Multiple Sclerosis Flashcards
General definition of multiple sclerosis? Evolution of the disease over time?
Muliple sclerosis is a chronic, mostly progressive, inflammatory, demyelinating and neurodegenerative disorder of the CNS. The most accredited theory explaining the pathological background of MS is that inflammatory demyelination and neurodegenerative axonal damage act together.
The diseases’ evolution over time can be defined in stages : preclinical, relapsing, secondary progressive and burnt out.
In the preclinical phase the biology of the disease is present without any clinical event.
From here most patients (85%) end up in the relapsing-remitting phase where they continuously relapse and then partially or completely recover.
50-60% of these patients then due to RAW will progress to the secondary progressive phase, where the disease progresses also in between relapses, aka PIRA.
Finally there is the burnout stage, where the disease is advanced and disability is high.
Concepts of RAW and PIRA in MS?
RAW, relapse associated worsening, refers to the accumulation of disabilities that occur as a direct result of relapses. Most common in the relapsing-remitting phase.
PIRA, progression independent relapse activity, describes the gradual worsening of the disability in the absence of any relapses. Most common in the secondary progressive phase.
Epidemiology, mortality and geographical distribution?
Epidemiology —> 2.5 million people affected, huge socioeconomic burden due to disability, affects women 2/3 times more frequently, starts around 20/30 years of age. 5% of patients experience demyelinating event during childhood. MS is rarely diagnoses after 65 as it is not a disease of the elderly.
Mortality —> MS patients have an increased mortality rate, 7/14 years reduced life expectancy. 50% of MS deaths are due to lesions in brainstem controlling heart and lungs. Other complications include infections in bedridden patients. Patients also could commit suicide to stop their sufferance.
Geographical distribution —> Higher prevalence at the poles and lower prevalence at the equator.
There are three main explanations which are not mutually exclusive.
The first one is that since MS is autoimmune, ,myelin is the target, and vitamin D is associated to the synthesis of myelin. At the poles where there is less sunlight, people have less vitamin D therefore less myelin production, exacerbating the damage caused by MS.
The second reason is a genetic aspect. Scandinavian countries have higher incidence and they inhabited the UK which had an empire. Leading to the distribution of affected genetics.
The last reason is the hygiene hypothesis. It states that individuals living in hyper clean environments lack the exposure to immune tolerizing microbes. The strongest known risk factor for MS is EBV.
Genetic susceptibility and environmental factors?
A genetic background is necessary but not sufficient. Genetic predisposition is characterized by specific HLA complex such as HLA-DRB15.01.
Environmental factors are associated with the development of MS. A study by askerio showed that people who had been infected by EBV had a 32 fold higher risk of developing MS. Other transmissible agents such as HHV6, MS associated human endogenous retrovirus and chlamydia pneumoniae are also associated to MS. Low sun exposure and smoking are also risk factors.
What is the pathology of MS characterized by?
Primary demyelination is the partially selective destruction of myelin with relative preservation of axons. Partially because recent studies show that although demyelination is prominent, neuro degeneration including axonal damage is present as well.
In the early phase of the disease the body can recover from damage with remyelinization. However as the disease progresses this process becomes less efficient. The newly formed myelin sheaths are generally thinner that the original. This leads to impaired nerve conduction, possibly a conduction block. In addition the alteration of the nodes of ranvier make the saltatory conduction more difficult.
Perivascular inflammation, macrophage involvement, reactive astrocytosis, axonal swelling.
What is perivascular inflammation, macrophage involvement, reactive astrocytosis and axonal swelling?
Perivascular inflammation —> at the microscopic level we see T cells lead the inflammation. They move from the bloodstream inside the CNS, crossing the BBB. It is evident from the presence of mononuclear cells surrounding vessels.
Macrophages are filled with proteolipid protein, positive particles which is myelin debris. This means that macrophages are bringing myelin away from the CNS.
Reactive astrocytosis —> abnormal increase of astrocytes in response to damage within the CNS. They contribute to the formation of glial scars which form around demyelinated plaques, inhibiting remyelination and exacerbating axonal damage.
Axonal swelling —> it occurs when axons are stripped of myelin. This leads to axonal stress, ion accumulation inside the axon, leading to swelling. This causes further degeneration and contributes to neurological deficits.
Different type of lesions of MS?
Acute active lesions —> newly formed lesions. Vast amount of transected axons, highly inflamed and immune cell infiltration. These lesions represent the early stages of tissue damage is MS. The lesions are damaged but not yet irreversibly lost.
Chronic active lesions —> the prior lesions over time transition in chronic. These lesions have a core region that has become inactive due to longstanding damage. The active aspect is seen at the margins of the lesions where the inflammatory processes continue to damage and gradually grow in size.
Slowly expanding lesions —> they have an inactive core and inflammatory activity at the margins but to a lesser degree than the chronic active lesions.
Inactive lesions —> the tissue has been fully destroyed. These lesion occur in the later stages of the disease.
What are shadow plaques?
Remyelination occurs when the body attempts to repaired the damaged myelin. Shadow plaques indicate regions where this has occurred.
Different types of cortical lesions and their distribution?
Type I —> mixed white and grey matter lesion. 1/3 of cortical lesion. Very typical lesion of MS.
Type II —> small lesion in the grey matter. 16% of cortical lesions.
Type III —> subpial lesion. Affects only a few outer layers of the cortex.
Type IV —> subpial lesion. Full cortical ribbon affected.
Type III and IV account for 50% of cortical lesions.
Cortical lesion can appear in various phases of MS include acute MS. In RRMS cortical lesion start to emerge and are present alongside white matter plaques. In PPMS and SPMS cortical lesions become much more frequent.
What are subpial lesions?
They occur just under the pia mater, the delicate membrane that lines the brains surface. This positioning means that they only affect the outer layers of the cortex.
Subpial demyelination is specific to MS and does not occur in conditions like Progresssive Multifocal Leukoencephalopathy or Subacute Sclerosing Panencephilitis.
What is normal appearing white matter? Types of tissue damage in NAWM? Imaging?
NAWM refers to white matter areas in the brain which look unaffected on conventional MRI scans, but exhibit subtle pathological changes contributing significantly to MS symptoms.
The diffuse damage is most common in progressive MS, especially in SPMS.
Types of tissue damage :
- Chronically activated microglia —> these immune cells remain persistently activated and contribute to low level inflammation.
- Degenerating axons.
- Reactive astroglia.
- Compromised BBB
MRI is not sensitive enough to detect these subtle changes. Non conventional approaches like Magnetization Transfer Ratio and Diffuse Tensor Imaging have been developed to examine NAWM in vivo.
Pathology in the spinal cord in MS?
Since MS typically affects highly myelinated areas, regions with more extensive myelination such as the periventricular regions in the brain and the spinal cord are commonly affected.
In the spinal cord the primary affected areas are posterior columns which contain fibers critical for the proprioceptive system and the lateral columns which contain major nerve tracts such as the corticospinal and the spinothalamic tract. There is also grey and white matter involvement.
Pathology of MS?
Early phase —> initial inflammation occurs because of immune cells crossing the BBB. T cells cross into the CNS and recognize antigens with the help of APC. Then the B cells release pro inflammatory chemicals like cytokines and chemokines that lead the attack on myelin. As axons are damaged they become more vulnerable.
Later phase —> as MS progresses inflammation becomes compartmentalized within the CNS leading to lower intensity but persistent immune activity. This gradual process of tissue damage is associated with PIRA. Persistent inflammation mediators like TNF-alpha contribute to axonal loss, demyelination and oligodendrocyte apoptosis.
Clinical phenotypes of MS?
Relapsing Remitting MS —> most common initial form, 80% of cases, between the ages of 20-40, higher incidence in female 3:1. Characterized by episodes of symptoms followed by periods of recovery, in time leading to gradual accumulation of disabilities.
Primary Progressive MS —> 15% of cases, generally beginning at the age of 40, nearly equal gender distribution. Manifests with continuous disability accumulation, 9th out distinct relapses.
Secondary Progressive MS —> Most RRMS cases transition to SPMS. Studies show 41% of RRMS cases develop SPMS within 6-10 years, increasing to 58% in 11-15 years and up to 80% in 20 years.
Benign MS —> rare case of MS where after 15-20 years disability remain minimal. Defined as Expanded Disability Status Scale below 3 after 15 years.
What is EDSS?
Expanded Disability Status Scale. It is a 10 point scale. 0 means no disability with normal neurological examination, until 10 which is death due to MS. The scale evolves in half points.
Clinical manifestations in RRMS?
Clinically isolated syndrome is the first clinical episode suggestive of CNS demyelination, lasting 24 hours. It marks the earliest recognizable manifestation of MS but it still isn’t considered RRMS as an additional relapse is needed.
Symptoms may vary, such as unilateral sensory disturbances and vision loss but must occur in absence of fever or infection. This is because they rule out other DDX such as migraines, vascular events.
The absence of fever is also important to differentiate it from Acute Disseminated Encelophalomyelitis, an autoimmune condition typically seen in children.
There is a sub clinical phase where the patient might have had some demyelination. A rise in body temp whether by got shower, intense exercise or sun exposure, can worsen this condition and trigger a reaction.
Patients in RRMS phase are advised to not raise their body temo and may be put on paracetamol to avoid the temp increasing over 38 degrees.
Clinical course for RRMS? What is a pseudorelapse?
RRMS affects approximately 85% of MS patients. This stage is characterized by episodes of acute or subacute neurological dysfunction, known as relapses. They typically develop over days and weeks, last at least 24h, reach a plateau and the partially or fully resolve. These relapses can recur at irregular intervals with an average of one a year during this phase.
A pseudorelaps can occur when external factors like elevated temperatures, stress and infections temporarily exacerbate MS symptoms.
Clinical course of SPMS?
RRMS may transition into this progressively worsening from. This phase is marked by ongoing neurodegeneration. The likelihood of developing SPMS increases with time.
Clinical course of SPMS and PPMS?
SPMS —> RRMS may transition into this progressively worsening from. This phase is marked by ongoing neurodegeneration. The likelihood of developing SPMS increases with time.
PPMS —> PPMS usually presents as gradual onset of asymmetric leg weakness or gait disturbances. Other presentations may include sensory, brianstem/cerebellar or sphincter dysfunctions. Patients tend to develop walking disabilities about 50% faster than those with RRMS because PPMS starts with progressive symptoms.
Optic neuritis and its connection to MS?
Optic neuritis is a classic presentation in MS. It often provides the initial clue to the disease. The disease is characterized by : sudden vision loss, central scotoma, dyschromatopsia (impaired color vision), pain with eye movement (this is specific to MS as in infection there is constant pain while with vascular events no pain).
Diagnosis —> the optic disc may appear normal or slightly swollen. MRI may show hyper intense signal due to inflammatory demyelination. Vision loss occurs subacutely unlike due to retinal vein blockage which occurs instantly.
Optic neuritis usually gradually resolves over 2 to 4 weeks. Conditions like B12 deficiencies, as B12 is critical in the production of myelin, can cause more severe and sustained optic nerve damage.
Typical characteristics of brain stem and cerebellar involvement in MS?
Brainstem :
CN VI involvement —> This nerve is frequently affected because it has a long path through the brainstem, making it susceptible to lesions. Damage to CN VI results in lateral gaze palsy, often presenting as double vision (diplopia).
Internuclear Ophthalmoplegia (INO) —> Caused by a small lesion in the medial longitudinal fasciculus , which connects CN VI with the contralateral CN III nerve, specifically the medial rectus component. INO results in a horizontal gaze palsy, where one eye fails to adduct properly when looking sideways.
Cerebellar :
They are uncommon at onset of MS but may appear as the disease progresses. Symptoms include nystagmus, dysarthria, limb ataxia, intention tremor, truncated ataxia and gait ataxia.
DDX could be infection if fever and meningismus or genetic causes.
Spinal cord involvement in MS?
Spinal cord involvement is a common and often early manifestation in MS, presenting with a range of sensory, motor, and autonomic symptoms.
Sensory Symptoms :
- Altered Sensations : Patients may experience numbness, tingling, or a “pins and needles” sensation in affected limbs. During neurological examination, all sensory areas may reveal abnormalities, including both superficial (e.g., light touch, pain, temperature) and profound (e.g., vibration, proprioception) sensations.
- Severe Lesions and the “Oppenheim Hand”: A lesion in the posterior columns of the cervical spinal cord may cause a specific symptom called the “Oppenheim hand.” This condition is marked by the loss of proprioception, or position sense, in the hand, resulting in a “useless hand.” Patients lose the ability to perceive and control different segments of their hand, significantly impairing function and dexterity.
Motor impairments :
- Weakness and spasticity : lesions affecting the corticospinal tract can cause motor deficits such as muscle weakness, stiffness and spasticity. May also cause clonus.
- Anterior spinal cord : lesion in this area may lead to reduced muscle tone, weakness and muscle wasting.
Autonomic dysfunctions :
- Bowel dysfunction : constipation is common in MS due to impaired bowel motility from spinal cord involvement.
- Bladder dysfunction : bladder issues are frequent and can impact QOL. They can cause urge incontinence (failure to store) or urinary hesitancy (failure to empty).
- Sexual dysfunction : can affect both men and women with arousal and sensation.
