Multiple sclerosis
MS
MS is the most common central demyelinating disease, in which the myelin sheath of nerve cells in the brain and spinal cord is damaged, disrupting the transmission capacity of parts of the nervous system and resulting in a range of signs and symptoms, including physical and mental damage. Symptoms include diplopia, vision loss, muscle weakness, and difficulty feeling or coordination. Relapses can occur with new symptoms or accumulate over time. Between attacks, symptoms may disappear completely, but some permanent neurological damage can persist and accumulate.
The underlying mechanism of the disease may be disruption of the immune system or failure of myelin-producing cells. Genetic and environmental factors such as viral infection may be involved.
There is currently no cure for MS. Improving post-ictal function and preventing new episodes is the current principle of treatment.
MS is the most common autoimmune disease of the central nervous system. The latest estimate of the total number of MS patients is 2.8 million worldwide, with an estimate of 36 per 100,000. Prevalence varies widely in different parts of the world. In Africa, MS is diagnosed in 5 per 100,000 people, compared to 9 per 100,000 in South-East Asia, 112 per 100,000 in the Americas, and 133 per 100,000 in Europe. MS usually begins between the ages of 20 and 50 and is twice as common in women as in men.
Signs and symptoms
Autonomic, visual, motor, and sensory problems are the most common, but any neurological symptoms or signs can occur. Specific symptoms are related to the location of the lesion within the nervous system and may include loss of sensitivity or sensory changes such as tingling, pins and needles, or numbness; muscle weakness, blurred vision, muscle spasms, difficulty moving, difficulty coordinating and balance, speech or swallowing problems, vision problems (nystagmus, optic neuritis, or diplopia), feeling tired, acute or chronic pain; and bladder and bowel problems. In more advanced stages, there may be difficulty walking and an increased risk of falls.
Thinking difficulties and emotional problems such as depression or emotional instability are also common. The main deficit in cognitive function in MS patients is slowed information processing and memory are often affected. Intellectual, verbal, and semantic memory is usually unaffected, and the level of cognitive impairment varies widely in people with MS.
Special features of MS include 1) the Uhthoff phenomenon, in which symptoms worsen due to exposure to higher-than-usual temperatures, and 2) Lhermitte sign, which is the electrical sensation that runs down the back when the neck is bent. The primary measure of disability and severity is the Extended Disability Status Scale (EDSS).
About 85% of cases present with clinically isolated syndrome (CIS) within days of onset. Of these, 45 percent had motor or sensory problems, 20 percent had optic neuritis, and 10 percent had symptoms associated with dysfunction, while the remaining 25 percent experienced multiple previous difficulties. The course of symptoms initially has two main patterns: 1) sudden onset of deterioration (relapse) lasting from a few days to several months, followed by improvement (85% of cases), 2) gradual deterioration over time without a recovery period (10-15% of cases). A combination of these two patterns may also occur, i.e. relapse and remission may begin and then develop gradually.
Relapses are usually unpredictable and occur without warning. Acute exacerbations rarely occur more than twice a year. However, some relapses are preceded by common triggers, such as more frequent occurrence in spring and summer. Similarly, viral infections such as the common cold, flu, or gastroenteritis increase their risk. Stress can also trigger attacks.
Pathophysiology
MS refers to scarring that forms in the nervous system and is thought to be an immune-mediated disease caused by an attack by the autoimmune system on the nervous system. Its three main features are plaque formation in the central nervous system, inflammation, and neuronal myelination destruction, which interact to destroy nerve tissue, resulting in signs and symptoms of disease. MS most commonly affects the optic nerve, brainstem, basal ganglia, white matter in the spinal cord, or white matter tracts near the lateral ventricles, while the peripheral nervous system is rarely affected.
MS involves the loss of oligodendrocytes, which are important cells for producing and maintaining myelin sheaths. Destruction or complete loss of the myelin sheath (i.e., demyelinating) can further lead to the breakdown of neuronal axons. In the early stages of the disease, the myelin sheath undergoes a regenerative repair process, but the myelin sheath cannot be completely reconstructed. Recurrent episodes of the disease result in poor remyelination and eventually scar-like plaques forming around damaged axons. Due to the brain’s self-healing mechanisms, a small amount of scarring does not have noticeable consequences.
In addition to demyelinating, another sign of the disease is inflammation. From an immunological point of view, the inflammatory process is caused by T cells. T cells trigger other immune cells and release soluble factors such as cytokines and antibodies. Disruption of the blood-brain barrier also triggers more damaging effects, such as swelling, macrophage activation, activation of cytokines, and more other damaging proteins such as complement. After repairing themselves, T cells can become trapped inside the brain.
The onset of MS is associated with subpopulations of MHC II-restricted CD4 T cells Th1, Th2, Thl7, and Treg. Th1 (inflammatory) cells, producing IFN-γ, IL-2, lymphophototoxin (LT), and TNFα. Th1 cytokines activate macrophages to gain cellular immunity with the help of IgG1 secreted by B cells. In contrast, CD41 T cells that produce IL-4, IL-5, IL-10, or IL-13 are called Th2 (anti-inflammatory) cells and show protective effects in EAE. Th2 cytokines work with IgG4 to promote humoral immune responses. Th17 cells are considered pro-inflammatory and secrete cytokines IL-17A and IL-17FIL-21 and IL-22, these cytokines are closely related to the pathogenesis of autoimmune diseases. Regulatory T cells (Tregs) are a subset of T cells involved in the regulation of the immune system, maintaining tolerance to autoantigens, and monitoring for autoimmune diseases. MS is associated with homeostatic defects in Treg, and the activation of Treg is thought to provide protection against MS. TIM-3 is implicated in regulating Th1 and Th17 cytokine secretion.
The latest theory suggests that when peripheral autoreactive effector CD4+ T cells are activated and enter the CNS, the MS mechanism is initiated. Once antigen-presenting cells enter the central nervous system, they locate and reactivate autoreactive effector CD4-T cells, attracting more T cells and macrophages to form inflammatory lesions. In MS patients, macrophages and microglia accumulate in areas where demyelinating and neurodegeneration are active, microglial activation is more pronounced in the white matter of MS patients, and astrocytes produce neurotoxic chemicals such as NO and TNFαAttracting monocytes to the central nervous system, causing a series of problems such as astrocytosis.
Diagnosis
Clinical symptoms are an important basis for the diagnosis of MS, and can be assisted by medical imaging and medical testing. The McDonald criteria are the most commonly used diagnostic tools and include clinical, test, and radiomedical evidence. In 2016, the European Society for MS MRI proposed the MAGNIMS consensus, added imaging judgments, and revised the content of the Mai standard. If the patient has multiple episodes of events with high specificity, MS may be diagnosed directly from clinical evidence. However, if there has been only one episode, other tests must be done to aid the diagnosis. The most common tools are neuroimaging, cerebrospinal fluid analysis, and evoked potential testing. MRI images can show areas of the brain or spinal cord that are demyelination, as well as lesions such as plaques. Intravenous gadolinium-containing contrast agents can mark active plaques and also visualize asymptomatic plaque lesions.
Treatment
There is currently no cure for MS, and the goal of treatment is to restore function and prevent recurrence and disability.
FDA-approved therapy for MS:
| Brand | Outcome | Mechanism of action | |
| IFN-01a （IM Weekly) | Avonix® | • The recurrence rate is reduced by one-third • Reduces new MRI T2 lesions and increases T2 lesion volume • Reduce the number and volume of Gd-enhancing lesions • Slows brain atrophy | • Interference with endothelial adhesion by T cells by binding VLA-4 on T cells, or by interfering with HLA class II and co-stimulatory molecules B7/CD28 and CD40 to inhibit the T cell expression of MMP, thereby acting on the blood-brain barrier: CD40L • Immunobias of Th2 to Th1 cytokine profiles • Normalized ratio of IFN-γ1 Foxp3+ Tregs |
| lFN-01a (SC three times a week). | Rebiv ® | • Same as IFN-B1a | Same as IFN-B1a |
| IFN-(31b (SC every other day).) | Beta Theron, Extavia ® | • Same as IFN-B1a | Same as IFN-B1a |
| Grammer acetate (SC daily). | Kopason ® | • The recurrence rate is reduced by one-third • 57% reduction in the number and volume of GD-enhancing lesions | Induces the transformation of cytokines from pro-inflammatory cytokines to anti-inflammatory and regulatory cytokines |
| Natalizumab (monthly intravenous). | Tisaburi ® | • Reduce recurrence rates by up to 68% and develop new MRI lesions | Monoclonal antibodies that block α 4-integrins on surface T cells, preventing them from crossing the blood-brain barrier |
| Mitoxantrone (intravenous, infusion every 3 months). | Novanquinone ® | • 67% reduction in recurrence rate • Slows the progression of EDSS, walking index, and MRI disease activity | • Anti-tumor insertion of DNA • Inhibits cellular and humoral immune responses |
| Fingolimod (orally, once daily). | Gillenya ® | • The risk of recurrence was reduced by 54%. • 30% reduction in risk of progressive disability | • S1P agonist, which causes S1P [receptor internalization] on lymph node T cells • Subsequently, the migration of activated lymphocytes into the circulation decreases |
| Teriflunomide (Taken orally once daily) | Obazio ® | • 36% lower risk of recurrence • 31% reduction in risk of progressive disability | • Inhibits de novo nucleotide synthesis • Reduces T cell and B cell proliferation • Interrupts T cell and APC interactions • Subsequently has anti-inflammatory properties |
| Dimethyl fumarate BG-12 (orally, twice daily). | Tekfedra ® | • The risk of recurrence was reduced by 49%. • 38% reduction in risk of progressive disability | • Inhibits immune cells and molecules • Reduces damage to the myelin sheath of the central nervous system • Has antioxidant properties to prevent damage to the brain and spinal cord |