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Multiple Sclerosis: Current Treatment and New and Emerging Therapies

Depression, General, Mental Health | November 2, 2014 | Author: The Super Pharmacist

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Multiple Sclerosis: Current Treatment and New and Emerging Therapies

Multiple sclerosis is believed to be an autoimmune disease affecting the central nervous system (CNS)—the brain, spinal cord, and optic nerves. Normally, the immune system defends the body against foreign invaders such as viruses or bacteria. An autoimmune disease is one in which the body, through its immune system, launches a defensive attack against its own tissues.

The nerves in the CNS are surrounded by a protective fatty material called myelin, which helps nerve fibres conduct electrical impulses. In MS, it is thought that the immune system attacks the myelin surrounding the nerve fibres resulting in the formation of dense, scar-like tissue called sclerosis. These scars (also known as lesions) occur in multiple places throughout the CNS. Such assaults may be linked to an unknown environmental trigger, perhaps a virus. The scar tissue affects the way electrical impulses travel along the nerve fiber, distorting and interrupting signals coming to and from the brain and spinal cord. This produces the various symptoms of MS.

Risk factors for MS

Scientists have yet to confirm whether or not geography, ethnicity, genetics and other factors contribute to the disease. MS appears to be more common in populations farther away from the equator. Although MS occurs in most ethnic groups (including African-Americans, Asians and Hispanics/Latinos), Caucasians of northern European ancestry are the majority. Evidence suggests that African-Americans may tend to have more severe problems with MS than do other ethnic groups.

Symptoms of MS

Most people experience their first symptoms of MS between the ages of 20 and 40. The initial symptom of MS is often blurred or double vision, red-green color distortion, or even blindness in one eye. Most MS patients experience muscle weakness in their extremities and difficulty with coordination and balance. These symptoms may be severe enough to impair walking or even standing. In the worst cases, MS can produce partial or complete paralysis.  Most people with MS also exhibit paresthesias, transitory abnormal sensory feelings such as numbness, prickling, or "pins and needles" sensations. 

Some may also experience pain. Speech impediments, tremors, and dizziness are other frequent complaints. Occasionally, people with MS have hearing loss. Approximately half of all people with MS experience cognitive impairments such as difficulties with concentration, attention, memory, and poor judgment, but such symptoms are usually mild and are frequently overlooked.

Depression is another common feature of MS. Patients usually experience a first neurologic event suggestive of MS known as 'Clinically Isolated Syndrome' (CIS). It lasts for at least 24 hours, with symptoms and signs indicating either a single lesion (monofocal) or more than one lesion (multifocal) within the central nervous system.

Diagnosing MS 

Imaging studies help to confirm a diagnosis of MS. The most common test done is a magnetic resonance image, or MRI. CT scans, while helpful in finding some brain injuries, are unable to reveal the changes associated with multiple sclerosis with as much detail as an MRI. MRIs can be used to image the brain and the spinal cord. An MRI can detect the distinctive lesions or scars in the central nervous system (brain, spine and optic nerve) that give multiple sclerosis its name. A spinal tap, or lumbar puncture, is done to collect a small amount of cerebrospinal fluid. Testing can be done on this fluid to confirm the presence of protein, inflammatory markers, and other substances. With the routine use of MRI, performing a spinal tap is not considered mandatory, unless there are questionable findings on the MRI or other questions to answer. Evoked potential testing (visual evoked potentials, brainstem auditory evoked potentials, and somatosensory evoked potentials) can show slowed response times in the optic nerve, the auditory nerve, the spinal cord, or the brainstem. While helpful, these tests are not specific for changes seen in multiple sclerosis.

Different Types of MS

There are 4 types of MS named based on the progression of the disease over time.

1. Relapsing-Remitting multiple sclerosis (RRMS)

This is the most common form of multiple sclerosis. About 85% of people with MS are initially diagnosed with RRMS. It is characterised by clearly defined attacks of worsening neurologic function. These attacks, also called relapses, flare-ups or exacerbations, are followed by complete recovery periods or partial recovery periods.4 RRMS is defined by attacks of inflammation (relapses) in the CNS. People with RRMS tend to have more brain lesions — also called plaques or scars — on brain MRI scans, and these lesions contain more inflammatory cells. RRMS is diagnosed earlier than the progressive disease courses:

  • Most people with RRMS are diagnosed in their 20s and 30s (although it can occur in childhood or later adulthood).
  • The transition to SPMS generally occurs in people who have been living with RRMS for at least 10 years.
  • In RRMS, women are affected two to three times as often as men.

The most common symptoms reported in RRMS include episodic bouts of fatigue, numbness, vision problems, spasticity or stiffness, bowel and bladder problems, and problems with cognition (learning and memory or information processing). People with progressive forms of MS are more likely to experience gradually worsening problems with walking and mobility.

2. Secondary-Progressive multiple sclerosis (SPMS)

The name for this course comes from the fact that it follows after the relapsing-remitting course. Most people who are initially diagnosed with RRMS will eventually transition to SPMS, which means that the disease will begin to progress more steadily (although not necessarily more quickly), with or without the occurrence of relapses and remissions.5 SPMS occurs in people who initially had a relapsing-remitting disease course. In other words, SPMS occurs as a second phase of the disease for many individuals. In SPMS, people may or may not continue to experience relapses caused by inflammation; the disease gradually changes from the inflammatory process seen in RRMS to a more steadily progressive phase characterised by nerve damage or loss.

3. Primary-Progressive multiple sclerosis (PPMS)

This type of MS is not very common, occurring in about 10% of people with MS. PPMS is characterised by steadily worsening neurologic function from the beginning. Although the rate of progression may vary over time with occasional plateaus and temporary, minor improvements, there are no distinct relapses or remissions.4 People with PPMS, as a group, differ in several ways from people with relapsing forms of MS. Relapsing forms of MS are defined by inflammatory attacks on myelin. PPMS involves much less inflammation of the type seen in relapsing MS. As a result, people with PPMS tend to have fewer brain lesions (also called plaques) than people with relapsing MS and the lesions tend to contain fewer inflammatory cells.  People with PPMS also tend to have more lesions in the spinal cord than in the brain. Together, these differences make PPMS more difficult to diagnose and treat than relapsing forms of MS. The average age of onset is approximately 10 years later in PPMS than in relapsing MS. People with PPMS tend to experience more problems with walking and have more difficulty remaining in the workforce.

4. Progressive-Relapsing multiple sclerosis (PRMS)

Progressive-relapsing multiple sclerosis (PRMS) is the least common of the four disease courses, occurring in approximately five percent of people with MS. Like those with primary-progressive MS (PPMS), people with PRMS experience steadily worsening neurologic function — disease progression — from the very beginning, in addition to occasional relapses like those experienced by people with relapsing-remitting MS.

Treating MS

During an acute exacerbation, steroids given through an IV are commonly prescribed, and often help patients recover more rapidly. If a patient cannot receive steroids, plasma exchange can be used.

Once a diagnosis of multiple sclerosis has been confirmed, disease-modifying therapy is often recommended. This therapy can decrease the number of exacerbations that a patient experiences; often, the exacerbation may not be as severe when a disease-modifying therapy has been used.

Ten medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, including RRMS, SPMS, and PRMS.

All have been shown to reduce the number of relapses and the number of new lesions (plaques or scars on MRI), and they may slow disease progression.

 

Most MS experts recommend that people consider starting one of these medications as soon as the diagnosis of RRMS has been confirmed.

Five injectable medications (Avonex, Betaseron, Copaxone, Extavia and Rebif), three oral medications (Gilenya, Aubagio and Tecfidera), and one infused medication (Tysabri) are available as first-line treatment options for RRMS. Novantrone, the other infused medication, is approved for people with worsening RRMS — in other words, those whose RRMS is progressing in spite of treatment with one of the first-line medications. Therefore, a person who has been on one of the interferon medications during the initial RRMS phase of the disease will likely continue on it unless his or her physician feels that it is no longer adequately controlling disease activity. At that time, the physician will likely recommend changing to Novantrone (mitoxantrone), a chemotherapeutic agent, the only medication that has been approved by the FDA specifically for SPMS, as well as worsening RRMS. The interferon beta medications (Avonex, Betaseron, Rebif and Tysabri) are approved by the FDA for use in relapsing forms of MS, which includes PRMS. If the interferon medication does not adequately control disease activity in PRMS, changing to Novantrone® is likely to be recommended. At the present time, there are no medications approved by the FDA for the treatment of PPMS. Because all of the approved disease-modifying therapies work primarily by reducing inflammation in the CNS, they do not work well in a disease course that is characterised by nerve degeneration rather than inflammation.

Useful Therapies for MS

While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some patients.  Although improvement of optic symptoms usually occurs even without treatment, a short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by treatment with oral steroids is sometimes used. Spasticity, which can occur either as a sustained stiffness caused by increased muscle tone or as spasms that come and go, is usually treated with muscle relaxants and tranquilizers such as baclofen, tizanidine, diazepam, clonazepam, and dantrolene

Useful Therapies for MSPhysical therapy and exercise can help preserve remaining function, and patients may find that various aids -- such as foot braces, canes, and walkers -- can help them remain independent and mobile.

Avoiding excessive activity and avoiding heat are probably the most important measures patients can take to counter physiological fatigue. If psychological symptoms of fatigue such as depression or apathy are evident, antidepressant medications may help.  Other drugs that may reduce fatigue in some, but not all, patients include amantadine (Symmetrel) and pemoline (Cylert).

The FDA has also approved dalfampridine (Ampyra) (10mg orally twice daily) to improve walking in individuals with MS. The exact mechanism of action for the effect of dalfampridine on walking is unknown. It is hypothesized that improved transmission of neural impulses occurs in multiple impaired axons, leading to better modulation of important complex motor acts such as walking.

Clinical trials with sustained-release 4-aminopyridine (Fampridine) have also shown improvement in walking speed and muscle strength in the lower extremities of MS patients. This is thought to be related to improved conduction of action potentials in demyelinated nerve fibres.

Dextromethorphan/quinidine (Nuedexta) is indicated for the treatment of pseudobulbar affect, which is defined by involuntary, sudden, and frequent episodes of laughing and/or crying that are generally out of proportion or inappropriate to the situation.

OnabotulinumtoxinA (Botox) (200 units/30 mL) is indicated to treat urinary incontinence due to bladder muscle overactivity in MS.7 The recommended total dose is 200 units of onabotulinumtoxinA per treatment, delivered as 1mL (~6.7 units) injections across 30 sites into the bladder.

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References

Frankel D, James H. Living With Multiple Sclerosis. New York, NY: National Multiple Sclerosis Society; 2011.

Multiple Sclerosis. National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm/Updated Mar 2014. Accessed 26 Oct 2014.

Kappos L, Polman CH. Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006; 67: 1242-1249.

Hooper K. Managing Progressive MS. New York, NY: National Multiple Sclerosis Society; 2011.

Types of MS. National Multiple Sclerosis Society. http://www.nationalmssociety.org/What-is-MS/Types-of-MS/ (n.d.) Accessed 26 Oct 2014.

Castro-Borrero W, Graves D, Frohman TC, et al. Current and Emerging Therapies in Multiple Sclerosis: A Systematic Review. Ther Adv Neurol Disorders. 2012;5(4):205-220.

The Multiple Sclerosis Emerging Therapies Collaborative. http://ms-coalition.org/emergingtherapies/   Updated 16 Sept 2014. Accessed 26 Oct 2014.

Summary of Research Progress Reported at the World’s Largest MS Meeting. National Multiple Sclerosis Society.http://www.nationalmssociety.org/About-the-Society/News/Summary-of-Research-Progress-Reported-at-the-World/Published 14 Sept 2014. Accessed 26 Oct 2014.

Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. The Lancet. 2012; 380 (9856): 1819-1828.

Boye Jensen H, Ravnborgm M, Dalgas U, Stenager E. 4-Aminopyridine for Symptomatic Treatment of Multiple Sclerosis: A Systematic Review. Ther Adv Neurol Disorders. 2014; 7(2):97-113.

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