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Overview
Multiple Sclerosis is an abnormal immune-mediated response to the myelinated nerve fibers of the Central Nervous System (CNS). Throughout the course of the disease, a type of immune cells called T Cells attack the myelinate nerve fibers causing the build-up of scar tissue referred to as sclerosis in the CNS. The damage to the fibers results in the distortion of nerve impulses which leads to a variety of symptoms including but not limited to muscle spasticity, cognitive changes, walking difficulties, and vision problems. Multiple Sclerosis consists of four phenotypes or disease courses, Clinically Isolated Syndrome (CIS), Relapsing Remitting MS (RRMS), Primary Progressive MS (PPMS), and Secondary Progressive MS (SPMS). Of those four disease courses, two are relapsing (CIS and RRMS) and two are progressive (RRMS and PPMS) Phenotypes. Although there are numerous treatment options used to delay onset of symptoms and control the progression of the disease, there is no cure for Multiple Sclerosis.
Phenotypes
CLINICALLY ISOLATED SYNDROME (CIS)
Clinically Isolated Syndrome is the first onset of neurological symptoms in Multiple Sclerosis. This first episode is due to the inflammation and demyelination of nerves in the CNS. In order to officially be classified as CIS, the episode must last more than 24 and must have no accompanying fever or infection. If a MRI shows evidence of brain lesions, a second episode is highly likely to occur, eventually leading to a RRMS diagnosis. While neurological symptoms may persist for a time after the first episode has ended, patients generally make a full recovery.
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FIG. 1 – An example of a nerve before and after demyelination due to T Cells

CLINICALLY ISOLATED SYNDROME AND MS
Does CIS always lead to a MS diagnosis?
  • While patients who have been diagnosed with CIS are considered to be at high risk for developing MS, they typically do not have enough symptoms to warrant an MS diagnosis and the disease may not progress farther.
  • If an episode is accompanied by lesions there is a 60-80% chance of a second episode and an eventual MS diagnosis.
  • If no lesions appear in a MRI after the episode, there is only about a 20% chance of a second episode and diagnosis. This is barring any evidence of scar tissue or past injury in the brain that may be indicative of an undiagnosed episode.
Are there different types of episodes?
  • Monofocal episodes indicate that a patient only experienced one neurological symptom.
  • Multifocal episodes occur when the patient experiences more than one neurological sign or symptom.
How does CIS differ from MS?
  • A person with CIS has only experienced one episode, whereas someone with MS has experienced many that have caused lasting damage.
  • CIS patients generally have damage located only in one area of the brain.
Who can get CIS?
  • 70% of CIS diagnoses occur in patients between 20 and 40 years old.
  • CIS is two to three times more likely to affect women than men.
SYMPTOMS
There is a wide variety of symptoms that a patient with CIS may present with. The difficulty in pinpointing a list of general symptoms comes from the idea that each form of MS is very unique, with no particular area of the brain or spinal cord that is always attacked. There are three main areas that may be effected by CIS, the spinal cord, the optic nerve, and the brainstem.
Partial or transverse myelitis of the spinal cord can have a myriad of side effects including:
  • Muscle Weakness
  • Tingling in Toes
  • Bladder or Bowel Problems
  • L’Hermitte’s Symptom
Optic neuritis, or swelling of the optic nerve can lead to:
  • Blurred Vision
  • Ipsilateral Sight Loss
  • Pain Behind Eyes
  • Severely Impaired Perception of Color
  • Blind Spots Surrounded by Normal Vision
Lesions on the brain stem have been known to cause:
  • Nausea and Vomiting
  • Double Vision
  • Dizziness
  • Hearing Loss
  • Unsteady Gait

TREATMENT
Since CIS is an early form of MS, there are many cases in which the disease resolves on its own. That being said, physicians may choose to give a precautionary high dosage of Methyprednisolone, a steroid frequently used to treat inflammation. For high risk cases of CIS, a disease modifying therapy used for one of the other forms of MS may be recommended.

RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS)
As the most common phenotype, approximately 85% of all Multiple Sclerosis patients are initially diagnosed with Relapsing-Remitting Multiple Sclerosis (RRMS). This disease course differs from that of CIS because it is characterized by multiple clearly defined episodes and new or increasing neurological symptoms. These attacks or episodes are followed by times of remission during which a full or partial recovery of lost neurological function occurs. During the periods of remission, the patient may still be symptomatic but so long as there is no new MRI activity or inflammation, their condition is not progressing or worsening.

RRMS vs CIS
There are many similarities between CIS and RRMS, mainly due to the fact that CIS often progresses into RRMS. Much like CIS, RRMS patients suffer from localized areas of damage in the brain due to inflammation. Unlike CIS, however, RRMS consists of multiple episodes, causing damage to multiple areas of the brain and sometimes the brain stem. Similarly to CIS, the lesions, also called plaques or scars, on the brain have far more inflammatory cells than progressive forms of MS indicating that the T Cells are continuing to attack the myelinated neurons.


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FIG 2. An MRI scan indicating multiple lesions on the brain, indicating signsof Relapsing-Remitting Multiple Sclerosis.
Like CIS, RRMS is two to three times more likely to affect women than men but diagnoses typically occur between 20 to 30 years old.
Diagnosing Relapsing-Remitting Multiple Sclerosis requires evidence of at least two separate areas of damage to the myelin in the CNS (i.e. brain, brain stem, spinal cord). RRMS consists of four classifications:
  1. Active – relapsing and/or new MRI activity
  2. Not Active – in remission
  3. Worsening – confirmed increased disability after 6 to 12 months have passed since the last episode.
  4. Not Worsening – no increase in disability between neurological testing.

SYMPTOMS
Symptoms associated with RRMS include fatigue, numbness, vision problems, muscle spasticity/stiffness, bowel or bladder problems, difficulty processing information and memory loss.

TREATMENT
There are thirteen FDA approved medications used for reducing the number of relapses and lesions a RRMS patient experiences. The of those, seven are injectable (Avonex, Betaseron, Copazone, Extavia, Glatopa, Plegridy, and Rebif), three are oral (Aubagio, Gilenya, and Tecfidera), and three are infused (Letrada, Novantone, and Tysabri). Novantrone is generally prescribed by doctors for patients whose symptoms are rapidly worsening. In addition to medication, rehabilitation is often necessary to regain and maintain neural functioning.

PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS (PPMS)
Unlike CIS and RRMS, Primary Progressive Multiple Sclerosis (PPMS) is not a relapsing form of Multiple Sclerosis. Rather than having a series of episodes spread over a period of time, PPMS causes a decrease in neurological function from onset that slowly progresses without periods of remission. While PPMS is only known to affect 15% of Multiple Sclerosis patients, it is much more difficult to recognize than other relapsing forms of the disease, making diagnosing patients much harder.

PATHOLOGY
Since PPMS patients do not suffer from relapses or recurring episodes of inflammation, they are likely to have fewer brain lesions. The lesions that can be found are generally located on the spinal cord and have very few inflammatory cells. PPMS has four classifications: (1) Active – occasional relapse or new MRI activity (2) Not Active – no new MRI activity (3) With Progression – evidence of disease worsening (i.e. decreased neurological function) with or without new MRI activity (4) Without Progression – neurological function remains stable. Of these classifications, most PPMS patients remain in stage three from the onset of the disease.

SYMPTOMS AND DIAGNOSIS
Primary Progressive Multiple Sclerosis causes a gradual but steady change in functional ability, namely related to balance and gait. In order to be diagnosed with PPMS, a patient must present with one year of consistent disease progression with no signs of remission. Additionally, they must have at least two of the following:
  1. A lesion on the brain consistent with those caused by Multiple Sclerosis.
  2. Two or more lesions of a similar type located on the spinal cord.
  3. Evidence of the presence of Oligoclonal Band (a protein) and IgG (Immunoglobin G) in the Cerebrospinal Fluid but not in the blood, both of which are indicative of an inflammatory infection or disease of the CNS.
Unlike CIS and RRMS, disease onset usually occurs much later in life, affecting equal numbers of men and women.

TREATMENT
At this time, there are not FDA approved medications used to treat Primary Progressive Multiple Sclerosis. While there are a few Clinical Trials available, there has been no evidence that they have been effective. Clinicians will generally treat PPMS by managing symptoms and prescribing rehabilitation to recover and maintain as much neurological function as possible.

SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS (SPMS)
Secondary Progressive Multiple Sclerosis (SPMS) initially follows a relapse-remitting disease course, eventually transitioning into a progressive form of the disease. Most patients who are originally diagnosed with RRMS will transition to SPMS treatment plans within a few years to attempt to compensate for progressive neurological function deterioration. While relapses are not uncommon with SPMS, the progressive decrease in function is primarily due to nerve damage and/or loss from early attacks of inflammation. Much like RRMS AND PPMS, SPMS consists of four classifications: (1) Active – occasional relapse or new MRI activity (2) Not Active – no new MRI activity (3) With Progression – evidence of disease worsening (i.e. decreased neurological function) with or without new MRI activity (4) Without Progression – neurological function remains stable.

TREATMENT
Generally, once a patient has transitioned from RRMS to SPMS, they will continue on one of the thirteen medications prescribed to RRMS patients until it is no longer adequately controlling the disease. As the disease progresses, patients typically placed on Novantrone, a chemotherapudic drug that suppresses T Cells, B Cells, and Macrophages preventing further attacks on the myelinated nerves of the CNS.

Immunology
ABNORMAL IMMUNE MEDIATED DISEASE
As noted earlier, MS is officially classified as an abnormal immune-mediated response rather than an autoimmune disease. By definition, an autoimmune disease is “a disease in which the body produces antibodies that attack its own tissues, leading to the deterioration and in some cases to the destruction of such tissue.” [1] Although most experts in the field would classify the disease at autoimmune, since the antigen the antibodies attack is still unknown there is still a chance, albeit minute, that the antibodies are attacking a foreign substance found in either the myelinated sheathes or nerve fibers.

T CELLS
The immune cells that are responsible for the degeneration of nerve fibers in the CNS are a type of lymphocyte called T Cells that are created in the Thymus gland. The cells are created to single out attack foreign substances found in the body such as bacteria, viruses, and foreign tissue. In addition to fighting antigens, T Cells are responsible for creating cytokines, which aid in the recruitment of more antibodies. There are three classifications of T Cells: Helper T Cells, Regulatory T Cells, and Cytotoxic “Killer” T Cells. Helper T Cells are responsible for recognizing foreign antigens and stimulating the production of other T Cells and cytokines. Regulatory T Cells are responsible for shutting off the immune response to self-antigens.

Risk Factors
Although much is still unknown about the exact cause of Multiple Sclerosis, there have been extensive studies conducted trying to get to the bottom of this degenerative disease.

ENVIRONMENTAL
Multiple Sclerosis has been found to be much more prevalent in areas located further from the equator, namely north of the equator. This could be evidence of a connection between vitamin D and the onset of the disease, as areas closer to the equator receive much more sunlight year round, exposing them to large amounts of vitamin D. As vitamin D has been proven to support immune function, it is possible that the lack of sunlight could allow for the immune system to weaken or misfire causing the T Cells to attack the CNS.
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FIG 3. – Depiction of the regional distribution of Multiple Sclerosis cases reported across the globe.
GENETIC
Although no direct genetic link has been found, having a first degree relative (i.e. a parent or sibling) with the disease does increase a person’s likelihood of developing the disease.

Conclusion

While we have yet to find a cure for this degenerative disease, Multiple Sclerosis is not something to be afraid of. Everyday researchers and clinicians throw themselves into their work searching for a cure, searching for ways to improve quality of life. Although the exact causes are unclear and there do not seem to be any preventative measures, it is important to continue to move forward - researching, testing, and eventually succeeding.

Further Reading

American Physical Therapy Association - http://ptjournal.apta.org/collection/multiple-sclerosis
Cleveland Clinic - http://my.clevelandclinic.org/services/neurological_institute/mellen-center-multiple-sclerosis/diseases-conditions/multiple-sclerosis
National Institute of Neurological Disorders and Stroke - http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm
National MS Society - http://www.nationalmssociety.org/What-is-MS

Quiz
  1. 1. T/F – When Oligoclonal Bands and Immunoglobin G are found in the blood but not the cerebrospinal fluid, a patient likely has SPMS.
  2. 2. More cases of Multiple Sclerosis are reported of the equator than of the equator.
  3. 3. Why is MS considered an abnormal immune mediated response rather than an autoimmune disease?
  4. 4. When is a patient more likely to suffer from subsequent episodes and an eventual MS diagnosis after an initial CIS diagnosis?
  5. 5. T/F - In order to confirm increased disability, six to twelve months must have passed with no increase (or regaining) of neurological function.
  6. 6. Which disease course or phenotype of Multiple Sclerosis has yet to be successfully treated by drug therapy?
  7. 7. T/F Progressive MS lesions differ from Relapse MS lesions because they contain more inflammatory cells.
  8. 8. Which category of T Cells produce cytokines?
    1. a. Helper T Cells
    2. b. Regulatory T Cells
    3. c. Cytotoxic T Cells
    4. 9. Why do symptoms vary so greatly for each Multiple Sclerosis patient?
    5. 10. Which phenotype of MS is generally seen as ‘phase two’ of the disease?
      1. a. Clinically Isolated Syndrome
      2. b. Relapse-Remitting Multiple Sclerosis
      3. c. Primary Progressive Multiple Sclerosis
      4. d. Secondary Progressive Multiple Sclerosis

Answers:
  1. 1. False - When Oligoclonal Bands and Immunoglobin G are found in the Cerebrospinal Fluid but not blood, a patient likely has SPMS.
  2. 2. North/South
  3. 3. The specific antigen which the T Cells target has not yet been identified
  4. 4. If there is evidence of lesions on the MRI of the brain and spinal cord (especially if there is evidence of previous damage)
  5. 5. True
  6. 6. Primary Progressive Multiple Sclerosis
  7. 7. False – Relapse MS lesions contain more inflammatory cells
  8. 8. A – Helper T Cells
  9. 9. The difficulty in pinpointing a list of general symptoms comes from the idea that each form of MS is very unique, with no particular area of the brain or spinal cord that is always attacked – symptoms vary based on the area of the CNS effected by the demyelination.
  10. 10. D – Secondary Progressive Multiple Sclerosis

Glossary
Cytokines – Cells that aid in coordinating immune response to inflammation and infection.
Demyelination – The damage or removal of the myelin sheath surrounding the neurons in the Nervous System.
Episode – An exacerbation of MS that causes new or worsening symptoms due to new lesions or areas of inflammation in the CNS.
L’Hermitte’s Symptom – A tingling or electric sensation that runs down the back.
Self-Antigens – A heathy cell in the body that during in an autoimmune disease triggers antibody development that act to fight it.
Spasticity – Abnormal stiffness of skeletal muscle.
Transverse myelitis – Inflammation across one section of the spinal cord.

References

"Dictionary.com - The World's Favorite Online Dictionary!" Dictionary.com. N.p., n.d. Web. 18 Nov. 2016. <http://www.dictionary.com/>.

Mayo Clinic Staff Print. "Multiple Sclerosis." Mayo Clinic. N.p., 01 Oct. 2015. Web. 18 Nov. 2016. <http://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/home/ovc-20131882>.

Mayo Clinic Staff Print. "Optic Neuritis." Overview - Optic Neuritis - Mayo Clinic. N.p., 04 Nov. 2016. Web. 17 Nov. 2016. <http://www.mayoclinic.org/diseases-conditions/optic-neuritis/home/ovc-20263583>.

McNamara, Lindsay. "What Is Multiple Sclerosis (MS)? | The Johns Hopkins Multiple Sclerosis Center." What Is Multiple Sclerosis (MS)? | The Johns Hopkins Multiple Sclerosis Center. N.p., n.d. Web. 17 Nov. 2016. <http://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/multiple_sclerosis/conditions/>.

National Multiple Sclerosis Society. N.p., 15 Nov. 2016. Web. 17 Nov. 2016. <http://www.nationalmssociety.org/>.


PHOTO REFERENCES
Figure One – Mayo Foundation for Medical Education and Research
Figure Two – Mayo Foundation for Medical Education and Research
Figure Three - https://multiplesclerosis.net/what-is-ms/statistics/


[1] Dictionary.com