Multiple sclerosis was first described by a neurologist, Dr. Jean Martin Charcot in 1868 and named sclerose en plaque. The signs and symptoms including dysarthria, ataxia, and tremor were called ‘Charcot’s triad‘.

• Multiple sclerosis was first described by a neurologist, Dr. Jean martin Charcot in 1868.
• Previously, Dr. Robert Hooper (1773-1835), Robert Carswell (1793-1857), and Jean Cruveilhier (1791-1873) had noticed some of the MS clinical manifestations, but for the first time, Dr. Charcot described it as a distinct disease and named sclerose en plaque.
• The signs and symptoms including dysarthria, ataxia, and tremor, were called charcot’s triad by Dr. Charcot for the first time.

• One of the first suspected MS patients in history is Saint Lidwina (1380-1433). She had symptoms such as pain, lower extremities weakness, and vision loss.^[1][2]
• The other MS suspected patient in history is Augustus Frederick d’este (1794-1848). His symptoms began at the age of 28 with vision loss, bladder dysfunction, numbness, weakness of legs and sexual dysfunction.^[3]

Multiple sclerosis may be classified into four groups according to the clinical course of the disease. This includes relapsing-remitting, secondary-progressive, primary-progressive, and progressive-relapsing.

• Multiple sclerosis may be classified according to its clinical course into four groups:^[1][2]
• In 1996, US National Multiple Sclerosis Society (NMSS) defined multiple sclerosis subtypes according to clinical manifestations.
• The fact that the clinical course of the disease is a dynamic process makes it possible that the subtypes switch to each other over time.

• In recent studies a new subtype of multiple sclerosis was defined as “clinically isolated syndrome (CIS).” It is when the clinical presentation of a disease is suggestive of myelin sheath inflammation but cannot fulfill the diagnostic criteria of MS.^[2][3]

• Another associated termination regarding MS classification is “radiologically isolated syndrome (RIS).” It defines as radiological findings of myelin sheath inflammation without any sign or symptoms in patient. RIS can be an indicator of early stages of MS disease, but it’s not a subgroup of MS because radiological finding of inflammatory demyelination without any sign or symptoms of the disease is nonspecific.^[2]

Multiple sclerosis is a disease of the central nervous system and it’s known to be multi factorial. Whatever the trigger is, it will lead to an acquired immune response followed by inflammatory reactions. These reactions lead to secretion of cytokines in the CNS parenchyma and activation of resident microglia. Microglia cells activate astrocytes to release more inflammatory cytokines, leading to recruitment and infiltration of circulatory leukocytes. This burst events cause destruction of myelin sheath and forms focal sclerotic white matter plaques, which are characteristic of multiple sclerotic disease. There is some evidence proving genetic involvement in onset of MS so that it increases the risk of developing MS from 0.1% in general population to 3% in those who have siblings with MS and 25% in those with a monozygote twin affected. Based on studies performed on post mortem brain tissue of patients with multiple sclerosis, there are four types of white matter lesion pathology. Damage to myelin sheath is prominent in type 1 and 2 while type 3 and 4 characteristic is dying oligodendrocytes. the etiology of oligodendrocytes death known to be multifactorial or followed by hypoxia, mitochondrial dysfunction and macrophages.

• Soma is the neuronal cell body which is a closed area with cell membrane.^[1]

• Dendrites are branched processes which lead the impulse into the neuronal cell body.

• Axons in a single process which lead the impulse away from the neuronal cell body.

• Myelin sheath is the oligodendrocyte membrane which wraps around the axons.
• Myelin sheath is insulated against electrical impulses and is separated by nodes of Ranvier which can transfer the electrical impulse.

• This structure leads to fast traveling of electrical impulses.

• Multiple sclerosis is a disease of the central nervous system and it’s known to be multi factorial.^[2]
• There are both inflammation and degeneration in the course of the disease, but as it progress, degeneration becomes more prominent.
• There are variety of different cells participating in MS pathophysiology. Whatever the trigger is, it will lead to an acquired immune response followed by inflammatory reactions.
• These reactions lead to secretion of cytokines in CNS parenchyma and activation of resident microglia. Microglia cells activate astrocytes to release more inflammatory cytokines leading to recruitment and infiltration of circulatory leukocytes.^[3][4][5]
• This burst events cause destruction of myelin sheath and CNS tissue and releasing more auto antigens including myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP).^[6][7]
• Focal sclerotic white matter plaques, which are characteristic of multiple sclerotic disease, are mostly located in the optic nerve, periventricular white matter, juxtacortical border, cerebellum, brain stem, and cervical spine.^[8] This pattern of lesion formation is specific for MS.^[9]
• Appearing of new white matter lesions is a way to estimate the efficacy of our therapy since it is an indicator of continued inflammation.^[10]
• In the acute phase of the disease there is several evidence of blood brain barrier disruption.^[11]
• Formation of white matter lesions is started by CD8+ T cells and then, CD4+ T cells, B cells, plasma cells and macrophages but the most common cells in lesions are macrophages and microglial cells.^[12][13][14]
• There is some evidence of cortical (gray matter) demyelination in MS patients.^[15][16] It correlates with cognitive deficits and seizures in patients.^[17][18] It is not clear yet that whether the pathphysiology of cortical demyelination is similar to white matter demyelination and is a consequence of it or it is a completely different phenomenon.
• Cortical demyelination tends to be global in contrast with focal white matter lesions.^[19]
• In post mortem brain tissue of patients with MS, gray matter lesions show blood brain barrier dysfunction, macrophages filled with myelin, T cells, B cells and meningeal inflammation. These findings are suggestive of inflammation as an underlying cause of these lesions.^[20]
• Cortical demyelination is more prominent in PPMS and SPMS but it can also be seen in RRMS.^[15]

• There are some lesions called “shadow plaques”. Remyelination occurs in these lesions and they have a large number of oligodendrocyte precursor cells (OPC) and mature oligodendrocytes.^[21][22]
• It may be because of more permissive environment that this event occurs mostly in cortical lesions rather than white matter lesions.^[21]
• Remyelination occurs equally among patients with RRMS, SPMS and PPMS.^[23]
• The loss of mature oligodendrocytes in chronic MS is a sign of failure in the course of maturation.
• Several inhibitory mediators have been found to have a role in this and prevent the axonal attachment and expressing myelin-specific genes.^[24][25]
• There are no imaging techniques which can differentiate remyelinated plaques from early demyelinating lesions. It seems that remyelinated plaques are more susceptible to demyelination attacks.

• There is some evidence proving genetic involvement in onset of MS so that it increases the risk of developing MS from 0.1% in general population to 3% in those who have siblings with MS and 25% in those with a monozygote twin affected.^[26]
• HLA alleles seems to have a huge relationship with MS susceptibility.^[27]

Based on studies performed on post mortem brain tissue of patients with multiple sclerosis, there are four types of white matter lesion pathology:^[28][8]

• Microscopic pathology type 1: Found in 10% of patients especially those with less than 1 year of disease history. In this type, the lesions have sharp borders and perivascular T cell infiltration. Demyelination process is still active and microglia cells and macrophages are full of myelin.
• Microscopic pathology type 2: Found in 55% of patients. IgG and complement (C9neo) deposition with sever macrophage and T cell infiltration.

• Microscopic pathology type 3: Found in 30% of patients. The borders of lesion in this type are not sharply defined. There are evidences of vessel inflammation and dying oligodendrocytes.
• Microscopic pathology type 4: Found in 5% of patients with PPMS. Degeneration of oligodendrocytes and infiltration of T cells and macrophages are seen in this type of lesions.^[29]

NOTE: Damage to myelin sheath is prominent in type 1 and 2 while type 3 and 4 characteristic is dying oligodendrocytes.^[8][30] the etiology of oligodendrocytes death known to be multifactorial or followed by hypoxia, mitochondrial dysfunction and macrophages.^[31][32]

Multiple sclerosis may be caused by different categories of causes include: Autoimmunity, genetic, infectious and degeneration.

Common causes of multiple sclerosis may include:

• Autoimmunity:
  • The primary hypothesis regarding MS etiology states that it is caused by an autoimmune reaction against the central nervous system (CNS).^[1]
  • Self reactive T cells which has been activated by a foreign (such as virus) or native factor will attack the myelin sheath around the neurons.^[2]
  • Presence of autoreactive T cells and myelin basic protein-specific CD4+ T cells in the peripheral blood smear of MS patients supports the autoimmune hypothesis.^[3][4]

• Infectious:
  • Infections including Epstein-Barr virus, chlamydia, and herpes virus seems to have some relations to MS based on finding pathogenic proteins and nucleic acids in post mortem patients.^[5][6][7]

• Degeneration:
  • In a progressive form of MS, axonal degeneration and cortical atrophy are more prominent rather than contrast- enhancing lesions.^[8]
  • Therefore, degeneration is suggested as an independent cause in pathology of multiple sclerosis.^[9]

Multiple sclerosis must be differentiated from other diseases that can mimic this disease clinically or radiologically such as systemic lupus erythematosis, Sjögren’s syndrome, vasculitis, neuro-behçet’s disease, sarcoidosis, antiphospholipid (Hughes) syndrome , susac syndrome, lyme disease, syphilis, HTLV-1 infection, HIV-Related Disorders of the CNS, migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, leber’s hereditary optic neuropathy, vitamin B12 deficiency, metachromatic leukodystrophy, Fabry’s disease, Krabbe’s disease, adrenoleukodystrophy, mitochondrial encephalopathy epilepsy lactic acidosis and stroke like episode, stroke, primary CNS lymphoma , and dural arteriovenous fistula and true malformations.

Multiple sclerosis must be differentiated from other diseases that can mimic this disease clinically or radiologically such as:

• systemic lupus erythematosus: Systemic lupus erythromatosus can cause neurological manifestations such as seizures, movement disorders, transverse myelitis, cranial and peripheral neuropathies, and optic nerve involvement. In the brain MRI of SLE patients, there are pieces of evidence of atrophy and subcortical white matter lesions. SLE is diagnosed based on systemic manifestations, present of oligoclonal bands and IgG in CSF and high titer of antinuclear antibodies.
• Sjögren’s syndrome: Sjogren disease can cause neurological manifestations including cerebral vasculitis, myopathy, transverse myelitis and acute optic neuropathy. There are evidence of oligoclonal band and increased IgG in CSF and white matter lesions in MRI. Sicca syndrome, rheumatic manifestation and high titers of ANA. SSRo and SS-La will confirm the diagnosis.
• Vasculitis: Wegener’s granulomatosis and polyarteritis nodosa are sometimes categorized as a differential diagnosis of MS, but the most common vasculitis which can mimic MS, is isolated angitis of the central nervous system (IACNS). IACNS is an inflammatory disease with an unknown cause. It affects small and medium sized arteries in the brain parenchyma and meninges. Neurological manifestation of this disease is headache, personality change, paresis, seizures, cranial neuropathy and intracerebral /subarachnoid hemorrhages. There are monoclonal bands and increased protein and lymphocytic pleocytosis and IgG levels in the CSF of this patients. MRI may show patchy or diffuse increased signal in periventricular and subcortical white matter. diagnosis is made by evidences of vasculitis changes in angiography or biopsy.
• Neuro-behçet’s disease: Behcet’s disease is an idiopathic inflammatory disorder and can manifest as a triad of oral and genital ulcers and anterior uveitis. Lungs, gastrointestinal tract, joint, and skin can be involved too. Rarely, neurological signs can be the first manifestation of the disease. The most common neurological manifestation of behcet’s disease is psychiatric symptoms, intranuclear ophthalmoplegia, headache and sensory/motor deficits. The course of the disease can be relapsing remitting or progresive. In the CSF specimen we can see high levels of protein, pleocytosis (granulocytic, unlike MS) and oligoclonal bands (which can be suppressed by corticosteroid treatment). In MRI the most common involvement can be seen in brain stem and basal ganglia.
• sarcoidosis: Sarcoidosis is an inflammatory disease with formation of non caseating epitheloid granulomata. It’s a multisystem disease but affects lungs more than other organs. There is a 5-10% change of neurological involvement and in 50 % of these patients neurological involvement can be the first sign or symptoms. It usually affects cranial nerves, hypothalamus and pituitary gland. involvement of optic nerve, brain stem and spinal cord can mimic MS symptoms. In MRI we can see an isolated or diffuse lesion in brain parenchyma or even periventricular white matter lesion like MS. CSF analysis can be very same to MS but in sarcoidosis we have elevated amount of angiotensin converting enzyme.

• Antiphospholipid (Hughes) syndrome: In antiphospholipid syndrome, the presence of anticardiolipin and/or lupus anticoagulant can cause arterial and venous thrombosis. It can cause neurological manifestations like transient ischemic attack, ischemic encephalopathy, thrombosis of cerebral veins, seizure, headache, guillain barre syndrome, dementia, chorea and optic nerve neuropathy. In MRI there is evidence of white matter T2 hyperintense and/or cortical lesions. The latter is in favor of APS. In CSF analysis lack of oligoclonal bands is against the MS diagnosis. Differentiating MS from APS is so difficult that it’s recommended to treat MS patients for APS too.
• Susac syndrome: Susac syndrome is an idiopathic disease that causes microangiopathy of brain, retina, and cochlea arterioles. Involvement of this arterioles leads to visual disturbance, hearing loss, and encephalopathy. In MRI there is white and gray matter lesions and leptomeningeal involvement. CSF analysis shows elevated protein level and pleocytosis.

• Lyme disease: Borrelia burgdorferi is transmitted through a tick bite and can cause rash (erythema chronica migrans) typical for lyme disease. This disease can affect cranial nerves especially seventh nerve. It is usually easily differentiated from MS because of meningitis involvement in MRI and pleocytosis as well as high lyme titer in CSF.
• syphilis: Neurosyphilis, more commonly seen in HIV+ patients can be in two forms. One can be seen in late secondary or early tertiary stages as meningovascular involvement and the other one can be seen in later stages as parenchymal involvement. Meningovascular lesions can present like a stroke while the other one cause gummas (contrast enhancing lesions). In CSF, there are pieces of evidence of oligoclonal bands, pleocytosis, and elevated gammaglobulin.
• Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) is cause by activation of JC virus and is more commonly seen in immunocompromised patients. Some evidences shows the relation between PML and drug natalizumab. In MRI of PML patients we see multiple white matter lesions that can become confluent with no enhancement in T1. Diagnosis of PML is based on detecting JC virus in CSF.
• HTLV-1 infection: Human T lymphotrophic virus, transmitted through sexual activity, can cause tropical spastic paraparesis. The involvement of spinal cord and MRI pattern of Tropical spastic paraparesis can mimic MS disease. In CSF we have positive HTLV-1 titer, lymphocytic pleocytosis, oligoclonal bands and high level of proteins.
• HIV-Related Disorders of the CNS: HIV infection frequently involves CNS and can be the initial manifestation of the disease. In an MRI, there are white matter lesions. In a CSF analysis, there are high levels of proteins and cell counts but oligoclonal bands are rarely seen.

• Migraine: Migraine is a throbbing headache, which worsens by sound and light. It can cause a variety of transient neurological manifestation including sensory loss, visual loss, ophtalmoparesis, and vertigo. These manifestations can occur before or with the migraine headache but in some cases, which we call “amigrainous migraine”, we have neurological problems without headache. In an MRI of these patients, we can see small areas of deep frontal white matter lesions.
• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy:
• Leber’s hereditary optic neuropathy: Leber’s hereditary optic neuropathy is caused by mitochondirial DNA mutation. It presents as acute bilateral blindness. The MRI finding of MS and LHON are alike and make it difficult to differentiate them.

• Vitamin B12 deficiency: B12 deficiency can cause neurological manifestation including peripheral neuropathy, optic neuropathy, cervical myelopathy, and fatigue. MRI findings include contrast enhancement of posterior and lateral spinal cord columns preferably in cervical and thoracic levels.
• Lysosomal disorders:

1. Metachromatic leukodystrophy: MLD is an autosomal recessive lysosomal storage disease that leads to accumulation of galactosyl sulfatide.
2. Fabry’s disease: X-linked disease with impaired activity of a-galactosidase leading to accommodation of globotriaosylceramide in many organs including ganglion cells of the autonomic nervous system.
3. Krabbe’s disease: Autosomal recessive disease with impaired activity of galactocerebrosidase leading to destruction of CNS and PNS myelin and axonal degeneration.

• Adrenoleukodystrophy: ALD disease causes accumulation of long chain fatty acids. X-linked type of this disease (adrenomyeloneuropathy) will cause spinal cord disease and peripheral neuropathy and can be considered as a differential diagnosis of MS disease.
• mitochondrial encephalopathy epilepsy lactic acidosis and stroke: One of the mitochondrial diseases that can categorized as a MS differential diagnosis in mitochondrial encephalopathy epilepsy lactic acidosis and stroke (MELAS). The manifestations include: Seizures, exercise intolerance, limb weakness, stroke like episodes, hemiparesis and hemianopia. There are evidences of calcium deposition in caudate nucleus and globus pallidus in CT scan and cortical involvement in MRI imaging.

Primary CNS lymphoma is mostly diffuse large B-cell lymphoma (DLBCL). These patients more commonly present with neurological manifestation rather than B symptoms. In MRI evaluation, because of high cell count and scant cytoplasm lesions become isotense to hypointense on T2. In CSF analysis, there are increased number of WBC and proteins, low levels of glucose and positive cytology for cells with enlarged nucleus and course chromatin.

Dural arteriovenous fistula and true malformations can be mistaken with MS since they can all cause thoracic myelopathy.

Multiple sclerosis (MS) occurs worldwide, but its frequency varies substantially between countries and geographic regions. Contemporary global epidemiologic data estimate that approximately 2.9 million people are living with MS worldwide. The global incidence is approximately 2.1 cases per 100,000 people per year, although incidence and prevalence vary considerably between populations and regions.^[1]

MS is more common in women than men, and disease onset most commonly occurs in young and middle adulthood, although MS can occur in children and older adults. Geographic, genetic, demographic, environmental, and infectious factors contribute to variation in MS risk and distribution.^[2]

• The incidence of multiple sclerosis varies substantially among countries and populations. The Atlas of MS reports a global incidence of approximately 2.1 cases per 100,000 people per year among countries with available incidence data.^[1]

• Differences in incidence between populations should be interpreted in the context of variation in population structure, case ascertainment, access to neurological and MRI services, diagnostic criteria, and completeness of national registries and surveillance systems.^[2]

• The prevalence of MS varies substantially among countries and geographic regions. Updated Atlas of MS data estimate that approximately 2.9 million people worldwide are living with MS.^[1]

• Reported MS prevalence has increased in many countries over time. This increase may reflect several factors, including improved case ascertainment, greater access to diagnostic services, changes in diagnostic criteria, increased survival, population growth and ageing, as well as possible changes in disease occurrence.^[1][2]

• Comparisons of prevalence estimates between countries should therefore consider differences in study methodology, healthcare access, diagnostic practices, registry coverage, and the quality and completeness of epidemiologic data.^[2]

• MS is a chronic neurological disease rather than an acutely fatal disorder. Mortality and survival among people with MS are influenced by disease-related disability, comorbidities, complications, demographic factors, and access to healthcare.

• Historical mortality estimates should be interpreted cautiously because survival, diagnosis, disease classification, and management of MS have changed substantially over time.

• MS can occur at almost any age, but diagnosis most commonly occurs in young and middle adulthood. In the third edition of the Atlas of MS, the mean age at diagnosis across reporting countries was approximately 32 years.^[2]

• Pediatric-onset MS is recognized but is substantially less common than adult-onset disease. The Atlas of MS has identified at least 30,000 children and adolescents younger than 18 years living with MS worldwide, although this is likely to be an underestimate because pediatric epidemiologic data remain incomplete in many countries.^[1]

• MS may also present in older adults. Age should therefore not be used alone to exclude the diagnosis when the clinical and paraclinical findings are otherwise compatible with MS.^[3]

• The epidemiology of MS is more diverse than suggested by older descriptions of MS as predominantly a disease of White populations. MS occurs across racial and ethnic groups, and contemporary population-based studies demonstrate substantial disease burden among Black, Hispanic, and other populations.^[4]

• Differences in reported MS prevalence between racial and ethnic groups may reflect a combination of genetic ancestry, environmental exposures, socioeconomic and healthcare factors, migration, diagnostic access, case ascertainment, and other determinants. Race and ethnicity should therefore not be used in isolation to determine whether an individual is likely to have MS.^[4]

• Multiple sclerosis is more common among women than men. Globally, females are approximately twice as likely to have MS as males, although the female-to-male ratio varies between countries and populations.^[2]

• Sex differences in MS frequency are likely to reflect complex interactions among biological, genetic, hormonal, environmental, and other factors rather than a single determinant.^[5]

• Multiple sclerosis occurs worldwide, but prevalence varies substantially between geographic regions and individual countries. Higher prevalence has historically been reported in many populations in Europe and North America, while lower reported prevalence has been observed in several regions of Africa and Asia.^[2]

• Geographic differences should not be interpreted as evidence that MS is absent or necessarily rare in populations for which high-quality epidemiologic data are limited. Differences in healthcare access, neurological services, MRI availability, disease awareness, diagnostic criteria, registries, and surveillance may influence reported prevalence.^[2]

• Geographic variation in MS probably reflects interactions among genetic susceptibility and environmental exposures rather than a single geographic factor. Latitude, ultraviolet radiation exposure, vitamin D status, smoking, infectious exposures, migration, and other environmental factors have been investigated as potential contributors to variation in MS risk. Observational associations should not automatically be interpreted as proof of causation.

• Historical migration studies have contributed to evidence that environmental exposures during childhood and adolescence may influence subsequent MS risk. However, the effect of migration varies between populations and studies and should not be expressed as a universal age-specific rule.^[6]

• Interpretation of older epidemiologic studies should also account for changes in MS diagnostic criteria and improved recognition of alternative inflammatory and demyelinating disorders. The revised 2024 McDonald criteria incorporate contemporary clinical, imaging, and laboratory evidence and include additional provisions intended to improve diagnostic accuracy across different populations and clinical settings.^[3]

• Smoking: Cigarette smoking is associated with increased risk of MS in epidemiologic studies. Among people with established MS, smoking is also associated with increased disability progression. The National Institute for Health and Care Excellence (NICE) advises people with MS not to smoke because smoking increases progression of disability.^[7][8]

• Family history and genetic susceptibility: Having a family member with multiple sclerosis is associated with increased MS risk, supporting an important contribution of genetic susceptibility. However, MS is not inherited in a simple Mendelian pattern, and most relatives of people with MS do not develop the disease.^[9][10]

• Female sex: Multiple sclerosis is more common in females than males. Female sex is therefore an important demographic association with MS, although sex alone does not determine individual disease risk.^[2][5]

• Low vitamin D status and ultraviolet exposure: Lower vitamin D status and reduced ultraviolet radiation exposure have been associated with increased MS risk in observational studies. These associations do not establish vitamin D deficiency as a sufficient cause of MS, and epidemiologic association should be distinguished from evidence that vitamin D supplementation prevents MS.^[11][12]

• Epstein-Barr virus (EBV): EBV infection has a strong epidemiologic association with MS. A large longitudinal study demonstrated a marked increase in MS risk following EBV infection, providing some of the strongest epidemiologic evidence linking an infectious exposure with MS. However, EBV infection is extremely common in the general population and only a small proportion of infected individuals develop MS; EBV seropositivity alone is therefore not diagnostic of MS.^[13][14]

• Environmental and geographic factors: Geographic variation in MS risk probably results from interactions among genetic susceptibility and multiple environmental exposures. Latitude, ultraviolet exposure, vitamin D, smoking, EBV infection, migration, and other factors have been investigated. No single environmental factor alone adequately explains the worldwide geographic distribution of MS.^[2]

• Diagnostic ascertainment: Changes in diagnostic criteria, access to MRI, recognition of MS mimics, registry quality, and healthcare access can alter measured incidence and prevalence. Epidemiologic comparisons across different time periods should therefore account for changes in diagnostic ascertainment. The revised 2024 McDonald criteria represent the current international diagnostic framework.^[3]

Common risk factors in the development of multiple sclerosis are smoking, genetic, ethnic, infection, low vitamin D, and stress. Less common risk factors in the development of multiple sclerosis include African Americans, Mexicans, Japanese, Chinese and Filipinos race and Epstein-Barr virus.

• Common risk factors in the development of multiple sclerosis include:
  • Smoking: Various studies show that smoking, beside cardiovascular diseases and cancer, can be a risk factor of multiple sclerosis.^[1][2]
  • Genetic: Studies demonstrate that MS has a strong genetic base. The first degree family of a MS patient is at a 10-25 times greater risk than normal population, so genetically susceptible people are more likely to develop MS disease.^[3][4]
  • Gender: Prevalence of MS disease is higher in female. This can be hormone related or more susceptibility to environmental risk factors.^[5][6]
  • Vitamin D: Low vitamin D level seems to be a risk factor for developing MS since the prevalence of MS is lower in regions where people take vitamin D supplement or have higher sunlight exposure.^[7][8]
  • Stress: Stressful life events can be a risk factor for MS disease. In patients who already have MS, stress and anxiety can lead to exacerbation of their disease.^[9][10]

• Less common risk factors in the development of multiple sclerosis include:
  • Ethnic: MS prevalence is lower in African Americans, Mexicans, Japanese, Chinese and Filipinos people rather than white men.^[11]
  • Epstein-Barr virus: Patients affected with Epstein-Barr virus seems to be more susceptible to developing MS. Studies shows that high titre of EBV antibodies is a risk factor for MS disease.^[12][13]

There is insufficient evidence to recommend routine screening for multiple sclerosis.

There is insufficient evidence to recommend routine screening for multiple sclerosis.

Multiple sclerosis usually start between age of fifteen to forty years, rarely before age fifteen or after age sixty with symptoms such as optic neuritis, diplopia, sensory or motor loss, vertigo and balance problems. It may be classified into four groups according to clinical course of the disease including relapsing-remitting, secondary-progressive, primary-progressive, and progressive-relapsing. Complications that can develop as a result of multiple sclerosis are: medication complication, Fatigue, mood problems, Spasticity, Bowel and bladder dysfunction, Cognitive impairment, Heat sensitivity., Incoordination, Pain, Sexual dysfunction, Sleep disorders, vertigo, visual loss. there are some factors associated with a particularly poor prognosis among patients with multiple sclerosis such as: Relapsing versus progressive disease, early symptoms, Demographics, Sex, Smoking.

• Multiple sclerosis usually start between age of fifteen to forty years, rarely before age fifteen or after age sixty with symptoms such as optic neuritis, diplopia, sensory or motor loss, vertigo, and balance problems. In young adult eye and sensory problems are prominent while in older patients we see motor problems more often.^[1]
• The natural history of the disease is either relapsing or progressive.
• Relapsing-remitting multiple sclerosis is defined by acute attacks of neurological dysfunction followed by full or partial recovery. Patient clinical symptoms are stable between the attacks.
• It can switch to secondary progressive disease when the neurological symptoms progressively worsen between the attacks.
• There is also primary progressive type, which is defined by continuously worsening of neurological dysfunction with no distinct attacks and remissions.
• Progressive relapsing type is a mixture of relapsing and progression and is defined by progression of disease from the beginning with acute attack episodes.^[2]
• The most common symptoms in all of the MS patients are fatigue, mood problems, spasticity, bowel and bladder dysfunction, cognitive impairment, eye movement abnormalities, heat sensitivity, incoordination , pain, sexual dysfunction, sleep disorders, vertigo, and visual loss.^{[3][4][5][6][7][8][9][10][11][12][13][14][15]}

Complications that can develop as a result of mutiple sclerosis include:

• Medication complications: Insufficient blood supply to the bone can cause avascular osteonecrosis. After trauma, corticosteroid treatment is the most common cause of AVN.^[16][17]

• Fatigue: Fatigue is seen in almost 80% of MS patients. They commonly feel exhausted and out of energy. We can see fatigue exacerbation before acute attacks in MS and for a while after that.^[18]

• Mood problems: Psychiatric disorders especially depression is common and can be seen in almost 50% of MS patients.^[5] Some studies show higher risk of suicide in MS patient.^[19][20]

• Spasticity: Damage to the upper motor neurons and decrease inhibition of lower motor neurons in MS can increase muscle tone and rigidity in 75% of MS patients.^[6]

• Bowel and bladder dysfunction: Bowel and bladder dysfunction is common in MS patients and occurs in more than 50% of cases.^[7] bladder dysfunction can be the result of Detrusor overactivity, Detrusor sphincter dyssynergia, Inefficient bladder contractility and Abnormal sensation and bladder hypoactivity.^[21] the most common bowel problems include Constipation, poor defecation and incontinence.^[22]

• Cognitive impairment: Cognitive disorders is common in MS patients and can even present at early stages of disease. These disorders are in attention, short term memory, and information processing. Relapsing-remitting type of MS seems to have a lower cognitive problems.^{[8][23][24][25]}

• Heat sensitivity: Patients with MS disease are more sensitive to heat. A slight increase in body temperature of these patients will lead to worsening of their signs and symptoms.^[10]
• Incoordination: Involvement of cerebellar tracts can cause problems in Gait and balance, poor coordinated actions, and slurred speech. Intention tremor is present in most of these patients.^[11]

• Pain: Pain is a very common symptom in MS. Patients can be either from neurogenic source leading to burning or ice-cold dysesthesias or from long immobilization and spasm.^[12][26]

• Sexual dysfunction: Sexual dysfunction can be due to involvement of motor and sensory pathways or from psychological problems. Either way, it’s a very common symptom. In women, we can see reduced libido and orgasm, dyspareunia and decrease vaginal sensation. Presentations of sexual dysfunction in men are decreased libido and premature ejaculation, erectile dysfunction and decreased penile sensation.^[13][27]

• Sleep disorders: Many patients with multiple sclerosis suffer from sleep disorders and daytime somnolence. This can be the result of so many conditions including restless leg syndrome, nocturia, pain, and medication side effects. Having more cervical lesions lead to experiencing restless leg syndrome more often.^[14][28][29]

• Vertigo: Benign positional paroxysmal vertigo is the most common cause of vertigo in an MS patient. In the course of the disease about 30-50% of patients experience this symptom.^[15]

• Visual loss: Optic neuritis is the most common eye involvement and presents as an acute unilateral eye pain, followed by some degree of vision loss.^[3]

There are some factors associated with a particularly poor prognosis among patients with multiple sclerosis. However, we can’t surly say what is the prognosis of MS patients.^[30]

• Relapsing versus progressive disease: Progressive form of MS seems to have a worse prognosis in comparison to relapsing remitting form of MS. Disabilities start sooner in progressive form^[31][32][33] but some studies showed that age of onset is more important in MS disability than the form of the disease.^[34][35]

• Early symptoms: Some first manifestations of MS disease like bowel and bladder dysfunction seem to have a worse prognosis.^[36]. Another study demonstrated that having so many symptoms at the onset of the disease have a worse prognosis than being monosymptom.^[37]

• Demographics: Onset of MS in Black Americans is in later age and they are more susceptible of having multifocal signs and symptoms and involvement of optic nerve and spinal cord.^[38]

• Sex: Women seems to have younger age of onset and so better prognosis than men.^[31]

• Smoking: Transition of RRMS to SPMS can be accelerated with smoking.^[39]

• Lipid specific immunoglobulin level: Lipid specific immunoglobulin level in CSF can predict long term outcomes of MS disease.^[40]