Coastal Neurological
Medical Group, Inc.

CURRENT CONCEPTS IN MULTIPLE SCLEROSIS;
DIAGNOSIS AND TREATMENT FORMAT

Dee E. Silver, M.D.
Scripps Memorial Hospital, La Jolla
Medical Director, Parkinson’s disease Association, San Diego

This paper will discuss the following areas:
1. Epidemiology.
2. Signs and symptoms of MS.
3. Pathophysiology.
4. Treatment format.

Under treatment, we will discuss the foundation drug or drugs from the pivotal trials, which are considered immunomodulators. We will also discuss second tier or second level drugs, most of which are immunosuppressors, except for fingolimod, which is considered an immunomodulator. We will next outline a rescue algorithm. Future drugs will also be discussed.

The epidemiology of multiple sclerosis is fairly well established. There are about 500,000 people in the United States that have multiple sclerosis. There are probably, three million people worldwide that have multiple sclerosis (MS). About two-thirds of the patients with MS have their onset of symptoms between the ages 20 and 40. The peak is somewhere between 24 and 25 years of age. Women are twice as likely to get MS as men, but in the later onset, the men and women incidence is almost the same. MS is more common among Caucasian, particularly those of Northern European descent. It also is more common in northern latitude, most notably in Europe and United States.

The natural history of relapsing MS is noted fairly characteristically in relapsing remitting MS. In the early stages, the patient will have a symptom occur and then they will have an intermittent remission between episodes of acute worsening of a neurological sign or symptom. This is followed by a variable degree of recovery with a stable course between attacks. To be a relapse, the symptoms have to last longer than 24 hours. The MRI scan may show intermittent disease activity even if there is an absence of clinical exacerbation. It is said that there are five silent MS lesions for every one exacerbation. The majority of people with relapsing MS will develop secondary progressive MS, which is a state were the patient has \ accumulating neurological deficits and is characterized by gradual progression of disability with and without occasional relapses. There may be minor remission and plateaus that occur. Studies show that the average MS patient will develop secondary progressive MS somewhere between 11 and 19 years after the onset of the first symptom.

There are four types of MS; relapsing remitting MS, which has relapses and remission and later may be associated with some neurological deficits. Secondary progressive MS starts with relapsing remitting MS, but then later acquires a fairly gradual progressive accumulation of neurological deficit. Progressive relapsing MS is a progressive clinical picture of neurological deficits with periods of worsening and slight improvement. Primary progressive MS, which is about 10% of MS cases, is a gradual accumulation of progressive neurological deterioration without evidence of relapses or remission. Early in the 1980s, the Poser criteria was established for the diagnosis of MS. This criteria stated that the patient had to have two attacks and clinical evidence of two separate lesions. The McDonald criteria was first established in 2001 revised in 2005 and 2010. This criteria incorporated MRI findings and specific lesions to help establish the diagnosis and focus on neurological history and exam as well as laboratory and MRI findings.

Over time, the diagnostic criteria has changed with the evolution and increased sensitivity of the MRI. At the present time, for MRI diagnosis, it is considered any two lesions with any new lesion.

Radiological isolated syndrome is a diagnosis where the patient has no symptoms or signs. An MRI is done in these cases, usually, in the emergency room or in the office, for trauma, headaches, or other nonspecific signs and symptoms. The MRI is considered radiological isolated syndrome if it shows any two lesions in specific areas and any new lesion or multiple characteristic lesions.

Clinically isolated syndrome (CIS) is a patient’s first neurological episode, one event that may fit with a diagnosis of MS and the MRI findings are abnormal in the appropriate area. Again, stating any two and any new.

The symptoms that are seen in MS can be many and are very heterogeneous. There can be associated problems with walking, gait, coordination, balance, or emotional changes. Depression, dizziness, vertigo, fatigue, pain, and sexual dysfunction are also seen as symptoms. Changes in cognitive function, visual problems especially optic neuritis, numbness, bowel and bladder dysfunction, and spasticity are also symptoms of MS.

A case that exemplifies MS is demonstrated in a 21-year-old female who had an episode of optic neuritis in the left eye. The history stated that she had an episode of numbness in her right leg a year ago that lasted three weeks. It was noted she had increased reflexes in the left arm. No treatment was given for the numbness, but when she was diagnosed at this time with optic neuritis, she was given three days of methylprednisolone. The MRI of the brain with and without contrast showed multiple lesions, enhancing lesion and T2 lesions that was scattered throughout the hemispheres. After steroids, the symptoms resolved, but 10 months later, she developed vertigo, right facial numbness, tingling, and unsteady gait and an MRI revealed a new pontine lesion, but a C-spine MRI was normal and the patient was started on an interferon beta-1a. Nine months later, the patient experienced gait difficulty in her right lower extremity and possible paraparesis and the MRI of the brain showed two new non-enhancing right parietal subcortical lesions and the MRI of the spinal cord showed a cervical spine abnormality at C4 with gadolinium enhancing and it was in the center of the cord without any evidence of edema. This patient had MS and was switched to another immunomodulator. These patients who have progressive acquired deficits may show significant cerebral atrophy over a number of years. Even with early MRI lesions and signs and symptoms, they will develop increasing cerebral atrophy (cortical and enlarged ventricles).

The natural history of MS can be seen in a preclinical state, relapsing remitting state, and then secondary progressive. Early on and before symptoms, there are probably documented MRI changes that are consistent with MS. As the disease progresses and the patients have the first clinical symptoms, the MRI lesions accumulate and the patient’s MRI may show T2 enhancing lesions and black holes, which are evidence of axonal loss. During the relapsing-remitting state, the patient gradually has more frequent MRI lesions for the first two years and then develops secondary progressive disease with accumulation of neurological deficits and advancing scores on the EDSS (Expanded disability status scale). There was good evidence that the percentage of patients that sustained a relapse will have a significant increase in their EDSS over the next number of months. Initially, about 25% will have an increase of 1 point and 50% will have an increase of 0.5 on the EDSS. At two to three months, the percentage is about the same as it is at greater than three months.

Many trials have been done to evaluate clinically isolated syndrome (CIS). Some of these trials have been CHAMPS (interferon beta-1a), the Benefit trial (Betaseron) and the Precise trial (Copaxone). All of these double-blind placebo-controlled trials that were randomized showed that the time to clinically definite MS is significantly delayed. In the Benefit trial, there was 37% relative risk reduction over five years. Those patients who were initially on Betaseron did much better than those who were on initially placebo and then converted to Betaseron. 51% of the patients who had the delayed use of Betaseron developed clinically definite MS at three years, whereas 37% of the patients who were always on Betaseron developed clinically definite MS.

The time to confirmed disease progression was delayed in patients who got immediate Betaseron as compared to those who got initial placebo and then had delayed use of Betaseron. At three years, the percentage of patients on immediate Betaseron that had confirmed disease progression was 16% and as compared to those with delayed Betaseron, it was 24%. At five years, there was still a difference, but it was not statistically significant. The P value at three years was a P = 0.022 whereas the P value at five years for the difference in P = 0.177. Hence, the Benefit trial, which was a five-year trial, delayed the risk of clinically definite MS and delayed progression of the disease. The study showed a sustained improvement in cognitive function over five years. It was also noted that neutralizing antibodies (Nab) had no effects on clinical outcome (time to clinically definite MS and annualize relapse rate).

The Precise trial used glatiramer acetate injection (Copaxone) and showed that Copaxone significantly delayed the time to second clinical event by 45%. New T2 lesions were also significantly reduced in patients who received Copaxone as compared to placebo.

MRI abnormalities in MS are described with specific lesions. T2 lesions indicate inflammation and edema, demyelination and/or gliosis, and axonal loss. T1 non-enhanced lesions indicate demyelinating and/or gliosis, which are chronic black holes. These black holes indicate axonal loss. T1 enhanced lesions are considered to be predominantly acute inflammatory lesions and indicate acute active lesions.

In the optic neuritis treatment trial carried out over five years, the MRI predicted the development of clinically definite MS. If there were no lesions in five years, only 16% of the patients had clinically definite MS. If they had one to two lesions, 37% developed clinically definite MS and if there are greater than three lesions, 51% of the patients developed clinically definite MS. It has also been shown that MRI lesions correlate with disease progression. In a study, that documented MRI in patients with greater than 10 lesions and less than 10 lesions, the patients who had greater than 10 lesions had a significant higher percentage of patients with an EDSS greater than 3 at 10 years, 75% to 15% (greater than 10 lesions versus less than 10 lesions). In patients who had an EDSS greater than 6 after 10 years, 35% had greater than 10 lesions and 10% had less than 10 lesions indicating, again, patients that had more lesions were more likely who have had higher EDSS scores.

Other studies have shown that early relapses affect long-term disability. This study was done by Dr. Weinshenker in 1989. It showed the patients that had greater than five relapses in two years had much greater incidence of disability. Patients who had three to four attacks in three years were in the intermediate group for disability. Those that only had zero to one attacks in two years had the lowest disability level.

MS is an autoimmune disease where the immune system gets confused and attacks healthy tissue. In this case, a lymphocyte or T-cell travels to the CNS and attack the myelin and damages the myelin and also later the axon is damaged. These T-cells are considered TH-1 cells which are pro-inflammatory. TH-2 cells are considered anti-inflammatory.

The pathology of MS is a continuous ongoing process and in many cases it will lead to permanent disability. The inflammatory activity occurs early at the onset of MS and often silently. There is ongoing inflammatory injury and demyelination and often irreversible axonal damage. Even though there are periods of clinical remission, it is thought that there is ongoing disease activity. Axonal transection is seen in pathological specimens in active and chronic lesion in early cases and in late cases.

Our immune system is based upon white cells that are seen in lymph nodes, thymus, bone marrow, and spleen and these white cells normally protect us from inflammation, infection, and other inflammatory processes. The T-cells, which are lymphocytes, are constantly circulating.

The pathophysiology of MS involves a number of cells. These are pro-inflammatory immune cells that get into the brain by breaking through the blood brain barrier. They release pro-inflammatory cytokines. There are other T-cells that are undesignated and later attached to an antigen-presenting cell and then become pro-inflammatory immune cell or anti-inflammatory T-cells.

The mechanism of action of glatiramer acetate is thought to be a process where there is an induction in the T cell types that give anti-inflammatory immune cells. From there, there are anti-inflammatory cytokines and possible other substances that are released. It is thought this may diminish or prevent nerve damage and reduce demyelination. The glatiramer acetate is thought to present itself to the antigen-presenting cells and hence has some action on a T-cell which becomes a Th2 cell or anti-inflammatory. These Th2 cells migrate through the blood-brain barrier and reduce the cytokines or produce anti-inflammatory cytokines or other substances. This process is called bystander suppression.

The interferons like glatiramer acetate are considered to be immunomodulators or act through immunomodulation. The interferon is thought to reduce proinflammatory cytokines levels and reduce the amount of lymphocytes that go through the blood-brain barrier. Hence, reducing the number of proinflammatory immune cells that are available to attack the myelin or axon.

Natalizumab or Tysabri has a mechanism where there is reduction in cell trafficking across the blood brain barrier. It inhibits the alpha 4 mediated adhesion molecule 1, by which the lymphocytes or T-cells are attached to a vascular cell. This significantly reduces the number of proinflammatory cells that pass the blood brain barrier. It also reduces a number of cells that may be protective to some infection in the CNS.

Fingolimod (Gilenya) prevents lymphocytes from leaving the lymph nodes in other areas and sequesters them in those regions. This reduces the number of lymphocytes that entered the blood stream and the brain. It is thought that Fingolimod modulates sphingosine-1-phosphate receptor on lymphocytes. There are also many other organs that have these sphingosine-1-phosphate receptors such as the heart and the lung. Fingolimod is considered by the FDA as an immunomodulator like the interferons and glatiramer acetate.

Oral Cladribine is thought to be cytotoxic to proinflammatory immune cells. It is thought that this drug crosses the immune cell membrane and cumulates inside of the cell and inhibits DNA synthesis, repair and hence reduces a number of blood cells that may bring about demyelination and axonal loss in the brain. It was first used in hairy cell leukemia.

Clinical trials on some of the first Tier 1 drugs started in the late 1980s and Betaseron was released in 1995. Betaseron is an every other day subcutaneous injection and is an interferon 1b. Avonex, the interferon 1a, which is an intramuscular injection once a week, was released second. Then Copaxone, an everyday subcutaneous injection, (glatiramer acetate), which is a sequence of amino acids and then next Novantrone (mitoxantrone). Next came Rebif in 2000, an interferon 1a and is given subcutaneous three times a week. Oral Fingolimod or Gilenya was released in 2011. Other drugs pending release are cladribine, laquinimod, and alemtuzumab or Campath. Fumarate or BG-12 has been carefully studied and is in phase three trials as is teriflunomide.

In the Pivotal trial, in the Tier 1 medication, all of which are immunomodulators, most of the patient had the disease for five to seven years. Hence, many of these patients already had a cumulative burden on their MRI and clinical symptoms that had been ongoing. It is considered that many had significant demyelination and axonal loss. The natural history of annual relapse rate (ARR) is that of 1.7 per year. There are a number of studies that document that. With the clinical trials using the Posner criteria, the reduction in annual relapse rate went from 1.7 per year, which was considered to be the natural history, down to about 0.7 on average. You can never compare clinical trials, meaning that data from one clinical trial cannot be compared to another. With the development of Tysabri, the Ttransform and the Freedom trial showed an annual relapse rate about 0.2, which was a significant reduction but most of these patients had symptoms for only a year or so. Then the Regard and Beyond trial, which was comparing Rebif against Copaxone, and Betaseron against Copaxone showed a reduction of the annual relapse rate to about 0.3. Other trials have shown the annual relapse rate to be also somewhere between 0.2 and 0.3. The percentage of relapse-free patients was also improved in the later trial with Tysabri. A trial using glatiramer acetate at 40 mg subcutaneous daily as compared to 20 mg sub q showed no increased efficacy at the higher dose but did show higher adverse side effects.

There have been numbers of papers that document that when the immunomodulator is discontinued or withdrawn, the patient worsens and has a higher incidence of annual relapse and probably progression. The Transform trial using fingolimod against an interferon showed the fingolimod at 0.5 mg had a significant reduction in annual relapse rate as compared to the interferon. This annual relapse rate for fingolimod was 0.16 and for the interferon, it was 0.33. The Freedom trial using fingolimod versus placebo again showed a significant reduction in the annual relapse rate, but these are very early patients and the placebo annual relapse rate was 0.40 and fingolimod at 0.5 mg was 0.18.

There have been number of studies, which show the relapse rate is reduced with a change in therapy with all drugs. If the patient is having more relapses and seemingly progressing, whatever immunomodulator drug they are on, if they are switched, they all consistently have a reduced annual relapse rate. The reason for this is uncertain, but it probably has to do with the mechanism of action of the drug.

Adverse side effects are significant in all of these drugs. The immunomodulators, which are glatiramer acetate, interferon beta-1a and b and fingolimod all have adverse side effects. Glatiramer acetate has an immediate post-injection reaction which is associated with dizziness, chest pain, weakness and other symptoms, but it is transitory. It usually goes away in minutes and infrequently it can recur. Glatiramer acetate also has injection site reactions and lipoatrophy. The patients on glatiramer acetate do not have to worry about PML, flu symptoms, depression, hepatic or blood abnormalities, neutralizing antibodies, or any anaphylaxis. It is also a pregnancy category B. However, there are no good studies documented in pregnant women.

High-dose interferon beta is associated with ejection-type reactions and flu-like symptoms, which may be significant, but often can be treated. Interferon’s have a warning on depression and it should be carefully monitored and any signs of suicidal ideations should be seriously considered. There may be hepatic and WBC abnormalities and interferons do have neutralizing antibodies, but their significance is uncertain. There have been rare examples of anaphylaxis. Interferons are not associated with PML, lipoatrophy, or other severe immunosuppressive infection. It is a pregnancy category C. Natalizumab is considered an immunosuppressant drug and PML is the greatest concern. Now that we can test the CSF and serum anti-JC virus antibody we can reduce the risk of PML by not giving it to patients who are positive for JC virus. As of December 1, 2011, there have been 193 cases of PML and severity of involvement is really divided into thirds. Immunosuppressive concerns for serious infections are a definite warning. There can be hepatic injuries, anaphylaxis, and there are neutralizing antibodies whose significance is uncertain. It is a pregnancy category C.

Gilenya (fingolimod) is a new immunomodulator. It is an oral drug and the patient should be evaluated for macular edema and lung abnormalities, varicella titers should be obtained, and the patient should be monitored after the administration for any cardiac arrhythmias up to six hours. There have been some significant concerns now with 39 deaths of various types. There are concerns about possible serious cardiac event that can occur. There have been significant concerns about herpes infection such as herpes zoster or herpes encephalitis. Other infections are also a concern.

Rescue therapy for acute relapses of MS is fairly well established. The methylprednisolone (MP) can be given at 1000 mg IV with three to five days. MP orally can be given and there is some evidence that high dose prednisone maybe as effective. Acthar can be used for relapses if the patient does not improve with methylprednisolone or cannot take methylprednisolone. The dose of oral prednisone is not certain but the high dose for numbers of days could be considered. It may be as effective as methylprednisolone IV or orally as documented by some studies.

The alemtuzumab is a monoclonal humanized antibody that is directed against CD52 antigen. This CD52 is a cell surface glycoprotein and the alemtuzumab binds to CD52 and this depletes B cells, T cells, and monocytes. This is thought to be effective in the treatment of demyelination. Safety and intolerability of this drug is a concern since autoimmune disorders may develop. There can be an acute cytokine release syndrome. There may develop opportunistically illnesses and infections. In the clinical trials, deaths and cancer cases were noted and there were significant serious infusion reactions, which occur in about 1% to 1.5% of the cases.

Laquinimod is a possible future drug for MS and it’s mechanism of action is shifting Th1 to Th2 cells shifting to Th2 anti-inflammatory cells. There is some evidence of improvement in the clinical picture, but the future as a single drug for the treatment of MS is uncertain. It may more likely be used as an adjunctive drug.

BG000112 is dimethyl fumarate and is being used to treat MS. The studies apparently show significant reduction in relapse rates. It is used in psoriasis and it induces a significant lymphocytopenia and down regulates proinflammatory cytokines. It also increases IL-10, which is anti-inflammatory. The actual spectrum of safety and adverse side effect is not yet known.

Discussion: We have discussed epidemiology, the signs and symptoms of MS, and pathophysiology including the immunology, and we discussed treatment format. We discussed immunomodulators which were involved in pivotal trials and tier 2 drugs such as immunosuppressors, and we talked about future drug. It is obvious that we have made major headway in diagnosing MS and also it is well documented now that is important to diagnose MS as soon as possible. Treating the patient as soon as possible with immunomodulators and then watching for relapses allows for the best therapy. Watching for relapses, switching the drug if needed and using rescue drugs are all best therapy for MS.

Dee E. Silver, M.D.

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