Multiple Sclerosis

Multiple sclerosis (MS) is a discreet and demyelinating disease of the central nervous system.  It causes a variety or combination of symptoms of motor sensory and coordination impairments.  MS is the most commonly diagnosed neurologic disorder of young to middle aged adults.  It has a very unpredictable course from occasional mild relapses over an entire lifetime to a rapid progression, to complete disability in a few months.

MS is the third leading cause of significant disability, after trauma and arthritis, in the 20-50 age range. There are at least 8,000 new cases of MS diagnosed in the United States each year.

Multiple sclerosis is characterized by focal inflammatory lesions that are scattered throughout the white matter of the central nervous system (CNS).  These lesions or plaques have been described as scars that occur in the brain or the spinal cord region.  These lesions or plaques can recur enlarged or develop new inflammatory lesions alongside old gliotic lesions.  The initial discreet points of white matter inflammation, enlarged by outward extension and coalescence - a typical pattern of multiple sclerosis lesions, can be readily visualized on magnetic resonance imaging.  In active lesions, marked massive edema due to damage in the blood-brain barrier can accompany a marked inflammatory response.

Lymphocytes that are immunocompetent are then presumed to leave the circulation and enter the CNS in response to an antigen accumulation.  Lamellae are then sequentially stripped from axons and ingested by activated macrophages (the body’s own cells that attack foreign substances).  Ultimately, the axons are stripped and left bare, but they may remain relatively well preserved even in older chronic lesions.  Older lesions are progressively less inflammatory as oligodendrocytes are destroyed and astrocytes proliferate.  These are different type of nerve cells.  Astrocytes lay down glenoid fibers and bare axons become invested by astrocytic processes.  These lesions assume a firm sclerotic “texture”.

Neurologic disorders are the direct result from either the complete partial or intermittent block of the ability of the nerve to conduct through demyelinated areas, such as in demyelinated peripheral neuropathies.  If a nerve impulse, upon reaching a demyelinated area, is unable to continue by normal conduction, it presents a buildup of electrical potentials, which normally occur along nerve fibers. A demyelinated region also cannot conduct current nerve impluses sequentially, because the internodes act on the membrane, lacking the necessary sodium potassium channels.  Additionally, demyelination may relate to increased nerve excitability, which can result in sustained paraesthesias (numbness and tingling sensation) or dysesthesias (abnormal sensation).  The inability to sustain high frequency transmission in the neurofibrils, results in muscle weakness and easy fatigability.  In addition, cross activation of the nerve segments may produce paroxysmal (intermittent symptoms).

 There have been many possible theories and factors indicated in the development of multiple sclerosis, and many different types of agents have been tried in addressing treatment.  Despite all the research and development of different types of medications (which often have significant side effects and can be extremely expensive), no one particular agent has been found to be significantly effective for all patients.  In some forms, the demyelinated central nervous system nerve may regain some nerve conduction, but it remains extremely slow, less than five percent of normal.  This may occur by transmission through sodium potassium channels, which allow a sequential conduction similar to demyelinated fibers.  When conduction barely occurs as the myelin becomes very thin, even the stressors or environmental insults can produce a complete block.  The environmental factors that can temporarily block a marginally or barely functioning nerve and cause a brief aggravation of the neurological symptoms, include: relatively mild elevation of core body temperature (such as getting into a hot bath tub or hot tub), edema, emotional stress, hypoglycemia and certain types of chemical exposures.

Although the cause of multiple sclerosis is unknown, subsets or characteristics of people who appear to be at higher risk for the evolvement of multiple sclerosis have been identified, and include:

1) Residence in a temperate climate before age 15 years

2) Social economic level, higher > lower, age; onset 20-40

3) Racial background, white > than black > than Asian

4) Family history of multiple sclerosis, siblings > than parents > than others

5) Sex, females predominant over males 2 to 1

There may be multifactorial etiologies or a cascade of events that occurred after being exposed to common environmental agents that trigger the immune system in a genetically susceptible person to develop multiple sclerosis.

There may be an environmental agent that is present in temperate climates and in economically developing countries that are triggering factors, but have yet to be clearly identified.  Epidemics in isolated populations are certainly compatible with the series spread of infectious etiological agent; however, this has yet to be identified and may indeed be viral in nature.

Susceptibility to multiple sclerosis is definitely under some type of genetic transmission, as family risk is approximately 10 times greater than the general population.  Increased risk is associated with certain HOA antigens and racial backgrounds, yet the disease itself is not inherited, as monozygotic twins do not show a high rate of developing multiple sclerosis.  Therefore, it appears exposure to some environmental agent, coupled with a genetic predisposition, leads to the development of symptoms.

A theory that a virally-induced immunopathologic state occurs, has led to treatment with immunosuppressive agents, despite identifying a specific agent as the culprit.  Important T-lymphocytes and macrophage with lesions appear to be involved in the primary disease process.  It has been demonstrated that using low levels of Interferon leads to a poor ability to protect ourselves against enviro-infected cells, and thus immunosuppressive therapies have been used with success in certain patients.

Signs and Symptoms of MS

The signs and symptoms of multiple sclerosis (MS) depends upon the location of the lesions or plaques, whether it is primarily localized in the brain or spinal cord, the size, the intensity and the inflammatory reaction of the lesion or plaque.  These lesions or plaques follow specific nerve tracts.  A few involve gray matter, but none show predilection for certain CNS white matter regions, resulting in typical impairments.

1) Optic nerves (optic neuritis)

2) Cerebrum (especially periventricular areas or the frontal lobes affecting cognitive behavioral changes)

3) Spinal cord, especially the cervical region resulting in weakness, spasticity, numbness, and bowel, bladder and sexual dysfunction

4) The brain stem leading to vertigo nystagmus, internuclear ophthalmoplegia (dysphagia) and dysarthria

5) The cerebellum and basal ganglia, resulting in ataxia (unsteadiness of gait and tremor)

Common signs of multiple sclerosis and symptoms in young adults are trigeminal neuralgia and Lhermitte’s sign - which is a transient electric-like sensation radiating down the spine following flexion of the neck.  This is classic, but not pathognomonic for multiple sclerosis.

Infrequent symptoms can include epilepsy, aphasia (inability to speak), paroxysmal attacks of brief repetitive sensory motor patterns, impaired hearing or taste, movement disorders, autonomic disturbances (sweating and cardiovascular symptoms).

Other common signs and symptoms are incoordination, weakness, spasticity, numbness, paraesthesias, pain frequency and urgency of the bladder or incontinence, constipation, sexual dysfunction such as impaired erections, decreased genital sensation, decreased libido and decreased vaginal sensation.

The overall mood and affect of the brain can be affected to varying extents including memory problems, attention deficits, difficulty concentrating, difficulty problem solving, depression, emotional lability and even oddly enough euphoria. Easy fatigability and heat intolerance are classic signs as well.

There are four types of patterns and characteristics of multiple sclerosis.

These are:

1) Benign – Mild symptoms, full remissions, little or no cumulative disability.  Occurs in 20-30 percent of patients.

2) Relapsing-remitting

A) This results in nearly full remissions and long periods of stability.  It occurs in 40-60 percent of MS patients.  One third of relapsing-remitting patients have this type.

B) Incomplete remissions evolving into chronic progressive multiple sclerosis.  This occurs in 2/3 of relapsing-remitting patients.

3) Chronic progressive – An insidious onset type of multiple sclerosis with progression despite treatment.  Significant disability occurs within two to 10 years.  This occurs in 20-30 percent of multiple sclerosis patients.

4) Malignant – This form of MS is characterized by severe rapid progression.  Death often occurs within weeks to months due to critical location of plaques or malignant disease activity.  This occurs in less than five percent of all multiple sclerosis patients.

The initial course for 85 percent of MS patients is relapsing-remitting progression from onset and is seen more commonly in older patients.  Although most people with a remitting pattern eventually develop progressive disease as relapses tend to last longer and resolve less completely.  A cumulative effect of impairment occurs and is very dependent on the type and rate of deterioration.  Based upon the location and the progression, a poor prognosis is more accurately predicted than a favorable one.

Life expectancy from onset is normal in 85 percent of patients diagnosed with multiple sclerosis.  Death is less commonly associated directly to the multiple sclerosis lesions causing events such as respiratory failure or intractable seizures, rather it is due to secondary complications of pneumonia, renal involvement to decubitus ulcers, septicemia, depression.  Also, complications from medications and significant side effects can occur and lead to associated morbidity and hospitalization.

Diagnosis of MS

The diagnosis of multiple sclerosis (MS) must be confirmed and demonstrated that white matter damage has occurred in multiple areas on more than one occasion in time and space.  No single symptom, sign or laboratory abnormality is specific to multiple sclerosis.  Thus a number of schemes to define diagnostic categories have been formulated, such as laboratory-supported evidence demonstrating CSF or super spinal fluid (immunological abnormalities), paraclinical evidence identifying multiple sites of CMS damage (such as on magnetic resonance imaging [MRI] scan), cerebral spinal fluid analysis revealing increased protein cells relative increase in IgG, oligoclonal bands (this is the greatest sensitivity), and electrodiagnostic test (such as visual evoked potential, brain stem auditory evoked potential, evoked potential blink reflex.  This is demonstrated by a prolonged latency in the conduction of the nerve.)

Imaging studies such as magnetic resonance imaging of the spinal cord and brain, or computed tomography (CT) with contrast, must both show multiple lesions, and a CT scan with contrast will show enhancing lesions.

Multiple sclerosis is not the only illness that can present with multiple relapsing or progressive symptoms.  The other possible etiologies or differential diagnosis include: central nervous system; primary or metastatic, neoplasms such as cancers; vascular disorders; connective tissue disorders; chronic infections; and cervical spondylopathy (significant spinal compression) in the cervical spinal region.  It is obvious with so many other symptoms, there are multiple approaches in trying to treat the course of multiple sclerosis.

Theoretical cause approaches with a proposed intervention:

1) Disorder immune regulation or autoimmunity – The proposed intervention would be an antigen immune block suppression drug, such as Cyclopamine, Cyclophosphamide, Azathioprine, Copolymer I, Cyclosporine A, monoclonal antibodies, total lymphoid irradiation.

2) Immune Complex or demyelinated serum factors – The proposed treatment intervention would be to remove the offending agent by plasmapheresis.

3) Persistent virus causing direct damage or immune dysregulation – The proposed intervention would be antiviral or stimulation of natural killer cells of our body and the treatment would be selected Interferon therapy.

Disease Modifying Agents

There are new agents proposed as disease modifying agents.  In 1996, the drug Copaxone became available.  It is an agent that decreases activity of the immune system like Interferon, but has less of the Interferon-based side effects.  Copaxone is more useful for relapsing-remitting MS.  It is injected daily with a small insulin-type needle for 6-9 months for the full effect to occur, and long term it decreases 80 percent of relapses.  It can cause a rare acute panic attack.  Side effects are usually limited to local lipoatrophy at the injection site, which can be common.  Copaxone is very expensive -  a 30-day supply can cost $23,000-$34,000 per year.

Other disease modifying agents include:

1) Novantrone functions by slowing the progression of secondary progressive MS.  It is an injectible solution.  It may be given in 8-12 doses over a two to three year period.  Side effects can include: damage to the heart, secondary acute leukemia, and various other serious side effects.  Novantrone is less expensive than Copaxone - its approximate cost is $5,000 per year.

2) Cellicept is a more recent immunosuppressant agent, generally given orally.

The choice of anti-lymphocyte antibodies for use is controversial.  Currently, only two are approved by the FDA for use in transplantation in renal and cardiac transplant.

3) Polygonal antibody (ATGM and monoclonal antibody OKT III)

It requires a central line for administration.  Both are extremely expensive and the potential is great for significant side effects, which present as a viral infection, especially CMV (Cytomegalovirus) and EBV (Epstein Barr virus).  ATGM OKT III can be used with the peripheral vein.  Patients are usually started on Methylprednisolone IV and converted to an oral Prednisone.

4) Imuran was then started, but many transplant units are now using oral Cellicept instead.

5) Ampyra (Dalfampridine) is indicated as treatment to improve walking, specifically walking speed, in patients with multiple sclerosis.  The mechanism of action is thought to involve a calcium channel blocker, but the exact mechanism is unknown.  It is similar to a previous compound for 4-aminopyridine.  It is the most recently approved drug by the FDA (2009) and patients are usually started on 10 mg twice per day, 12 hours apart.  Side effects include urinary tract infection, insomnia, dizziness, headache, nausea, dysthymia, back pain, balance disorders, MS relapse, paraesthesias, constipation, dyspepsia, nasal laryngitis, and pharyngolaryngeal pain.  There are no drug interactions, so it may be used in conjunction with other agents commonly used to treat multiple sclerosis.  Treatment is directly used for walking problems, which are frequently lower extremity symptoms which occur frequently and can have a great impact on the patient’s functional ability. So, this can be a very useful agent.  The only contraindication is with moderate to severe renal impairment or in patients who have high risk for seizures or a history of seizures.  Ampyra is expensive – approximately $1000 per month. 

6) Corticosteroids are often used intravenously for exacerbations.

Symptom Specific Management

1.  Spasticity

A) Baclofen

B) Diazepam

C) Gantralin

D) Clonazepam

2. Cerebral incoordination

A) Isoniazid

B) Pyridoxine

C) Propanol

3.  Dysesthesias (painful sensory disturbance)

A) Carbamazepine or Tegretol

B) Tricyclotonic depressants

C) Baclofen 5-20 mg TID or QID

D) Phenytoin (Dilantin) generally used 300 mg QD

4. Pseudobulbar palsy (paroxysmal involuntary facial expression)

A) Amitriptyline or Elavil – depression

B) Tricyclic antidepressants – SSRI or selective Serotonin uptake inhibitors

5.  Bladder hyperactivity

A) Propantheline

B) Oxybutynin

C) Imipramine

6) Fatigue

A) Amantadine

7) Vertigo/Nausea

A) Meclizine

B) Scopolamine skin patches

Physical Medicine and Rehabilitation specialists, or physiatrists, are often important members of the team in treating multiple sclerosis.  Physiatrists are trained to look at the entire person and not just focus on one symptom or symptoms management.  They also focus on functional levels and how to improve overall quality of life, which is an essential component in treating most patients with chronic disease processes.  For athletes or people suffering with an orthopedic injury, maintaining the highest level of function in essence equates to having a good quality of life.  Focusing on the individual and all the issues that play a role in their health are often missed components in chronic neurological disease processes.

As previously stated, stress exacerbates multiple sclerosis.  MS stress management techniques incorporated into one’s lifestyle can help manage symptoms.  Additionally, stress exacerbates cortisol levels, which, if chronically elevated, tend to have an effect on other hormones of the body, specifically testosterone, growth hormone and DHEA sulfate.  Patients with multiple sclerosis are often managed with chronic corticosteroid therapy, which provide doses higher than the normal cortisol level supplied by one's adrenal gland.  Extreme doses of corticosteroid, especially with IV corticosteroid therapy, have a much greater impact on the other endocrine hormones by suppressing the pituitary access, so it is frequently noted that patients will have greatly diminished testosterone and growth hormone levels as a result.

There have been numerous studies addressing growth hormone replacement, which have shown a beneficial effect.  One Harvard study noted that 89 percent of study-patients felt improvement, seven percent felt no change in their condition and four percent reacted badly.  It has been noted, that the administration of growth hormones to patients on immunosuppressant treatment, that these two treatments may interact in a negative fashion.  In these situations, if growth hormone is being considered, it is recommended that other forms of management of multiple sclerosis be entertained first.  Growth hormone improves weakness and fatigue, which are two important components of not only debility, but are frequently noted symptoms of multiple sclerosis.  The addition of testosterone, if the testosterone level is low, will also help with muscle weakness.

Thyroid function tests should be performed, as the thyroid gland is an important regulator in normal metabolism.  Thyroid dysfunction can occur as a result of side effects of multiple medications used in the treatment of multiple sclerosis.  Impaired metabolism results in weight gain.  Corticosteroids are also noted for causing excessive weight gain with increasing dosages being administered.  Additionally, some experts believe corticosteroids (in animal studies) significantly reduce the proliferation of oligodendrocytes, which are nerve precursors found through the white/gray matter of the brain.   Some specialists do not understand the role of using growth hormone and testosterone, since they do not have a background in endocrinology or in hormone replacement therapy, and therefore will discourage using these therapies.

Most patients with chronic illness who are treated for diminished testosterone or growth hormone levels will note almost immediate improvement in endurance and lean muscle mass.  An increase in endurance also helps to improve the immune system.  All of these are beneficial in multiple sclerosis.

A study done by Bickford et al, and Shytle has demonstrated that nutrients or nutraceuticals can have a greater positive effect in the human body than what a pharmacologic induced stem cell enhancing-agent (Blastocyst-Colony Stimulating Factor) can have.  This phenomenon of using natural compounds or nutraceuticals is being incorporated into the treatment of many chronic pain syndromes and in chronic disease states with great success.

Omega 3 fish oils have been found to have a beneficial anti-inflammatory effect.  Omega 3 has been shown to have many benefits on many disease states, including arthritis, coronary artery disease and neurological disorders.  The pharmaceutical industry has actually joined the nutraceutical bandwagon, producing their own version, since it is currently the number one nutraceutical being consumed.  Most patients are ill-informed about Omega 3 fish oil – the proper type to take and the proper dosage to take.  When considering nutraceutical administration, patients should consult with a physician skilled in understanding not only the medical disorders and medications that the patient is taking, but also their overall health picture, including hormones of the endocrine system.

There are preparations that help with cognitive impairment of Alzheimer’s, which can be used in Parkinson’s and Multiple Sclerosis as well.  COQ10, Ginkgo Biloba, Phosphatidylserine antioxidants, Vitamin C, A and E, and several others have been recommended for management of chronic neurological disorders.

It is rare to find a physician who understands the medical condition, the rehabilitation and quality of life issues, in conjunction with managing specific symptoms, managing the disease process, the use of hormone replacement therapy, in addition to knowing which nutraceuticals would have a concomitant benefit.  In other words, it is rare to find a physician who understands how to put all of the tools to work.

If you have the diagnosis of multiple sclerosis and you feel your symptoms are being inadequately controlled, please feel free to contact Dr. Dennis Lox, a rehabilitation and regenerative medicine specialist, who has extensive knowledge in all of these areas.