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Journal of Neuro-Ophthalmology 21(1): 46–61, 2001. 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Systemic Disease and Neuro-ophthalmology: Anthony C. Arnold, MD, and Andrew G. Lee, MD In part I of this annual update, we review current as- Some authors have proposed the use of high-dose pects of multiple sclerosis and stroke therapy and the (e.g., 500 mg) oral MP (9), and there may be a role for paraneoplastic syndromes of the retina and optic nerve.
oral therapy in selected cases. Survey information hasshown wide variability in the dose, route of administra- THERAPY OF MULTIPLE SCLEROSIS
tion, duration, venue, and indication for steroid use inMS among treating neurologists (76). The issues sur- Multiple sclerosis (MS) is a common demyelinating rounding oral versus intravenous steroids remain contro- disease of the central nervous system (1–86), with sub- versial. Both prednisone and MP are well absorbed stantial long-term neurologic consequences (1,4,9,25,34, orally, and oral therapy is less expensive than intrave- 52,54,55,57,60,63,65). After 10 years with MS, 50% of nous therapy. Some clinicians use low-dose oral pred- patients are unable to perform household and occupa- nisone for minor exacerbations and reserve intravenous tional responsibilities; after 15 to 20 years, 50% are un- therapy for major relapses (70). Although some authors able to walk without assistance; after 25 years, 50% are have used intravenous pulse MP for progressive disease, unable to ambulate. The average annual cost of MS in the there is only limited evidence that steroid treatment im- United States is greater than 6.8 billion dollars (1). There pacts the long-term course of MS (51).
are three main subtypes of the disease: relapsing remit- High oral doses theoretically increase the risk for gas- ting (RR), secondary progressive (SP), and primary pro- tric ulceration. Metz et al. (24) studied 17 patients treated with 1250 mg of oral prednisone per dose and 1000 mg This update reviews the current status of MS therapy of intravenous MP. Three (25%) patients in the oral (1–86). We have chosen to focus on the new and emerg- group and two (40%) patients in the intravenous group ing immunomodulatory therapies for disease relapses had modestly abnormal gastric permeability (95% CI and the treatments to prevent disease progression. We do 34–64%, p ס 0.6). These authors concluded that short- not review the treatments for common MS-related sen- term high-dose oral prednisone was not associated sory and motor symptoms, fatigue, or depression (35).
with greater gastric damage when compared to intrave-nous MP.
Corticosteroids in optic neuritis. The Optic Neuritis
Corticosteroids such as prednisone, dexamethasone, Treatment Trial (ONTT) previously established that in- and methylprednisolone (MP) have been the mainstays travenous MP in typical optic neuritis improved the of therapy for acute exacerbation in MS (1,4,9,25, speed of visual recovery but did not impact final visual 34,52,54,55,57,60,63,65,67). The mechanisms of action outcome. Oral steroids in conventional doses increased include reduction in CD 4 cells, decreased cytokine re- the rate of new attacks and were discouraged by the lease, and decreased class II expression. Although there ONTT. Wakakura et al. (84) reported a randomized con- have been few studies demonstrating advantages of one trolled clinical trial comparing intravenous MP with a type of steroid rather than another, intravenous MP has control drug (mecobalamin) for managing optic neuritis.
emerged as the most frequently used acute short-term The intravenous MP group showed faster recovery of (3–5 days) therapy for exacerbations.
vision, but the visual function at 12 weeks and 1 yearwere essentially the same in the two treatment groups.
Sellebjerg et al. (85) assessed the efficacy of oral high- Manuscript received August 9, 2000; accepted December 1, 2000.
From the Jules Stein Eye Institute, Department of Ophthalmology dose MP in acute optic neuritis. These authors concluded (ACA), University of California, Los Angeles, California, and the De- that oral high-dose MP improved speed of recovery, but partments of Ophthalmology, Neurology, and Neurosurgery (AGL), there was no difference in outcome at 8 weeks or on University of Iowa Hospitals and Clinics, Iowa City, Iowa.
Address correspondence and reprint requests to Anthony C. Arnold, Trobe et al. (86) performed a survey to determine MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles,CA 90095-7005.
whether the ONTT results altered the practice patterns of ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I ophthalmologists and neurologists. In accordance with MS and controls. They reported an increased CSF level the ONTT, nearly all surveyed ophthalmologists and of TNF-sRp55 in response to steroids.
neurologists had reduced their use of oral prednisone Cytokine studies in experimental autoimmune enceph- alone, and most of these professionals used intravenous alomyelitis (EAE) suggest that there is an inflammatory MP. Many clinicians, however, mistakenly believed type 1 cytokine response and a beneficial type 2 response that intravenous MP improved final visual outcome.
(5,18,30,45). Induction of these type 2 cytokines is one Only 7% of neurologists and 36% of ophthalmologists possible IFN effect (18). Duddy et al. (30), however, (p ס 0.0001) in this survey were adhering to the ONTT demonstrated no sustained change in plasma type 1 suggestion to use MRI findings as a basis for treatment.
(IL-12, IL-1␤, and TNF-␣) or type 2 (IL-6, IL-10) cy-tokines. There were repeated inductions of both types of Immunomodulatory agents
cytokines, however, suggesting that IFN ␤-1a causes Interferons. Four classes of interferon (IFN ␣, ␤, ␥,
transient modulation of cytokine expression. Sinigaglia and ␻) are recognized. Initial studies of IFN ␥ showed an et al. (5) reviewed the molecular basis for the type I IFN increase in relapse rate in MS, despite the fact that it (IFN-␣ and IFN-ß) effect on selective induction of Th1- reduced experimental allergic encephalitis in mice. IFN type immune responses. These authors discussed the po- is not currently used in MS therapy. IFN ␣ and ␤ are tential effects of treatment and the value of the Th1/Th2 type I IFN and have many effects that counter IFN ␥.
paradigm in MS. Lou et al. (44) investigated the effects IFN-␣ trials, however, have provided mixed results.
of IFN-␤ on leukocyte transendothelial migration and In some studies, IFN ␣-2a reduced exacerbation rate concluded that inhibition of this migration may be an- and magnetic resonance (MR) activity in MS (13). Myhr et al. (66), however, in a randomized placebo-controlled Ossege et al. (45) investigated the influence of IFN trial of IFN ␣-2a (n ס 97), reported reduced MR lesions ␤-1b on the mRNA expression of the immunosuppres- but no treatment effect on exacerbation rate, progressionof disability, or quality of life (QoL). The value of IFN sive cytokine TGF ␤-1 and the proinflammatory media- IFN ␤ is an immunomodulatory agent that affects T- Treatment results of interferons. Interferon ␤-1b has cell function and has an established beneficial role in MS multiple effects in RR MS, including reduction of relapse (2,5–7,9–16,27–29,30,32–33,36,41,44–46,49,50,56,58– rate (33%), reduction of new MRI lesions, and reduction 59,70–73,75,78–83). Interferon ␤-1b (Betaseron; Berlex of MRI lesion volume. IFN ␤-1b may also reduce relapse Laboratories, Richmond, CA) is a nonglycosylated Es- rate, clinical disability progression, and MRI lesion vol- cherichia coli recombinant product. It differs from IFN ume in SP MS. IFN ␤-1a has been shown to reduce ␤-1a by one amino acid and is administered subcutane- progression of disability, rate of relapse, new MRI le- ously. IFN ␤-1a (Avonex [Biogen, Cambridge, MA]) is sions, and MRI lesion volume (2,5–7,9–16,27–29,30,32, a glycosylated protein derived from Chinese hamster 33,36,41,44–46,49,50,56,58,59,70–73,75,78–83).
ovary cells. It is identical to human IFN and is injected More recent studies have confirmed the benefit of IFN intramuscularly once weekly (1,4,9,25,34,52,54,55,57, ␤ therapy seen in previous clinical trials. Weekly IFN ␤-1a has been shown to decrease the rate of new enhanc- Mechanism of action of interferons. The mechanisms ing lesions on MRI. Gasperini et al. (79) showed a sta- of action for IFN effect in MS are largely unknown. IFN bilizing effect on T1-weighted hypointense lesion vol- have been documented to inhibit migration of T cells, ume (n ס 67) in RR MS. Miller et al. (27) performed enhance major histocompatibility complex (MHC) class a randomized placebo-controlled trial of IFN ␤-1b I and inhibit MHC class II expression on monocytes, (n ס 718) in SP MS with a follow-up period of up to have antiviral effects (2,5–7,9–16,18,27–29,30,32– 3 years. There was a 15% increase in MR lesions from 33,36,41,44–46,49,50,56,58–59,70–73,75,78–83), and baseline to last MR scan in the placebo group. In con- trast, there was a significant reduction in MR lesions at The role of cytokines in the development of MS has year 1 (4%) and year 2 (5%) for the treatment group.
been intensively investigated. T cells (CD4+) may dif- Paolillo et al. (46) reported that the duration of MR en- ferentiate into Th1 and Th2 cells with varying effect on hancement and the number of new enhancing lesions cytokine production (13) (e.g., interleukin [IL]-2, tumor were lessened by IFN ␤-1a treatment. The clinical sig- necrosis factor [TNF], and IFN-␥). This effect may play nificance of these changes in MR findings is still de- a role in the formation of demyelinating plaque in MS bated. There is increasing evidence that MR abnormali- (5,18,30,37). The mechanism of steroid treatment benefit ties are objective and quantifiable measures of treatment in MS is probably multifactorial (65,67) and may overlap effect in MS. Rovaris (11,77), however, reviewed MRI with the mechanism for IFN action. Tumor necrosis fac- findings and long-term disease evolution in MS in trials.
tor-alpha (TNF-␣) is a cytokine that can cause myelin They found only a variable clinical correlation ranging damage. Steroids may up-regulate expression of soluble receptors for IL-1 and TNF-␣, reducing cytokine effect.
Li and Paty (50) reported the results of the Prevention Franciotta et al. (37) measured plasma and cerebrospinal of Relapses and Disability by Interferon-beta-1a Subcu- fluid (CSF) levels of TNF-␣ and its soluble receptors taneously in Multiple Sclerosis (PRISMS) trial. This (TNF-sRp55 and TNF-sRp75) in 18 patients with active study was a double-masked, randomized, multicenter, J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 phase III, placebo-controlled study of IFN ␤-1a reported that “resources could be used more efficiently (n ס 560). The results of treatment showed a reduced elsewhere”. The issue of cost effectiveness for IFN treat- number of relapses, increased number of relapse-free pa- ment remains controversial and continued study is tients, prolonged time to relapse, reduced number of moderate or severe relapses, and delayed progression of Side effects of interferons. Adverse effects with IFN ␤ disability. Over 2 years, there was a progressive increase are common and especially frequent during the first in MRI burden of disease (10.9%) for placebo when weeks of treatment. Flu-like symptoms occur in as many as 75% of patients. The side effects include fever, chills, There was also a small dose difference of 1.2% for myalgia, insomnia, anorexia, weight loss, fatigue, and IFN at a 44-␮g dose and 3.8% for IFN at a 22-␮g dose.
injection-site reactions (7,10,22,28,59). The effects may Rudick et al. (56) reviewed the results of CSF analyses in be more frequent in women (10). Transient laboratory a subset of RR MS patients in a placebo-controlled, abnormalities, neuropsychiatric changes, menstrual dis- double-masked, phase III clinical trial. IFN ␤-1a signifi- orders, and increased spasticity may also occur. Walther cantly reduced CSF white blood cell (WBC) counts, but reviewed other possible side effects including various there was no treatment-related change in CSF IgG index, autoimmune reactions, capillary leak syndrome, anaphy- kappa light chains, or oligoclonal bands.
lactic shock, thrombotic-thrombocytopenic purpura, in- Dosage of interferons. The ideal dose for IFN in MS is somnia, headache, alopecia, and depression (28). These not determined (2,5–7,9–16, 27–29,30,32–33,36,41,44– side effects may result in reduced treatment compliance 46,49,50,56,58,59,70–73,75,78-83).
or discontinuation of therapy. Efforts to minimize thesereactions include appropriate management of mild side Blumhardt (41) reviewed and summarized data sug- effects with analgesics and antipyretics such as ibupro- gesting that low doses administered once weekly are fen, acetaminophen, and pentoxifylline. The use of cor- relatively less effective than higher and more frequent rect preparation, careful injection technique, and modi- doses of IFN. The Once Weekly Interferon for MS Study fication of the dosage may be helpful. Bayas et al. (7) Group reported a randomized double-masked study of reviewed the management of these adverse effects. Ibu- IFN ␤-1a at 22 ␮g, at 44 ␮g, or placebo administered by profen and gradual introduction of the drug may reduce weekly subcutaneous injection for 48 weeks (81). These the incidence of flu-like symptoms to rates comparable authors concluded that there was a beneficial effect on MRI findings of IFN ␤-1a at low dose in MS. There was Quality of life and interferon therapy. Patients with a dose–effect relationship for clinical and MRI variables.
MS often have a normal lifespan, and, therefore, QoL Patti et al. performed a double-masked randomized trial parameters are important outcome measures. Rice et al.
of natural IFN ␤ (n ס 58). In the treated RR MS group, (33) reported that patients with RR MS (n ס 117) treated there was a significant reduction in the exacerbation rate, with IFN ␤-1b had a better QoL than untreated patients.
an increase in the probability of remaining exacerbation Nortvedt et al. (32) performed a randomized double- free, and an improvement in mean disability score at 24 masked placebo-controlled treatment trial of 97 RR MS months. The number and activity of lesions on MRI was patients. These authors found a relationship between new significantly reduced in treated RR patients. In the enhancing MR lesions and reduced QoL among the pla- treated SP MS group, there was a significant reduction in cebo patients but not the IFN patients. Treatment with disability score and a significant reduction in active le- IFN ␣-2a does not seem to improve patient QoL after 6 sion number. There was only a marginally significant months, despite marked effect measured by MRI. The favorable difference in total lesion burden and no sig- Canadian Burden of Illness Study Group reported that nificant effect on the number of gadolinium-enhancing the QoL of MS patients falls drastically and early in the MRI lesions (83). Waubant et al. (82) reported a reduced disease. Treated patients with RR MS had better QoL number of new MR-enhancing and T2-weighted lesions than untreated historical controls. This finding was es- on serial MR scans (n ס 8) in patients with MS treated pecially true for those patients with an Expanded Dis- with weekly IFN ␤-1a (30 ␮g) (p ס 0.016).
ability Status Scale (EDSS) less than 3.0. Continued Cost analysis of interferon therapy. The cost of IFN work on QoL measures will be important for future treat- therapy may be as much as 8000 to 10,000 U.S. dollars per year. Parkin et al. (6) evaluated the cost effectiveness Neutralizing antibodies to interferons. Neutralizing of IFN ␤-1b for RR MS. IFN ␤-1b produced some short- antibodies (NAbs) to IFN develop in 8 to 40% of cases.
term gains. The authors believed that they translated into The clinical significance of this finding is unclear but only small quality-adjusted life-year (QALY) gains.
may be associated with reduced IFN efficacy (29). An- They concluded that the IFN costs were larger than the tonelli et al. (29) examined the specificity of NAbs to cost savings. Forbes et al. (14) evaluated the cost utility IFN ␤-1a or IFN ␤-1b and studied the effect of switching of IFN ␤-1b in SP MS, finding that for every 18 people from IFN ␤-1a to IFN ␤-1b. All positive sera indepen- treated for 30 months, six relapses would be prevented.
dent of the source may recognize both forms of IFN ␤.
These authors concluded the cost per QALY gained from They concluded that it was unlikely that administration treatment was high. The high-cost variables in their of IFN ␤-1b to anti-IFN ␤-1a NAbs-positive patients analysis included the drug expense, relatively modest could overcome any inhibitory effect exerted by the se- clinical effect, and significant opportunity cost. They J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I Glatirimer acetate (Copaxone). Glatirimer acetate
of developing CDMS was 35% in the treated group ver- (Copaxone; Teva Pharmaceuticals USA, Kansas City, sus 50% with placebo. The volume of new, enlarging, MO), formerly Copolymer I, is a synthetic polypeptide and enhancing MR lesions was significantly lower in the of four amino acids, including glutamic acid, lysine, ala- treated group. Treatment with IFN ␤-1a reduced, by ap- nine, and tyrosine. The chemical structure resembles my- proximately 50%, the rate of development of CDMS elin basic protein (1,4,9,25,34,52,54,55,57,60,63,65). Its within 3 years after an initial event. The practical clinical mechanism of action is unknown but it has been shown implications of the study for therapy of patients with to reduce the relapse rate in MS (29%). It has also been initially isolated optic neuritis have yet to be established.
reported to slow disease progression. The effect of glatir- Immunoglobulin therapy. Intravenous immunoglob-
imer acetate on the number and activity of lesions on MR ulin (IVIg) therapy has been shown to variably reduce is less clear than the beneficial effect seen for IFN. The exacerbations and MR-enhancing lesions in MS. The drug is administered subcutaneously once per day mechanism is unknown but may be related to anti- idiotypic effects or TNF-␤ suppression (1,4,9,25,34,52, Side effects of glatirimer acetate. The side effects of 54,55,57,60,63,65). In several small nonrandomized glatirimer acetate are mild and include injection-site re- studies, there was a reduced rate of disability and activity actions. There are idiosyncratic reactions in as many as of disease on MRI. In animal models and in a few open 15% of patients and the self-limited symptoms include trials, IVIg treatment enhanced central nervous system facial flushing, palpitations, and chest tightness (1,4,9, remyelination (8,61,65,73). Stangel et al. (8) conducted a 25,34,52,54,55,57,60,63,65). NAbs to glatirimer acetate double-masked placebo-controlled pilot study (n ס 10) are of unknown clinical significance.
of IVIg at a dose of 0.4-gm/kg body weight for 5 con- Comparing the three immunomodulatory agents
secutive days. There was no difference in the primary (IFN -1b, IFN -1a, and glatirimer acetate). There
outcome of central motor conduction times after treat- are no data directly comparing the relative efficacy of ment. IVIg is associated with minor side effects includ- these three drugs in a single study (1,4,9,25,34,52,54,55, ing fever, malaise, headache, and rash. There are a few 57,60,63,65). Rudick (1) summarized the supporting evi- major side effects, including aseptic meningitis, renal dence for the use of each agent. The arguments for IFN failure, and thrombosis. The availability of alternative ␤-1b when compared to IFN ␤-1a include: 1) more ben- immunomodulatory agents such as IFN and glatirimer eficial MRI effect on T2-weighted lesion accrual after 2 acetate therapy, the high cost of 1800 dollars per infusion years, 2) higher weekly dose, and 3) larger reduction in for IVIg, and the recent decreased availability of IVIg relapse rate. The arguments for IFN ␤-1a include: 1) in the United States have limited its use for MS (8,61, reduced disability progression, 2) fewer injection-site re- actions, 3) less theoretic immunogenicity, 4) improvedpatient convenience enhanced by weekly dose, and 5) Immunosuppressive therapy
more favorable side-effect profile. The arguments for Azothioprine, methrotrexate, cyclosporine, and cy-
glatirimer acetate are: 1) it is better tolerated than IFN ␤ clophosphamide. Nonspecific immunosuppressive
and 2) it circumvents the problem of NAbs.
agents such as azathioprine (Imuran; Faro Pharmaceuti- Prophylactic interferon therapy: Controlled High- cals, Bedminster, NJ), methotrexate (Rheumatrex; Led- Risk Subjects Avonex Multiple Sclerosis Prevention erle Pharmaceuticals, Pearl River, NY), cyclosporine, Study. Whereas treatment with IFN has been shown to and cyclophosphamide (Cytoxan; Bristol-Myers Squibb, benefit patients with established MS, its value for the Princeton, NJ) have shown some limited efficacy in MS prevention or reduction of later development of demye- (1,4,9,19,24,25,34,40,52,54,55,57,60,63,65). Azathio- linating lesions after a first clinical event has been un- prine works by cell-mediated and humoral immune proven. Initial results from the Controlled High-Risk mechanisms. In meta-analyses of randomized controlled Subjects Avonex Multiple Sclerosis Prevention Study trials, this drug reduced relapse rates by one third and (CHAMPS) suggest that treatment with IFN ␤-1a may reduced progression of disability in MS (80). Side ef- reduce the risk of clinically definite multiple sclerosis fects, including hematologic and gastrointestinal effects, (CDMS) after such an event (87). The study was a mul- however, may outweigh its benefit. Methotrexate also ticenter randomized, double-masked, placebo-controlled works by cell-mediated and humoral immune mecha- trial of 383 patients with an initial neurologic event con- nisms and has reduced progression of upper limb impair- sistent with demyelination, including 192 (50%) patients ment, but not other measures, in one study (51,80). Cy- with optic neuritis and MR evidence of subclinical brain closporin A may also have a modest effect on MS pro- lesions (at least 2 typical MS lesions 3 mm in diameter).
gression but has significant nephrotoxicity (80). Further Subjects were treated with intravenous and oral cortico- studies are needed to determine the potential role of steroids within 14 days of the event and subsequently randomized to weekly intramuscular injections of either Several nonmasked nonrandomized trials have shown placebo or 30 ␮g of IFB ␤-1a within 27 days of the initial a potential benefit for cyclophosphamide in MS (19,40).
event. The trial was terminated at the interim analysis of Other studies, however, including one randomized, efficacy after 3 years, when a beneficial effect was dem- masked, placebo-controlled trial showed no improve- onstrated. Data indicated that the cumulative probability ment in SP MS (40). Hohol et al. (19) studied combined J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 pulse therapy with cyclophosphamide and MP at 4- to cell antibody that blocks transport across the blood–brain 8-week intervals in an open-label trial of 95 subjects with barrier. It showed no clinical effect in one trial (40).
MS. They concluded that there was some benefit to treat- Plasma exchange. Anecdotal reports of plasma ex-
ment, especially for SP MS, that was refractory to im- change have suggested benefit for patients with MS, al- munosuppressive therapy, recommending that earlier in- though the mechanism is unknown (26,31,43,62). Wein- tervention should be considered in these patients. Gob- shenker et al. (26) conducted a randomized, sham- bini (40) evaluated cyclophosphamide in five MS controlled, double-masked study of plasma exchange patients who failed an average of three previous other without concomitant immunosuppressive treatment for treatments. All patients showed a rapid reduction in MR patients with recently acquired severe neurological defi- contrast-enhancing lesion frequency (40).
cits resulting from attacks of inflammatory demyelinat- Mitoxantrone and mizoribine. Mitoxantrone is an
ing disease. All of these patients had failed to recover antineoplastic DNA-reactive agent that has demonstrated after treatment with intravenous corticosteroids. Moder- a significant reduction in relapse rate, delayed time to ate improvement in neurologic disability occurred in 8 of first relapse, and slowed progression of disease in SP MS 19 (42.1%) courses of treatment, compared with 1 of 17 (9). Unfortunately, significant side effects, including car- (5.9%) courses in sham treatment. The Canadian Apher- diac toxicity and neutropenia, may limit its use. Mizor- esis Group reviewed their data on 103,416 plasma ex- ibine (MZR) is an imidazole nucleotide that inhibits pu- change procedures, including management of MS. In the rine synthesis and helper T-cell function and is used in meta-analysis, there was no apparent benefit if the stud- Japan as an immunosuppressant for chronic rheumatoid ies were corrected for multiple comparisons, blinded ob- arthritis. MZR, in one multicenter, double-masked, pla- servations, and exclusion of patients not adhering to stan- cebo-controlled trial, showed no benefit in the primary endpoints of relapse rate and MR lesion area (47). Saida Extracorporeal photopheresis. Rostami et al. (48)
et al. reported 24 MS patients treated with MZR and performed a randomized, double-masked, placebo- corticosteroids in an open trial. The mean relapse rate per controlled with sham therapy trial of monthly extra- year at entry was decreased after 2 years (47).
corporeal photopheresis therapy in progressive MS(n ס 16). No serious side effects occurred, but the treat- Other therapies
ment did not alter the course of disease.
Sulfasalazine. Sulfasalazine is an anti-inflammatory
Lenercept. Tumor necrosis factor is a proinflamma-
drug used in the treatment of various rheumatologic dis- tory cytokine that has been implicated in MS because it eases. The Mayo Clinic–Canadian Sulfasalazine Study is toxic to oligodendrocytes and worsens experimental was a randomized, double-masked, placebo-controlled allergic encephalitis (EAE). Lenercept is a recombinant trial of 199 RR and SP MS patients (17). The trial re- TNF-receptor p55 immunoglobulin fusion protein ported that sulfasalazine temporarily reduced relapse and (sTNFR-IgG p55) that has been shown to be protective in progression rates, delayed time to first relapse, increased EAE. The Lenercept Multiple Sclerosis Study Group and the number of relapse-free patients, and decreased MR The University of British Columbia MS/MRI Analysis activity of MS. The effect was seen in the first 18 months Group performed a double-masked placebo-controlled of the trial but not thereafter. The authors concluded that phase II study (n ס 168) of Lenercept, failing to show the drug did not prevent EDSS progression.
any benefit in MRI study measures. Interestingly, the Roquinimex. Roquinimex is a synthetic immuno-
number of treated patients experiencing exacerbations modulatory agent that has been studied in three phase III was significantly increased (p ס 0.007) (39). Studies of trials, all showing marginal efficacy. Substantial adverse anti-TNF-␣ antibody have also had a negative result. The effects, including musculoskeletal pain and myocardial reason for the increased exacerbation rates is not clear.
T-cell vaccination. Myelin basic protein (MBP)–
Cladribine (Leustatin). Cladribine (Leustatin; Ortho
reactive T cells may be pathogenic in MS and may be Biotech, Inc., Raritan, NJ) is a specific antilymphocyte depleted by T-cell vaccination (TCV). Immunization agent that may reduce disability, MR lesions, and CSF with autoreactive inactivated T cells may elicit specific oligoclonal bands in MS (9,42,57,74,76). Romine et al.
immunity to pathogenic T cells. This approach is under (74) conducted an 18-month, randomized, placebo- active study by Hermans et al. (12). TCV with myelin controlled, double-masked, phase II study of cladribine basic protein–reactive clones can induce T-cell immune in 52 patients with RR MS. There was a statistically response and a clonal depletion of MBP-reactive T cells.
significant favorable effect on the frequency and severity Five years after TCV, MBP-reactive T cells were seen in of relapses and MRI disease activity. Cladribine is well five of nine MS patients, and these clones had a different tolerated but may cause lymphopenia and may potentiate clonal origin from those isolated before vaccination.
herpes zoster virus (25%) or other opportunistic infec- Oral myelin. Oral tolerance to fed antigen may result
in active immune suppression or anergy (9). Oral myelin Intercellular adhesion molecule inhibitors. Trans-
was not successful in reducing relapse rate, and there was migration of leukocytes across the blood–brain barrier no MRI effect when compared with placebo. Future stud- into the CNS may play a role in demyelination and oli- ies with recombinant myelin peptides, possibly in con- godendrocyte damage in MS. Leukarrest is a white blood junction with IFN therapy, may be forthcoming (57,76).
J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I Monoclonal antibody (e.g., humanized anti-alpha 4
beta 1 integrin). Humanized anti-alpha 4 beta 1 inte-
grin, in a randomized double-masked study, was well
Antithrombotic therapy
tolerated. It reduced MR lesions in RR and SP MS. Other Acute ischemic strokes may occur with white clots, studies, however, of humanized anti-CD 11/CD 18 inte- because of platelet fibrin, or red clots, because of eryth- grin monoclonal antibody failed to show a clinical or rocyte-fibrin pathology. White clots tend to occur in ar- MRI benefit (38). Monoclonal anti-CD4 antibody failed eas of high blood flow and red clots in areas of low blood to show positive results in a double-masked, placebo- flow. Antiplatelet therapy includes aspirin (ASA), dipy- controlled, MR-monitored phase II trial (80).
rimadole, ticlopidine, and clopidogrel. These agents Bone marrow and stem cell transplant. Bone mar-
would thus be theoretically better for white clots includ- row and stem cell transplants are being explored as po- ing carotid plaque disease without significant stenosis.
tential management options in MS. These therapies have Anticoagulation agents include heparin, low-molecular- been tried in only a few patients (20). The morbidity and weight heparin, heparinoids, and Coumadin (DuPont mortality rate of the procedure is significant (0.5–2.5%), Pharma, Wilmington, DE). These drugs would theoreti- and the results to date have been inconclusive.
cally be better for red clots. The red clot disorders in- Alternative therapy. Newland (64) reviewed the use
clude venous occlusive disease, large artery disease, or and effectiveness of alternative therapy in MS. The au- cardiogenic thrombo-embolism (88). The guidelines forantithrombotic therapy in cerebrovascular disease were thor reviewed massage, imagery, acupuncture, aroma- reviewed by Albers and Tjissen (89). In this section, we therapy, herbalism, therapeutic touch, and nutritional review the emerging therapies for stroke, including an- therapy. Increasing use of these alternative treatments by tiplatelet agents, anticoagulation, thrombolysis, statins, patients with MS may warrant further study, but there is and neuroprotective agents (88–137).
little controlled clinical data to support efficacy.
Use of multiple sclerosis therapies in pregnancy
Antiplatelet agents
and children. Olek (9) summarized the use of the se-
Several clinical trials have indicated that patients with lected MS treatments in pregnancy by category. Cat- atherothrombotic stroke or transient ischemia may ben- egory A drugs have not been shown to be harmful. Cat- efit from antiplatelet treatment. First-line therapy, there- egory B drugs show no harm in animal studies, but no fore, might include ASA, ASA plus dipyridamole, ticlo- human studies have been conducted. Category B drugs pidine, or clopidogrel (88). Transient monocular blind- include glatiramer acetate. Animal data show harm to ness (“amaurosis fugax”) resulting from transient fetus in category C drugs, but no controlled human stud- ischemia is one possible indication for antiplatelet ies have been conducted. Category C drugs include cor- therapy. The large studies of ASA and other antiplatelet ticosteroids and IFN. Category D drugs are known to agents were not designed to consider this subgroup of cause fetal harm in pregnant women. Category D agents include azathioprine, cladribine, and cyclophosphamide.
Aspirin. Aspirin inhibits platelet release, aggrega-
Category X drugs are contraindicated in pregnancy and tion, and adhesion by blocking cyclo-oxygenase, pros- taglandins, prostacyclins, and thromboxane A2. It is the Although there have been no randomized clinical trials best studied and least expensive of the antiplatelet on IFN in children, Adams (49) reported good long-term agents, and many large interventional studies have treatment results with IFN ␤-1b of a 7-year-old male shown that ASA given within 48 hours modestly reduces with RR MS. More data is needed before recommenda- mortality after stroke or transient ischemic attack (90,91). The ideal dosage is controversial, with no con- Future therapeutic strategies. Noseworthy (76)
sensus even among stroke experts; although many clini- summarized possible future therapeutic strategies for MS cians in the United States use a 325-mg per day dose of in a 1999 review: 1) antiviral drugs such as valacyclovir ASA, some patients may require a higher dosage for and acyclovir, 2) cytokine and anticytokine strategies including TNF and other inhibitors, 3) “immune devia- Albers and Tijssen (89), in a meta-analysis of ten clini- tion strategies” to enhance Th2 cell/cytokine predomi- cal trials, reported a 13% relative risk reduction (RRR) in nance (pentoxifylline and TGF ß, IL-10), 4) matrix met- stroke, heart attack, or vascular death independent of alloproteinase inhibitors such as D-penicillamine and hy- ASA dose. ASA use was associated with an increased droxyamatate, 5) trimolecular complex strategies such as risk of hemorrhage of as many as two intracranial hem- anti-MHC monoclonal antibodies, MHC class II hyper- orrhages and four extracranial hemorrhages per 1000 variable peptide vaccines, anti-T cell monoclonal anti- treated patients, but the risk was offset by reductions in bodies, altered peptide ligands, T-cell vaccination, and
short- and long-term death and disability rates. Kalra et adhesion molecules, 6) cathepsin B inhibitors, 7) oxygen al. (92) performed a prospective cohort study of 1457 radical scavengers, 8) autologous bone marrow trans- patients, 650 (45%) of whom were using ASA at a me- plantation, and 9) gene therapy and implantation oligo- dian dose of 75 mg and a range 75 to 300 mg. ASA was dendroglial precursors. Scolding (21) provided an inter- associated with lower 4-week mortality of 14% versus esting discussion of the potential managements for long- 20% (p < 0.01), independent of age, gender, and other term repair and remyelination in MS.
risk factors. Masuhr and Einhaupl (93) also found that J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ASA was clearly effective in reducing early death or Investigators performed a randomized, double-masked, stroke recurrence within the first few weeks.
placebo-controlled, dose-escalation trial in 74 patients Aspirin can be safely combined with low-dose subcu- after ischemic stroke (97). There were no cases of major taneous heparin for deep venous thrombosis prophylaxis intracranial hemorrhage. Asymptomatic parenchymal (90). Its use should be delayed by at least 24 hours if hemorrhages were detected on CT scan in 4 of 54 (7%) patients on abciximab compared with 1 of 20 (5%) pa- Nonarteritic anterior ischemic optic neuropathy and tients on placebo. Six additional abciximab patients had aspirin. Kupersmith et al. (134), in a retrospective study, asymptomatic hemorrhagic lesions detected by unsched- suggested that aspirin may reduce second eye involve- uled brain imaging during their follow-up period. Inves- ment in nonarteritic anterior ischemic optic neuropathy tigators concluded that abciximab was probably safe (NAION). Beck et al. (135), however, showed little or no when administered up to 24 hours after stroke onset, and long-term benefit to aspirin in reducing the risk of it might improve functional outcome.
NAION in the fellow eye. These authors recommendedcaution in interpreting the results, because neither of Anticoagulant therapy
these studies was prospective or controlled. It remains Heparin and heparin analogs. Heparin is a bio-
logic substance derived from bovine lungs and porcine controversial whether ASA should be routinely recom- intestine, which can be separated into low- and high- mended after NAION alone. The role of antiplatelet regi- molecular-weight fractions. Its anticoagulant effect re- mens other than ASA in the prophylaxis of NAION is lates to binding of antithrombin III, inactivating throm- bin and other serum protease coagulation factors, antago- Dipyridamole. Dipyridamole (DP) is a phosphodi-
nizing thromboplastin, and interfering with the reaction esterase inhibitor that decreases platelet function by in- of thrombin with fibrinogen to form fibrin. It does not creasing levels of cyclic adenosine monophosphate and potentiate recanalization of occluded arteries, and it has guanosine monophosphate. Conflicting data exist regard- no neuroprotective properties; to date, no short-term or ing the efficacy of ASA alone versus ASA combined long-term benefit of heparin in acute ischemic stroke has with DP. Sivenius et al. (94) reported the data on 6602 been established. Heparin may, however, be useful for patients in The Second European Stroke Prevention the following disorders: 1) acute intracranial dural and Study (ESPS2). In this study, there were four treat- venous thrombosis, 2) presumed cardiogenic emboli with ment groups: 1) placebo, 2) 2 × 25 mg of ASA, 3) 2 × high risk of intracranial embolism, and 3) acute thrombi 200 mg of DP, and 4) combination of 50 mg of ASA and or severe large artery stenosis. Heparin is not recom- 400 mg of DP per day. ESPS2 showed a benefit from mended for hemorrhagic stroke or in cases with uncon- antiplatelet treatment compared with placebo and an ad- trolled hypertension or high risk of bleeding.
ditional benefit using ASA combined with DP rather Heparinoids are heparin analogs that have anti- than either agent alone. ESPS2 data suggest that anti- coagulant effects. Low-molecular-weight heparins platelet therapy does not influence the severity of recur- (LMWH), such as enoxaparin, dalteparin, nadroparin, rent stroke using the Rankin scale but does lengthen the and tinzaparin, have better bioavailability and pharma- cokinetics than heparin, and they result in fewer hemor- Ticlopidine and clopidogrel. Ticlopidine is a
rhagic complications, presumably because of their re- thienopyridine inhibitor of platelet aggregation. The duced effect on platelet function and vascular permeabil- Ticlopidine Aspirin Stroke Study showed that it reduces ity. Either low-dose unfractionated heparin (UFH) or the risk of stroke when combined with ASA or when LMWH has been recommended for acute ischemic compared to ASA alone (95), but it has a high rate of side stroke patients with immobilized or paralyzed limbs who effects, including diarrhea (20%) and rash (10%). Seri- are at high risk for venous thromboembolism (VTED).
ous and potentially life-threatening complications, in- Lensing et al. (98) reported that anticoagulation in high- cluding neutropenia and thrombotic-thrombocytopenic risk patients reduced the risk of deep venous thrombosis purpura, may occur in as many as 1% of patients.
and pulmonary embolism, but there was an increased risk Clopidogrel is an analogue of ticlopidine with an ad- of intracranial bleeding within 14 days of treatment. The ditional carboxymethyl side group and fewer hemato- incidence of thromboembolic events was 20% in patients logic side effects. In the Clopidogrel versus Aspirin in randomized to enoxaparin compared with 35% in the Patients at Risk of Ischaemic Events (CAPRIE) trial UFH-treated group. In the Thromboembolism Prevention (96), it reduced the risk of stroke but was no more ef- in Cardiopulmonary Diseases with Enoxaparin (PRINCE) trial, once-daily enoxaparin was compared to Glycoprotein platelet IIb/IIIa complex antagonists.
three-times-daily UFH. The PRINCE trial found that The glycoprotein platelet IIb/IIIa complex is the binding enoxaparin was at least as effective as UFH in reducing site for adhesive proteins such as fibrinogen. These pro- the risk of thromboembolic events by 19%. In high-risk teins activate platelet aggregation and adhesion to blood predefined subgroups with heart failure, enoxaparin was vessels. Abciximab (ReoPro; Eli Lilly and Co., India- napolis, IN) is a fragment of chimeric human/mouse Warfarin. Warfarin (Coumadin), an oral anticoagu-
monoclonal antibody that acts as a platelet glycoprotein lant, inhibits vitamin K, a requirement for synthesis of IIb/IIIa antagonist. The Abciximab in Ischemic Stroke factors II, VII, IX, and X. After acute use of heparin in J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I thromboembolic disease (TED), warfarin allows clot or- significantly increased the risk of symptomatic intrace- ganization and adherence to the vessel wall. Several rebral hemorrhage (ICH) at 10 days (11%) versus pla- studies have documented its efficacy, at a target interna- cebo (0%) (p < 0.01). The mortality rate at 90 days was tional normalized ratio (INR) of 2.5, in atrial fibrillation.
also increased (23%) versus placebo (7%) (p < 0.01).
It may also be beneficial in other high-risk cardiac em- Albers et al. (107) performed a prospective, moni- bolic diseases, and this question is being studied in clini- tored, postapproval, multicenter trial with 389 consecu- cal trials. Patients with cardiac thrombi or arrhythmia, tive patients in the Standard Treatment with Alteplase to prothrombotic cardiac lesions such as prosthetic heart Reverse Stroke Study (STARS). The median time to valves, or some hypercoagulable states, including the treatment was 2 hours and 44 minutes. The median base- presence of lupus anticoagulant, may require indefinite line NIHSS score was 13. Thirty-five percent of patients had very favorable outcomes on the modified Rankin Oral anticoagulant treatment for prevention of recur- score (0–1), and 43% were functionally independent on rent stroke in atherothrombotic, noncardiogenic embolic the same scale (0–2). Thirteen patients (3.3%) experi- stroke, however, has not been sufficiently proven and enced symptomatic ICH, of which seven were fatal.
may lead to increased hemorrhagic complications (89).
Twenty-eight patients (8.2%) had an asymptomatic ICH.
Protocol violations were reported for 127 patients Thrombolytic therapy
(32.6%). The following were favorable predictors: 1) Intravenous thrombolysis. Tissue plasminogen acti-
less severe baseline NIHSS score, 2) absence of efface- vator. Since 1990, clinical trials of intravenous throm- ment or hypodensity of greater than 33% of the middle bolysis for ischemic stroke have involved more than cerebral artery (MCA) territory or a hyperdense MCA on 3000 patients (100). Tissue-type plasminogen activator CT scan, 3) age less than 85 years, and 4) lower mean (tPA) was approved by the Food and Drug Administra- tion (FDA) in 1996 after a large randomized placebo- Tanne et al. (108) reported on 30 patients more than 80 controlled study by the National Institute of Neurological years old compared with counterparts less than 80 years Disorders and Stroke (NINDS). The NINDS study old (n ס 159) included in the tPA Stroke Survey. In showed a significant improvement in 3-month and 12- logistic regression models, there were no differences in month outcomes with tPA at a dose of 0.9 mg/kg within odds ratio for favorable or poor outcome except for a 3 hours of onset. Hacke et al. (101–103) and Lyden (104) tendency for higher in-hospital mortality in elderly pa- have reviewed the data from the NINDS and the first and tients (odds ratio, 2.8; 95% CI, 0.81–9.62; p ס 0.10).
second European Cooperative Acute Stroke Studies Caplan (109) reviewed seven studies of 370 patients of (ECASS I and II). The European trials showed compa- intravenous thrombolysis with rtPA. One third of pa- rable results but did not reach statistical significance for tients showed significant recanalization compared with their primary endpoints. Nevertheless, the risk/benefit 5% of 58 controls. MCA occlusions seemed to demon- profile of tPA therapy based on the results of these three trials suggested that treatment was beneficial for selected The major risk of tPA is ICH. The reported incidence eligible patients if administered within the 3-hour time of ICH is somewhat variable, including 3.3% in STARS, window. At the 6-hour time window, a combined analy- 6.4% in NINDS, 9% in the OSF Stroke Network (110), sis of the three studies shows the number of disabled or and as much as 20% in other series (111). Katzan et al.
dead patients was reduced. Devuyst and Bogousslavsky (112) reported a historical prospective cohort study of (105) believed that the results of these three studies must 3948 patients with ischemic stroke. Seventy patients be interpreted with caution, however, and concluded that (1.8%) admitted with ischemic stroke received intrave- ECASS II was an “equivocal” study. Specifically, it was nous tPA. Of these patients, 11 (15.7%) had a symptom- negative for the primary end point but positive in the post atic ICH, and six of these were fatal. Half of the cases hoc analysis of modified Rankin scale scores dichoto- had deviations from national treatment guidelines. The mized for death or dependency. These authors summa- authors concluded that the community Cleveland area rized the reasons for the controversy: 1) possible selec- experience with tPA for acute ischemic stroke may differ tion bias, 2) use of an uncommon primary end point, and from that reported in clinical trials.
Buchan et al. (113) emphasized the need to follow Clark et al. (106), in the Thrombolytic Therapy in protocol. They reviewed 68 consecutive patients with Acute Ischemic Stroke Study, assessed the efficacy and acute ischemic stroke treated with intravenous tPA safety of intravenous rtPA in 142 patients with acute within 3 hours of symptom onset. Fifty-seven patients (0–6 hours) ischemic stroke in a phase II, placebo- were treated according to the NINDS protocol, with a controlled, double-masked randomized study. A higher mean baseline NIHSS score of 15 ± 6. Of these 57 pa- percentage of rtPA patients (40%) had a four-point im- tients, 26 (38%) made a full recovery, and 39 (57%) provement on the National Institutes of Health Stroke made an independent recovery. Eleven patients violated Scale (NIHSS) at 24 hours compared with placebo (21%) protocol and had a lower probability of independence (p ס 0.02). This early effect was reversed by 30 days (p < 0.02) or full neurologic recovery (p < 0.02). These when comparing the placebo group (75%) with the r patients also had a higher probability of symptomatic tPA group (60%) (p ס 0.05). Treatment with rtPA hemorrhage (p < 0.05) or death (p < 0.01).
J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 Intravenous thrombolysis is believed to be most effec- evidence, however, of improved clinical neurologic out- tive clinically under the following conditions: 1) when come. Ueda et al. (117) reviewed 66 patients treated with the occluded arteries are intracranial and relatively small, IA thrombolysis within 6 hours of symptom onset. Mul- 2) when the thrombus is acute, 3) when recanalization tiple regression analysis suggested that age, residual ce- occurs, and 4) for emboli rather than in situ thrombi in rebral blood flow (CBF), neurological score at baseline atheromatous plaques. Trouillas et al. (114) reported an and the following day, and recanalization grade corre- open trial of intravenous rtPA (alteplase) for smaller in- lated significantly with long-term outcome.
tracranial arterial events administered within 7 hours of Thrombolysis and central retinal artery occlusion. symptom onset. Seven of nine patients with anterior cho- Hattenbach et al. and Wirostko et al. (136,137) have roidal artery (AChA) territory infarct had a primary early reported anecdotal successful thrombolysis in central recovery within 6 hours after rtPA. Recovery was com- retinal artery occlusion (CRAO). In the absence of plete in five of seven patients. The authors concluded prospective controlled clinical data, however, the benefit that AChA-territory strokes responded well to intrave- of thrombolysis for intraocular thrombosis remains nous rtPA and hypothesized that this finding resulted from the small size of the artery and the clot.
Role of new neuroimaging modalities. Newer imaging Streptokinase. The three important randomized trials modalities for stroke include combined diffusion- of intravenous streptokinase are the Multicentre Acute weighted and perfusion magnetic resonance (MR) scans, Stroke Trial–Italy (MAST-I), the Multicentre Acute MR angiography, xenon CT and CT angiography, trans- Stroke Trial–Europe (MAST-E), and Australian Stroke cranial Doppler ultrasound, and positron-emission tomo- Trial (115). These three trials were stopped because of graph (PET) scans. These new modalities can provide high rates of brain hemorrhage, and this agent is not important information about vascular occlusion, poten- generally recommended. Wardlaw et al. (116) reviewed tial reversibility of ischemia, and brain function (121).
the influence of baseline risk postthrombolysis outcome Albers (120) emphasized the expanding role for early in the MAST-I. The risk with streptokinase was similar MR imaging in acute stroke, suggesting that such acute in “severe” and “mild” strokes.
MR imaging may eventually prove superior to CT for Intra-arterial thrombolysis. Two trials of intra-arterial identification of patients eligible for thrombolytic (IA) prourokinase confirm the benefits of treatment for therapy. Tong and Albers (122) reviewed the utility, in- highly selected patients with angiographically confirmed dications, and potential future role for diffusion/perfu- proximal MCA occlusion if instituted within 6 hours sion-weighted MR imaging, which may play a substan- after the onset of symptoms. IA direct thrombolysis tial role in determining the suitability of acute stroke has theoretical advantages over intravenous therapy: patients for thrombolytic therapy. Early perfusion- 1) faster and higher rates of complete recanalization, weighted imaging (PWI) may show blood flow abnor- 2) lower required dosage of thrombolytic agent, and malities and acute dysfunctional brain tissue. Acute dif- 3) smaller risk of hemorrhage (117). Abou-Chelb and fusion-weighted imaging (DWI) lesion may correspond Furlan (118) reviewed several IA thrombolysis studies to the core of the early infarction. Mismatch between the and believed that IA therapy was at least as effective as acute PWI lesion and the smaller DWI lesion may rep- intravenous thrombolysis. They cautioned, however, that resent potentially salvageable but poorly perfused brain unresolved issues remain before such therapy can be- tissue surrounding the infarct. In patients with PWI/DWI come a part of the standard of care. Caplan (109) re- mismatch, early reperfusion may be associated with viewed 17 (n ס 449 patients) nonrandomized studies of clinical improvement and reversal or reduction of DWI IA thrombolysis. The drugs used included urokinase, streptokinase, and urokinase tissue plasminogen activa- Alexandrov et al. (123) reported the use of transcranial tor. Of the 449 patients, 299 (64%) experienced effective doppler (TCD) with low MHz frequency to determine recanalization. Mainstem and divisional MCA occlu- arterial occlusion and continuously monitor recanaliza- sions (62%) had the best response. Basilar artery occlu- tion in 40 patients treated with tPA. Clinical lack of sions had a 62% recanalization rate. Internal carotid ar- improvement or worsening was associated with no reca- tery (ICA) occlusions had less response (45%). Distal nalization, late recanalization, or reocclusion on TCD MCA occlusions did not respond as well as proximal (p < 0.01). Recovery was associated with recanalization MCA occlusions. Forty-two percent (n ס 197) of pa- tients had a “good” outcome overall, and 18.5% of pa- Central benzodiazepine receptor ligands, such as 11C flumazenil (FMZ), are markers of neuronal integrity and Lewandowski et al. (119) reported a double-masked, may be useful in the future for differentiation of func- randomized, placebo-controlled multicenter phase I pilot tional and morphologic stroke damage. Heiss et al. (124) study of intravenous rtPA or intravenous placebo fol- studied 11 patients with acute hemispheric ischemic lowed by immediate cerebral arteriography and local mi- stroke treated with alteplase using cortical cerebral blood crocatheter IA rtPA (n ס 35). Recanalization was better flow, FMZ binding, and PET. Hypoperfusion was ob- (p ס 0.03) in the intravenous/IA group. This pilot study served in all cases, and they concluded that FMZ PET demonstrated that combined intravenous/IA treatment is may distinguish between irreversibly damaged and vi- feasible and provides better recanalization. There was no able penumbra tissue early after acute stroke.
J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I Other potential agents in stroke therapy
TABLE 1. Neuroprotective agents in stroke
Statins (3-hydroxy-3-methylglutaryl (HMG)-
coenzyme (Co) A reductase inhibitors). 3-hydroxy-3-
Voltage-sensitive calcium-channel antagonists methylglutaryl (HMG)-coenzyme (Co) A reductase is Noncompetitive N-methyl-D-aspartate (NMDA)–receptor the rate-limiting enzyme in cholesterol formation in the liver. HMG-CoA reductase inhibitors (statins) lower se- Competitive NMDA antagonists (excitory amino acid receptors) rum cholesterol and especially lower the LDL compo- nent and may reduce the incidence of stroke; they in- clude pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, and cerivastatin. Hess et al. (125) reviewed several randomized trials of coronary artery disease and Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole priopionic statins. Pravastatin lowered average cholesterol levels Gamma-aminobutyric acid–receptor agonists and reduced the risk of stroke in patients with coronary Presynaptic modulation of glutamate release artery disease. Simvastatin reduced the risk of the com- bined endpoint of stroke and transient ischemic attack in hypercholesterolemia and coronary artery disease. The precise way in which statins reduce risk is unclear and Polypeptide, neurotrophic, nerve and fibroblast growth factors may not be solely related to cholesterol or low-density lipoprotein reduction. Vaughn et al. (126) reviewed other Phosphatidylcholine synthesis and apoptosis inhibitors important mechanisms: 1) nonsterol effects on vascular Opiod-receptor antagonistsSerotonin 1A–receptor agonists endothelial cells, 2) anti-inflammatory effects, 3) deple- tion and stabilization of the lipid core of plaques, 4) strengthening of the fibrous cap of plaques, 5) decreasedformation of platelet–fibrin thrombi, 6) decreased depo-sition of clot on endothelial surfaces, 7) reduced throm- Clomethiazole enhances gamma-aminobutyrate type bogenicity, and 8) antithrombotic effects on macro- A (GABA ) receptor activity. Efficacy and safety were phages, platelets, and smooth muscle cells. Rosenson tested in the Clomethiazole Acute Stroke Study (127) proposed several mechanisms for cerebrovascular (CLASS) (133). Investigators studied clomethiazole us- protection by statins. These mechanisms include reduc- ing a 24-hour infusion of 75 mg/kg versus placebo in 94 tion of cardiac, aortic, and carotid embolization sites; acute hemorrhagic stroke patients. The number of stabilization and reduction progression of vulnerable ca- patients reaching functional independence on the rotid atherosclerotic plaque; and improvement in cere- Barthel index score (> 60) was 59.6% for clomethiazole bral blood flow. Statins also reduce the size of cerebral versus 53.2% for placebo. No substantial safety issues infarction in a murine stroke model, possibly via a neu- Devuyst and Bogousslavsky (105) and De Keyser et al. (130) reviewed the discrepancy between experimental Neuroprotection
and clinical results for multiple neuroprotective agents, Several treatments aimed at neuroprotection and sal- suggesting possible reasons: 1) single drug trials, 2) het- vation of ischemic neurons in stroke are being studied erogeneity of stroke population, therapeutic dose, and (128). A multitude of agents considered for study are adverse effects, and 3) therapeutic time window.
listed in Table 1 (129). Lutsep and Clark (131) reviewed The role of neuroprotective agents in stroke remains to those treatments that have reached the late stage of de- velopment, including N-methyl-D-aspartate (NMDA)-receptor antagonists, antileukocyte antibodies (intercel-lular adhesion molecule (ICAM)-1 antibody), GABA PARANEOPLASTIC SYNDROMES
agonists (clomethiazole), citicolen (phospholipid me- Paraneoplastic syndromes represent visual or neuro- tabolism), opiod receptor antagonists (nalmefene), and logic dysfunction in the setting of known or suspected sodium channel blockers (fosphenytoin).
malignancies, without direct involvement of the eye or Promising results have been reported in animal stroke nervous system by tumor, antineoplastic agent toxicity, models. Unfortunately, to date, there is no clear and con- or opportunistic infection. They are thought to originate vincing evidence in randomized controlled clinical trials from an autoimmune process, and circulating antibodies to specific neuronal antigens have been identified in The North American Glycine Antagonist in Neuropro- some cases. Syndromes of neuro-ophthalmologic signifi- tection (GAIN) Investigators (132) reported on cance primarily involve the retina, optic nerve, brain- GV150526, a selective blocker of glycine and an obliga- stem, and cerebellum. In this review, we focus on disor- tory coagonist with glutamate of the NMDA receptor.
ders of the retina and optic nerve (138–171).
This agent reduces infarct volume in rats with focal ce-rebral ischemia. Two randomized, double-masked, and placebo-controlled trials were reviewed, but no clinical Paraneoplastic retinopathies include primarily the can- conclusions could be drawn regarding efficacy.
cer-associated retinopathy (CAR), melanoma-associated J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 retinopathy (MAR), and bilateral diffuse uveal melano- Antiretinal antibodies directed against other antigens cytic proliferation (BDUMP) syndromes.
have been detected in several recent reports of paraneo- Cancer-associated retinopathy is the most common vi- plastic retinopathy. Ohkawa et al. (144) described bilat- sual paraneoplastic disorder. The presenting manifesta- eral severe progressive retinopathy in a patient with en- tions for cone-related disorders include hemeralopia, dometrial cancer who demonstrated serum antibodies photopsias, central acuity loss, color dysfunction, and against only a 34-kd retinal protein. Autoantibodies to a paracentral or central scotomas. Predominantly rod- 60-kd retinal protein were found in a patient with small- affected patients may present with nyctalopia, impaired cell lung carcinoma with clinical and electrophysiologic dark adaptation, visual dimming, ring scotoma, or pe- features of CAR syndrome but negative testing for the ripheral visual-field loss. A case of isolated cone dys- 23-kd CAR antibody (145). Antibodies against the 46-kd function has recently been reported by Jacobson and protein enolase-␣, a ubiquitous glycolytic enzyme (146) Thirkill (138), corroborating three previously reported that is also elaborated by several tumor types, have been cases. Symptoms develop for weeks to months, and in as documented in patients with CAR. The antibodies were many as 50% of cases, the symptoms begin before the also detected in patients with vasculitis, other tumors underlying malignancy is identified. Patients experience without retinopathy, and in healthy patients, though the progressive deterioration and eventual bilateral involve- levels were lower. The antienolase antibodies found in ment with severe visual loss. The fundus examination patients with retinopathy have also been shown to induce may initially be normal, although the ERG is typically apoptosis in E1A.NR3 rat retinal cells, whereas those in markedly reduced in amplitude even in the early stages.
healthy patients have not; the effect of these antibodies in As the course progresses, the retinal arterioles become attenuated, the retinal pigment epithelium (RPE) be- Progressive retinopathy resembling the CAR syn- comes thinned and mottled, and the optic discs become drome was reported by Mizener et al. (148) in two pa- atrophic. Less commonly, aqueous or vitreous cellular tients without malignancy during a 5- to 7-year follow- reaction and retinal periphlebitis are seen. Elevated CSF up period but with evidence of autoimmune disease and protein level and lymphocytosis may be seen. Although strong family history of autoimmune disease. Visual loss corticosteroid therapy has been reported to stabilize vi- was unilateral and severe, with demonstration of a ring sual loss in isolated cases, the visual prognosis is gener-ally poor.
scotoma but normal fundus appearance. The ERG was Most reported cases of CAR involve patients with flat in one case and, in the other case, showed evidence small-cell carcinoma of the lung (SCCL), although other of inner retinal dysfunction with selective b-wave loss lung tumors, breast malignancies, uterine malignancies, and abnormal oscillatory potentials. Circulating antireti- and cervical malignancies have been implicated. Inves- nal antibodies reactive against the retinal inner plexiform tigators believe that, in the majority of patients, the tu- layer but not against CAR antigen or other previously mor expresses an antigen that is homologous to a 23-kd reported retinal antigens were identified. Whitcup et al.
retinal photoreceptor protein, originally termed the (149) reported a case of similar progressive retinopathy “CAR antigen,” more recently identified to be the cal- with severe depression of the rod-mediated ERG and cium-binding protein recoverin. The human recoverin autoantibodies against recoverin, but no documented ma- gene has been mapped to a region of chromosome 17 lignancy 3 years after onset of visual loss. They termed containing other cancer-related loci (139). Recoverin has the disease recoverin-associated retinopathy; to distin- been identified in tumor cells of patients with SCCL guish it from the CAR syndrome, Keltner and Thirkill (140), endometrial carcinoma (141), and malignant (150) further described the distinction in a separate mixed mullerian tumor (142). Circulating autoantibodies against the tumor-associated antigen presumably cross Management of CAR syndrome has generally been react with retinal recoverin to produce immune-mediated ineffective, but a benefit has been reported in certain photoreceptor degeneration. The exact mechanism is un- cases, using systemic corticosteroids, plasmapheresis, or clear. McGinnis et al. (139) postulate that inactivation of intravenous immunoglobulin (IVIg). Keltner et al. (151) the p53 tumor suppressor gene may increase expression described a patient whose antibody levels diminished of recoverin by tumor cells outside the eye, with subse- and visual function improved and stabilized on cortico- quent autoantibody production. Regardless of specific steroid therapy. More recently, Murphy et al. (152) de- mechanisms, most investigators believe it to be primarily scribed a patient in whom oral corticosteroid therapy a humoral immunity response based on the circulating combined with plasmapheresis resulted in recovery of antibodies and the lack of substantial inflammatory in- vision. The vision improved from counting fingers to filtrate in most retinas examined microscopically; how- 20/200 OD and from 20/40 to 20/25 OS. This visual ever, some cases have demonstrated inflammatory cells acuity was maintained at least 4 months with response of (147), suggesting a component of cellular immunity as the tumor to chemotherapy and reduction of antiretinal well. The 23-kd antiretinal antibodies have been detected (60-kd) antibody levels from 1 to 2000 to 1 to 200.
in the majority of the reported cases of CAR. Adamus et Guy and Aptsiauri (152) reported response to IVIg (400 al. (143) have demonstrated induction of apoptosis in mg/kg/day during 5 days in one case and during 1 day in E1A.NR3 rat retinal cells by serum antirecoverin autoan- the other case) in two of three patients with paraneoplas- tic retinopathy. Visual acuity in the first case improved J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 ANNUAL UPDATE OF SYSTEMIC DISEASE: PART I within 24 hours of the first dose from hand motions OU progressive bilateral visual loss over months, related to to 20/50 OD, 20/200 OS, with further improvement of damage to retinal pigment epithelium and photorecep- OS to 20/40 after 72 hours. In the second case, visual tors. Clinical findings include multiple reddish rounded acuity remained stable, but visual fields improved after spots at the level of the posterior retinal pigment epithe- lium—which are hyperfluorescent on angiography— Melanoma-associated retinopathy is a very rare visual multiple pigmented and nonpigmented focal melanocytic paraneoplastic syndrome associated with cutaneous ma- proliferations and diffuse thickening throughout the lignant melanoma, predominantly affecting men, though uveal tract, exudative retinal detachments, and rapidly melanoma occurs relatively equally in men and women.
In contrast to CAR, it is a disorder primarily of rods, with The differential diagnosis includes choroidal me- corresponding symptoms of photopsias, shimmering col- tastases, lymphoma, leukemia, sarcoidosis, uveitis, ored visual phenomena, and nyctalopia, usually develop- scleritis, uveal effusion, and Harada disease. Comparison ing rapidly for weeks to months but occasionally with and contrast to CAR were highlighted in recent reports sudden onset and eventually involving both eyes. The by Brink et al. (163) and Gass (164).
clinical examination often initially reveals normal visual Murphy et al. (165) recently described clinical features acuity, color vision, and central visual field, with periph- in a woman with uterine carcinoma who developed vi- eral constriction, midperipheral scotomas, or generalized sual loss, exudative retinal detachments, and prominent depression of the most common field abnormalities. Cen- conjunctival vascular dilation and tortuosity suggestive tral scotomas are unusual. The fundus may be normal or of arterialized blood vessels. The diagnosis of dural cav-ernous sinus fistula was considered, but cerebral angiog- may show RPE irregularity, retinal arteriolar attenuation, raphy was negative, and she subsequently developed and optic disc pallor in cases that have been symptomatic choroidal lesions typical for BDUMP. Conjunctival hy- for months. Unlike the CAR syndrome, visual function peremia and congestion has been reported in a number of may remain stable and nonprogressive in MAR. Visual previous cases, presumed secondary to ciliary body in- symptoms typically develop in the setting of previously diagnosed melanoma, and metastasis is often found with The pathogenesis of BDUMP is unknown. It has been the development of visual loss. No treatment has been suggested that retinal photoreceptor damage occurs be- proven effective for MAR (153–156).
cause of toxic or immune factors independent of, or in The ERG abnormalities in patients with MAR syn- response to, melanocytic proliferation, which may result drome suggest rod dysfunction, with severe impairment from trophic hormone production by the tumor or from a of the dark-adapted b-wave, sparing the a-wave re- coexistent oncogenic factor. Overexpression of p53 pro- sponse. Oscillatory potentials are reduced in a manner tein, a postulated mechanism for development of similar to other retinal disorders that are characterized by BDUMP, was not confirmed in recent studies by Margo failure of neural transmission from outer to inner retina et al. (167). There remains no effective treatment.
through the bipolar cell layer. Moreover, immunofluo-rescent staining of the retinal bipolar cell layer by circu- Paraneoplastic optic neuropathy
lating IgG autoantibodies has been demonstrated A syndrome of acute optic nerve dysfunction has been (154,157–159). Histopathologic evidence of dropout in described in patients with carcinoma, particularly SCCL the bipolar neurons of the inner nuclear layer of the retina or lymphoma, in the absence of meningeal tumor infil- has recently been documented by Gittinger and Smith tration; it is a presumed paraneoplastic neuropathy, al- (160). It is postulated that antimelanoma antibodies may though its etiology is unproven (168,169). Patients cross react with these bipolar cells to produce the syn- present with the rapid onset of progressive visual loss, drome (155). The antigen is as yet unidentified, although usually bilateral, and in most cases associated with optic a membrane-associated lipid is suspected. Lei et al. (161) disc edema. Many of the reported cases also demon- demonstrated that intravitreal injection of circulating IgG strated brainstem and cerebellar dysfunction suggestive antibodies from humans with MAR resulted in alteration of a paraneoplastic syndrome. CSF analysis often shows of the retinal ON-pathway response of the monkey ERG, mild to moderate lymphocytosis and elevated protein suggesting an autoimmune effect on the depolarizing levels but no evidence of malignant cells. The ERG re- sults are typically normal. Testing for CAR antibody is Bilateral diffuse uveal melanocytic proliferation is a negative. At autopsy, most cases have shown demyeli- rare paraneoplastic disorder that has been reported in nation in the affected tissues, associated with a perivas- association with ovarian, lung, gall bladder, cervical, cular lymphocytic infiltrate typical of findings in other uterine, kidney, pancreatic, breast, esophageal, and co- lorectal cancers in more than half of the cases before Luiz et al. (170) recently described a case of bilateral identification of the underlying malignancy. Occasion- optic neuropathy and cerebellar degeneration in a 59- ally, the syndrome has developed coexistent with recur- year-old woman eventually diagnosed with SCCL. She rence of a previously diagnosed tumor (162). There is a presented with acute bilateral painless loss of vision, op- slight predisposition for women. Benign melanocytic tic disc edema, and severe visual field constriction, along proliferation and infiltration of the uveal tract is the char- with slurred speech, lower extremity weakness, ataxia, acteristic feature. The syndrome presents with painless and other cerebellar signs. All testing results for brain J Neuro-Ophthalmol, Vol. 21, No. 1, 2001 metastasis and meningeal infiltration was negative, al- 16. Napier JC. Interferon beta in multiple sclerosis. Lancet 1999;354: though CSF lymphocytosis (122 WBC/mm3) and el- 17. Paty DW. The Mayo Clinic-Canadian cooperative trial of sul- evated protein (111 mg/dl) were noted. ERG results were fasalazine in active multiple sclerosis. Neurology 1999;53:437.
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