What Are the Phenotypes of Multiple Sclerosis (MS)?

Medically Reviewed on 6/3/2022
What Are the Phenotypes of Multiple Sclerosis (MS)
Phenotypes can be useful for clinical diagnosis by characterizing the most typical patterns of progression identified in MS patients

According to the International Advisory Committee on Multiple Sclerosis (MS) Clinical Trials, there are four basic phenotypes of MS:

  1. Clinically isolated syndrome (CIS)
  2. Relapsing-remitting (RRMS)
  3. Secondary progressive (SPMS)
  4. Primary progressive (PPMS)

Phenotypes can be useful for clinical diagnosis by characterizing the most typical patterns of progression identified in MS patients. MS takes years to develop, and knowing the phenotypes increases the likelihood of early diagnosis and treatment.

What is clinically isolated syndrome (CIS)?

  • CIS is an episode of MS symptoms that lasts at least 24 hours.
  • This is a one-time occurrence that occurs before any other MS symptoms, and it often prompts a visit to the doctor, who may prescribe a magnetic resonance imaging (MRI) scan.
  • Some people who have CIS will never develop MS. However, if lesions are apparent on an MRI, the chance of MS development is increased.
  • This information is critical as early therapy with disease-modifying medicines has been shown to postpone the emergence of MS in persons with CIS and lesions.

What is relapsing-remitting MS (RRMS)?

  • RRMS is seen in around 85% of MS patients and characterized by phases of relapse and recovery.
  • During a relapse, neurological symptoms arise and remain until the recovery stage, when symptoms completely or partially resolve.
  • RRMS cycles are unique to each patient and must be analyzed to determine whether a treatment strategy is effective.
  • Many people with RRMS recover completely or considerably after each incident, while each case offers its own set of obstacles.
  • Ideally, an early diagnosis means a faster path to optimal treatment for living a full and active life.

What is secondary progressive MS (SPMS)?

  • SPMS has similar cycles of relapse and remission, but a person's level of impairment can progressively develop without an attack.
  • Many people experience a protracted development of symptoms without remission.
  • Prior to the availability of disease-modifying medications, over half of all patients with RRMS reported symptoms that progressed to SPMS within 10 years.
  • Experts believe that these newer medications have an impact, but there hasn't been enough research done to evaluate their effect on MS progression.

What is primary progressive MS (PPMS)

  • PPMS is the rarest of the four primary types of MS, occurring in about 10%-15% of individuals.
  • People with PPMS typically experience an increasing level of impairment over time, with no early periods of relapse and remission.
  • PPMS is more difficult to treat and frequently leads to a level of impairment that requires more support for daily tasks.


What Is Multiple Sclerosis? MS Symptoms, Causes, Diagnosis See Slideshow

What are the sub phenotypes of MS?

Depending on disease activity, phenotypes of MS are further divided into two sub phenotypes:

  • Active: Development of a clinical relapse or the appearance of new T2 or gadolinium-enhancing lesions during a certain period (contrast-enhancing T1-hyperintense lesions, new T2-hyperintense lesions, or enlarging T2-hyperintense lesions)
  • Nonactive: Absence of active disease for a year or longer, referred to as "no evidence of disease activity"

Depending on relapse, MS is further divided into three sub phenotypes:

  • True relapse of MS: An MS relapse occurs when nerves in the brain and spinal cord become inflamed. The nerves lose myelin, which covers and protects them, and leads to lesions called plaques. Plaques in the brain or spinal cord alter the electrical signals that go up and down neurons. They can become slower, distorted, or stop completely, causing MS symptoms. They often last for a few days to many weeks; some may last for months. MS relapses can be treated with corticosteroids, which reduces inflammation. They can make the flare-up shorter and less severe if used for a short period of time.
  • Pseudo-relapse of MS: Sometimes, a symptom flare-up has nothing to do with the progression of your disease and occurs as a result of anything that worsens your condition, such as a fever, infection, or hot weather. This condition is called pseudo-relapse of MS.
  • Remission of MS: Remission does not indicate that all of the symptoms of MS have disappeared. Instead, you basically revert to how you were prior to the last relapse.

What are cognitive phenotypes?

In 2021, investigations were made regarding a new categorization of cognitive traits for MS patients. Researchers performed latent profile analysis (LPA) on cognitive test z scores to define cognitive phenotypes, and statistical analysis was used to compare demographic, clinical, and radiological aspects of each phenotype. 

They found these five cognitive traits using LPA.

  • Preserved cognition
  • Mild-verbal memory/semantic fluency
  • Mild-multidomain
  • Severe-executive/attention
  • Severe multidomain

Summary of the study is as follows:

  • Patients with mild-verbal memory/semantic fluency phenotypes were younger and had shorter illness duration than patients with mild-multidomain, severe-executive/attention and severe-multidomain phenotypes.
  • From early RRMS to late RRMS to SPMS, the relative frequency of severe-executive/attention and severe-multidomain phenotypes rose.
  • On MRI, those with mild-verbal memory/semantic fluency had lower hippocampal volume, those with mild-multidomain phenotype had lower cortical gray matter, those with severe-executive/attention had higher mean T2 hyperintense lesion volume and those with severe multidomain phenotype had lower volume in most brain structures.

The study had several limitations, including a cross-sectional design, data based on a clinical sample that may not be typical of the broader MS population, and MRI examinations completed in just a subset of patients. 

However, according to the findings, a new categorization of cognitive abnormalities in patients with MS may be useful in diagnosing clinical disability, guiding treatment decisions and tailoring cognitive rehabilitation treatments.

What are the signs and symptoms of multiple sclerosis?

Multiple sclerosis is a disease that targets the central nervous system. MS destroys the myelin sheath, slowing or blocking communication between the brain and the rest of the body.

Some early warning signs may include:

  • Optic neuritis or vision disorder
    • Inflammation of the optic nerve in the eye(s) can cause vision disturbance in one or both eyes.
    • MS can also produce blurred or double vision or vision loss, as well as difficulty recognizing contrast and vibrant colors.
    • Looking up or down can cause discomfort.
  • Tingling and numbing sensations
    • Loss of myelin sheath interferes with nerve impulse conduction.
    • This may result in symptoms such as tingling or numbness. These symptoms might be felt in the legs, arms, fingers, toes,and face.
  • Muscle weakness
    • A typical symptom is uncontrolled and painful movements of the limbs, as well as muscle or joint stiffness.
    • The legs are usually the most afflicted, but back discomfort is also common.
  • Coordination and balance
    • Gait issues result from a lack of stability and coordination.
    • There may be vertigo or light-headedness.
  • Cognitive issues
    • MS also causes memory problems, melancholy, organizational problems, linguistic difficulties, short attention spans, and emotional abnormalities such as mood swings, impatience, and episodes of uncontrollable laughter and sobbing (pseudobulbar affect).

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What are the causes and risk factors of MS?

MS has an unknown etiology, although experts believe it is an autoimmune disease. Its onset may be caused by a mix of hereditary and environmental factors. Smoking can modestly increase the risk of acquiring MS.

Risk factors of MS apart from smoking include:

  • Age: Most people diagnosed with MS are between the ages of 15 and 60 years, and it often starts between the ages of 20 and 40 years.
  • Autoimmune disorders: People with another autoimmune disease (such as thyroid disease, type I diabetes, or inflammatory bowel disease) are slightly more likely to develop MS.
  • Climate: MS is more common in temperate climates, such as Canada, northern United States, New Zealand, and southeastern Australia and Europe.
  • Race/ethnicity: Caucasians, especially those of Northern European descent, are at the highest risk of developing MS.
  • Family history: If a parent or sibling has MS, a person is more likely to develop the disease.
  • Sex: Women are twice as likely to develop MS as men.
  • Viruses: Certain viruses such as Epstein-Barr, which causes mononucleosis, have been linked to MS.

What are treatment options for MS?

There is no cure for multiple sclerosis. Depending upon the patient’s condition, doctors may recommend a tailored approach:

  • Corticosteroids: These are synthetic hormones that can be given through injections or orally and can help to lessen nerve irritation.
  • Plasma exchange: Plasma is extracted and separated from blood cells. Blood cells are then combined with a protein solution and transfused to the body.
  • Alternative medicine: Exercise, massage, yoga, dietary modifications, acupuncture, relaxation techniques, and other complementary therapies may help some individuals with MS manage symptoms including fatigue and discomfort.
  • Physical therapy: Stretching and strengthening exercises can improve mobility, relieve discomfort, and make daily chores easier. A physical therapist can also assist clients with mobility devices such as canes and walkers, which may be prescribed if walking is impaired.
  • Beta interferons: These drugs are injected beneath the skin or into the muscle to prevent or minimize inflammation. Long-term usage may result in flu-like symptoms, injection site reactions, and liver damage.

Other medicines may be prescribed, including those that suppress immune responses, decrease white blood cells, and lower relapse frequency and intensity. However, because these medications suppress immunity, they have a wide range of potentially negative side effects. 

Doctors may also prescribe drugs to address depression and anxiety, pain, sexual dysfunction, and bladder/bowel dysfunction associated with MS.

What are the complications of MS?

Common complications of multiple sclerosis include:

Can MS be prevented?

There is no proven strategy to prevent multiple sclerosis. However, greater levels of vitamin D have been associated with a decreased risk of MS in certain studies.

Taking a vitamin D supplement (if recommended by your doctor) and eating foods rich in or fortified with vitamin D may be beneficial.

What is the prognosis for MS?

Most people with multiple sclerosis have relapsing-remitting illness, which means they have periods of symptoms or relapses that last days or weeks before improving partially or fully. Remission may span months or even years.

Some people with MS have a constant development of signs and symptoms without remission, which is known as primary-progressive MS.

What is the life expectancy for people with MS?

Life expectancy for MS has improved due to advances in treatment options, improved health care, and lifestyle changes.

According to recent studies, patients with MS may live roughly 7 years less than the general population due to disease complications or other medical issues. However, many of these issues are controllable or preventable. Attention and dedication to health and well-being can help lower the risk of aggravating medical disorders such as heart disease and stroke. Only in rare cases does MS advance swiftly to death.

MS can be difficult to notice and diagnose, as symptoms vary greatly from person to person. In each situation, diligent monitoring of symptoms and diverse treatment strategies often result in the best outcomes.

Medically Reviewed on 6/3/2022
Image Source: iStock Image

Multiple Sclerosis Phenotypes as a Continuum: https://cp.neurology.org/content/11/4/342

Determining Multiple Sclerosis Phenotype from Electronic Medical Records: https://www.jmcp.org/doi/pdf/10.18553/jmcp.2016.22.12.1377

Redefining multiple sclerosis phenotypes using MRI: https://www.medrxiv.org/content/10.1101/19011080v1.full.pdf

What is MS? https://www.nationalmssociety.org/What-is-MS

Multiple Sclerosis: https://www.ncbi.nlm.nih.gov/books/NBK499849/