Multiple Sclerosis Flashcards
What is myelin?
Layers of membrane wrapped around neuronal processes, derived from glial cells (oligodendrocytes in the CNS and Schwann cells in the PNS)
These cells are found particularly in the axons of the CNS, motor neurones from the spinal cord to muscle/organ and sensory processes from receptors to the spinal cord.
It has a high water content (40% in situ) and its dry mass is 70-80% lipid and 15-30% protein.
Its function is to increase the speed at which axons carry signals, called saltatory conduction.
What types of diseases affect myelin?
Demyelinating - myelin is destroyed:
Multiple Sclerosis
Guillain Barre syndrome (acquired immune mediated inflammatory disorder of the PNS)
Dysmyelinating - abnormal makeup of myelin:
Adrenoleucodystrophy (excess of fatty acid component of myelin, which can result in dementia_
Tay-Sachs disease (lipid storage disease characterised by motor regression in infants)
What tissue changes occur in multiple sclerosis?
In the early stages, the blood brain barrier is damaged by activated lymphocytes which pass through the barrier where they release the cytokines IL-2, INF-gamma and TNF-ß. A chain reaction is triggered resulting in damage to the myelin sheath and formation of localised region of inflammation (plaques). The activated lymphocytes recruit macrophages which also attack the myelin directly. matrix metalloproteins are also destroyed.
The damage to the myelin interferes with the saltatory conduction, causing symptoms which differ depending on the location.
Major sites of lesion include the optic nerve, spinal and cranial nerves, white matter close to the cerebral hemispheres, the pons, cerebellum and spinal cord.
What is remyelination?
When the plaques form, the oligodendrocyte damage can be reversed, and the myelin reforms. However, with repeated relapses, the remyelination is imperfect, and nerve impulse transmission does not fully recover. Over time, individual axons die and scar tissue forms at the site of the inflammatory plaque. This corresponds to the progressive stage of MS, when disability accumulates.
Under laboratory conditions, stem cells are very capable of remyelinating axons, so inflammatory conditions or axonal damage must inhibit stem cell differentiation.
What is the initial trigger to demyelination in multiple sclerosis?
One possibility is a certain bacteria or virus share structural similarities with key protein in myelin. During infection, activation of T lymphocytes can attack the myelin.
Myelin basic protein accounts for 30% of the protein in myelin and is considered to be the main potential protein in which the initial immune attack is against. T cells responding to MBP are found in peripheral blood in normal individuals and in higher levels when people have active MS.
How can geographical location cause multiple sclerosis?
There is a vide geographic variance in MS incidence. The condition is very rare in equatorial regions and more common in temperate zones of both hemispheres. There is also great variation across short distances, as MS is 5 times higher in the Orkney islands in comparison to southern England.
However, Japan is a low risk area and Europe is a high risk area, and they are on the same equatorial line. This is lilely due to be because of racial differences
Geographic contribution has bee atributed to differences in diet, toxins and infectious diseases. Sunlight exposure has shown to have a big effect, as a decreased vitamin D production may contribute to MS, as it has been shown to be an important immune system regulator.
When people migrate during childhood, their MS risk is that of the country they have moved too. if they move after childhood, it remains that of where they lived.
How can gender effect risk of multiple sclerosis?
Women are more likely to be affected. this is likely to be due to female sex hormones being pro-inflammatory whereas male sex hormones are anti-inflammatory.
What genetic factors influence the development of multiple sclerosis?
There is strong evidence that there is a genetic link as there is a 30% concordance in identical twins, but only 305% concordance in non identical twins.
Research shows that it is rare for MS to be passed from father to son, and less rare for it to be passed.
No genetic linkage studies have identifies disease casing genes, but some point to HLE regions on chromosome 6, which are important genes in the immune response.
What are the different subtypes of multiple sclerosis?
Benign
Relapse-remitting: 90% of patients have this, and is characterised by unpredictable attacks followed by months to years of relatively quiet periods, The deficits may resolve and become benign, or may be permanent.
Primary progressive - 10% of patients have this, they have no remission and decline slowly without distinct attacks
Secondary progressive - 80& of relapse-remitting patients have this, patients have a neurological decline between acute attacks with no clear remission. This type results in the greatest amount of disability.
What are the symptoms of multiple sclerosis?
Initial:
Changes in arm, leg and face sensation
Optic neuritis, if this gets better patients are often left with less vivd colour vision
Internuclear opthalmoplegia which occurs when MS affects the medial longitudinal fascicles, responsible for communication between eyes. The medial rectus do not contract in synchrony causing a disconjugate gaze and double vision.
Physical:
Flickering eye movements
tremor
Hand clumsiness
Cognitive:
Difficulty multitasking
Difficulty following detailed instructions
Emotional:
Clinical depression
Anger and anxiety
Suicidal thoughts
What diagnostic procedures are used in multiple sclerosis?
Requires evidence of 2 anatomically separate demyelination events occurring 30 days apart
MRI shows demyelination as bright lesions on T2-weighted images of fluid attention incursion recovery sequences (FLUID). Gadolinium enhancement shows active plaques on T1-weighted images. This can also show legions which occurred but caused no clinical symptoms.
CSF examination shows evidence of chronic inflammation. SDS-PAGE of CSF shows oligoclonal bands representing antibodies which are made in the blood and passed into the CNS. These bands are often found in meningitis, encephalitis, cerebral infarction and other inflammatory conditions. The intensity of the band does noes not correlate with the disease severity.
Evoked potential studies using an EEG and testing responses to different stimuli can be used. Results are compared (eye vs eye, limb vs limb etc) to indicate if any lesions have occurred.
What is the treatment for multiple sclerosis?
There is no definitive cure for MS. Treatment is aimed at retuning full function after an attack and preventing new attacks.
INF-ß 1a or 1b dampen down the effect of INF-gamma
Glatiramer acetate - a mix of polypeptides which resembles myelin basic protein, and substitutes itself as a target of the immune system.
Intravenous corticosteroids can be used to reduce inflammation, such as methylprednisolone which ends the attack sooner leaving fewer disabilities.
injection of non-wild type gene encoding for myelin basic protein on chromosome 18 doubles the amount of myelin.
