Definition and Causes:

DEFINITION:

• Multiple sclerosis (MS) is a disease that affects the brain and spinal cord which is referred to as the central nervous system (CNS)
• Inflammation caused by the immune system leads to injury of the insulation (known as the myelin sheath) surrounding nerve cells (neurons) within the CNS
• This injury disrupts the normal function and signals that are sent from the brain and spinal cord to the rest of the body

CAUSES:

MS is an autoimmune disease, i.e. the body’s own immune cells, which are normally used to defend us against invading organisms, such as bacteria and viruses, somehow being to attack normal body tissue. In this case, the attack is against the insulation (or myelin) surrounding the neuron (nerve cells) within the brain and spinal cord.

The exact reason why the immune cells behave in this fashion is unknown, but there has been speculation about:

1. Environmental factors, it has been speculated that exposure to certain drugs, toxins, viruses or chemicals in the environment might trigger the immune system to malfunction, such that it begins attacking the myelin within the CNS
2. Genetic Factors, i.e some people may have genes that might have the tendency to allow the development of immune malfunction if they are exposed to certain toxins, viruses, etc.
3. The amount of MS cases in the population depends on the geographic location. MS is more prevalent in temperate countries as compared to tropical countries and developing MS is related to where a person lives during their first ~15 years of life, i.e. individuals who grew up in tropical regions before moving to a temperate country have a lower risk of developing MS, than someone who grew up in a temperate country then moved to the tropics. This observation has led to the notion that environmental factors play an important role in causing MS

Symptoms:

There are different types of MS which vary in severity and presentation.

Many patients will develop relapsing-remitting symptoms, with attacks interspersed with periods of normal functioning. There are 4 main types:

1. Primary progressive MS (PPMS)
   • Gradual progression with no remissions
2. Progressive relapsing MS (PRMS)
   • Steady cumulative progression of clinical neurologic damage with some relapses and remissions
3. Relapsing-remitting MS (RRMS) (most common initial presentation)
   • Periods of relapse (often new neurological symptoms), followed by periods of remission
4. Secondary progressive MS (SPMS)
   • Steady progression of neurologic symptoms and progressive worsening

MS Symptoms are varied and depend on the area of the central nervous system CNS that is affected. Symptoms may include:

Vision problems:

• Optic neuritis (inflammation of the optic nerve of the eye) can occur with or without MS
• The condition may affect one or both eyes
• Visual loss is variable and may be partial or complete
• Pain may occur and made worse by eye movements

Sensory disturbance:

• Can occur in any part of the body and patients may have a sense of numbness, tingling, pins-and-needles, coldness, and decreased sensitivity to touch

Reduced strength and coordination:

• Weakness and incoordination can affect any part of the body and may result in weakness of face, arm leg, difficulty speaking/drooling. There may be trouble coordinating movements such that writing, eating, dressing and walking

Bowel/Bladder:

• Frequent and urgent need to urinate
• Patients may need to be checked for urinary tract infections
• Constipation and loss of bowel control may occur

Sexual dysfunction:

• Men experience varying degrees of erectile dysfunction
• Women may experience a loss in sensation and pain during intercourse

Weakness with exposure to heat:

• Exposure to hot conditions (sun, sauna, hot-tubs, etc) increases body temperature and may cause transient worsening of symptoms

Fatigue:

• Fatigue is a common complaint in MS

Depression:

• Many patients (>50%) may have some degree of depression

Cognitive dysfunction:

• Mental impairment can occur in MS, and as the disease progresses may affect ~34-65% of patients

Epilepsy:

• 2 to 3% of patients may develop epilepsy

Investigations and Treatment:

Multiple sclerosis has no definitive diagnostic test. Diagnosis depends on clinical presentation as well as the results of investigative tests and ruling out other causes of myelin damage in the central nervous system.

INVESTIGATION:

History

• Patients will be asked to describe the history of their symptoms; when they first started, if they have ever gone into remission, how often, and to describe any relapses

Blood work

• Patient’s blood is examined for indicators of the presence of other diseases that may have similar symptoms.

Magnetic Resonance Imaging (MRI)

• A device used to take pictures of the internal organs, including the brain and spinal cord. This machine does not use x-rays. Instead, MRI uses magnetic fields over the body. The device looks like a long cylindrical tube. Patients will lie on a table that slides into the hollow tube. Computer analysis of magnetic fields within the machine can generate images of the internal structures of the body’s organs, including the brain. In an MS patient, an MRI of the brain or spinal cord will show the normal structures, plus any area of injury caused by inflammation will be commonly detected as white spots called plaques. Patients must lie still inside an MRI machine for several minutes. In some circumstances, a dye might be injected into the veins (enhanced MRI) just before the scan to help improve the detection of abnormalities. Patients who complain of claustrophobia (fear of small space) may be given a mild sedative to help relax prior to MRI scanning

Lumbar Puncture/Spinal tap for cerebrospinal fluid (CSF) analysis

• A small amount of fluid called cerebrospinal fluid (CSF) is removed from the patient’s spine in the low back (lumbar) area and sent for analysis. During the procedure, the physician will clean and drape the lumbar area. A local anesthetic is administered over the skin where the needle is to be placed. Since the spinal cord does not extend down into the lower lumbar region there is little or no chance of causing injury to the spinal cord. The CSF is extracted and sent for checking for special proteins that might be present in MS. The test is not specific for MS, but with the right clinical presentation and complimentary MRI findings this may help with the diagnosis of MS

Evoked Potentials

• This procedure is used to measure how well the nerve cells are conducting electrical signals within the brain and spinal cord. Electrodes (small wires) are placed on the skin at various locations on the arm or leg, spine, and head, and time taken for small electrical signals to reach the brain recorded. This can also be done using the vision (visual evoked potentials), hearing (auditory evoked potentials), and sensory nerves on the body (somatosensory evoked potentials). Observed delays in signal communication allow doctors to figure out where the damaged neurons in the body are located

TREATMENT:

Multiple sclerosis has no cure, however, newer agents may help reduce the inflammation and “slow down” the injury within the CNS; treatment, therefore, involves modifying the path of the disease and direct treatment of symptoms to minimize their effects on patients and improve quality of life.

Disease-Modifying therapy – helps to reduce inflammation within the CNS

May be used in relapsing-remitting MS and secondary progressive MS

• Steroids – given intravenously or orally
  • Helps to reduce the inflammation in the brain and spinal cord that’s associated with MS
  • Usually given for exacerbations (flare-ups) over several days
• Beta interferons (Rebif, Avonex)
  • Used to slow the progression of MS symptoms. Used to suppress the immune cells that are causing injury within the brain and spinal cord. May cause stress on the liver and so blood tests will be required to monitor liver function
• Glatiramer acetate (Copaxone)
  • This drug is injected under the skin once a day. It is believed that it blocks the immune system from attacking the myelin sheaths. Side effects include flushing and shortness of breath (transient and occurs soon after injection is administered)
• Fingolimod (Gilenya)
  • May help decrease certain types of immune cells within the CNS. May require intermittent monitoring of liver and heart function.
• Natalizumab (Tysabri)
  • Interferes with the movement of immune cells from the bloodstream to the brain and spinal cord, and helps prevent degradation of the myelin sheaths. This drug is usually prescribed as a last resort as there is a small but potential risk of developing a rare and extremely serious condition called Progressive Multifocal Leukoencephalopathy (PML) which has a high rate of death
• Ocrelizumab (Ocrevus)
  • Influence the immune system response in MS through its involvement with B cells
  • It helps to reduce inflammation and reduce attacks by the immune system on nerve cells
• Siponimod (Mayzent)
  • It works by entering the central nervous system (CNS) and preventing harmful immune cells from being activated and released from the lymph nodes and thymus gland into the central nervous system
  • It keeps the immune cells trapped in the lymph node, slowing MS disease progression
• Mitoxantrone (Novantrone)
  • Suppresses the immune system, lowering the likelihood of an attack on myelin sheaths. May slow the course of secondary progressive MS. Significant side effects require use with caution. May be associated with the development of leukemia and can also be harmful to the heart. As such, it is usually reserved for those refractory (resistant) to other forms of treatment
• Other agents include
  • Cyclophosphamide
  • Methotrexate
  • Azathioprine
  • Cladribine
  • Intravenous immunoglobulin (IVIG)
    • May reduce the clinical attack rate in Relapsing-Remitting MS; Some data suggestive of benefit but not conclusive.
• Other Therapies under investigation
  • Chronic Cerebrospinal Venous Insufficiency (CCSVI): A recent hypothesis suggesting that impaired venous drainage from the brain and spinal cord leads to injury within the central nervous system that is related to MS
  • Please see CCSVI.ca for position statements from the Canadian Medical Association (CMA) and the Canadian Institutes of Health Research (CIHR)

Symptomatic Treatment

Symptomatic treatment is necessary and complex due to the widespread effect of the disease on the function of the central nervous system. Some symptoms requiring treatment are as follows:

Spasticity

• To prevent stiffness and muscle spasms, patients may be prescribed muscle relaxants such as baclofen and tizanidine. Side effects include weakness and drowsiness

Fatigue

• Patients may be prescribed drugs such as amantadine to help reduce their fatigue. Antidepressants may also be recommended for fatigue associated with depression

Pain

• Patients complaining of acute or chronic pain may be prescribed usual analgesics (acetaminophen, ibuprofen). Depending on the type and location of pain other drugs which might consider includes: Neurontin, Lyrica, Tramadol, Cymbalta, and Tegretol among others

Bladder dysfunction

• Patients suffering from bladder spasms may require drugs to help control them (e.g. Ditropan). Patients who have lost the ability to control their bladder may have to use intermittent self-catheterization which involves sliding a thin tube through the urethra (channel from balder to the exterior of penis/vagina) into the bladder, allowing urine to drain freely

Bowel dysfunction

• Drugs may be prescribed to help with control. Patients may be recommended to use fiber and stool softeners to treat constipation

Sexual dysfunction

• Males with erectile dysfunction may be offered treatment with agents such as tadalafil (Cialis), sildenafil (Viagra) and vardenafil (Levitra). Caution is advised in the elderly and those with cardiac disease. Water-based lubricants may be suggested to women with insufficient natural vaginal lubrication

Risk Factors and Prevention:

No definite cause has yet been discovered for multiple sclerosis, however, the following have been observed.

• Typical age of onset is between 20-40 years old; average age at onset is 32 years old
• Females are twice as likely as Males to develop MS
• Family history may have a weak genetic link (<5%)
• Infection: Epstein-Barr virus has been suggested
• Caucasians are more likely than other races to develop MS
• Location – temperate climate

Outcome:

There is no known cure for MS. Treatments are geared at slowing the progression of attacks and reducing the effects of symptoms on the body.

• If untreated, more than 30% of patients with multiple sclerosis will develop significant physical disability within 20-25 years from onset
• 70% of patients lead active, productive lives with prolonged remissions
• 30% relapse in 1 year, 20% in 5-9 years, and 10% in 10-30 years
• Patients with MS are thought to have a slightly lower average life expectancy; 5-7 years shorter than that of the general population