In part I of this annual update, we review current aspects of multiple sclerosis and stroke therapy and the paraneoplastic syndromes of the retina and optic nerve. THERAPY OF MULTIPLE SCLEROSIS Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system (1–86), with substantial long-term neurologic consequences (1,4,9,25,34,52,54,55,57,60,63,65). After 10 years with MS, 50% of patients are unable to perform household and occupational responsibilities; after 15 to 20 years, 50% are unable to walk without assistance; after 25 years, 50% are unable to ambulate. The average annual cost of MS in the United States is greater than 6.8 billion dollars (1). There are three main subtypes of the disease: relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP). This update reviews the current status of MS therapy (1–86). We have chosen to focus on the new and emerging immunomodulatory therapies for disease relapses and the treatments to prevent disease progression. We do not review the treatments for common MS-related sensory and motor symptoms, fatigue, or depression (35). Corticosteroids Corticosteroids such as prednisone, dexamethasone, and methylprednisolone (MP) have been the mainstays of therapy for acute exacerbation in MS (1,4,9,25,34,52,54,55,57,60,63,65,67). The mechanisms of action include reduction in CD 4 cells, decreased cytokine release, and decreased class II expression. Although there have been few studies demonstrating advantages of one type of steroid rather than another, intravenous MP has emerged as the most frequently used acute short-term (3–5 days) therapy for exacerbations. Some authors have proposed the use of high-dose (e.g., 500 mg) oral MP (9), and there may be a role for oral therapy in selected cases. Survey information has shown wide variability in the dose, route of administration, duration, venue, and indication for steroid use in MS among treating neurologists (76). The issues surrounding oral versus intravenous steroids remain controversial. Both prednisone and MP are well absorbed orally, and oral therapy is less expensive than intravenous therapy. Some clinicians use low-dose oral prednisone for minor exacerbations and reserve intravenous therapy for major relapses (70). Although some authors have used intravenous pulse MP for progressive disease, there is only limited evidence that steroid treatment impacts the long-term course of MS (51). High oral doses theoretically increase the risk for gastric ulceration. Metz et al. (24) studied 17 patients treated with 1250 mg of oral prednisone per dose and 1000 mg of intravenous MP. Three (25%) patients in the oral group and two (40%) patients in the intravenous group had modestly abnormal gastric permeability (95% CI 34–64%, p = 0.6). These authors concluded that short-term high-dose oral prednisone was not associated with greater gastric damage when compared to intravenous MP. Corticosteroids in optic neuritis. The Optic Neuritis Treatment Trial (ONTT) previously established that intravenous MP in typical optic neuritis improved the speed of visual recovery but did not impact final visual outcome. Oral steroids in conventional doses increased the rate of new attacks and were discouraged by the ONTT. Wakakura et al. (84) reported a randomized controlled clinical trial comparing intravenous MP with a control drug (mecobalamin) for managing optic neuritis. The intravenous MP group showed faster recovery of vision, but the visual function at 12 weeks and 1 year were essentially the same in the two treatment groups. Sellebjerg et al. (85) assessed the efficacy of oral high-dose MP in acute optic neuritis. These authors concluded that oral high-dose MP improved speed of recovery, but there was no difference in outcome at 8 weeks or on subsequent attack frequency. Trobe et al. (86) performed a survey to determine whether the ONTT results altered the practice patterns of ophthalmologists and neurologists. In accordance with the ONTT, nearly all surveyed ophthalmologists and neurologists had reduced their use of oral prednisone alone, and most of these professionals used intravenous MP. Many clinicians, however, mistakenly believed that intravenous MP improved final visual outcome. Only 7% of neurologists and 36% of ophthalmologists (p = 0.0001) in this survey were adhering to the ONTT suggestion to use MRI findings as a basis for treatment. Immunomodulatory agents Interferons. Four classes of interferon (IFN α, β, γ, and ω) are recognized. Initial studies of IFN γ showed an increase in relapse rate in MS, despite the fact that it reduced experimental allergic encephalitis in mice. IFN γ is not currently used in MS therapy. IFN α and β are type I IFN and have many effects that counter IFN γ. IFN-α trials, however, have provided mixed results. In some studies, IFN α-2a reduced exacerbation rate and magnetic resonance (MR) activity in MS (13). Myhr et al. (66), however, in a randomized placebo-controlled trial of IFN α-2a (n = 97), reported reduced MR lesions but no treatment effect on exacerbation rate, progression of disability, or quality of life (QoL). The value of IFN α in clinical use is uncertain. IFN β is an immunomodulatory agent that affects T-cell function and has an established beneficial role in MS (2,5–7,9–16,27–29,30,32–33,36,41,44–46,49,50,56,58–59,70–73,75,78–83). Interferon β-1b (Betaseron; Berlex Laboratories, Richmond, CA) is a nonglycosylated Escherichia coli recombinant product. It differs from IFN β-1a by one amino acid and is administered subcutaneously. IFN β-1a (Avonex [Biogen, Cambridge, MA]) is a glycosylated protein derived from Chinese hamster ovary cells. It is identical to human IFN and is injected intramuscularly once weekly (1,4,9,25,34,52,54,55,57,60,63,65). Mechanism of action of interferons. The mechanisms of action for IFN effect in MS are largely unknown. IFN have been documented to inhibit migration of T cells, enhance major histocompatibility complex (MHC) class I and inhibit MHC class II expression on monocytes, have antiviral effects (2,5–7,9–16,18,27–29,30,32–33,36,41,44–46,49,50,56,58–59,70–73,75,78–83), and have cytokine effects. The role of cytokines in the development of MS has been intensively investigated. T cells (CD4+) may differentiate into Th1 and Th2 cells with varying effect on cytokine production (13) (e.g., interleukin [IL]-2, tumor necrosis factor [TNF], and IFN-γ). This effect may play a role in the formation of demyelinating plaque in MS (5,18,30,37). The mechanism of steroid treatment benefit in MS is probably multifactorial (65,67) and may overlap with the mechanism for IFN action. Tumor necrosis factor-alpha (TNF-α) is a cytokine that can cause myelin damage. Steroids may up-regulate expression of soluble receptors for IL-1 and TNF-α, reducing cytokine effect. Franciotta et al. (37) measured plasma and cerebrospinal fluid (CSF) levels of TNF-α and its soluble receptors (TNF-sRp55 and TNF-sRp75) in 18 patients with active MS and controls. They reported an increased CSF level of TNF-sRp55 in response to steroids. Cytokine studies in experimental autoimmune encephalomyelitis (EAE) suggest that there is an inflammatory type 1 cytokine response and a beneficial type 2 response (5,18,30,45). Induction of these type 2 cytokines is one possible IFN effect (18). Duddy et al. (30), however, demonstrated no sustained change in plasma type 1 (IL-12, IL-1β, and TNF-α) or type 2 (IL-6, IL-10) cytokines. There were repeated inductions of both types of cytokines, however, suggesting that IFN β-1a causes transient modulation of cytokine expression. Sinigaglia et al. (5) reviewed the molecular basis for the type I IFN (IFN-α and IFN-β) effect on selective induction of Th1-type immune responses. These authors discussed the potential effects of treatment and the value of the Th1/Th2 paradigm in MS. Lou et al. (44) investigated the effects of IFN-β on leukocyte transendothelial migration and concluded that inhibition of this migration may be another important mechanism. Ossege et al. (45) investigated the influence of IFN β-1b on the mRNA expression of the immunosuppressive cytokine TGF β-1 and the proinflammatory mediator TNF-α in vitro. Treatment results of interferons. Interferon β-1b has multiple effects in RR MS, including reduction of relapse rate (33%), reduction of new MRI lesions, and reduction of MRI lesion volume. IFN β-1b may also reduce relapse rate, clinical disability progression, and MRI lesion volume in SP MS. IFN β-1a has been shown to reduce progression of disability, rate of relapse, new MRI lesions, and MRI lesion volume (2,5–7,9–16,27–29,30,32,33,36,41,44–46,49,50,56,58,59,70–73,75,78–83). More recent studies have confirmed the benefit of IFN β therapy seen in previous clinical trials. Weekly IFN β-1a has been shown to decrease the rate of new enhancing lesions on MRI. Gasperini et al. (79) showed a stabilizing effect on T1-weighted hypointense lesion volume (n = 67) in RR MS. Miller et al. (27) performed a randomized placebo-controlled trial of IFN β-1b (n = 718) in SP MS with a follow-up period of up to 3 years. There was a 15% increase in MR lesions from baseline to last MR scan in the placebo group. In contrast, there was a significant reduction in MR lesions at year 1 (4%) and year 2 (5%) for the treatment group. Paolillo et al. (46) reported that the duration of MR enhancement and the number of new enhancing lesions were lessened by IFN β-1a treatment. The clinical significance of these changes in MR findings is still debated. There is increasing evidence that MR abnormalities are objective and quantifiable measures of treatment effect in MS. Rovaris (11,77), however, reviewed MRI findings and long-term disease evolution in MS in trials. They found only a variable clinical correlation ranging from poor to moderate. Li and Paty (50) reported the results of the Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial. This study was a double-masked, randomized, multicenter, phase III, placebo-controlled study of IFN β-1a (n = 560). The results of treatment showed a reduced number of relapses, increased number of relapse-free patients, prolonged time to relapse, reduced number of moderate or severe relapses, and delayed progression of disability. Over 2 years, there was a progressive increase in MRI burden of disease (10.9%) for placebo when compared to IFN treatment. There was also a small dose difference of 1.2% for IFN at a 44-μg dose and 3.8% for IFN at a 22-μg dose. Rudick et al. (56) reviewed the results of CSF analyses in a subset of RR MS patients in a placebo-controlled, double-masked, phase III clinical trial. IFN β-1a significantly reduced CSF white blood cell (WBC) counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or oligoclonal bands. Dosage of interferons. The ideal dose for IFN in MS is not determined (2,5–7,9–16,27–29,30,32–33,36,41,44–46,49,50,56,58,59,70–73,75,78-83). Blumhardt (41) reviewed and summarized data suggesting that low doses administered once weekly are relatively less effective than higher and more frequent doses of IFN. The Once Weekly Interferon for MS Study Group reported a randomized double-masked study of IFN β-1a at 22 μg, at 44 μg, or placebo administered by weekly subcutaneous injection for 48 weeks (81). These authors concluded that there was a beneficial effect on MRI findings of IFN β-1a at low dose in MS. There was a dose–effect relationship for clinical and MRI variables. Patti et al. performed a double-masked randomized trial of natural IFN β (n = 58). In the treated RR MS group, there was a significant reduction in the exacerbation rate, an increase in the probability of remaining exacerbation free, and an improvement in mean disability score at 24 months. The number and activity of lesions on MRI was significantly reduced in treated RR patients. In the treated SP MS group, there was a significant reduction in disability score and a significant reduction in active lesion number. There was only a marginally significant favorable difference in total lesion burden and no significant effect on the number of gadolinium-enhancing MRI lesions (83). Waubant et al. (82) reported a reduced number of new MR-enhancing and T2-weighted lesions on serial MR scans (n = 8) in patients with MS treated with weekly IFN β-1a (30 μg) (p = 0.016). Cost analysis of interferon therapy. The cost of IFN therapy may be as much as 8000 to 10,000 U.S. dollars per year. Parkin et al. (6) evaluated the cost effectiveness of IFN β-1b for RR MS. IFN β-1b produced some short-term gains. The authors believed that they translated into only small quality-adjusted life-year (QALY) gains. They concluded that the IFN costs were larger than the cost savings. Forbes et al. (14) evaluated the cost utility of IFN β-1b in SP MS, finding that for every 18 people treated for 30 months, six relapses would be prevented. These authors concluded the cost per QALY gained from treatment was high. The high-cost variables in their analysis included the drug expense, relatively modest clinical effect, and significant opportunity cost. They reported that “resources could be used more efficiently elsewhere”. The issue of cost effectiveness for IFN treatment remains controversial and continued study is warranted. Side effects of interferons. Adverse effects with IFN β are common and especially frequent during the first weeks of treatment. Flu-like symptoms occur in as many as 75% of patients. The side effects include fever, chills, myalgia, insomnia, anorexia, weight loss, fatigue, and injection-site reactions (7,10,22,28,59). The effects may be more frequent in women (10). Transient laboratory abnormalities, neuropsychiatric changes, menstrual disorders, and increased spasticity may also occur. Walther reviewed other possible side effects including various autoimmune reactions, capillary leak syndrome, anaphylactic shock, thrombotic-thrombocytopenic purpura, insomnia, headache, alopecia, and depression (28). These side effects may result in reduced treatment compliance or discontinuation of therapy. Efforts to minimize these reactions include appropriate management of mild side effects with analgesics and antipyretics such as ibuprofen, acetaminophen, and pentoxifylline. The use of correct preparation, careful injection technique, and modification of the dosage may be helpful. Bayas et al. (7) reviewed the management of these adverse effects. Ibuprofen and gradual introduction of the drug may reduce the incidence of flu-like symptoms to rates comparable with placebo. Quality of life and interferon therapy. Patients with MS often have a normal lifespan, and, therefore, QoL parameters are important outcome measures. Rice et al. (33) reported that patients with RR MS (n = 117) treated with IFN β-1b had a better QoL than untreated patients. Nortvedt et al. (32) performed a randomized double-masked placebo-controlled treatment trial of 97 RR MS patients. These authors found a relationship between new enhancing MR lesions and reduced QoL among the placebo patients but not the IFN patients. Treatment with IFN α-2a does not seem to improve patient QoL after 6 months, despite marked effect measured by MRI. The Canadian Burden of Illness Study Group reported that the QoL of MS patients falls drastically and early in the disease. Treated patients with RR MS had better QoL than untreated historical controls. This finding was especially true for those patients with an Expanded Disability Status Scale (EDSS) less than 3.0. Continued work on QoL measures will be important for future treatment trials. Neutralizing antibodies to interferons. Neutralizing antibodies (NAbs) to IFN develop in 8 to 40% of cases. The clinical significance of this finding is unclear but may be associated with reduced IFN efficacy (29). Antonelli et al. (29) examined the specificity of NAbs to IFN β-1a or IFN β-1b and studied the effect of switching from IFN β-1a to IFN β-1b. All positive sera independent of the source may recognize both forms of IFN β. They concluded that it was unlikely that administration of IFN β-1b to anti-IFN β-1a NAbs-positive patients could overcome any inhibitory effect exerted by the serum NAbs and vice versa. Glatirimer acetate (Copaxone). Glatirimer acetate (Copaxone; Teva Pharmaceuticals USA, Kansas City, MO), formerly Copolymer I, is a synthetic polypeptide of four amino acids, including glutamic acid, lysine, alanine, and tyrosine. The chemical structure resembles myelin basic protein (1,4,9,25,34,52,54,55,57,60,63,65). Its mechanism of action is unknown but it has been shown to reduce the relapse rate in MS (29%). It has also been reported to slow disease progression. The effect of glatirimer acetate on the number and activity of lesions on MR is less clear than the beneficial effect seen for IFN. The drug is administered subcutaneously once per day (57,80). Side effects of glatirimer acetate. The side effects of glatirimer acetate are mild and include injection-site reactions. There are idiosyncratic reactions in as many as 15% of patients and the self-limited symptoms include facial flushing, palpitations, and chest tightness (1,4,9,25,34,52,54,55,57,60,63,65). NAbs to glatirimer acetate are of unknown clinical significance. Comparing the three immunomodulatory agents (IFN β-1b, IFN β-1a, and glatirimer acetate). There are no data directly comparing the relative efficacy of these three drugs in a single study (1,4,9,25,34,52,54,55,57,60,63,65). Rudick (1) summarized the supporting evidence for the use of each agent. The arguments for IFN β-1b when compared to IFN β-1a include: 1) more beneficial MRI effect on T2-weighted lesion accrual after 2 years, 2) higher weekly dose, and 3) larger reduction in relapse rate. The arguments for IFN β-1a include: 1) reduced disability progression, 2) fewer injection-site reactions, 3) less theoretic immunogenicity, 4) improved patient convenience enhanced by weekly dose, and 5) more favorable side-effect profile. The arguments for glatirimer acetate are: 1) it is better tolerated than IFN β and 2) it circumvents the problem of NAbs. Prophylactic interferon therapy: Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study. Whereas treatment with IFN has been shown to benefit patients with established MS, its value for the prevention or reduction of later development of demyelinating lesions after a first clinical event has been unproven. Initial results from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) suggest that treatment with IFN β-1a may reduce the risk of clinically definite multiple sclerosis (CDMS) after such an event (87). The study was a multicenter randomized, double-masked, placebo-controlled trial of 383 patients with an initial neurologic event consistent with demyelination, including 192 (50%) patients with optic neuritis and MR evidence of subclinical brain lesions (at least 2 typical MS lesions 3 mm in diameter). Subjects were treated with intravenous and oral corticosteroids within 14 days of the event and subsequently randomized to weekly intramuscular injections of either placebo or 30 μg of IFB β-1a within 27 days of the initial event. The trial was terminated at the interim analysis of efficacy after 3 years, when a beneficial effect was demonstrated. Data indicated that the cumulative probability of developing CDMS was 35% in the treated group versus 50% with placebo. The volume of new, enlarging, and enhancing MR lesions was significantly lower in the treated group. Treatment with IFN β-1a reduced, by approximately 50%, the rate of development of CDMS within 3 years after an initial event. The practical clinical implications of the study for therapy of patients with initially isolated optic neuritis have yet to be established. Immunoglobulin therapy. Intravenous immunoglobulin (IVIg) therapy has been shown to variably reduce exacerbations and MR-enhancing lesions in MS. The mechanism is unknown but may be related to anti-idiotypic effects or TNF-β suppression (1,4,9,25,34,52,54,55,57,60,63,65). In several small nonrandomized studies, there was a reduced rate of disability and activity of disease on MRI. In animal models and in a few open trials, IVIg treatment enhanced central nervous system remyelination (8,61,65,73). Stangel et al. (8) conducted a double-masked placebo-controlled pilot study (n = 10) of IVIg at a dose of 0.4-gm/kg body weight for 5 consecutive days. There was no difference in the primary outcome of central motor conduction times after treatment. IVIg is associated with minor side effects including fever, malaise, headache, and rash. There are a few major side effects, including aseptic meningitis, renal failure, and thrombosis. The availability of alternative immunomodulatory agents such as IFN and glatirimer acetate therapy, the high cost of 1800 dollars per infusion for IVIg, and the recent decreased availability of IVIg in the United States have limited its use for MS (8,61,65,73). Immunosuppressive therapy Azothioprine, methrotrexate, cyclosporine, and cyclophosphamide. Nonspecific immunosuppressive agents such as azathioprine (Imuran; Faro Pharmaceuticals, Bedminster, NJ), methotrexate (Rheumatrex; Lederle Pharmaceuticals, Pearl River, NY), cyclosporine, and cyclophosphamide (Cytoxan; Bristol-Myers Squibb, Princeton, NJ) have shown some limited efficacy in MS (1,4,9,19,24,25,34,40,52,54,55,57,60,63,65). Azathioprine works by cell-mediated and humoral immune mechanisms. In meta-analyses of randomized controlled trials, this drug reduced relapse rates by one third and reduced progression of disability in MS (80). Side effects, including hematologic and gastrointestinal effects, however, may outweigh its benefit. Methotrexate also works by cell-mediated and humoral immune mechanisms and has reduced progression of upper limb impairment, but not other measures, in one study (51,80). Cyclosporin A may also have a modest effect on MS progression but has significant nephrotoxicity (80). Further studies are needed to determine the potential role of these agents. Several nonmasked nonrandomized trials have shown a potential benefit for cyclophosphamide in MS (19,40). Other studies, however, including one randomized, masked, placebo-controlled trial showed no improvement in SP MS (40). Hohol et al. (19) studied combined pulse therapy with cyclophosphamide and MP at 4-to 8-week intervals in an open-label trial of 95 subjects with MS. They concluded that there was some benefit to treatment, especially for SP MS, that was refractory to immunosuppressive therapy, recommending that earlier intervention should be considered in these patients. Gobbini (40) evaluated cyclophosphamide in five MS patients who failed an average of three previous other treatments. All patients showed a rapid reduction in MR contrast-enhancing lesion frequency (40). Mitoxantrone and mizoribine. Mitoxantrone is an antineoplastic DNA-reactive agent that has demonstrated a significant reduction in relapse rate, delayed time to first relapse, and slowed progression of disease in SP MS (9). Unfortunately, significant side effects, including cardiac toxicity and neutropenia, may limit its use. Mizoribine (MZR) is an imidazole nucleotide that inhibits purine synthesis and helper T-cell function and is used in Japan as an immunosuppressant for chronic rheumatoid arthritis. MZR, in one multicenter, double-masked, placebo-controlled trial, showed no benefit in the primary endpoints of relapse rate and MR lesion area (47). Saida et al. reported 24 MS patients treated with MZR and corticosteroids in an open trial. The mean relapse rate per year at entry was decreased after 2 years (47). Other therapies Sulfasalazine. Sulfasalazine is an anti-inflammatory drug used in the treatment of various rheumatologic diseases. The Mayo Clinic–Canadian Sulfasalazine Study was a randomized, double-masked, placebo-controlled trial of 199 RR and SP MS patients (17). The trial reported that sulfasalazine temporarily reduced relapse and progression rates, delayed time to first relapse, increased the number of relapse-free patients, and decreased MR activity of MS. The effect was seen in the first 18 months of the trial but not thereafter. The authors concluded that the drug did not prevent EDSS progression. Roquinimex. Roquinimex is a synthetic immunomodulatory agent that has been studied in three phase III trials, all showing marginal efficacy. Substantial adverse effects, including musculoskeletal pain and myocardial infarction, were noted (80). Cladribine (Leustatin). Cladribine (Leustatin; Ortho Biotech, Inc., Raritan, NJ) is a specific antilymphocyte agent that may reduce disability, MR lesions, and CSF oligoclonal bands in MS (9,42,57,74,76). Romine et al. (74) conducted an 18-month, randomized, placebo-controlled, double-masked, phase II study of cladribine in 52 patients with RR MS. There was a statistically significant favorable effect on the frequency and severity of relapses and MRI disease activity. Cladribine is well tolerated but may cause lymphopenia and may potentiate herpes zoster virus (25%) or other opportunistic infections (74). Intercellular adhesion molecule inhibitors. Transmigration of leukocytes across the blood–brain barrier into the CNS may play a role in demyelination and oligodendrocyte damage in MS. Leukarrest is a white blood cell antibody that blocks transport across the blood–brain barrier. It showed no clinical effect in one trial (40). Plasma exchange. Anecdotal reports of plasma exchange have suggested benefit for patients with MS, although the mechanism is unknown (26,31,43,62). Weinshenker et al. (26) conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment for patients with recently acquired severe neurological deficits resulting from attacks of inflammatory demyelinating disease. All of these patients had failed to recover after treatment with intravenous corticosteroids. Moderate improvement in neurologic disability occurred in 8 of 19 (42.1%) courses of treatment, compared with 1 of 17 (5.9%) courses in sham treatment. The Canadian Apheresis Group reviewed their data on 103,416 plasma exchange procedures, including management of MS. In the meta-analysis, there was no apparent benefit if the studies were corrected for multiple comparisons, blinded observations, and exclusion of patients not adhering to standard entry criteria (43). Extracorporeal photopheresis. Rostami et al. (48) performed a randomized, double-masked, placebo-controlled with sham therapy trial of monthly extracorporeal photopheresis therapy in progressive MS (n = 16). No serious side effects occurred, but the treatment did not alter the course of disease. Lenercept. Tumor necrosis factor is a proinflammatory cytokine that has been implicated in MS because it is toxic to oligodendrocytes and worsens experimental allergic encephalitis (EAE). Lenercept is a recombinant TNF-receptor p55 immunoglobulin fusion protein (sTNFR-IgG p55) that has been shown to be protective in EAE. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group performed a double-masked placebo-controlled phase II study (n = 168) of Lenercept, failing to show any benefit in MRI study measures. Interestingly, the number of treated patients experiencing exacerbations was significantly increased (p = 0.007) (39). Studies of anti-TNF-α antibody have also had a negative result. The reason for the increased exacerbation rates is not clear. T-cell vaccination. Myelin basic protein (MBP)–reactive T cells may be pathogenic in MS and may be depleted by T-cell vaccination (TCV). Immunization with autoreactive inactivated T cells may elicit specific immunity to pathogenic T cells. This approach is under active study by Hermans et al. (12). TCV with myelin basic protein–reactive clones can induce T-cell immune response and a clonal depletion of MBP-reactive T cells. Five years after TCV, MBP-reactive T cells were seen in five of nine MS patients, and these clones had a different clonal origin from those isolated before vaccination. Oral myelin. Oral tolerance to fed antigen may result in active immune suppression or anergy (9). Oral myelin was not successful in reducing relapse rate, and there was no MRI effect when compared with placebo. Future studies with recombinant myelin peptides, possibly in conjunction with IFN therapy, may be forthcoming (57,76). Monoclonal antibody (e.g., humanized anti-alpha 4 beta 1 integrin). Humanized anti-alpha 4 beta 1 integrin, in a randomized double-masked study, was well tolerated. It reduced MR lesions in RR and SP MS. Other studies, however, of humanized anti-CD 11/CD 18 integrin monoclonal antibody failed to show a clinical or MRI benefit (38). Monoclonal anti-CD4 antibody failed to show positive results in a double-masked, placebo-controlled, MR-monitored phase II trial (80). Bone marrow and stem cell transplant. Bone marrow and stem cell transplants are being explored as potential management options in MS. These therapies have been tried in only a few patients (20). The morbidity and mortality rate of the procedure is significant (0.5–2.5%), and the results to date have been inconclusive. Alternative therapy. Newland (64) reviewed the use and effectiveness of alternative therapy in MS. The author reviewed massage, imagery, acupuncture, aromatherapy, herbalism, therapeutic touch, and nutritional therapy. Increasing use of these alternative treatments by patients with MS may warrant further study, but there is little controlled clinical data to support efficacy. Use of multiple sclerosis therapies in pregnancy and children. Olek (9) summarized the use of the selected MS treatmen
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