Arnold, Anthony C. MD; Lee, Andrew G. MD
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 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.
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.
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).
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).
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 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; 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).
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).
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.
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.
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 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.
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 treatments in pregnancy by category. Category A drugs have not been shown to be harmful. Category B drugs show no harm in animal studies, but no human studies have been conducted. Category B drugs include glatiramer acetate. Animal data show harm to fetus in category C drugs, but no controlled human studies have been conducted. Category C drugs include corticosteroids and IFN. Category D drugs are known to cause fetal harm in pregnant women. Category D agents include azathioprine, cladribine, and cyclophosphamide. Category X drugs are contraindicated in pregnancy and include methotrexate.
Although there have been no randomized clinical trials on IFN in children, Adams (49) reported good long-term treatment results with IFN β-1b of a 7-year-old male with RR MS. More data is needed before recommendations can be made for children.
Future therapeutic strategies.
Noseworthy (76) summarized possible future therapeutic strategies for MS in a 1999 review: 1) antiviral drugs such as valacyclovir and acyclovir, 2) cytokine and anticytokine strategies including TNF and other inhibitors, 3) “immune deviation strategies” to enhance Th2 cell/cytokine predominance (pentoxifylline and TGF β, IL-10), 4) matrix metalloproteinase inhibitors such as D-penicillamine and hydroxyamatate, 5) trimolecular complex strategies such as anti-MHC monoclonal antibodies, MHC class II hypervariable peptide vaccines, anti-T cell monoclonal antibodies, altered peptide ligands, T-cell vaccination and adhesion molecules, 6) cathepsin B inhibitors, 7) oxygen radical scavengers, 8) autologous bone marrow transplantation, and 9) gene therapy and implantation oligodendroglial precursors. Scolding (21) provided an interesting discussion of the potential managements for long-term repair and remyelination in MS.
THERAPY OF STROKE
Acute ischemic strokes may occur with white clots, because of platelet fibrin, or red clots, because of erythrocyte-fibrin pathology. White clots tend to occur in areas of high blood flow and red clots in areas of low blood flow. Antiplatelet therapy includes aspirin (ASA), dipyrimadole, ticlopidine, and clopidogrel. These agents would thus be theoretically better for white clots including carotid plaque disease without significant stenosis. Anticoagulation agents include heparin, low-molecular-weight heparin, heparinoids, and Coumadin (DuPont Pharma, Wilmington, DE). These drugs would theoretically be better for red clots. The red clot disorders include venous occlusive disease, large artery disease, or cardiogenic thrombo-embolism (88). The guidelines for antithrombotic therapy in cerebrovascular disease were reviewed by Albers and Tjissen (89). In this section, we review the emerging therapies for stroke, including antiplatelet agents, anticoagulation, thrombolysis, statins, and neuroprotective agents (88–137).
Several clinical trials have indicated that patients with atherothrombotic stroke or transient ischemia may benefit from antiplatelet treatment. First-line therapy, therefore, might include ASA, ASA plus dipyridamole, ticlopidine, or clopidogrel (88). Transient monocular blindness (“amaurosis fugax”) resulting from transient ischemia is one possible indication for antiplatelet therapy. The large studies of ASA and other antiplatelet agents were not designed to consider this subgroup of patients.
Aspirin inhibits platelet release, aggregation, and adhesion by blocking cyclo-oxygenase, prostaglandins, prostacyclins, and thromboxane A2. It is the best studied and least expensive of the antiplatelet agents, and many large interventional studies have shown that ASA given within 48 hours modestly reduces mortality after stroke or transient ischemic attack (90,91). The ideal dosage is controversial, with no consensus even among stroke experts; although many clinicians in the United States use a 325-mg per day dose of ASA, some patients may require a higher dosage for therapeutic effect.
Albers and Tijssen (89), in a meta-analysis of ten clinical trials, reported a 13% relative risk reduction (RRR) in stroke, heart attack, or vascular death independent of ASA dose. ASA use was associated with an increased risk of hemorrhage of as many as two intracranial hemorrhages and four extracranial hemorrhages per 1000 treated patients, but the risk was offset by reductions in short-and long-term death and disability rates. Kalra et al. (92) performed a prospective cohort study of 1457 patients, 650 (45%) of whom were using ASA at a median dose of 75 mg and a range 75 to 300 mg. ASA was associated with lower 4-week mortality of 14% versus 20% (p < 0.01), independent of age, gender, and other risk factors. Masuhr and Einhaupl (93) also found that ASA was clearly effective in reducing early death or stroke recurrence within the first few weeks.
Aspirin can be safely combined with low-dose subcutaneous heparin for deep venous thrombosis prophylaxis (90). Its use should be delayed by at least 24 hours if thrombolysis therapy is employed.
Nonarteritic anterior ischemic optic neuropathy and aspirin.
Kupersmith et al. (134), in a retrospective study, suggested that aspirin may reduce second eye involvement in nonarteritic anterior ischemic optic neuropathy (NAION). Beck et al. (135), however, showed little or no long-term benefit to aspirin in reducing the risk of NAION in the fellow eye. These authors recommended caution in interpreting the results, because neither of these studies was prospective or controlled. It remains controversial whether ASA should be routinely recommended after NAION alone. The role of antiplatelet regimens other than ASA in the prophylaxis of NAION is poorly defined.
Dipyridamole (DP) is a phosphodiesterase inhibitor that decreases platelet function by increasing levels of cyclic adenosine monophosphate and guanosine monophosphate. Conflicting data exist regarding the efficacy of ASA alone versus ASA combined with DP. Sivenius et al. (94) reported the data on 6602 patients in The Second European Stroke Prevention Study (ESPS2). In this study, there were four treatment groups: 1) placebo, 2) 2 × 25 mg of ASA, 3) 2 × 200 mg of DP, and 4) combination of 50 mg of ASA and 400 mg of DP per day. ESPS2 showed a benefit from antiplatelet treatment compared with placebo and an additional benefit using ASA combined with DP rather than either agent alone. ESPS2 data suggest that antiplatelet therapy does not influence the severity of recurrent stroke using the Rankin scale but does lengthen the stroke-free interval.
Ticlopidine and clopidogrel.
Ticlopidine is a thienopyridine inhibitor of platelet aggregation. The Ticlopidine Aspirin Stroke Study showed that it reduces the risk of stroke when combined with ASA or when compared to ASA alone (95), but it has a high rate of side effects, including diarrhea (20%) and rash (10%). Serious and potentially life-threatening complications, including neutropenia and thrombotic-thrombocytopenic purpura, may occur in as many as 1% of patients.
Clopidogrel is an analogue of ticlopidine with an additional carboxymethyl side group and fewer hematologic side effects. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (96), it reduced the risk of stroke but was no more effective than ASA alone.
Glycoprotein platelet IIb/IIIa complex antagonists.
The glycoprotein platelet IIb/IIIa complex is the binding site for adhesive proteins such as fibrinogen. These proteins activate platelet aggregation and adhesion to blood vessels. Abciximab (ReoPro; Eli Lilly and Co., Indianapolis, IN) is a fragment of chimeric human/mouse monoclonal antibody that acts as a platelet glycoprotein IIb/IIIa antagonist. The Abciximab in Ischemic Stroke Investigators performed a randomized, double-masked, placebo-controlled, dose-escalation trial in 74 patients after ischemic stroke (97). There were no cases of major intracranial hemorrhage. Asymptomatic parenchymal hemorrhages were detected on CT scan in 4 of 54 (7%) patients on abciximab compared with 1 of 20 (5%) patients on placebo. Six additional abciximab patients had asymptomatic hemorrhagic lesions detected by unscheduled brain imaging during their follow-up period. Investigators concluded that abciximab was probably safe when administered up to 24 hours after stroke onset, and it might improve functional outcome.
Heparin and heparin analogs.
Heparin is a biologic substance derived from bovine lungs and porcine intestine, which can be separated into low-and high-molecular-weight fractions. Its anticoagulant effect relates to binding of antithrombin III, inactivating thrombin and other serum protease coagulation factors, antagonizing thromboplastin, and interfering with the reaction of thrombin with fibrinogen to form fibrin. It does not potentiate recanalization of occluded arteries, and it has no neuroprotective properties; to date, no short-term or long-term benefit of heparin in acute ischemic stroke has been established. Heparin may, however, be useful for the following disorders: 1) acute intracranial dural and venous thrombosis, 2) presumed cardiogenic emboli with high risk of intracranial embolism, and 3) acute thrombi or severe large artery stenosis. Heparin is not recommended for hemorrhagic stroke or in cases with uncontrolled hypertension or high risk of bleeding.
Heparinoids are heparin analogs that have anticoagulant effects. Low-molecular-weight heparins (LMWH), such as enoxaparin, dalteparin, nadroparin, and tinzaparin, have better bioavailability and pharmacokinetics than heparin, and they result in fewer hemorrhagic complications, presumably because of their reduced effect on platelet function and vascular permeability. Either low-dose unfractionated heparin (UFH) or LMWH has been recommended for acute ischemic stroke patients with immobilized or paralyzed limbs who are at high risk for venous thromboembolism (VTED). Lensing et al. (98) reported that anticoagulation in high-risk patients reduced the risk of deep venous thrombosis and pulmonary embolism, but there was an increased risk of intracranial bleeding within 14 days of treatment. The incidence of thromboembolic events was 20% in patients randomized to enoxaparin compared with 35% in the UFH-treated group. In the Thromboembolism Prevention in Cardiopulmonary Diseases with Enoxaparin (PRINCE) trial, once-daily enoxaparin was compared to three-times-daily UFH. The PRINCE trial found that enoxaparin was at least as effective as UFH in reducing the risk of thromboembolic events by 19%. In high-risk predefined subgroups with heart failure, enoxaparin was significantly more effective (99).
Warfarin (Coumadin), an oral anticoagulant, inhibits vitamin K, a requirement for synthesis of factors II, VII, IX, and X. After acute use of heparin in thromboembolic disease (TED), warfarin allows clot organization and adherence to the vessel wall. Several studies have documented its efficacy, at a target international normalized ratio (INR) of 2.5, in atrial fibrillation. It may also be beneficial in other high-risk cardiac embolic diseases, and this question is being studied in clinical trials. Patients with cardiac thrombi or arrhythmia, prothrombotic cardiac lesions such as prosthetic heart valves, or some hypercoagulable states, including the presence of lupus anticoagulant, may require indefinite warfarin therapy.
Oral anticoagulant treatment for prevention of recurrent stroke in atherothrombotic, noncardiogenic embolic stroke, however, has not been sufficiently proven and may lead to increased hemorrhagic complications (89).
Tissue plasminogen activator.
Since 1990, clinical trials of intravenous thrombolysis for ischemic stroke have involved more than 3000 patients (100). Tissue-type plasminogen activator (tPA) was approved by the Food and Drug Administration (FDA) in 1996 after a large randomized placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS). The NINDS study showed a significant improvement in 3-month and 12-month outcomes with tPA at a dose of 0.9 mg/kg within 3 hours of onset. Hacke et al. (101–103) and Lyden (104) have reviewed the data from the NINDS and the first and second European Cooperative Acute Stroke Studies (ECASS I and II). The European trials showed comparable results but did not reach statistical significance for their primary endpoints. Nevertheless, the risk/benefit profile of tPA therapy based on the results of these three trials suggested that treatment was beneficial for selected eligible patients if administered within the 3-hour time window. At the 6-hour time window, a combined analysis of the three studies shows the number of disabled or dead patients was reduced. Devuyst and Bogousslavsky (105) believed that the results of these three studies must be interpreted with caution, however, and concluded that ECASS II was an “equivocal” study. Specifically, it was negative for the primary end point but positive in the post hoc analysis of modified Rankin scale scores dichotomized for death or dependency. These authors summarized the reasons for the controversy: 1) possible selection bias, 2) use of an uncommon primary end point, and 3) problems of power significance.
Clark et al. (106), in the Thrombolytic Therapy in Acute Ischemic Stroke Study, assessed the efficacy and safety of intravenous rtPA in 142 patients with acute (0–6 hours) ischemic stroke in a phase II, placebo-controlled, double-masked randomized study. A higher percentage of rtPA patients (40%) had a four-point improvement on the National Institutes of Health Stroke Scale (NIHSS) at 24 hours compared with placebo (21%) (p = 0.02). This early effect was reversed by 30 days when comparing the placebo group (75%) with the r tPA group (60%) (p = 0.05). Treatment with rtPA significantly increased the risk of symptomatic intracerebral hemorrhage (ICH) at 10 days (11%) versus placebo (0%) (p < 0.01). The mortality rate at 90 days was also increased (23%) versus placebo (7%) (p < 0.01).
Albers et al. (107) performed a prospective, monitored, postapproval, multicenter trial with 389 consecutive patients in the Standard Treatment with Alteplase to Reverse Stroke Study (STARS). The median time to treatment was 2 hours and 44 minutes. The median baseline NIHSS score was 13. Thirty-five percent of patients had very favorable outcomes on the modified Rankin score (0–1), and 43% were functionally independent on the same scale (0–2). Thirteen patients (3.3%) experienced symptomatic ICH, of which seven were fatal. Twenty-eight patients (8.2%) had an asymptomatic ICH. Protocol violations were reported for 127 patients (32.6%). The following were favorable predictors: 1) less severe baseline NIHSS score, 2) absence of effacement or hypodensity of greater than 33% of the middle cerebral artery (MCA) territory or a hyperdense MCA on CT scan, 3) age less than 85 years, and 4) lower mean arterial pressure at baseline.
Tanne et al. (108) reported on 30 patients more than 80 years old compared with counterparts less than 80 years old (n = 159) included in the tPA Stroke Survey. In logistic regression models, there were no differences in odds ratio for favorable or poor outcome except for a tendency for higher in-hospital mortality in elderly patients (odds ratio, 2.8; 95% CI, 0.81–9.62;p = 0.10).
Caplan (109) reviewed seven studies of 370 patients of intravenous thrombolysis with rtPA. One third of patients showed significant recanalization compared with 5% of 58 controls. MCA occlusions seemed to demonstrate the best response.
The major risk of tPA is ICH. The reported incidence of ICH is somewhat variable, including 3.3% in STARS, 6.4% in NINDS, 9% in the OSF Stroke Network (110), and as much as 20% in other series (111). Katzan et al. (112) reported a historical prospective cohort study of 3948 patients with ischemic stroke. Seventy patients (1.8%) admitted with ischemic stroke received intravenous tPA. Of these patients, 11 (15.7%) had a symptomatic ICH, and six of these were fatal. Half of the cases had deviations from national treatment guidelines. The authors concluded that the community Cleveland area experience with tPA for acute ischemic stroke may differ from that reported in clinical trials.
Buchan et al. (113) emphasized the need to follow protocol. They reviewed 68 consecutive patients with acute ischemic stroke treated with intravenous tPA within 3 hours of symptom onset. Fifty-seven patients were treated according to the NINDS protocol, with a mean baseline NIHSS score of 15 ± 6. Of these 57 patients, 26 (38%) made a full recovery, and 39 (57%) made an independent recovery. Eleven patients violated protocol and had a lower probability of independence (p < 0.02) or full neurologic recovery (p < 0.02). These patients also had a higher probability of symptomatic hemorrhage (p < 0.05) or death (p < 0.01).
Intravenous thrombolysis is believed to be most effective clinically under the following conditions: 1) when the occluded arteries are intracranial and relatively small, 2) when the thrombus is acute, 3) when recanalization occurs, and 4) for emboli rather than in situ thrombi in atheromatous plaques. Trouillas et al. (114) reported an open trial of intravenous rtPA (alteplase) for smaller intracranial arterial events administered within 7 hours of symptom onset. Seven of nine patients with anterior choroidal artery (AChA) territory infarct had a primary early recovery within 6 hours after rtPA. Recovery was complete in five of seven patients. The authors concluded that AChA-territory strokes responded well to intravenous rtPA and hypothesized that this finding resulted from the small size of the artery and the clot.
The three important randomized trials of intravenous streptokinase are the Multicentre Acute Stroke Trial–Italy (MAST-I), the Multicentre Acute Stroke Trial–Europe (MAST-E), and Australian Stroke Trial (115). These three trials were stopped because of high rates of brain hemorrhage, and this agent is not generally recommended. Wardlaw et al. (116) reviewed the influence of baseline risk postthrombolysis outcome in the MAST-I. The risk with streptokinase was similar in “severe” and “mild” strokes.
Two trials of intra-arterial (IA) prourokinase confirm the benefits of treatment for highly selected patients with angiographically confirmed proximal MCA occlusion if instituted within 6 hours after the onset of symptoms. IA direct thrombolysis has theoretical advantages over intravenous therapy: 1) faster and higher rates of complete recanalization, 2) lower required dosage of thrombolytic agent, and 3) smaller risk of hemorrhage (117). Abou-Chelb and Furlan (118) reviewed several IA thrombolysis studies and believed that IA therapy was at least as effective as intravenous thrombolysis. They cautioned, however, that unresolved issues remain before such therapy can become a part of the standard of care. Caplan (109) reviewed 17 (n = 449 patients) nonrandomized studies of IA thrombolysis. The drugs used included urokinase, streptokinase, and urokinase tissue plasminogen activator. Of the 449 patients, 299 (64%) experienced effective recanalization. Mainstem and divisional MCA occlusions (62%) had the best response. Basilar artery occlusions had a 62% recanalization rate. Internal carotid artery (ICA) occlusions had less response (45%). Distal MCA occlusions did not respond as well as proximal MCA occlusions. Forty-two percent (n = 197) of patients had a “good” outcome overall, and 18.5% of patients had ICH.
Lewandowski et al. (119) reported a double-masked, randomized, placebo-controlled multicenter phase I pilot study of intravenous rtPA or intravenous placebo followed by immediate cerebral arteriography and local microcatheter IA rtPA (n = 35). Recanalization was better (p = 0.03) in the intravenous/IA group. This pilot study demonstrated that combined intravenous/IA treatment is feasible and provides better recanalization. There was no evidence, however, of improved clinical neurologic outcome. Ueda et al. (117) reviewed 66 patients treated with IA thrombolysis within 6 hours of symptom onset. Multiple regression analysis suggested that age, residual cerebral blood flow (CBF), neurological score at baseline and the following day, and recanalization grade correlated significantly with long-term outcome.
Thrombolysis and central retinal artery occlusion.
Hattenbach et al. and Wirostko et al. (136,137) have reported anecdotal successful thrombolysis in central retinal artery occlusion (CRAO). In the absence of prospective controlled clinical data, however, the benefit of thrombolysis for intraocular thrombosis remains controversial.
Role of new neuroimaging modalities.
Newer imaging modalities for stroke include combined diffusion-weighted and perfusion magnetic resonance (MR) scans, MR angiography, xenon CT and CT angiography, transcranial Doppler ultrasound, and positron-emission tomograph (PET) scans. These new modalities can provide important information about vascular occlusion, potential reversibility of ischemia, and brain function (121). Albers (120) emphasized the expanding role for early MR imaging in acute stroke, suggesting that such acute MR imaging may eventually prove superior to CT for identification of patients eligible for thrombolytic therapy. Tong and Albers (122) reviewed the utility, indications, and potential future role for diffusion/perfusion-weighted MR imaging, which may play a substantial role in determining the suitability of acute stroke patients for thrombolytic therapy. Early perfusion-weighted imaging (PWI) may show blood flow abnormalities and acute dysfunctional brain tissue. Acute diffusion-weighted imaging (DWI) lesion may correspond to the core of the early infarction. Mismatch between the acute PWI lesion and the smaller DWI lesion may represent potentially salvageable but poorly perfused brain tissue surrounding the infarct. In patients with PWI/DWI mismatch, early reperfusion may be associated with clinical improvement and reversal or reduction of DWI lesion growth.
Alexandrov et al. (123) reported the use of transcranial doppler (TCD) with low MHz frequency to determine arterial occlusion and continuously monitor recanalization in 40 patients treated with tPA. Clinical lack of improvement or worsening was associated with no recanalization, late recanalization, or reocclusion on TCD (p < 0.01). Recovery was associated with recanalization on TCD.
Central benzodiazepine receptor ligands, such as 11C flumazenil (FMZ), are markers of neuronal integrity and may be useful in the future for differentiation of functional and morphologic stroke damage. Heiss et al. (124) studied 11 patients with acute hemispheric ischemic stroke treated with alteplase using cortical cerebral blood flow, FMZ binding, and PET. Hypoperfusion was observed in all cases, and they concluded that FMZ PET may distinguish between irreversibly damaged and viable penumbra tissue early after acute stroke.
Other potential agents in stroke therapy
Statins (3-hydroxy-3-methylglutaryl (HMG)-coenzyme (Co) A reductase inhibitors).
3-hydroxy-3-methylglutaryl (HMG)-coenzyme (Co) A reductase is the rate-limiting enzyme in cholesterol formation in the liver. HMG-CoA reductase inhibitors (statins) lower serum cholesterol and especially lower the LDL component and may reduce the incidence of stroke; they include pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, and cerivastatin. Hess et al. (125) reviewed several randomized trials of coronary artery disease and statins. Pravastatin lowered average cholesterol levels and reduced the risk of stroke in patients with coronary artery disease. Simvastatin reduced the risk of the combined endpoint of stroke and transient ischemic attack in hypercholesterolemia and coronary artery disease. The precise way in which statins reduce risk is unclear and may not be solely related to cholesterol or low-density lipoprotein reduction. Vaughn et al. (126) reviewed other important mechanisms: 1) nonsterol effects on vascular endothelial cells, 2) anti-inflammatory effects, 3) depletion and stabilization of the lipid core of plaques, 4) strengthening of the fibrous cap of plaques, 5) decreased formation of platelet–fibrin thrombi, 6) decreased deposition of clot on endothelial surfaces, 7) reduced thrombogenicity, and 8) antithrombotic effects on macrophages, platelets, and smooth muscle cells. Rosenson (127) proposed several mechanisms for cerebrovascular protection by statins. These mechanisms include reduction of cardiac, aortic, and carotid embolization sites; stabilization and reduction progression of vulnerable carotid atherosclerotic plaque; and improvement in cerebral blood flow. Statins also reduce the size of cerebral infarction in a murine stroke model, possibly via a neuroprotective effect.
Several treatments aimed at neuroprotection and salvation of ischemic neurons in stroke are being studied (128). A multitude of agents considered for study are listed in Table 1 (129). Lutsep and Clark (131) reviewed those treatments that have reached the late stage of development, including N-methyl-D-aspartate (NMDA)-receptor antagonists, antileukocyte antibodies (intercellular adhesion molecule (ICAM)-1 antibody), GABA agonists (clomethiazole), citicolen (phospholipid metabolism), opiod receptor antagonists (nalmefene), and sodium channel blockers (fosphenytoin).
Promising results have been reported in animal stroke models. Unfortunately, to date, there is no clear and convincing evidence in randomized controlled clinical trials to support efficacy in humans.
The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators (132) reported on GV150526, a selective blocker of glycine and an obligatory coagonist with glutamate of the NMDA receptor. This agent reduces infarct volume in rats with focal cerebral ischemia. Two randomized, double-masked, and placebo-controlled trials were reviewed, but no clinical conclusions could be drawn regarding efficacy.
Clomethiazole enhances gamma-aminobutyrate type A (GABAA) receptor activity. Efficacy and safety were tested in the Clomethiazole Acute Stroke Study (CLASS) (133). Investigators studied clomethiazole using a 24-hour infusion of 75 mg/kg versus placebo in 94 acute hemorrhagic stroke patients. The number of patients reaching functional independence on the Barthel index score (> 60) was 59.6% for clomethiazole versus 53.2% for placebo. No substantial safety issues were raised.
Devuyst and Bogousslavsky (105) and De Keyser et al. (130) reviewed the discrepancy between experimental and clinical results for multiple neuroprotective agents, suggesting possible reasons: 1) single drug trials, 2) heterogeneity of stroke population, therapeutic dose, and adverse effects, and 3) therapeutic time window.
The role of neuroprotective agents in stroke remains to be defined.
Paraneoplastic syndromes represent visual or neurologic dysfunction in the setting of known or suspected malignancies, without direct involvement of the eye or nervous system by tumor, antineoplastic agent toxicity, or opportunistic infection. They are thought to originate from an autoimmune process, and circulating antibodies to specific neuronal antigens have been identified in some cases. Syndromes of neuro-ophthalmologic significance primarily involve the retina, optic nerve, brainstem, and cerebellum. In this review, we focus on disorders of the retina and optic nerve (138–171).
Paraneoplastic retinopathies include primarily the cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse uveal melanocytic proliferation (BDUMP) syndromes.
Cancer-associated retinopathy is the most common visual paraneoplastic disorder. The presenting manifestations for cone-related disorders include hemeralopia, photopsias, central acuity loss, color dysfunction, and paracentral or central scotomas. Predominantly rod-affected patients may present with nyctalopia, impaired dark adaptation, visual dimming, ring scotoma, or peripheral visual-field loss. A case of isolated cone dysfunction has recently been reported by Jacobson and Thirkill (138), corroborating three previously reported cases. Symptoms develop for weeks to months, and in as many as 50% of cases, the symptoms begin before the underlying malignancy is identified. Patients experience progressive deterioration and eventual bilateral involvement with severe visual loss. The fundus examination may initially be normal, although the ERG is typically markedly reduced in amplitude even in the early stages. As the course progresses, the retinal arterioles become attenuated, the retinal pigment epithelium (RPE) becomes thinned and mottled, and the optic discs become atrophic. Less commonly, aqueous or vitreous cellular reaction and retinal periphlebitis are seen. Elevated CSF protein level and lymphocytosis may be seen. Although corticosteroid therapy has been reported to stabilize visual loss in isolated cases, the visual prognosis is generally poor.
Most reported cases of CAR involve patients with small-cell carcinoma of the lung (SCCL), although other lung tumors, breast malignancies, uterine malignancies, and cervical malignancies have been implicated. Investigators believe that, in the majority of patients, the tumor expresses an antigen that is homologous to a 23-kd retinal photoreceptor protein, originally termed the “CAR antigen,” more recently identified to be the calcium-binding protein recoverin. The human recoverin gene has been mapped to a region of chromosome 17 containing other cancer-related loci (139). Recoverin has been identified in tumor cells of patients with SCCL (140), endometrial carcinoma (141), and malignant mixed mullerian tumor (142). Circulating autoantibodies against the tumor-associated antigen presumably cross react with retinal recoverin to produce immune-mediated photoreceptor degeneration. The exact mechanism is unclear. McGinnis et al. (139) postulate that inactivation of the p53 tumor suppressor gene may increase expression of recoverin by tumor cells outside the eye, with subsequent autoantibody production. Regardless of specific mechanisms, most investigators believe it to be primarily a humoral immunity response based on the circulating antibodies and the lack of substantial inflammatory infiltrate in most retinas examined microscopically; however, some cases have demonstrated inflammatory cells (147), suggesting a component of cellular immunity as well. The 23-kd antiretinal antibodies have been detected in the majority of the reported cases of CAR. Adamus et al. (143) have demonstrated induction of apoptosis in E1A.NR3 rat retinal cells by serum antirecoverin autoantibodies in CAR.
Antiretinal antibodies directed against other antigens have been detected in several recent reports of paraneoplastic retinopathy. Ohkawa et al. (144) described bilateral severe progressive retinopathy in a patient with endometrial cancer who demonstrated serum antibodies against only a 34-kd retinal protein. Autoantibodies to a 60-kd retinal protein were found in a patient with small-cell lung carcinoma with clinical and electrophysiologic features of CAR syndrome but negative testing for the 23-kd CAR antibody (145). Antibodies against the 46-kd protein enolase-α, a ubiquitous glycolytic enzyme (146) that is also elaborated by several tumor types, have been documented in patients with CAR. The antibodies were also detected in patients with vasculitis, other tumors without retinopathy, and in healthy patients, though the levels were lower. The antienolase antibodies found in patients with retinopathy have also been shown to induce apoptosis in E1A.NR3 rat retinal cells, whereas those in healthy patients have not; the effect of these antibodies in vasculitis is unproven (147).
Progressive retinopathy resembling the CAR syndrome was reported by Mizener et al. (148) in two patients without malignancy during a 5-to 7-year follow-up period but with evidence of autoimmune disease and strong family history of autoimmune disease. Visual loss was unilateral and severe, with demonstration of a ring scotoma but normal fundus appearance. The ERG was flat in one case and, in the other case, showed evidence of inner retinal dysfunction with selective b-wave loss and abnormal oscillatory potentials. Circulating antiretinal antibodies reactive against the retinal inner plexiform layer but not against CAR antigen or other previously reported retinal antigens were identified. Whitcup et al. (149) reported a case of similar progressive retinopathy with severe depression of the rod-mediated ERG and autoantibodies against recoverin, but no documented malignancy 3 years after onset of visual loss. They termed the disease recoverin-associated retinopathy; to distinguish it from the CAR syndrome, Keltner and Thirkill (150) further described the distinction in a separate editorial.
Management of CAR syndrome has generally been ineffective, but a benefit has been reported in certain cases, using systemic corticosteroids, plasmapheresis, or intravenous immunoglobulin (IVIg). Keltner et al. (151) described a patient whose antibody levels diminished and visual function improved and stabilized on corticosteroid therapy. More recently, Murphy et al. (152) described a patient in whom oral corticosteroid therapy combined with plasmapheresis resulted in recovery of vision. The vision improved from counting fingers to 20/200 OD and from 20/40 to 20/25 OS. This visual acuity was maintained at least 4 months with response of the tumor to chemotherapy and reduction of antiretinal (60-kd) antibody levels from 1 to 2000 to 1 to 200. Guy and Aptsiauri (152) reported response to IVIg (400 mg/kg/day during 5 days in one case and during 1 day in the other case) in two of three patients with paraneoplastic retinopathy. Visual acuity in the first case improved within 24 hours of the first dose from hand motions OU to 20/50 OD, 20/200 OS, with further improvement of OS to 20/40 after 72 hours. In the second case, visual acuity remained stable, but visual fields improved after the single dose.
Melanoma-associated retinopathy is a very rare visual paraneoplastic syndrome associated with cutaneous malignant melanoma, predominantly affecting men, though melanoma occurs relatively equally in men and women. In contrast to CAR, it is a disorder primarily of rods, with corresponding symptoms of photopsias, shimmering colored visual phenomena, and nyctalopia, usually developing rapidly for weeks to months but occasionally with sudden onset and eventually involving both eyes. The clinical examination often initially reveals normal visual acuity, color vision, and central visual field, with peripheral constriction, midperipheral scotomas, or generalized depression of the most common field abnormalities. Central scotomas are unusual. The fundus may be normal or may show RPE irregularity, retinal arteriolar attenuation, and optic disc pallor in cases that have been symptomatic for months. Unlike the CAR syndrome, visual function may remain stable and nonprogressive in MAR. Visual symptoms typically develop in the setting of previously diagnosed melanoma, and metastasis is often found with the development of visual loss. No treatment has been proven effective for MAR (153–156).
The ERG abnormalities in patients with MAR syndrome suggest rod dysfunction, with severe impairment of the dark-adapted b-wave, sparing the a-wave response. Oscillatory potentials are reduced in a manner similar to other retinal disorders that are characterized by failure of neural transmission from outer to inner retina through the bipolar cell layer. Moreover, immunofluorescent staining of the retinal bipolar cell layer by circulating IgG autoantibodies has been demonstrated (154,157–159). Histopathologic evidence of dropout in the bipolar neurons of the inner nuclear layer of the retina has recently been documented by Gittinger and Smith (160). It is postulated that antimelanoma antibodies may cross react with these bipolar cells to produce the syndrome (155). The antigen is as yet unidentified, although a membrane-associated lipid is suspected. Lei et al. (161) demonstrated that intravitreal injection of circulating IgG antibodies from humans with MAR resulted in alteration of the retinal ON-pathway response of the monkey ERG, suggesting an autoimmune effect on the depolarizing subset of retinal bipolar cells.
Bilateral diffuse uveal melanocytic proliferation is a rare paraneoplastic disorder that has been reported in association with ovarian, lung, gall bladder, cervical, uterine, kidney, pancreatic, breast, esophageal, and colorectal cancers in more than half of the cases before identification of the underlying malignancy. Occasionally, the syndrome has developed coexistent with recurrence of a previously diagnosed tumor (162). There is a slight predisposition for women. Benign melanocytic proliferation and infiltration of the uveal tract is the characteristic feature. The syndrome presents with painless progressive bilateral visual loss over months, related to damage to retinal pigment epithelium and photoreceptors. Clinical findings include multiple reddish rounded spots at the level of the posterior retinal pigment epithelium—which are hyperfluorescent on angiography—multiple pigmented and nonpigmented focal melanocytic proliferations and diffuse thickening throughout the uveal tract, exudative retinal detachments, and rapidly progressive cataracts.
The differential diagnosis includes choroidal metastases, lymphoma, leukemia, sarcoidosis, uveitis, scleritis, uveal effusion, and Harada disease. Comparison and contrast to CAR were highlighted in recent reports by Brink et al. (163) and Gass (164).
Murphy et al. (165) recently described clinical features in a woman with uterine carcinoma who developed visual loss, exudative retinal detachments, and prominent conjunctival vascular dilation and tortuosity suggestive of arterialized blood vessels. The diagnosis of dural cavernous sinus fistula was considered, but cerebral angiography was negative, and she subsequently developed choroidal lesions typical for BDUMP. Conjunctival hyperemia and congestion has been reported in a number of previous cases, presumed secondary to ciliary body infiltration (166).
The pathogenesis of BDUMP is unknown. It has been suggested that retinal photoreceptor damage occurs because of toxic or immune factors independent of, or in response to, melanocytic proliferation, which may result from trophic hormone production by the tumor or from a coexistent oncogenic factor. Overexpression of p53 protein, a postulated mechanism for development of BDUMP, was not confirmed in recent studies by Margo et al. (167). There remains no effective treatment.
Paraneoplastic optic neuropathy
A syndrome of acute optic nerve dysfunction has been described in patients with carcinoma, particularly SCCL or lymphoma, in the absence of meningeal tumor infiltration; it is a presumed paraneoplastic neuropathy, although its etiology is unproven (168,169). Patients present with the rapid onset of progressive visual loss, usually bilateral, and in most cases associated with optic disc edema. Many of the reported cases also demonstrated brainstem and cerebellar dysfunction suggestive of a paraneoplastic syndrome. CSF analysis often shows mild to moderate lymphocytosis and elevated protein levels but no evidence of malignant cells. The ERG results are typically normal. Testing for CAR antibody is negative. At autopsy, most cases have shown demyelination in the affected tissues, associated with a perivascular lymphocytic infiltrate typical of findings in other paraneoplastic syndromes.
Luiz et al. (170) recently described a case of bilateral optic neuropathy and cerebellar degeneration in a 59-year-old woman eventually diagnosed with SCCL. She presented with acute bilateral painless loss of vision, optic disc edema, and severe visual field constriction, along with slurred speech, lower extremity weakness, ataxia, and other cerebellar signs. All testing results for brain metastasis and meningeal infiltration was negative, although CSF lymphocytosis (122 WBC/mm3) and elevated protein (111 mg/dl) were noted. ERG results were normal, and testing results for CAR, Yo, Hu, and Ri serum antibodies were negative. However, autoantibodies reactive against a 60-kd neural protein similar to that previously reported by Murphy et al. in a case of CAR-antibody-negative retinopathy with SCCL were present. These antibodies appear to react against antigens in the retina, optic nerve, cerebellum, and spinal cord, although a causative relation with the optic neuropathy has not been proven. Similar antibodies were noted by Malik et al. (171). The patient demonstrated prolonged visual improvement and stabilization at the 1-year follow-up examination after chemotherapy and pulse intravenous methylprednisolone.
This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY.
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