Multiple Sclerosis: Phenotypes, Causes, Symptoms & Risk Factors
Learn about Multiple Sclerosis (MS), a chronic autoimmune disorder affecting the brain and spinal cord. Explore Phenotypes, Causes, Symptoms & Risk Factors.
Multiple sclerosis
Multiple sclerosis (MS) is chronic autoimmune neurodegenerative disorder of brain and spinal cord. In MS, patients suffer from myelin sheath degeneration, loss of axon and inflammation in neuron cells that further leads to physical and cognitive disabilities.
For MS, there is no specific diagnostic methods and no curative treatment and most of the current treatment are focused to reduce inflammation in nonspecific way. Most of the treatment are effective in the early stage of the disease, but when disease progress, and inflammation progress treatment fails to prevent the MS symptoms.
Phenotypes of multiple sclerosis
On the basis of the pattern of relapses, progression, and symptom changes over time, MS phenotypes are:
- Relapsing–Remitting MS (RRMS)
- Secondary Progressive MS (SPMS)
- Primary Progressive MS (PPMS)
- Progressive–Relapsing MS (PRMS)
Relapsing remitting multiple sclerosis (RRMS)
Relapsing–remitting multiple sclerosis is the most common type of MS, affecting about 85% of patients.
It is characterized by repeated attack of neurological symptoms that come and go. However, each attack of neurological dysfunction can leave some permanent damage, leading to impairment that accumulates over time.
RRMS attacks typically last from hours to days or weeks. These RRMS attacks are caused by inflammation that damages the protective myelin and the nerve fibers. Early repair of myelin can temporarily improve symptoms, but this repair mechanism weakens as the disease progresses and with aging, leading to lasting damage.
RRMS relapses can be triggered by respiratory infections or urinary tract infections (UTIs). Stress is not clearly proven but stress may contribute to RRMS activity through psychological and related factors. RRMS is also influenced by metabolic and immune changes during pregnancy. Relapse rates decrease during pregnancy but increase after delivery.
Progression to SPMS
With 19 years, approximately 50% RRMS patients gradually develop more severe form called Progression to SPMS. In this phase there is more damage in nerve cells, mitochondrial dysfunction and inflammation brain and spinal cord.
Factors that predict progression from RRMS to SPMS include male sex, older age at the onset of RRMS, spinal cord involvement, and incomplete recovery from RRMS attacks.
Primary progressive MS (PPMS)
Primary progressive multiple sclerosis (PPMS) affects about 10% of MS patients. It leads to gradual worsening of MS symptoms from rom the onset. Unlike relapsing–remitting MS (RRMS), PPMS does not involve episodic attacks with periods of recovery.
Modifiers of MS activity and progression
In MS, disease activity refers to signs that the disease is actively causing damage, such as relapses or new or enlarging lesions on MRI. Disease progression, on the other hand, describes the gradual worsening of disability over time, even without new attacks.
Progressive/relapsing multiple sclerosis (MS) is a rare form of the disease, affecting only about 5% of patients. In this type, individuals experience gradual worsening of symptoms from the very beginning, similar to primary progressive MS (PPMS). However, unlike PPMS, they also have occasional attacks or relapses, which are characteristic of secondary progressive MS (SPMS). This combination of steady progression and intermittent attacks makes progressive/relapsing MS a unique and uncommon subtype.
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Multi Sclerosis Status Worldwide
According to the Atlas of MS, approximately 2.9 million people worldwide are living with MS, with prevalence varying widely by region. MS prevalence increases with distance from the equator, with the highest rates in Europe and the Americas and the lowest in Africa and the Western Pacific.
In Europe, MS commonly begins between ages 20 and 40, affects women more than men (≈3:1), and increasingly affects older individuals due to rising late-onset cases and improved survival.
Early-life migration alters MS risk, highlighting the role of environmental factors such as EBV infection, sunlight exposure, and vitamin D levels alongside genetic predisposition.
MS incidence has increased over time particularly for relapsing remitting MS and among women though rates appear to have stabilized since around 2000, with higher incidence reported in Northern Europe.
Multiple Sclerosis Symptoms
The most common symptoms for MS are, one-sided vision loss with eye pain (Optic neuritis), One-sided sensory or motor problems, sometimes with bladder/bowel issues (Partial myelitis), Double vision, imbalance, or spinning or dizziness (Infratentorial syndrome).
So basically, MS symptoms depend on where the lesions occur in the CNS, affecting vision, movement, sensation, and balance.
MS sometimes presents with multifocal involvement of the CNS. Symptoms usually develop over hours to days, last at least 24 hours, and resolve over days to weeks. In some cases, symptoms are short-lived (seconds to minutes) but recur repeatedly over periods longer than 24 hours.
Relapses in MS often don’t fully resolve, leading to gradual disability that worsens with more frequent or severe attacks, sometimes progressing to secondary progressive MS.
Hidden symptoms such as fatigue, mood disturbances, and cognitive problems are common in MS but are not considered relapses unless accompanied by new neurological dysfunction.
Sometimes, MS patients experience pseudorelapses, which are different from true relapses. A pseudorelapse occurs when old MS symptoms temporarily worsen due to factors such as infections, fever, or stress, without the formation of new MS lesions in the brain or spinal cord.
Pseudorelapses or temporary worsening that happens when body temperature rises (e.g., hot weather, exercise, or fever), known as Uhthoff’s phenomenon.
Multiple Sclerosis Hidden Symptoms
Fatigue
Fatigue, feeling of extreme tiredness and exhaustion, affects 50–90% of MS patients. It can occur at any stage of MS.
Fatigue is classified into two types
- Primary fatigue
- Secondary fatigue
Primary MS fatigue is directly associated with MS related brain and nerve changes, including brain lesions, disrupted neural networks, nerve realted problems, and immune or metabolic factors.
Secondary MS fatigue is caused by other MS problems such as sleep disorders, like pain, spasticity, sphincter disorders, medications, or reduced activity.
Pain
About 63% of MS patients experience pain, which can be nociceptive, including relapse-related pain (e.g., optic neuritis), spasticity, low back pain, colic, iatrogenic pain, and migraine or neuropathic, affecting roughly 27% of patients.
Neuropathic pain arises from CNS lesions and can be continuous, often affecting the lower limbs and trunk, or paroxysmal, such as trigeminal neuralgia, painful tonic spasms, and dystonic episodes triggered by movement.
Continuous neuropathic pain may persist for months or years and does not respond to corticosteroids. Overall, pain in MS severely reduces health-related quality of life and impacts work and daily activities.
Cognitive impairment
Cognitive impairment (CI) affects up to 75% of people with MS across all disease phenotypes and is more frequent in progressive forms and with longer disease duration. It arises from demyelination, neurodegeneration, and inflammatory changes in both grey and white matter that disrupt neural networks and synaptic function.
CI is most commonly characterized by slowed information processing speed, along with deficits in attention, memory, and executive function, and it substantially reduces quality of life and daily functioning.
Mental health conditions
Depression most common symptom, affecting 20-25% MS patients’ population. Depression in MS arises from both brain changes caused by the disease and from social or psychological factors.
Depression and anxiety frequently affect people with MS, with anxiety occurring even more often than depression. MS patients who are suffering from both depression and anxiety have increased risk of self-harm, physical symptoms, and social dysfunction.
Disorders such as generalized anxiety, panic disorder, OCD, and social phobia are also more common in MS than the general population.
Multiple Sclerosis Risk Factors
MS development requires both genetic and environmental factors. However, the presence of both does not guarantee that a person will develop MS.
Genetic factors
Family and twin studies show that genetics plays a major role in MS risk, as individuals with a first-degree relative (parent, sibling, or child) with MS have a substantially higher lifetime risk compared to the general population.
MS shows a higher concordance rate in monozygotic twins (20–30%) compared with dizygotic twins (2–4%), further supporting a strong genetic contribution.
MS does not follow traditional mendelian inheritance genetic pattern, shows the involvement of multiple genes.
Environmental factors
Various environmental factors responsible for the MS including sunlight, vitamin D, viral infections, smoking, overweight, and gut-microbiota.
Sunlight and vitamin D
MS incidence increases with distance from the equator, a pattern linked to reduced ultraviolet (UV) radiation and lower vitamin D production. People living at higher latitudes receive less UV exposure, resulting in decreased endogenous vitamin D synthesis.
Vitamin D deficiency has therefore been investigated as a risk factor for MS. Higher vitamin D levels, particularly before the age of 20, are associated with a reduced risk of developing MS.
Epstein–Barr virus
Epstein–Barr virus (EBV) is most studied environmental factor that trigger MS. Although exact mechanism is not known, but EBV is thought to influence MS through complex interaction.
Out of multiple hypothesis, one hypothesis is molecular mimicry, in which EBV protein resemble the myelin proteins and cause the immune system mistakenly attack myelin, survival of autoreactive B cells, and direct EBV involvement in the CNS, which may trigger inflammation and worsen MS symptoms.
Other microorganism
In addition to EBV, other infectious microorganism such as human herpesvirus 6 (HHV-6), cytomegalovirus (CMV), human endogenous retroviruses (HERVs), and Chlamydia pneumoniae have been found for their involvement in MS.
Smoking
Smoking increases the risk of MS by promoting immune activation, oxidative stress, axonal degeneration, increased blood–brain barrier permeability, and chronic inflammation. In contrast, the role of passive smoking remains uncertain, as studies have reported conflicting results regarding its association with MS risk.
Obesity
Obesity, particularly in early life, is associated with an increased risk of MS and neuroinflammation, largely through immune modulation and vitamin D deficiency.
In RRMS, obesity is associated with inflammatory cytokine imbalance, altered lipid profiles, and increased brain atrophy, which correlates with greater disability. Its role in MS progression is not clear and may vary according to sex and smoking status. In contrast, dietary approaches such as ketogenic diets, caloric restriction, and omega-3 fatty acid intake show significant benefits by reducing inflammation, oxidative stress, and neuroprotection, whereas excessive intake of saturated fats may worsen neuroinflammation.
Gut microbiome imbalance
The gut microbiota also plays an important role in MS progression. Recent studies indicate that MS patients exhibit alterations in gut microbiota composition, including enrichment of Blautia and Akkermansia species and a reduced Bifidobacterium-to-Akkermansia ratio, which is associated with disease severity.
Other studies show that patients with autoimmune neurological diseases, including MS, have reduced levels of short-chain fatty acid (SCFA) producing bacteria (such as Faecalibacterium and Roseburia) and an increased abundance of pathogenic or opportunistic microbes (Streptococcus, Escherichia–Shigella). This imbalance in the gut microbiota may contribute to immune dysregulation and neuroinflammation.
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