[ Editorials | Letters | Selected Articles | Signature Series | Patient Handouts | Index ]

2002 Selected Articles

Multiple Sclerosis Part 1: Prompt Diagnosis and Early Intervention

Barbara Giesser, MD; Nancy Holland, EdD

Multiple sclerosis (MS) is a disease that predominantly strikes young women in their most productive and active years. Its socioeconomic impact is huge: Although more than 75% of MS sufferers participate in the work force, the disease itself costs the US economy almost $7 billion annually.¹ The course of MS is unpredictable and, in many cases, progressive. However, prompt diagnosis and early intervention, the focus of part 1 of this two-part series, can markedly improve functioning and quality of life (QOL), prevent complications, and slow the disease process. Part 2 of this series, will deal with MS symptom management.

EPIDEMIOLOGY

Three fourths of patients with MS are women. The disease typically arises during the 20s or 30s, although presentations at age 10 or younger and at age 60 or older have been documented.²

Geography has long been observed to affect MS prevalence. In general, higher latitudes are associated with greater risk and tropical regions with lesser risk. Furthermore, migration studies suggest that MS risk may be reduced by moving from a high-risk area to a lower-risk area before age 15.² The disease primarily afflicts whites of Northern European ancestry. It is much less common among blacks, Hispanics, and Asians, and it is rare among Native Americans, resulting in relatively MS-resistant populations even in high-risk areas. It is theorized that environmental factors—including climate, sunlight (as related to vitamin D production), and infectious agents—may interact with genetic factors to produce disease, but the precise nature of these relationships, as well as the genes that confer MS susceptibility or resistance, has yet to be determined.

IMMUNOPATHOLOGY

MS is widely held to be a disease of immune dysregulation. It is thought that peripheral T-cell sensitization to an as-yet-unspecified central nervous system (CNS) antigen occurs in genetically susceptible persons, possibly in response to an environmental stimulus. Activated T cells are then able to breech the blood–brain barrier and activate and recruit additional immune cells into the CNS to propagate an inflammatory and ultimately sclerotic response against myelin, axons, and oligodendrocytes (myelin-forming cells). Myelin destruction occurs via cellular attacks, complement-mediated myelinolysis, and the secretion of myelinotoxic cytokines.³ Recent data indicate that axonal destruction may occur even in areas of relatively intact myelin, suggesting that other processes in addition to primary demyelination may be involved.⁴ Neurologic signs and symptoms develop as a result of conduction blocks and axonal transection. Serial magnetic resonance imaging (MRI) studies reveal that immune-mediated activity directed against the CNS appears to be ongoing, even in the absence of clinical symptoms or frank relapses.⁵ These observations provide an important rationale for early intervention with disease-modifying agents.

DIAGNOSIS

The sine qua non for establishing an MS diagnosis is documentation of the presence of CNS white-matter lesions separated in time and space. If this cannot be accomplished with information provided by the clinical history and examination, then paraclinical tests such as MRI, cerebrospinal fluid (CSF) analysis, and/or evoked potentials may be used. New criteria incorporating these modalities allow for more precise assignment into diagnostic categories, and are important for research studies as well.⁶ More than two dozen conditions—including the vasculitides, infections, tumors, metabolic disorders, and other neurodegenerative diseases—may mimic MS; a thorough diagnostic eval-uation should include screening for these diseases. "Red flags" suggesting a diagnosis other than MS include unifocal disease; steadily progressive disease without clinical remission; absence of oculo-motor, optic nerve, sensory, or genitourinary (GU) involvement; and normal CSF findings.

The most common presenting signs and symptoms of MS are sensory—paresthesias, dysesthesias, or numbness. The second most common involve motor activity, usually a paraparesis, although any pattern of weakness may occur, even a hemiparesis simulating a stroke. Optic neuritis occurs as an initial symptom in approximately 15% of patients.⁷ On average, 60% of patients with optic neuritis go on to develop clinically definite MS; the risk is even higher if lesions are noted on MRI at presentation.⁷ Additional visual complaints include diplopia; blurred vision, especially with heat (Uhthoff's phenomenon); and oscillopsia. Other early signs and symptoms may include aching or tightness of muscles; dysesthesias radiating down the back with neck flexion (Lhermitte's sign); incoordination; unusual fatigue that is unrelated to exertion or sleep disturbance; GU dysfunction; and cognitive impairment. Rarer manifestations of MS include trigeminal neuralgia, facial paresis (Bell's palsy), dystonias, and seizures. At least 50% of patients with MS experience pain, which is usually neuropathic. This type of pain is a direct result of neural and myelin damage; it may be stabbing, lancinating, burning, prickling, or formicating. Spasticity may result in tightness, aching, or frank muscle cramping. Musculoskeletal pain may also develop as patients try to compensate for weakness or other mobility problems.

DISEASE COURSE

Approximately 65% of patients with MS start out with the relapsing/remitting (R/R) form of the disease, characterized by frank relapses followed by a return to baseline function. In at least two thirds of these patients, however, MS evolves into the secondary progressive form, characterized by an insidious progression of disability. Fifteen percent to 20% of patients with MS begin with primary progressive disease, sometimes with superimposed relapses (progressive relapsing).⁸ The remaining 15% to 20% of patients tend to have a more benign course, and do not incur major disability.
Early indicators tending to augur a more benign prognosis include the following: predominance of sensory symptoms, unifocal attacks with good recovery, few attacks in the first several years of the disease, younger age at onset, and smaller lesion burden on MRI. In addition, females, relative to males, tend to experience somewhat less severe forms of the disease. Overall, about 50% of MS patients are still ambulating independently after having the disease for 15 years.⁹

HORMONAL INFLUENCES

Female predominance in autoimmune conditions such as MS has led to intensive investigations of the actions of sex hormones on the immune system. Data from animal models and human studies indicate that progesterone, testosterone, and high levels of estrogen have immunoprotective effects, whereas low levels of estrogen and prolactin appear to enhance certain immune responses.¹⁰

Menstrual Cycle

According to three studies that have examined the effects of the menstrual cycle on MS symptoms, most women who notice an association of neurologic symptoms with their periods report worsening in the
week before menses onset.^11-13 Larger studies with objective measures of neurologic function are needed to confirm these observations.

Pregnancy

Extensive research has established that most gravidas with MS experience fewer relapses during pregnancy, particularly during the third trimester.^14,15 This may be due, at least in part, to the action of many immunosuppressive substances secreted during pregnancy, including progesterone, high-level estradiol, cortisol, and a-fetoprotein. An MRI study of two patients revealed less lesion activity during the second and third trimesters, with an increase in MRI lesion activity postpartum.¹⁶ This is consistent with observations that the relapse rate tends to increase during the first 6 months postpartum. However, longitudinal studies do not confirm increased long-term disability in women with MS who have borne children, as compared with a nulliparous cohort.¹⁴ A few studies have suggested that pregnancy may even exert a relatively protective effect and delay disease onset,¹⁷ but no large-scale studies have confirmed these observations. No data indicate that women with MS, as compared with healthy counterparts, have impaired fertility or higher rates of miscarriage. Health problems that do plague gravidas with MS are increased bladder and bowel dysfunction, impaired mobility due to weight gain and shift in the center of gravity, and increased fatigue.

Menopause

To date, no studies have been published on the relationship between MS and menopause, or on the effects of hormone replacement therapy (HRT) in postmenopausal women with MS. Regardless, no data indicate that women with MS should not use HRT. It has been reported that older women with MS are at increased risk for osteoporosis and pathologic fractures;¹⁸ immobility and corticosteroid use are probable contributors to this increased risk.

TREATMENT

The current standard of care for persons with MS mandates both symptomatic and maintenance treatment. Acute therapy must also be available for flare-ups. Most MS symptoms respond well to pharmacologic and/or rehabilitative therapies (see Part 2). These interventions are usually effective in improving QOL, maintaining function at home or in the workplace, and preventing secondary complications such as infection, contractures, and decubitus ulcers. Along with pharmacotherapy, exercise is very beneficial for patients with MS, producing improvement in both physical and psychological parameters.¹⁹ Patients are best managed by a multidisciplinary health care team that includes nurses, rehabilitation professionals, psychologists, case managers, and other specialist physicians, in addition to primary care physicians and neurologists.

Pharmacotherapy

Acute therapy.—Corticosteroids are the mainstay of therapy for acute MS exacerbations; intravenous methylprednisolone 1000 mg daily is usually given for 3 to 5 days.²⁰ This treatment, which may be administered on an outpatient basis, is usually well tolerated. Intravenous immunoglobulin has also been reported to be effective for treating acute attacks,^21,22 although it has not been approved by the US Food and Drug Administration (FDA) for such use. Patients whose disease appears to be active despite treatment with corticosteroids and/or immunomodulating or immunosuppressive agents are sometimes given a chemotherapeutic agent such as azathioprine, cyclophosphamide, or methotrexate.²³

Maintenance.—In 1993, the FDA approved the use of the immunomodulator interferon (IFN) b-1b (Betaseron) to treat R/R MS. Three years later the agency approved the use of IFN b-1a (Avonex) to treat R/R MS. That same year, glatiramer acetate (Copaxone), an immunosuppressive agent, was also approved by the FDA to reduce the frequency of relapses in patients with R/R MS. These three agents are known collectively as the ABC drugs because of their proprietary names (Avonex, Betaseron, and Copaxone). Double-blind, placebo-controlled trials have shown that these agents decrease the number and severity of disease exacerbations and reduce the number of new lesions on cerebral MRI in patients with R/R disease.^24-26

The most common adverse reactions to IFN b are fever, chills, myalgias, leukopenia, and liver enzyme elevations. A small proportion of IFN b users may also experience menstrual irregularities. In addition, some patients report onset of depression coincident with IFN b therapy. Glatiramer acetate's side-effect profile is more limited, and includes injection-site reactions and a 15% to 30% risk of an idiosyncratic, self-limited vasomotor reaction.

Because of the demonstrated efficacy and tolerability of these agents, as well as knowledge about the natural history of the disease, a panel of experts from the National Multiple Sclerosis Society issued a consensus statement in late 1998 recommending that patients with a definite diagnosis of R/R MS should be started on one of these drugs as early in the disease course as possible. These agents should not be used during pregnancy, however; IFN b-1a and -1b are Category C drugs and glatiramer acetate is a Category B drug. Patients and physicians should discuss the risks and benefits of delaying therapy to have children versus delaying starting a family to begin treatment. The ABC drugs are not thought to be teratogenic, but IFN b can cause miscarriages. If women receiving one of these agents wish to conceive, they should discontinue therapy for at least one to two menstrual cycles before attempting conception. As it is not known whether these agents are secreted in breast milk, lactating women should not use them.

In late 2000, the FDA approved mitoxantrone (Novantrone) to treat secondary progressive, progressive relapsing, and worsening R/R MS. This immunomodulator has been shown to reduce relapses, slow disability, and reduce accumulation of new lesions on MRI. Administration is limited by dose-related cardiotoxicity; the recommended maximum cumulative dose is 140 mg per m², which is usually given over 2 to 3 years. A Category D drug, mitoxantrone is contraindicated during pregnancy.

CONCLUSION

The unpredictability and chronic nature of MS can be very anxiety-provoking. Physicians should try to provide patients with as much information as possible about their disease, and empower them to take an active part in their treatment.

Barbara Giesser, MD, is associate professor, clinical neurology, Arizona Health Sciences Center, Tucson. Nancy Holland, EdD, is vice president of clinical programs, National Multiple Sclerosis Society, New York, NY.

REFERENCES

1. Whetten-Goldstein K, Sloan FA, Goldstein LB, et al. A comprehensive assessment of the cost of MS in the United States. Mult Scler. 1998;4(5):419-425.
2. Ebers GC, Sadnovik AD. Epidemiology. In: Paty D, Ebers G, eds. Multiple Sclerosis Contemporary Neurology Series. Philadelphia, PA: FS Davis; 1997;50:5-28.
3. Bansil S, Cook SD, Rohowsky-Kochan C. MS: Immune mechanism and update on current therapies. Ann Neurol. 1995; 37:S87-S101.
4. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of MS. N Engl J Med. 1998;338:328-337.
5. Willoughby EW, Grochowski E, Li DK, et al. Serial magnetic resonance scanning in MS: a second prospective study in relapsing patients. Ann Neurol. 1989;25:43-49.
6. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for MS: guidelines from the International Panel on the Diagnosis of MS. Ann Neurol. 2001;50:121-127.
7. Rodriguez M, Siva A, Cross SA, et al. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurol. 1995;45:244-250.
8. Lublin F, Reingold SC. Defining the clinical course of MS: results of an international survey. Neurol. 1996;46: 907-911.
9. Weinshenker BG, Bass B, Rice GP, et al. The natural history of MS: 1. clinical course and disability. Brain. 1989;112(pt 1): 133-146.
10. Whitacre CC, Reingold SC, O'Looney P, et al. A gender gap in autoimmunity. Science. 1999;283:1277-1279.
11. Giesser B, Cross A, Halper J, et al. MS symptoms fluctuate during the menstrual cycle. Neurol. 1990;40(suppl 1):141.
12. Smith R, Studd JW. A pilot study of the effect upon MS of the menopause hormone replacement therapy and the menstrual cycle. J Royal Soc Med. 1992;85:612-613.
13. Zordrager A, DeKeyser J. Menstrually related worsening of symptoms in MS. J Neurol Sci. 1997;149:95-97.
14. Damek DM, Shuster EA. Pregnancy and MS. Mayo Clin Proc. 1997;72:977-989.
15. Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in MS. N Engl J Med. 1998;339: 285-291.
16. Van Walderveen MA, Tas MW, Barkoff F, et al. Magnetic resonance evaluation of disease activity during pregnancy in MS. Neurol. 1994;44:327-329.
17. Runmarker B, Anderson O. Prognostic factors in a multiple sclerosis incidence cohort with 25 years of follow-up. Brain. 1993;116:117-134.
18. Cosman F, Nieves J, Komar L, et al. Fracture history and bone loss in patients with MS. Neurol. 1998;51:1161-1165.
19. Petajan J, Gappmaier E, White A, et al. Impact of training on fitness and quality of life in MS. Ann Neurol. 1992;39: 432-441.
20. Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high-dose methylprednisolone in patients with MS. J Neurol Neurosurg Psychiatry. 1987;50:511-516.
21. Achiron A, Gabbay U, Gilad R, et al. Intravenous immunoglobulin treatment in MS: effect on relapses. Neurol. 1998;50:398-402.
22. Fazekas F, Deisenhammer F, Strasser Fuchs S, et al. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing remitting MS. Austrian Immunoglobulin in MS Study Group. Lancet. 1997;349: 589-593.
23. Rudick RA, Cohen JA, Wienstock-Guttman B, et al. Management of MS. N Engl J Med. 1997;337(22):1604-1611.
24. Jacobs L, Cookfair D, Rudick R, et al. Intramuscular interferon beta 1-a for disease progression in relapsing MS. The MS Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285-294.
25. The IFNB MS Study Group. Interferon beta l-b is effective in relapsing-remitting MS: clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurol. 1993; 43:655-661.
26. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting MS: results of a phase III multicenter, double-blind, placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurol. 1995;45:1268-1276.

back to top