Multiple Sclerosis: Immune Response & Risk Factors

• Multiple sclerosis (MS) is a chronic auto-immune disorder.
• MS involves the destruction of the myelin sheath and neurons in the central nervous system (CNS).
• MS affects the brain and spinal cord.
• MS affects approximately 1 in 200 women and somewhat fewer men in the United States.

Characteristics of the Disease

• MS involves numerous affected areas of the brain and spinal cord.
• MS produces multiple neurologic symptoms that accrue over time.
• Plaques or sclerosed areas are the hallmark of MS.
• Sclerosis involves scars, inflammation, plaques in the brain.
• Multiple sclerosis involves multiple scars, inflammation, plaques that can be detected by MRI.

Epidemiology

• MS is usually diagnosed in patients between the ages of 15 and 45 years.
• Peak incidence occurs in the fourth decade of life.
• Women are afflicted more than men by a ratio of approximately 2:1.
• Men usually develop the first signs of MS at a later age than women.
• Men are more likely to develop the progressive form of the disease.
• Risk factors are geography, age, environmental influences, and genetics.
• In general, disease prevalence is higher the greater the distance from the equator.
• Within the United States, the prevalence of MS is higher in states above the 37th parallel.
• MS occurs more frequently in whites of Scandinavian ancestry than in other ethnic groups.

Normal Physiology

• The central nervous system includes the brain and spinal cord.
• The CNS communicates with other parts of the body by sending electrical signals/impulses from one neuron to another through the axon.
• The myelin sheath serves as a protective sheath and a support for the axon.
• The main function of the myelin sheath is to improve the speed of conduction of the nerve impulses/signals between neurons like an insulator.
• In the normal brain, there are no immune cells such as macrophages, white blood cells, and T-cells.

Multiple Sclerosis Physiology

• The blood brain barrier serves as a barrier to prevent entry of foreign objects into the brain.
• In patients with MS, immune cells can enter and be seen inside the brain.
• When T-cells are activated, it can easily pass through the blood brain barrier.
• The accumulation of immune cells will show up as plaque/sclerosis/scars (white spots).
• MS is an inflammation due to inflammatory cell infiltrate caused by autoimmune disorder where the immune system mistakenly attacks the body's own cells/tissue.
• In the normal brain, there should not be immune cells and the myelin sheath is mistakenly attacked.

Risk Factors That Increase T-Cell Activation

• Female (3:1) due to faster T-cell activation.
• Latitude, as people are further from the equator, which means less sun, results in vitamin D deficiency and increased T-cell activation.
• Smoking
• Genetic Predisposition
• Infection, especially when infected with Epstein-Barr Virus Type IV Hypersensitivity (Cell-Mediated)
• When T-cells enter, cytokines are released.
• These cytokines damage the myelin sheath, which causes demyelination.
• Cytokine release also dilates vessels, allowing other immune cells to enter, such as white blood cells, B-cells, and macrophages.
• Immune cells clump together inside, resulting in scarring or sclerosis.
• If the myelin sheath is damaged, results in loss of neurons or abnormal nerve conduction.

Gliosis

• In gliosis, glial cells are present as an immune cell that protects the brain from foreign bodies or infections.
• The body's own system targets the body cells (MS) glial cells undergo hypertrophy and proliferation which causes scar tissue or plaque formation.
• Plaques are diagnosed by Magnetic Resonance Imaging or Radio-imaging.

Pathophysiology

• The basic physiologic derangement in MS is the stripping of the myelin sheath surrounding CNS axons.
• Demyelination makes axons susceptible to damage, which becomes irreversible when they are severed.

Multiple Sclerosis Symptoms

• There are many different symptoms; the sensory, motor system, visual, genitourinary and psychiatric systems can be affected.
• MS Symptoms include:
  • Numbness, tingling 70.4%
  • Walking difficulty 76.1%
  • Fatigue 89.6%
  • Muscle spasms 60.8%
  • Depression 54%
  • Cognitive dysfunction 49%
  • Dizziness 41.6%
  • Vision problems 38.9%
  • Sexual dysfunction 38.1%
  • Itching 35.4%
  • Speech/swallowing problems 35.7%
  • Emotional changes 53.9%
  • Bladder dysfunction 50.8%
  • Headache 53.7%
  • Hearing loss 15.2%
  • Breathing problems 13.8%
  • Seizures 3.9%
  • Tremor 29.9%
  • Bowel dysfunction 26%

Sensory

• Paresthesia: Tingling or pricking sensation.
• Hypesthesia: Reduced or delayed touch sensation.
• Pain: Common symptom that can occur anywhere in the body.

Motor

• Weakness: Common in the limbs, usually after exercise, and can feel severe weakness.
• Loss of tendon reflex due to CNS reflex pathways.
• Muscle spasm or muscle spasticity.

Visual

• Optic neuritis: Diminished vision and decreased color perception.
• Diplopia: Double vision wherein the 6th cranial nerve is damaged.
• Retroorbital pain

Genitourinary

• Bladder dysfunction: Difficulty in initiating or stopping urination, urgency or frequent urination at night (nocturia).
• Sexual dysfunction: Usually common in male and they are being prescribed with Sildenafil to increase libido.
• Constipation: Patients with genitourinary symptoms are commonly given laxatives.

Psychiatric

• Depression: Very common.
• Loss of cognitive ability: Impaired function or memory or problem solving

Special Symptoms

• Uhthoff's symptoms: Heat sensitivity; exercise causes increase in body temperature and nerve conduction abnormality.
• Lhermitte symptoms: Electric shock like sensations, generated from the back and radiates to the legs.

Clinical Presentation of Multiple Sclerosis

• Most patients with MS presents with nonspecific complaints, visual problems or paresthesias.
• Optic neuritis, diplopia, retroorbital pain or blurring of vision are very common presentation.

Laboratory Tests

• MS is a diagnosis of exclusion.
• The following are tests that can be used:
  • Magnetic resonance imaging
  • Cerebrospinal fluid studies: Increased mononuclear cell count or intrathecal immunoglobulin G
  • Evoked potentials: Measures the time it takes for the nerves to respond to stimulation.
• Multiple sclerosis usually does not directly diminish life expectancy.
• Development of secondary complications e.g. pneumonia or septicemia or rapid progression of primary lesions affecting respiratory function can lead to a shorter than expected life span.

Prognostic Indicators in Multiple Sclerosis

• Favorable Prognosis:
• Age at onset: <40 years
  • Gender: Female
  • Initial Symptoms: Optic Neuritis or sensory symptoms
  • Attack frequency in early disease: Low
  • Course of disease: Relapsing/remitting
• Unfavorable Prognosis:
  • Age at onset: >40 years
  • Gender: Male
  • Initial Symptoms: Motor or cerebellar symptoms
  • Attack frequency in-early disease: High
  • Course of disease: Progressive
• Relapse and remission usually happens from 24 to 48 hours. MS usually affects ages 15-45 years old. Common in female since they have stronger T-cell response.

Treatment

• Treatment falls into three broad categories:
• Symptomatic Therapy
  • Treatment of Acute Attacks
  • Disease-Modifying Therapies (DMTs)
• Treatment decisions are based on individual patient wishes & goals

Treatment of Acute Exacerbations

• Functional ability is affected standard intervention is intravenous injection of high dose corticosteroids or may be given as PO or IV.
• If treatment with steroid is warranted, it is best to use intravenous methylprednisolone

Methylprednisolone IV

• Dose: 500 to 1000 mg/day
• Duration: Variable ~ 3 to (rarely) 10 days, depending on clinical response
• Longer durations are associated with acne and Fungal infections, mood Alteration, rarely, Gastrointestinal hemorrhage.

Disease-Modifying Therapy

• First agent proven to favorably alter the natural course of the illness
• Interferon (IFN)-1ß (Betaseron):
  • It downregulates the immune system; inhibit T Cell & B Cell; decreases chemotaxis
  • First agent proven to favorably the natural course of the illness.
  • Route: Subcutaneous
  • Dose: SC every other day; 8 million international units
  • Packaging: in partially premixed syringes; (0.3 mg in 15 prefilled blister units)
  • New Formulation: does not require refrigeration
  • Can be used with an autoinjector

Interferon ß1a (Avonex and Rebif)

• Avonex is a natural sequence glycosylated interferon produced in Chinese hamster ovary cells
  • Route: Intramuscularly (IM)
  • Dose: 30 mcg (6 million International Units)
• Rebif is made similar fashion as Avonex
  • Route: Subcutaneously (SC)
  • Dose: SC three times weekly; 22 or 44 mcg (0.5mL)

Most Common Adverse Effects Include

• Injection-site redness, swelling,
• Rarely necrosis,
• Flu-like symptoms (e.g., fever, chills, myalgias)
• Flu-like side effects; occur up to 24 hours after injection; abate within 1 to 3 months after starting the injections, but persists in some patients Agent/acetaminophen taken before and at regular intervals for 24 hours after administration may alleviate the flu-like symptoms.

Glatiramer Acetate (Copaxone) - Peptide

• Route: Subcutaneous
• Dose: daily 20-mg subcutaneous dose
• Storage: stored in the refrigerator / Can be kept at room temperature up to 1 week
• Have relatively mild adverse effect
• Frequent patient complains: Mild Pain, Pruritus at the injection site

Natalizumab (Tysabri)

• Monoclonal Antibody
• Prevents immune cells (lymphocytes) from binding into endothelium causing a decrease in CNS penetration
• Indicated as Monotherapy
• Route: Infusion
• Dose: 300 mg every 4 weeks, IV Infusion
• Storage: stored in the refrigerator
• Indicated for:
• Relapsing forms of MS to delay accumulation of physical disability Decrease number of relapses in patients who had inadequate response/intolerance to traditional MS therapies

Mitoxantrone (Novantrone) / Cladribine

• Member of the Anthracenedione family
• Decreases your immune activity
• Approved by FDA for reducing neurologic disability and frequency of clinical relapses
• Route: Intravenous infusion
• Dose: administered as a brief (5-15 minute), IV: 12 mg/m2 every 3 months

Other Potential Side Effects

• Nausea; Alopecia; Menstrual Disorder; Amenorrhea;
• Upper respiratory tract infection (URTI); Urinary Tract Infection (UTI);
• Leukopenia
• Many of the symptoms of MS do not require pharmacologic management or do not respond to it.
• The following symptoms are the ones usually managed with medications
• Gait Difficulties and Spasticity , Tremor, Bowel and Bladder Symptoms, Major Depression, Sensory Symptoms, Sexual Dysfunction, Fatigue

Gait Difficulties and Spasticity

• Gait problems can be caused by spasticity, weakness, ataxia, defective proprioception, or a combination of these factors.
• Spasticity is a condition in which certain muscles are continuously contracted that can effect normal movement
• Encountered commonly and tends to affect the legs more markedly than the arms
• Using muscle relaxants, do not decrease the tone

Baclofen (Lioresal)

• The preferred agent and usually is started in dosages of 10 mg three times daily and titrated upward to achieve the desired effect.
• Alternative agents: Tizanidine, Diazepam, Clonazepam, or Dantrolene

Cerebellar Symptoms

• Trouble with Tremor
• Treat with Propranolol, Primidone, and Isoniazid

Bowel and Bladder Symptoms

• Patients commonly complain of incontinence, urgency, frequency, and nocturia, which are indications of a hyperreflexic bladder
• A number of anticholinergic: Oxybutynin chloride (Ditropan), Tolterodine (Detrol), Propantheline, bromide, Hyoscyamine or Dicylomine hydrochloride (Bentyl)

Major Depression

• Major depression is common in patients with MS
• Patients should be monitored closely for the development of major depressive symptomatology and treated

Sensory Symptons

• Frequent
• Pain Syromes include acute or chronic,
• Carbamazepine (Tegretol) for Treatment
• Trigeminal Neuraliga

Sexual Dysfunction

• Sildenafil Citrate (Viagra), Tadalafil (Cialis), and Vardenafil (Levitra) can treat erectile dysfunction in men
• Alprostadil injection or Intraurethral for other men options

Fatigue

• Amantadine can provide releif
• Methylphenidate and Dextroamphetamine (Dexedrine) Commonly used for fatigue in MS
• Modafinil is helpful for MS related fatigue

Explore Multiple Sclerosis (MS), focusing on the autoimmune destruction of myelin sheaths and the pathological processes forming detectable plaques via MRI. Understand the increased risk at higher latitudes and the biological factors contributing to higher diagnosis rates in women. Also, learn about the direct consequences of myelin sheath damage on neuronal function and the role of T-cells.