Articles

Introduction

Multiple sclerosis (MS) poses perils and challenges for the patient as well as for the caregiver. This disease has the potential to disrupt and sometimes even devastate a young life as disabling physical, cognitive and emotional impairments develop. Plans and dreams for the future become uncertain. Sometimes symptoms persist for long periods of time before a firm diagnosis is established.

On the other hand, MS can summon the prospect of focused and effective medical care. For many patients, early treatment can lead to long-term and sometimes even permanent remission of symptoms. Exciting scientific breakthroughs have been developed over the past decade and a promise of more effective therapies seems just beyond our current horizon. In addition, care of the persons with MS can be ennobling for the caregiver. When close attention is paid to a patient’s various symptoms and when medical interventions succeed, there can be no more satisfying example of caregiver/patient collaboration.

Anatomy and Clinical Symptoms

MS is a disease of the central nervous system (CNS) - i.e. the brain, the brain stem and spinal cord. For many decades the clinical diagnosis of MS has been based on signs/symptoms that were disseminated in time (episodic) and space (symptoms arising from two or more areas of the central nervous system). Before the advent of MRI, more primitive and indirect methods were used for diagnosis such as the “hot bathtub test” (increasing a patients body temperature to see if new signs/symptoms developed) and arcane cerebrospinal fluid (CFS) abnormalities such as the “colloidal gold” test. With the advent of MRI imaging it is now possible to actually see discreet areas of disease involvement and to correlate these findings with the patient’s history and examination.

The symptoms of MS are varied and at times subtle, early on the diagnosis of MS can be hard to establish. One is reminded of clinicians of old who labeled syphilis as the “great imitator” because of its diverse clinical manifestations. Similarly, MS may present with such seeming unrelated complaints as visual disturbance, dizziness, unsteadiness, sensory disturbances and extremity weakness. Bladder dysfunction and impairment of sexual performance can occur. And certainly, the clinical course of MS in given individuals may be quite variable. There are generally considered to be three main types for MS: relapsing/remitting, secondary progressive and primary progressive. Data suggests that 80-85% of the time MS begins with a relapsing/remitting course; although, patients may eventually exhibit progressive disability. The prevalence of MS is estimated to be twice as high in females as males.1

Diagnostic Tests

In addition to the history and clinical examination, there are three principle forms of testing that can help establish a diagnosis of MS: magnetic resonance imaging (MRI), evoked potentials, and spinal fluid analysis. In MR imaging of the brain, flair and T2 weighted sequences can show demyelinating lesions of MS. Active plaques may show contrast enhancement. T1 weighted MR imaging may demonstrate so called black-holes or areas of axonal injury. While such T1 findings may resolve over time, black-holes may persist and signify permanent axonal injury. Sometimes diffuse atrophy is demonstrated as a manifestation of neuronal injury. MR imaging of the cervical and thoracic spine can also be helpful in identifying sites of demyelinization and further clarifying the extent of CNS disease involvement.

From the various evoked potential studies available, the visual evoked study (VER) is generally most helpful. When an individual has an optic neuritis, the latency (milliseconds) from a visual stimulus to occipital lobe response (the P100 latency) is delayed. An abnormal VER can sometimes signify an asymptomatic pathologic change, thereby fulfilling a clinical mandate to look for pathology “disseminated in space” in the nervous system.

In the spinal fluid the presence of oligoclonal bands suggest MS. Other indicators of cerebrospinal fluid inflammation may include pleocytosis (a small increase in the number of while cells in the CSF); an elevation of the IgG synthesis rate/index; and the occasional presence of an elevated myelin basic protein.

Ultimately, diagnosis of MS is made by a careful assessment of the patient’s clinical picture, coupled with the testing results. In some instances, the caregiver may view the diagnosis of MS as suspected, but not proven, generally, however, a firm diagnosis of MS can ultimately be established.

Pathophysiology

For decades there has been much research interest in the autoimmune, inflammatory aspects of MS. Specifically, it has been noted that persons with MS develop an inflammatory response against the myelin covering of neurons. Such inflammation can generate the patient’s symptoms and cause the white matter lesions seen on MRI. From an immunologic standpoint, so called Th1 lymphocytes become activated, cross the blood-brain barrier and promote an inflammatory response. In effect these Th1 cells overwhelm the anti-inflammatory Th2 lymphocytes.2

While most of today’s therapeutic options address this purported inflammatory process, there is growing evidence that primary axonal injury to the neurons also occurs in persons with MS. Sometimes this injury can be subclinical. Accumulation of axonal injury can lead to brain atrophy, cognitive impairment, and progressive neurologic symptoms. While there is considerable research interest in therapies that can halt axonal injury, to date there are no therapeutic interventions available that have clearly been demonstrated to halt or reverse axonal loss.3 Clearly, a growing consensus among MS experts supports the premise that the pathologic changes of MS reflect both direct axonal pathology as well as inflammatory injury to myelin.3

Therapies

For persons with relapsing/remitting MS, there are currently two categories of therapy available, interferon beta and glatiramer acetate. Both types of drugs work to reduce inflammation in the CNS but by different mechanisms. Interferon beta prevents inflammatory leucocytes (Th1) from entering the CNS. Glatiramer acetate works primarily inside the CNS to promote anti-inflammatory (Th2) activity.

Collectively, the interferons and glatiramer acetate are often referred to as immunomodulating or “platform” therapy. These drugs have collectively been show to reduce the number of clinical relapses and to protect against worsening white matter lesions in the CNS.4 Three types of interferon beta are available: interferon beta-1a as a subcutaneous injection three times a week (Rebif); interferon beta-1a as a weekly intramuscular injection (Avonex); and interferon beta-1b as an every other day subcutaneous injection (Betaseron). Glatirmaer acetate is used as a daily subcutaneous injection. The relative efficacy of the respective immunomodulating therapies is a subject of considerable debate among experts. Some argue that the treatment differences between the various agents are small.5 It has been suggested that the placebo-controlled randomized studies available have all demonstrated an approximate 30% decrease in annual relapse rate.6 One recent European study showed that while all immunomodulating therapies reduced relapse rates, there was no clear superiority of one interferon preparation over another. In this study the decrease in the relapse rate for glatiramer acetate was somewhat more robust than for the interferons.7 Some experts believe that higher dose/higher frequency interferon beta preparations are more beneficial than lower does although the data in this regard is not conclusive.8 There is also concern about those individuals who develop neutralizing antibodies (NABs) against interferon beta. NABs seem to develop in about 40% of patients although the incidence of NABs is less in low dose interferon beta-1a. Data suggests that significant NABs levels result in loss of clinical efficacy of interferon beta. NABs may not develop until 12-18 months after therapy is initiated.9,10

Most experts agree that a significant clinical flare of MS is best treated with a brief course of high dose steroids. Frequently 1000 mg of methylprednisolone is given for I to 5 days and seems to hasten improvement. The duration of steroids used generally depend on the severity of the exacerbation. Typically, these steroids are administered intravenously (IV), although methylprednisolone can be formulated orally as well. Sometimes in patients with active disease and fluctuating symptoms, a monthly maintenance of high dose methylprednisolone is used. In contrast to the episodic doses, there is no consensus or evidence that long-term daily steroids are of benefit. Certainly any patient who receives steroids regularly should be monitored for potential side effects, including osteopenia/ osteoporosis. A periodic bone density should be obtained.

Mitoxzanthrone (Novantrone), an IV chemotherapeutic agent, has been approved for patients with worsening relapsing-remitting disease.11 This drug is administered intravenously every three months. Dosage is calculated based on body mass. Generally a maximum of thirteen cycles of treatment is recommended because higher doses result in increased risk of cardiac toxicity. Many exerts today use a reduced number of cycles (for instance 6-8) in an effort to diminish the risk of cardiac problems and to an effort to diminish the risk of cardiac problems and to hold a portion of the drug in reserve for future use. A baseline echocardiogram is required before the onset of therapy.

A new drug currently promoted for relapsing/remitting disease is natalizumab (Tysabri). After its initial introduction, this agent was taken off the market for about a year after three treated patients developed progressive multifocal leukoencephalopathy (PML). Two of these patients had MS and had received a combination of natalizumab and interferon beta-la. Tysabri is now available again for use, but with strict guidelines at to monitoring. This drug is administered intravenously every four weeks.

For any patient experiencing a major flare if MS symptoms, especially one unresponsive to IV steroids, other chemotherapeutic agents are occasionally employed. These include cyclophosphamide (Cytoxan) and mycophenolate mofetil (CellCept). Multiple new drugs are being studied. One new agent is fingolimod (also known as FTY 720).13 This agent is administered orally and thus could potentially have great appeal for those persons resistant to subcutaneous or intramuscular injection.

An ongoing dilemma and frustration for patients and caregivers alike is the management of progressive MS symptoms due to either primary progressive or secondary progressive disease. To date, there are no satisfactory treatments for such patients. The interferon beta preparations and glatiramer acetate are not approved for progressive disease. Similarly, drugs like mitoxzanthrone and matalizumab are promoted as effective for patients with relapsing/remitting symptoms and not for inexorably progressive disease. In the face of progressive symptoms, some experts do employ other chemotherapeutic agents. These include azothiaprine (Imuran) and methotrexate. Occasionally high dose monthly steroids have been used for progressive disease but their efficacy has not been established. Presumably the current failure of most therapeutic agents for progressive disease reflects the fact that accumulated axonal loss most likely accounts for progressive symptoms rather than inflammatory demyelinization alone.

Many patients with chronic illnesses such as multiple MS have an abiding interest in complementary therapies. People tend to believe that testimonials they hear, and the internet has done much to tout various remedies for these illnesses. In recent memory, the therapies that have been promoted for MS include bee venom, colostrums from cows’ milk, hyperbaric oxygen, and the removal of old teeth fillings. A wide variety of herbs and vitamins have been recommended. It is important for the clinician to ascertain what remedies the patient may be taking and to hopefully find a way to acknowledge people’s belief in these therapies while encouraging the use of concomitant pharmaceuticals that have established efficacy.

Symptoms Large and Small

An exacerbation of MS warrants aggressive intervention. Sudden vision loss suggesting acute optic neuritis can signify an acute flare, as can the onset of new extremity numbness, weakness, or ataxia. These later symptoms may involve one or more extremities. A marked worsening in fatigue can also herald an exacerbation.

Often patients with MS suffer an accumulation of small burdens rather than major flares. Bladder difficulties are frequently encountered. Some patients experienced a small, hypertonic bladder. Such individuals have urgency and void frequent small amounts. Others are afflicted with a flaccid, hypotonic bladder that leads to hesitancy and difficulty emptying the bladder which is an ongoing risk for urinary tract infections. For persons with a hypertonic bladder, various medications to relax muscle tone are used, including oxybutynin (Ditropan) and tolterodine tartate (Detrol). At times, detrusor-sphincter dyssynergia can trap urine in the bladder, anticholinergic drugs and intermittent catherterization may be tried.14 Generally, for a significantly hypotonic bladder, intermittent catheritization is required.

The clinician should inquire about issues of sexuality as persons with MS may experience a decrease in the libido and sexual responsiveness. Various interventions to be considered include drugs like sildenafil catrate (Viagra) that may help erectile dysfunction in men.

Fatigue can be an overwhelming burden to some persons with MS. Although there may be no physical signs that are clearly evident to family and friends, the profound lack of energy may be disabling. A clinician should specifically investigate the degree to which fatigue is hampering daily functioning and should be aware of therapeutic options. Amantadine has been used for many years to help combat MS-related fatigue. Modafinal (Provigil) is commonly used in an off-label fashion to assist with MS fatigue. Some experts recommend episodic use of modafinal and other stimulants rather than taking them on a scheduled daily basis. Of course it is important to remember that fatigue may be the result of concomitant medical problems such as anemia, thyroid disease, or physical exhaustion. Before attributing fatigue to MS per se, the clinician must look for other treatable causes for diminished energy and lassitude.

Spasticity can cause significant distress and impairment in the person with MS. Frequently titrated doses of baclofen (Lioresal, Kemstro) or tizanidine (Zanaflex) can be of benefit.

When spasticity is severe and oral agents have failed, an intrathecal baclofen pump may be implanted, Botulinum toxin (Botox) is also a possible adjunct therapy for spasticity and contractures.

Summary

Clearly, MS can be associated with a host of burdensome, and sometimes progressive, symptoms. The therapeutic options for MS have been greatly enhanced over the past decade and research into more effective therapies continues to prosper. Prospects for new and more effective remedies remain promising. On the other hand, it is very important for the caregiver to rely on evidence-based therapeutic interventions when treating a patient with MS. For relapsing/remitting disease, the platform therapies of interferon beta and glatiramer acetate remain state-of-the-art. For progressive disease, the skilled clinician must recognize that empiric therapies with uncertain efficacy may remain the only option. Clinicians should also exhibit a commitment to address the varied array of symptoms that may hamper a patients daily functioning.

As the seasoned caregiver assists the patient over the irregular terrain of symptoms and treatment options, it is essential to recognize both the limitation of therapy and the importance of focused attention to the specifics of a patient’s situation. Oftentimes in MS, as in other chronic conditions, sweeping changes that transform disability are not possible. Rather incremental interventions that attend to the intimacies of patient’s symptoms and concerns can reap significant benefits. Care for patient with MS can serve as a paradigm for meaningful collaboration between clinician and patient as they strive to achieve balance. In those times of therapeutic uncertainty a commitment to caring can have an enduring influence.

References

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About the Authors:

Jerome Freeman, MD, Professor and Chair, Department of Neurosciences, Sanford School of Medicine of the University of South Dakota; Sanford Clinic Neurology.

Joanne Landis, RN, MSCN, Department of Neurosciences, Sanford Clinic Neurology.

Michelle VanDemark, RN, MSN, MSCN, Sanford USD Medical Center, Sanford School of Medicine of the University of South Dakota.

The Edge of Hope