually with no remissions/ relapses, although may have temporary plateaus.
Approx. 10% of people will never have remissions after the initial symptoms.
What is a risk factor for developing primary progressive MS?
Older age at disease onset
What is progressive relapsing MS? What proportion of MS patients have this?
Disease progresses gradually but is interrupted by sudden relapses. Very severe but is rare; less than 5% of MS patients have this
Without treatment, on average how common is a relapse of MS?
Usually 1 every 2 years, and not every relapse is symptomatic
What factors are related to a better prognosis of MS?
Caucasian
Monofocal onset
Females
Onset with optic neuritis or isolated sensory symptoms
Low relapse rate in first 2-5 years
Taking vitamin D
Long interval to second relapse
No or low disability at 5 years
What factors are related to a worse prognosis of MS?
African-American or non-white
Multifocal onset
Males
Onset with motor, bladder or cerebellar symptoms
High relapse rate in 2-5 years
High disability at 5 years
Smoking
High salt intake
What are the 3 main goals when treating MS?
1- Disease modification via biologic therapy
2- Treat relapses and acute exacerbations
3- Symptom control
What is the first line treatment for treating relapses of MS? Give examples
High-dose corticosteroids (once infection has been ruled out):
- Prednisolone - oral
- Methylprednisolone - 500mg/d orally for 5d, or 1g/d intravenously for 3-5d, if oral treatment has failed or symptoms are severe
What is the MOA of corticosteroids for treating MS relapses?
Suppresses the immune system, so can accelerate recovery by reducing inflammation. Glucocorticoids inhibit IL-1, IL-6 and TNF-a so reduce their effects.
However has no effect on disease progression and benefits diminish with consecutive courses.
What are some side effects of corticosteroids?
Suceptibility to infection
Weight gain
Fatigue
Gastritis
Osteoporosis
Hypertension
Low moods
Ulcers
What drugs are used to control the immune system in MS? Give their MOA
IFN-B= inhibits T helper cells
Glatiramer acetate= inhibits T cells and has G proteins similar to myelin so can also act as a T cell decoy
Monoclonal antibodies, including ocrelizumab, natalizumab, alemtuzumab = inhibit T and/or B lymphocytes
Which monoclonal antibody may increase risk of PML?
Natalizumab - increases risk of progressive multifocal leukoencphalopathy, a rare infection of brain and spinal cord caused by JC virus.
What drugs may be used for symptom control in MS?
> Spasticity and muscle spasms= anti-spasmatic agents
Walking problems = dalfampridine
Parasthesia= anti-seizure drugs, e.g. gabapentin and pregabalin, or tricyclic antidepressants
Depression = anti-depressants
Tremors = propanolol
What is emotion focused coping?
Focus on reducing distress, i.e. distracting yourself
What is problem focused coping?
Focus on dealing with the problem, through seeking infomation or problem solving
Compare approach-coping and avoidance-coping strategies
Approach coping strategy= proactive approach to dealing with the situation
Avoidance coping strategy= trying to avoid the problem, i.e. denial
What is depression?
A state of low mood and aversion to activity that can have a negative effect on a person’s thoughts, behaviour, feelings, world view and physical well-being
What are the two diagnostic classifications of ‘depression’?
Major depressive episode (MDE) = DSM-5
Depressive episode = ICD-10
What is the patient health questionaire for MDE? Give the checklist points
Based off 9 symptoms of MDE using DSM criteria, where the patient marks how common a symptom has been in the last 2 weeks:
- Anhedonia: little interest or pleasure doing things
- Feeling down, depressed or hopeless
- Trouble falling or staying asleep, or sleeping too much
- Feeling tired or having little energy
- Poor appetite or overeating
- Feeling down about yourself, i.e. feeling like a failure
- Trouble concentrating
- Moving or speaking so slowly that others have noticed, or the opposite (psychomotor retardation or psychomotor agitation)
- Suicidal ideation or self-harming thoughts
How is MDE diagnosed?
1: Likely MDE if 5 or more symptoms are present in the same 2-week period, and it represents a change from normal:
» Either anhedonia or depressed mood MUST be present (items 1&2)
» Cause significant distress or impaired functioning
» Not part of bipolar disorder
» Not due to substance abuse, i.e. drugs, alcohol
» Not better accounted for by bereavement
2: Prominent negative cognitions, e.g. self, world, future
3: When severe can involve psychosis (guilt, somatic delusions, auditory hallucinations), loss of colour vision, catatonic retardation and suicide
What are somatic delusions?
Fixed false beliefs related to the body, i.e. believing you’re rotting inside or hollow
What is catatonic retardation?
Death by dehydration, related to MDE
What is the hypothesised heritability of depression?
37%
How are dopamine and serotonin synthesised? What are they derived from?
In a 2 stage process:
1- Hydroxylation step
2- Decarboxylation step
Dopamine (a catecholamine) is derived from tyrosine.
Serotonin is derived from tryptophan
Where is majority of serotonin found in the body?
90% found in enterochromaffin cells in the GI tract
Where does the synthesis of noradrenaline and serotonin predominantly occur?
Noradrenaline= locus ceruleus in the dorsal pons
Serotonin= in a chain of brainstem nuclei; the ‘raphe nuclei’
What enzyme breaks serotonin down? What are the metabolites formed?
Monoamine oxidase (MAO-A)
Forms mainly 5-HIAA
What enzyme breaks noradrenaline down? What are the metabolites formed?
MAO-A or COMT
Forms mainly VMA and MHPG
What is the difference between MAO-A and MAO-B inhibitors?
MAO-A inhibitors = inhibits the enzyme that breaks down NA and 5-HT, i.e. iproniazid
MAO-B inhibitors= inhibits the enzyme that breaks down dopamine
What dietary requirements do patients have to follow when on MAO-A inhibitors and why?
They cannot metabolise other monoamines so have to have a diet low of dietary tyramine, i.e. no red wine, cheese, marmite etc. Otherwise it could lead to a hypertensive crisis and possibly a stroke
What is the Kindling hypothesis?
States that depressive episodes become more easily triggered over time, due to a lowering of threshold from the impact of stressful life events or by an increase in spontaneous dysregulation
Compare the roles of the dorsal and ventral neural systems, what structure do they both contain?
Ventral = important for identification of the emotional significance of stimuli, and the production of affective (mood) states. Contains the amygdala
Dorsal = integration of emotional inputs and performance of executive functions. Contains the hippocampus
How might the dorsal and ventral neural systems be affected in MDE?
Ventral: overactive in MDE = amygdala will preferentially process negative stimuli
Dorsal: underactive in MDE = hippocampus has impaired memory consolidation
What is the pathophysiology of MDE?
1: Chronic stress = high cortisol
2: excessive release of CRH from hypothalamus
3: CRH acts on pituitary to increase ACTH
4: ACTH acts on adrenal cortex= excessive release of glucocorticoids
5: High glucocorticoids dysregulates amygdala (processing bias towards sad stimuli)
6: increased adrenal activity leads to release of adrenaline
7: increased sympathetic tone= inflammatory cytokine release (TNF, IL-1, IL-6)
8: Cytokines and glucocorticoids upregulate MAO, so 5-HT, NA and dopamine decrease
9: Cytokines and glucocorticoids also decrease neutrophic factors, i.e. BDNF
10: Low BDNF leads to failure of neurogenesis in hippocampus = reduced hippocampal volume
11: dysregulated amygdala and hippocampus maintain abnormal glucocorticoids, BDNF and cytokines
How do SSRI’s work to treat MDE? Give some examples
Reversibly block the 5-HT reuptake transporter (SERT), increasing extracellular 5-HT levels
Examples: fluoxetine, sertraline, escitalopram
What are some side effects of SSRIs?
Agitation
Anxiety
GI disturbance, i.e. diarrhoea and nausea
Libido/ sexual dysfunction
(abrupt discontinuation can also cause these effects)
How long should SSRIs be used for?
Continued for at least 4-6 months after recovery, to reduce the chance of relapse
Why might SSRIs not work for MS patients?
If their serotonin neurone has been demyelinated then the SSRIs may not cause a marked effect on 5-HT
How do SNRIs work to treat MDE? Give some examples
Reversibly block SERT and the noradrenaline reuptake transporter (NET) proteins on presynaptic membrane. It also blocks recycling of dopamine as a secondary effect
Examples: venlafaxine, duloxetine
What are some side effects of SNRIs?
Nausea, dry mouth, anxiety, insomnia, sexual dysfunction, restlessness, headaches
How do tricyclic antidepressants work to treat MDE? Give some examples
Block re-uptake of 5-HT, NA and dopamine
Examples = amytriptiline, clomipramine
Why are SSRI’s used first line over TCA’s?
TCA’s arent as well tolerated as SSRIs (but are as efficacious)
What are some side effects of TCA’s? And give its potential risk
Dry mouth, blurring of vision, constipation, weight gain, urinary retention, drowsiness, dizziness
RISK = slowing of cardiac conduction
What is the name of a new anti-depressant that is dual-acting but only acts at one receptor?
Mirtazapine
What is the mode of action of mirtazapine?
A noradrenerigc a2-receptor antagonist: this receptor normally has negative feedback on autoreceptors to decrease NA release, and negative feedback on heteroreceptors to decrease 5-HT release.
Therefore antagonising the a2-receptor:
> Increased NA release
> Increased 5-HT release
By inhibiting negative feedback processes
What psychological treatments for MDE have the strongest evidence?
Cognitive behavioural therapy (CBT)
Interpersonal psychotherapy (IPT)
Problem solving therapy (PST)
What are some benefits/ cons of psychological therapy for MDE?
Benefits: patient preference (esp. for younger or female patients), more personalised and less medicalised, better tolerated than drugs
Cons: slower response, waiting lists/ availability, ability and willingness to attend sessions
How should mild depression be treated?
Do not give anti-depressants, unless history of severe depression or if symptoms have persisted >3 months
Instead prescribe low-intensity psychological intervention, i.e. computerised CBT
How should moderate or severe depression be treated?
Combination of anti-depressant medication and CBT. Antidepressants may be given step-wise for 6-8 weeks before assessing effect
What is the stepwise order for assessing antidepressants?
1: start with SSRI, i.e. sertraline
2: change to venlafaxine, mirtazapine, escitalopram or vortioxetine
3: Add augmenting agent, i.e. second generation antipsychotic (i.e. quetiapine) or lithium
4: Change anti-depressant to TCA: i.e. amytriptiline
5: Change anti-depressant to MAO-I: e.g. phenezline
How many patients with MS suffer from depression? What might be the cause?
Around 50%
Demyelination of the neurones involved in serotonin release can lead to depression due to low serotonin levels
What is an example of am MAO-I used for depression?
Iproniazid - high liver toxicity
Moclobomide
Why do depressed patients have high level of MAO-A?
MAO-A is upregulated due to cortisol and depressed patients have higher cortisol levels
What is a Lasting Power of Attorney?
Nominate someone to make healthcare decisions for you when you are not able to do so yourself, i.e. give them the legal right.
What is the Mental Capacity Act 2005?
Provides a legal framework for acting and making decisions on behalf of adults who lack the capacity to make particular decisions for themselves.
What is Advanced Care Planning?
A structured discussion with patients and their families or carers about their wishes and thoughts for the future
Give some examples of what advanced care planning should cover
- Wills, funeral arrangements
- Organ donations
- Pallative care
- Specific treatments, i.e. ventilation, advanced decisions, DNR
- Religion and spiritual needs
- Place of care
- Hopes and fears
- Lasting Power of Attorney
- Involvement of family and friends
What is an ‘Advanced Decision to Refuse Treatment’ (ADRT)?
A decision you make now about refusing a specific type of treatment in the future. it is legally binding
What decisions might ADRT address?
CPR, blood transfusions, hospital admission, transplants, ventilators
What is needed for an ADRT to be valid?
- Over 18
- Specify clearly what treatments
- Explain the circumstances in which you want to refuse the treatment
- Signed by you and a witness if refusing life-saving treatment
- Have made it on your own accord, without any harassment
- You haven’t said or done anything that would contradict the ADRT since you’ve made it
What is an Advanced Statement?
A written statement that sets down your preferences, wishes, beliefs and values regarding future care. The aim is to provide a guide for anyone that may make decisions for you in the future if you’re unable to make decisions or communicate them (i.e. lost capacity). It is NOT legally binding
