What is multiple sclerosis?
Multiple sclerosis is an inflammatory demyelinating disease of the CNS with a lifetime prevalence of 1 in 800.It typically presents itself in adults aged between 20-40 years with two-thirds of them being female.Multiple sclerosis is a progressive and incurable disease that ultimately results in chronic neurological disability.
What is inflammation?
Inflammation is a localised immune response and defence mechanism against infections or injury by removing injurous stimuli to initiate the healing process.
Acute inflammation
Acute inflammation is a localised immune response with a severe and rapid onset that occurs for a short duration of time. It is clinically characterised by five cardinal signs:1. redness2. loss-of-function3. swelling4. pain5. increased heat
Chronic inflammation
Chronic inflammation is generally much slower and less severe than acute inflammation. It typically lasts longer than six weeks and can even occur in the absence of injury or infection.If chronic inflammation does not resolve itself, it can cause widespread damage and trigger an inflammatory response that leads to disease.
Phases of inflammation
Onset phase: is a pro-inflammatory phase where immune cells are recruited to the site of infection or injury and start to recruit mediatorssuch as cytokines.Resolution phase: occurs after the onset phase and is the healing phase where tissue is restored to normal state.When the aute inflammatory response is unable to reach the resolution phase and initiate the healing process, it continues to occur in a low-grade irregular manner that eventually leads to chronic inflammation.
What is neuroinflammation?
Neuroinflammation refers to the inflammation of nervous tissue and by caused by infection, traumatic brain injury, toxic metabolites or autoimmunity.Neuroinflammation is characterised by:Leakage of the blood-brain barrierActivation of glial cells Inflammatory cytokines and secretions of neurotoxinsInfiltration of immune cells due to autoimmunity Demyelination and neurodegenerationCauses of neuroinflammation include: Autoimmunity via multiple sclerosis neuromyelitis opticaInfection via meningitis and encephalitis
What is demyelination?
The term demyelination refers to any condition that causes the damaging of the protective myelin sheath around neurons in the CNS. When the myelin sheath is damaged, nerve impulses slow or even stop.
Pathophysiology of multiple sclerosis
Multiple sclerosis is a chronic demyelinating disorder that causes the development of plaques and scars on white matter in the brain and spinal cord.The pathophysiology of multiple sclerosis consists of autoimmunity, which is the activation of the immune system and infiltration of cells into the CNS.Self-reactive lymphocytes are the main enforcers of inflammation in multiple sclerosis and enter the brain from peripheral circulation. Following this, these cells induce demyelination and trigger an inflammatory cascade that results in the:Infiltration of inflammatory immune cells: macrophages, monocytes and neutrophilsProduction of inflammatory cytokines and ROSThe consistent demyelination and destruction of oligodendrocytes consequently result in the formation of plaques and scars.
What are the different types of multiple sclerosis?
Progressive-Relapsing MS: is a rare form of MS (5%) and is characterised by a steadily worsening disease state from the beginning with acute relapses but no remission.Secondary-Progressive MS: symptoms progressively get worse over time with or without the occurrence of relapses and remissionsPrimary-Progressive MS: rare type of MS (10%) and consists of gradual worsening of symptoms without the occurrence of relapse or remission.Relapse-Remitting MS: most common form of MS and occurs in roughly 75-85% of patients. Characterised by temporary periods of unpredictable acute relapse and flare-ups followed by periods of remission. In relapse-remitting MS, demyelination and nerve damage can occur in the absence of symptoms.
What are the risk factors for multiple sclerosis?
Age and gender: MS typically occurs in adults aged between 20-40 years with two-thirds of them being female.Race: white people of Northern European descent are at the greatest risk of developing multiple sclerosis. With Asian, African and Native American people having the lowest risk.Genetics: mutations and first-degree relatives who have autoimmune diseases Vitamin D deficiencyEnvironment factors: Epstein-Barr Virus (EBV) in addition to smoking and drinking alcohol
Signs and symptoms of multiple sclerosis
Symptoms of multiple sclerosis often affect movement such as: Numbness or weakness in more than one limb Electric-shock sensations from certain neck movementsTremor, lack of coordination and unsteady gait Vision problems are also common and include:Partial or complete loss of vision Prolonged double vision, blurry vision Additional symptoms of multiple sclerosis include:Slurred speech and difficulty swallowing Cognitive impairment and depression Fatigue and dizziness Pain in body parts
Diagnosis of MS
Blood tests are used to help rule out other diseases with symptoms that are similar to multiple sclerosis. Tests for specific biomarkers are under development. Spinal tap (lumbar puncture) involves the extraction of cerebrospinal fluid from the spinal canal for analysis. This procedure can highlight abnormalities in antibodies and also help rule out other diseases.MRIs are used to generate images and identify presence of plaques and scars on the brain and spinal cord.Optical Coherence Tomography is a non-invasive method used to analyse nerve structure and identify thinning of unmyelinated retinal nerve axon.
Neuromyelitis Optica (NMO) and NMO Spectrum Disorders (NMOSD)
NMO and NMOSD are neuroinflammatory disorders of the CNS and are characterised by immune-mediated myelination and axonal damage that is predominantly targeting optic nerves and the spinal cord.
Pathophysiology of NMO and NMOSD
Pathophysiology of NMO is typically characterised by the abnormal production of auto-antibodies against the AQP4 water channel protein on astrocytes Pathophysiology of NMOSD is the abnormal production of anti-myelin oligodendrocyte glycoprotein, also known as anti-MOG antibodies.
Clinical features of NMO and NMOSD
NMO is a relapsing-remitting disease and during an acute relapse, damage to the optic nerve and spinal cord can accumulate to induce chronic disability.Symptoms are generally more severe after an NMO relapse in comparison to a MS attack.
Management of multiple sclerosis
Treatments of multiple sclerosis can be classified into:1. Relapse management therapies which treat acute attacks to shorten duration and severity of relapse.2. Disease-modifying therapies prevent relapses and slow the accumulation of chronic disability 3. Symptomatic treatments treat specific symptoms
Relapse management therapies
Relapse management therapies involve the treatment of acute attacks by shortening the duration and severity of diease exacerbations.Most common treatment for relapse management are corticosteroids, particularly glucocorticoids such as prednisone and methylprednisolone.Methylprednisolone is the first-line of treatment for severe relapse and mimics cortisol to reduce inflammation and accelerate recovery.
Mechanism of methylprednisolone
Methylprednisolone is a glucocorticoid that mimics cortisol to reduce inflammation by:Up-regulating expression of anti-inflammatory markersRepressing expression of pro-inflammatory markersInhibiting inflammatory cytokine cascade and activation of T cellsDecreases extravasation and infiltration of immune cells into CNS and facilitates apoptosis of self-activated immune cells.
Disease management therapies
Disease management therapies are used to prevent the risk of disease relapse and slow the accumulation of disability. Examples of disease management therapies include:Immunotherapies Beta interferon medications Monoclonal antibody Sphingosine 1-Phosphate (S1P) receptor modulators Glatiramer acetate peptide
Immunotherapies
Immunotherapies modify and reduce immune activity by suppressing the activation of self-reactive lymphocytes.These drugs reduce the frequency and severity of lymphocytes on the CNS by suppressing their traffic from lymph nodes into peripheral circulation.
Interferon beta medications
Another example of disease management therapy are interferon beta medications, which are cytokines that regulate the activity of self-reactive lymphocytes.There are two types of interferon beta medications:1. Interferon beta 1a 2. Interferon beta 1bBoth 1a and 1b can be administered via intramuscular or subcutaneous injection to treat relapsing-remitting multiple sclerosis. Interferon beta 1b is also used to treat secondary progressive multiple sclerosis.Interferon beta medications bind to the receptors on antigen-presenting dendritic cells which are involved in the activation and differentiation of T cells.They also bind to the receptors on microglia and macrophages to suppress their pro-inflammatory activity.
Glatiramer acetate peptide
Glatiramer acetate is a synthetic peptide that is administered via subcutaneous injection and treats relapsing-remitting multiple sclerosis.It works by preventing the presentation of myelin antigens to activated lymphocytes. Specifically, this synthetic peptide inhibits monocyte reactivity and also promotes the anti-inflammatory activity of type-2 monocytes.
Humanised monoclonal antibodies
Natalizumab is a monoclonal antibody that treats relapsing-remitting MS and is administered via intravenous injection.Upon injection, this monoclonal antibody binds to the alpha-4 integrin molecule which is expressed by lymphocytes and leukocytes in an inflammatory cascade.In MS, alpha-4 integrin binds to VCAM1 which resides on the blood-brain barrier. Following this, chemokines and cytokines are produced to alter the permeability and allow infiltration of activated immune cells.
Sphingosine 1-Phosphate receptor modulators
Siponimod and ozianimod are S1P modulators and are used to treat relapsing-remitting MS.Siponimod is also used to treat secondary-progressive MS.This class of drug is orally administered once a day.
Remyelination therapy
Remyelination is the regeneration of myelin sheaths following MS-induced demyelination and is critical for the re-establishment of axonal conduction activity and metabolic support to axons.Successful remyelination in the CNS depends on the activation, proiliferation and differentiation of oligodendrocyte progenitor cells (OPCs)
Basic research: animal models for immune activation
There are two mechanisms that could induce autoimmunity and the development of MS:1. Molecular mimicry involves the production of antibodies to fight against toxins and infections, which can cross-react with myelin and cause demyelination.2. Myelin antigens produced by toxins and Epstein-Barr Virus (EBV) can also have cross-reactivity with the myelin sheath and trigger the inflammatory cascade.
Epstein-Barr Virus
Recent evidence has shown that lifelong EBV-infected B cells can acquire molecular mimicry which means they produce antibodies against viral proteins. These antibodies have cross-reactivity with CNS antigens and trigger the inflammatory cascade.
Research on genetic factors
Research has found that the HLA-DRB1 gene is the strongest genetic risk factor for developing multiple sclerosis and is a fmaily of genes called the Human Leukocyte Antigen (HLA) complex.
Animal models of MS
Experimental autoimmune encephalomyelitis (EAE) is the most studied animal model for MS and imitates its histopathological and immunological features.The animal is injected with homogenates derived from CNS tissue or proteins containing myelin basic protein (MBP) or proteolipid protein (PLP). This injection produces a T-cell mediated immune response that causes subsequent inflammation in the brain and spinal cord as well as blood-brain barrier dysfunction and demyelination. This allows researchers to understand neuroinflammation and neurodegeneration as well as test the effectiveness of drugs.
Toxin-induced demyelination models
These models involve the toxic molecules - cuprizone and lysolecithin which when discontinued, trigger a spontaneous remyelination process that allows us to study remyelination and demyelination.Cuprizone is a copper chelating agent that causes oligodendrocyte death following oral administration.Ethidium bromide is a DNA binding agent which can be injected into white matter pathways.