Recent Progress In The Diagnosis And Treatment Of Multiple Sclerosis

Transcription

1 Journal of Clinical Neuroscience 6 (5) 1999, pp Copyright 1999 Published by Elsevier Ltd. Recent Progress In The Diagnosis And Treatment Of Multiple Sclerosis Michael P. Pender Department of Medicine, The University of Queensland, Royal Brisbane Hospital, Brisbane, Australia Abstract Magnetic resonance imaging (MRI) now provides valuable diagnostic and prognostic information for the management of multiple sclerosis (MS) but the diagnosis still largely rests on the clinical features of central nervous system (CNS) lesions disseminated in time and place. Recent histological and MRI studies indicate that extensive axonal damage can occur in MS, even early in the disease course, and is likely to be an important cause of accumulating disability. Several immunomodulating agents have now been shown to have beneficial effects in MS. High dose intravenous or high dose oral methylprednisolone therapy accelerates recovery from attacks of relapsing-remitting MS, but at present there is no convincing evidence that standard dose (intermediate dose) oral corticosteroid therapy is beneficial for such attacks. Interferon beta, copolymer 1 (glatiramer acetate) and i.v. immunoglobulin therapy each significantly reduce the frequency of attacks of relapsing-remitting MS. Interferon beta also inhibits the progression of disability in relapsing-remitting MS and secondary progressive MS, but its effect on primary progressive MS is unknown. Oral low dose methotrexate therapy slows the progression of disability in secondary progressive MS and possibly in primary progressive MS, but it is likely that the currently used dosage (7.5 mg weekly) is suboptimal. Further research is needed to determine the optimal doses and combinations of the above therapies in MS and to develop better therapies, particularly for primary progressive MS. Keywords multiple sclerosis; magnetic resonance imaging; interferon beta; axonal damage; corticosteroid therapy; immunoglobulin therapy; methotrexate; copolymer 1 Introduction Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system (CNS). It is a common cause of neurological disability, particularly in young adults. There is increasing evidence that MS is an autoimmune disease. 1,2 This review will focus on recent progress in the diagnosis, prognosis and treatment of MS. The sections on treatment will deal with immunomodulatory therapy aimed at modifying the disease course rather than with symptomatic therapy. The review will also discuss recent insights into the pathophysiology of MS that are relevant to patient management. Diagnosis and Prognosis The diagnosis of MS requires the demonstration of CNS lesions disseminated in time and place. 3 Thus it is not possible to make a definitive diagnosis of MS at the time of presentation of the first neurological episode, even if magnetic resonance imaging (MRI) of the brain reveals multiple lesions typical of MS. Nevertheless an MRI brain scan at the time of presentation of a clinically isolated syndrome of the optic nerve, brain stem or spinal cord can provide valuable prognostic information. O'Riordan et al. 4 have recently reported the results of a 10 year follow-up study on 81 patients who had T2-weighted brain MRI at the time of presentation of such clinically isolated

2 syndromes. Of those patients with an abnormal MRI, 83% had progressed to clinically definite MS whereas, of those with a normal MRI, only 11% had progressed to clinically definite MS. There was also a significant relationship between the number of brain MRI lesions at presentation and both disability and the type of disease at follow-up. Patients who followed a benign course of MS had few (median=3) MRI lesions at presentation, whereas those who developed secondary progressive MS with a high level of disability at 10 years' follow-up had many (median=18) lesions at presentation. Barkhof et al. 5 have evaluated the utility of individual brain MRI criteria at the time of first presentation in predicting the subsequent development of clinically definite MS. They found that gadolinium enhancement was the most predictive MRI parameter and that a combination of gadolinium enhancement (one or more lesions), juxtacortical (contiguous with the cerebral cortex) lesions (one or more), infratentorial lesions (one or more) and periventricular lesions (three or more) best predicted the development of clinically definite MS, with a sensitivity of 82%, a specificity of 78% and an accuracy of 80%. MS can be subdivided into a number of different clinical subtypes on the basis of the clinical course but, in the past, confusion has sometimes arisen from a lack of standardized terminology. As a result of an international survey, Lublin and Reingold 6 have proposed standardized definitions for the most common clinical subtypes of MS (Table 1). Table 1 Consensus definitions of the clinical subtypes of multiple sclerosis* Relapsing-remitting MS Clearly defined disease relapses with full recovery or with sequelae and residual deficit upon recovery; periods between disease relapses characterized by a lack of disease progression. Secondary progressive MS Initial relapsing-remitting course followed by progression with or without occasional relapses, minor remissions and plateau. Primary progressive MS Disease progression from onset with occasional plateaux and temporary minor improvements allowed. Progressive-relapsing MS Progressive disease from onset, with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression. Benign MS Disease in which the patient remains fully functional in all neurologic systems 15 years after disease onset. *From Lublin and Reingold 6 The diagnosis of relapsing-remitting MS and of secondary progressive MS is relatively straightforward; however, the definitive diagnosis of primary progressive MS using the criteria of Poser et al. 3 and Lublin and Reingold 6 remains difficult. 7,8 A diagnosis of laboratory supported definite primary progressive MS can be made when there is evidence of intrathecal immunoglobulin synthesis, a progressive neurological course and evidence of at least two separate lesions developing at different times. In the absence of evidence of intrathecal immunoglobulin synthesis, some would argue that a diagnosis of clinically definite primary progressive MS can be made if there is disease progression and symptoms and neurological signs of two separate lesions commencing at least one month apart, with the possibility of MRI or electrophysiological symptoms, of a second lesion. However, others would argue that using the criteria of Poser et el. 3 it is not possible to make a diagnosis of clinically definite primary progressive MS because the criteria require the presence of at least two discrete attacks, which by definition do not occur in primary progressive MS. 8 The diagnostic difficulty in primary progressive MS is compounded by the fact that brain MRI may be normal in this form of MS when there are multiple visible lesions in the spinal cord, 9 and by the fact that MRI brain lesions not due to MS are more frequent in the older age group in which primary progressive MS tends to occur. 7 At present it is often difficult to exclude confidently all other diseases that may mimic

3 primary progressive MS. There is, therefore, a need to define the diagnostic criteria of primary progressive MS more precisely; this is particularly important for therapeutic trials, as currently there is a paucity of reliable information concerning the treatment of primary progressive MS. It is possible that, with better diagnostic criteria, the current estimate that 10% of MS patients have a primary progressive course 7 will prove to be an underestimate. Pathophysiology Axonal damage Primary demyelination is the pathological hallmark of MS and is considered to be a major cause of the neurological symptoms and signs, but it has been known since the time of Charcot that axonal damage also occurs in MS. 10 Recent studies indicate that axonal damage is more common in MS and contributes to clinical disability to a greater extent than previously thought. In a histological study Trapp et el. 11 have shown that axonal transection is a consistent feature of the lesions of MS. They found that axonal transection was abundant in active and chronic active lesions from patients with durations of clinical disease ranging from 2 weeks to 27 years. The frequency of transected axons was related to the degree of inflammation within the lesion, suggesting that the axonal transection was caused by the acute inflammatory process rather than being a consequence of chronic demyelination. Ferguson et al. 12 have also shown that axonal damage, as indicated by the accumulation of amyloid precursor protein, is closely associated with inflammation in MS lesions. Recent studies employing MRI and magnetic resonance spectroscopy (MRS) indicate that axonal loss is an important cause of persistent neurological disability in MS. Using MRI to measure the cross-sectional area of the spinal cord at the C2 level, Losseff et al. 13 found a strong graded correlation between spinal cord atrophy (probably mainly due to axonal loss) and disability measured on the Kurtzke Expanded Disability Status Scale (EDSS). Similarly, the presence of cerebellar ataxia in MS is correlated with the presence of cerebellar atrophy on MRI and with a reduction in the concentration of the neuronal marker, N- acetylaspartate, in the cerebellar white matter on MRS. 14 Furthermore, a serial MRI study has revealed that progressive cerebral atrophy correlates with sustained deterioration in the EDSS score. 15 There is also a significant correlation between the progression of disability in secondary progressive MS and the accumulation of hypointense T1 lesions (black holes), 16 which represent regions of substantial axonal loss. 17 It has been hypothesized that the clinical course of MS may vary according to which antigens in the CNS are being targeted by the immune system. 18 Targeting of myelin antigens may lead to a relapsing-remitting course with clinical recovery due to remyelination; targeting of axonal antigens may lead to a progressive course from onset because axonal regeneration is limited in the CNS. The transition from relapsing-remitting MS to secondary progressive MS may involve the spreading of the immune response to axonal antigens or increased bystander damage to axons near to myelin directed immune attack. TM The occurrence of axonal damage in MS has implications for therapy. Therapy that inhibits the immune attack on the CNS would not be expected to restore neurological function if the axon is the major target of the immune attack whereas, if myelin is the major target, restoration of function may occur as a result of remyelination unhindered by repeated immune attacks. The occurrence of axonal damage in at least some cases of early MS emphasizes the need to develop treatments that prevent further immune mediated axonal damage and accumulating disability. Mechanism of fatigue Fatigue is a common severe disabling symptom of MS. The mechanism of fatigue in MS has been poorly understood, but two recent studies have shed light on its pathophysiology. In an electrophysiological study of the decline in strength during a sustained maximal muscular contraction, Sheean et al. concluded that the fatigue in MS patients originates in the CNS rather

4 than in muscle) 9 They found that the fatigue in MS patients is unlikely to result from frequency dependent conduction block in primary central motor pathways and suggested that it is due to an impaired drive to the primary motor cortex. This suggestion is supported by the study of Roelcke et el. 20 who used positron emission tomography and 18 F-fluorodeoxyglucose to measure cerebral glucose metabolism. They found that severe fatigue in MS is associated with a reduction in glucose metabolism in the prefrontal cortex, adjacent white matter and basal ganglia, and concluded that fatigue may result from demyelination of the frontal white matter. This is consistent with the previously reported correlation between fatigue and impaired cognition in the early stages of MS. 21 The possibility that fatigue may indicate primary demyelination or axonal damage in the cerebrum has implications for the treatment of MS. If this is confirmed by further research, severe fatigue may itself become an indication for the treatment of MS in order to minimize further CNS damage. Corticosteroid therapy Intravenous high dose methylprednisolone therapy, 500 mg daily for 5 days, accelerates recovery from acute attacks of relapsing-remitting MS compared to placebo; 22 it also results in improvement in patients with progressive MS although the benefit is considerably less than for acute attacks. Durelli et el. 23 have also shown that i.v. high dose methylprednisolone therapy accelerates recovery from attacks of relapsing-remitting MS, but they used a more complicated regimen of 15 mg per kg per day for 3 days followed by i.v. infusions of tapering doses for another 12 days and then oral prednisone for 120 days. Intravenous high dose methylprednisolone therapy, 1 g daily for 3 days, followed by oral prednisone therapy (1 mg per kg of body weight per day for 11 days) also accelerates recovery from acute optic neuritis compared to placebo. 24 The optimal dose of i.v. methylprednisolone therapy is unclear. Oliveri et al. 25 compared the efficacy of 2.0 g daily for 5 days with 0.5 g daily for 5 days in the treatment of MS relapses. They found that, although the two doses of i.v. methylprednisolone were equally efficacious in improving disability, the higher dose was significantly more effective in reducing the number of gadolinium enhanced MRI brain lesions at 30 and 60 days after the beginning of treatment; this greater efficacy was mainly due to a greater inhibition of new lesion formation. In contrast to i.v. high dose methylprednisolone, oral prednisone alone in standard (intermediate) doses (1 mg per kg per day for 14 days) has no beneficial effect on acute optic neuritis compared to placebo and may increase the risk of new episodes of optic neuritis. 24 One study has reported that oral intermediate dose methylprednisolone therapy alone for 21 days (48 mg daily for 7 days, followed by 24 mg daily for 7 days and then 12 mg daily for 7 days) is equally as effective as i.v. high dose methylprednisolone therapy (1 g daily for 3 days) for the treatment of acute relapses of MS. 26 The authors recommended that oral intermediate dose corticosteroid therapy be used instead of i.v. high dose methylprednisolone because the former is more convenient to use and more cost effective, as it does not require hospitalization. However, in that study, both oral therapy and i.v. therapy had marginal beneficial effects (0.5 EDSS points) compared to the previously reported effect (2.0 EDSS points) of i.v. high dose methylprednisolone. 22 The poor efficacy of i.v. methylprednisolone therapy may have been related to the high proportion of severely disabled patients (EDSS >6.0) in the study, 26 which raises the possibility that a considerable proportion of these patients had permanent neurological deficits due to axonal loss and would not have been expected to respond to corticosteroid therapy. Better evidence for a beneficial effect of oral intermediate dose corticosteroid therapy needs to be provided before it can be advocated for the treatment of MS relapses. Oral high dose methylprednisolone therapy (500 mg once daily for 5 days followed by a tapering dose over the next 10 days) has recently been shown to significantly accelerate recovery from attacks of relapsing-remitting MS, compared to placebo, 27 The treatment was generally well tolerated, although 38% of patients receiving oral high dose methylprednisolone experienced

5 gastrointestinal symptoms. An earlier study found that oral high dose methylprednisolone therapy (500 mg daily for 5 days) was as effective as the same dose of i.v. high dose methylprednisolone therapy in the treatment of acute relapses of MS. 28 It is unclear whether this regimen of oral high dose methylprednisolone can be safely used in routine clinical practice. A problem with the use of oral corticosteroid therapy is that, because of its ease of use, it tends to be prescribed frequently and for prolonged periods leading to chronic corticosteroid use, sideeffects and dependence. 29 In contrast, i.v. administration alerts both patients and physicians to the fact that the indication for its use has to be strong. Intravenous high dose methylprednisolone therapy is recommended for the treatment of moderate to severe attacks of MS not improving spontaneously. At the present time, mild attacks are probably best left untreated. Interferon beta The S.C. administration of 8 million international units of interferon beta-1b every second day has been shown to reduce the frequency of relapses of relapsing-remitting MS by one-third in a multicentre, randomized, double-blind, placebo-controlled trial. 30 This treatment also reduces the severity of relapses 30 and reduces the occurrence of new MRI brain lesions and the MRI detected burden of disease (accumulation of abnormal white matter on T2-weighted brain MRI). 31 The entry criteria for this study were a diagnosis of clinically definite or laboratory supported definite MS of the relapsing-remitting type, an EDSS score of (an EDSS score of 5.5 is equivalent to ambulation for 100 m, but not farther, without aid or rest), and at least two exacerbations in the previous 2 years. The beneficial effect of this therapy on the frequency of relapses and on the accumulation of MRI brain lesions was sustained for at least 5 years after commencement of therapy. 32 A lower dose (1.6 million units every second day) of interferon beta-1b also reduced the relapse rate and the accumulation of MRI lesions compared to placebo, but the effects were less than those of the dose of 8 million units. This study did not demonstrate a significant beneficial effect of interferon beta-1b therapy on the progression of disability; however, it was not originally designed to detect such an effect. Interferon beta-1b therapy also significantly reduces the number of gadolinium enhanced MRI lesions in patients with relapsing-remitting MS. 33 Gadolinium enhancement indicates a breakdown of the blood-brain barrier and correlates with a marked perivascular accumulation of inflammatory cells; 34 it precedes other MRI abnormalities and clinical evidence of the new lesion. 35 In general, treatment with interferon beta-1b is well tolerated. The most common adverse effects are flu-like symptoms and injection site reactions. 36 The flu-like symptoms include fever, chills, myalgia, headache and malaise. The increase in body temperature may transiently aggravate the symptoms and signs of MS by reversibly increasing conduction block in previously demyelinated fibres. These flu-like symptoms tend to resolve after the first few months of therapy and can be controlled by the use of paracetamol or ibuprofen just prior to injection and 4 h later. The most common injection site reaction is redness which is sometimes painful; this tends to resolve after the first month of therapy. Bruising (with pain) and cutaneous or S.C. infections usually indicate a poor injection technique. Subcutaneous atrophy may occur and rarely painful necrotic lesions can occur at the injection sites. Education of the patient, for example by a trained nurse, regarding the injection technique is very important in reducing injection site reactions and maximizing compliance. The injections are usually given in the buttocks, anterior thighs or lower abdomen and are facilitated by the use of an automatic self-injecting device. It is also recommended that the initial seven doses be halved to 4 million units as this appears to lower the incidence of flu-like symptoms and injection site reactions. Interferon beta-1b may also cause anaemia, leukopaenia, thrombocytopaenia or elevation of hepatic enzyme levels. It is unclear whether it aggravates depression and increases the frequency of suicide attempts, but active severe depression should be regarded as a contraindication to the use of interferon beta-1b. 36

6 Interferon beta-1b is also contraindicated in pregnant women, in those who are actively attempting to become pregnant and in those who are breastfeeding. Neutralizing antibodies to interferon beta have been reported to occur in 35% of patients treated with interferon beta-1b and to be associated with a reduction in the beneficial effect of therapy on relapse rate and MRI lesions. 37 It is also possible that binding, nonneutralizing antibodies may interfere with the bioactivity of interferon beta. 38 Further research is needed to determine the clinical significance of antibodies to interferon beta and to detetmine which is the best assay to measure these antibodies. Another form of interferon beta, namely interferon betala, has also been shown to have a beneficial effect on relapsing-remitting MS. 39 Interferon beta-la is a natural sequence, glycosylated, recombinant Chinese hamster ovary product whereas interferon beta-1b is a serine substituted, non-glycosylated recombinant protein produced by Escherichia coli. The intramuscular injection of 6 million units (30 µg) of interferon beta-1a (Avonex, Biogen Inc.) weekly has been shown to reduce the frequency of relapses of relapsingremitting MS by one-third and to reduce the number and volume of gadolinium enhanced MRI brain lesions. 39 Importantly it significantly delayed the time to sustained progression of disability. Neutralizing antibodies also develop in patients treated with interferon beta-1a. 40 The frequency (6%) of neutralizing antibodies after 18 months of interferon beta-la therapy was found to be considerably lower than after a similar period of treatment with interferon beta-1b, but it is unclear whether this was related to differences in the dose, frequency of administration or route of administration, chemical differences between the two forms of interferon beta, or other factors. It should be noted that those treated with interferon beta-1b were studied after they decided to discontinue treatment, whereas the group treated with interferon beta-la were beginning interferon beta therapy for the first time. This raises the possibility that the presence of neutralizing antibodies in the group discontinuing interferon beta-1b may have influenced the decision to stop the drug, thus questioning the validity of the comparison. 41 A recent study has examined the effects of two different doses of interferon beta-la (Rebif, Ares-Serono) in relapsing-remitting MS. 42 Interferon beta-la was given subcutaneously because it has been shown that the bioavailability Of interferon beta-la is equivalent after the s.c. or intramuscular administration of Rebif and intramuscular administration of Avonex 43 and because the s.c. route is more convenient for the patient than the intramuscular route. In this large study patients with EDSS scores of and at least two relapses in the previous 2 years were randomized to receive s.c. recombinant interferon beta-1a (Rebif) 22 µg (6 million units), interferon beta-1a 44 µg, or placebo, three times weekly for 2 years. Both doses of interferon beta-1a significantly reduced the number of relapses (22 µg, 27% reduction; 44 µg, 33 % reduction) compared to placebo. Interferon beta-1a treatment significantly delayed progression of disability (first quartile of time to progression: placebo, 11.9 months; 22 µg, 18.5 months; 44 µg, 21.3 months) and decreased accumulated disability during the study. The number of active MRI lesions and the MRI detected burden of disease were reduced in both treatment groups. The reduction in active MRI lesions was significantly greater in patients receiving the higher dose than in those receiving the lower dose. Interestingly, the 44 µg dose of interferon beta-1a was associated with a lower rate of neutralizing antibodies at 2 years than the 22 µg dose (12.5% vs 23.8%). Furthermore, in the group of patients with a baseline EDSS>3.5, who are likely in the short term to develop secondary progressive MS, the 44 µg dose delayed progression of disability significantly better than either the 22 µg dose or placebo. Both doses of interferon beta-la were generally well tolerated and there was no increased incidence of depression or suicide attempts in either treatment group compared to placebo. All of the above studies have been performed on patients with relapsing-remitting MS. A recent European multi-centre, placebo-controlled trial has shown that interferon beta-1b (8 million international units subcutaneously every second day) significantly slows the progression of disability in patients with secondary progressive MS. 44 This beneficial effect was observed in

7 both those with and without superimposed relapses and was consistent throughout the entire EDSS range studied ( ). It was estimated that interferon beta-1b delayed the progression of disability by 9-12 months in a study period of 2-3 years. Treatment with interferon beta-1b also significantly reduced the mean MRI T 2 lesion volume and the number of newly active MRI lesions. The effect of interferon beta in primary progressive MS is unknown. The mechanism of action of interferon beta in MS is unclear but one possibility is that it may prevent activated T lymphocytes from trafficking into the CNS. Interferon beta therapy leads to an increase in the serum level of soluble vascular cell adhesion molecule-1 (VCAM-1) which correlates with the decrease in the number of gadolinium enhanced MRI lesions. 45 Binding of soluble VCAM-1 to its lymphocyte ligand, very late antigen-4 (VLA-4), may be responsible for the observed decrease in the expression of VLA-4 by peripheral blood lymphocytes in MS patients treated with interferon beta. 46 As the interaction between VLA-4 and VCAM-1 may play a role in the entry of lymphocytes into the CNS, it has been suggested that the down-regulation of lymphocyte expression of VLA-4 may contribute to the beneficial effect of interferon beta in MS. 46 Another possible mechanism for the beneficial effect of interferon beta is the induction of the immunosuppressive cytokine, interleukin-10. Rudick et al, 47 have shown that interferon beta increases interleukin-10 levels in the serum and cerebrospinal fluid (CSF) of patients with relapsing-remitting MS; they also found that increased CSF levels of interleukin-10 correlated with a favourable therapeutic response. Copolymer 1 (Glatiramer Acetate) Copolymer 1 (glatiramer acetate) is a mixture of random synthetic polypeptides composed of L- alanine, L-glutamic acid, L-lysine and L-tyrosine in a molar ratio of 6.0:1.9:4.7:1.0. It was designed to simulate myelin basic protein, a putative target antigen in MS. After it was found to inhibit experimental autoimmune encephalomyelitis (EAE), a pilot study suggested that it had a beneficial effect in relapsing-remitting MS. 48 An extensive multi-centre, double-blind, placebocontrolled trial has now shown that the daily S.C. injection of 20 mg of copolymer 1 for 2 years significantly reduces the relapse rate of relapsing-remitting MS by 29% compared to placebo. 49 There was also some evidence that copolymer 1 had a beneficial effect on the progression of disability. The treatment was well tolerated. The most common adverse effect was an injection site reaction consisting of erythema and induration which occurred in 90% of patients receiving copolymer 1. The other adverse effect was a transient self limited systemic reaction consisting of flushing and chest tightness, sometimes with dyspnoea, palpitations or anxiety; this occurred after one or more injections in 15% of patients. The mechanism responsible for the beneficial effect of copolymer 1 in MS is unclear. Copolymer 1 may have a place in the treatment of those patients with relapsing-remitting MS who become resistant to interferon beta therapy because of the development of antibodies against interferon beta. However, further studies are required to determine the effects of long-term treatment with copolymer 1. I.V. Immunoglobulin Therapy Intravenous immunoglobulin therapy is effective in the treatment of a number of autoimmune diseases, although the mechanism of action is unclear. A randomized, placebo-controlled trial has shown that the monthly i.v. infusion of immunoglobulin ( g per kg) for 2 years significantly reduced the relapse rate of relapsing-remitting MS by 59% and had a significant beneficial effect on the progression of disability, compared to placebo9 The treatment was well tolerated. A similar beneficial effect of i.v. immunoglobulin on relapse rate was found in a smaller study in which patients received a loading dose of 0.4 g per kg per day for 5 consecutive days, followed by single booster doses (0.4 g per kg) once every 2 months for 2 years. 51 A very high dose of i.v. immunoglobulin (1 g per/2g daily for 2 consecutive days every month for 6

8 months) significantly reduced the number of gadolinium enhanced MRI brain lesions compared to placebo; 52 however/this is clearly above the maximum tolerated dose, as it resulted in a high frequency of severe eczema which usually commenced in the palms of the hands and developed 2-4 days after the first or later courses of i.v. immunoglobulin. On present evidence, i.v. immunoglobulin therapy may be as effective as interferon beta in the treatment of relapsingremitting MS, 50 but further studies are needed to determine the effects of its long-term use in MS. Immunosuppressive therapy Given the increasing evidence that MS is an autoimmune disease and the fact that other autoimmune diseases respond to immunosuppressive therapy, it would be anticipated that such therapy would be beneficial in MS. Most of the clinical trials of immunosuppression in MS have been performed on patients with progressive MS rather than relapsing-remitting MS. As much of the persistent disability in progressive MS is probably due to axonal damage, it is likely that the main benefit able to be obtained from effective immunosuppression is the prevention of an increase in disability rather than reversal of pre-existing disability. This may account for the modest and disappointing effects of immunosuppressive therapy in progressive MS in the studies performed to date. Azathioprine A meta-analysis of the results of published blind, randomized, controlled trials of azathioprine therapy (2-3 mg per kg per day) in relapsing-remitting MS and progressive MS showed that this therapy reduces the frequency of relapses and possibly slows the progression of disability. 53 It is doubtful whether the slight beneficial effect of azathioprine outweighs its side-effects. Cyclosporin A Cyclosporin A therapy has a modest beneficial effect on the progression of disability in progressive MS, 54 but the high incidence of severe adverse effects, particularly renal impairment and hypertension, makes it an unsuitable therapeutic agent for MS. As low dose cyclosporin A therapy converts acute EAE into chronic relapsing EAE, the possibility that cyclosporin A may aggravate MS in some patients needs to be considered. 55 Methotrexate Oral low dose methotrexate therapy is an effective and relatively safe treatment for the common chronic autoimmune diseases, rheumatoid arthritis and psoriasis. A randomized, double-blind, placebo-controlled trial has shown that oral methotrexate 7.5 mg weekly for 2 years significantly reduces the rate of progression of disability in progressive MS. 56 The beneficial effect was evident in tests of upper limb function but not in the ambulation index or the EDSS score which is mainly determined by walking ability. The clinical benefit was observed in patients with secondary progressive MS, but too few patients with primary progressive MS were included to assess efficacy in the latter group. The methotrexate therapy also had a beneficial effect on the total T 2 -weighted lesion area in MRI brain scans. 57 It is highly likely that the 7.5 mg dose is inadequate, as considerably higher weekly doses (12.5 mg) are regularly used in the management of patients with rheumatoid arthritis. An insufficient dose may account for the failure of the therapy to slow deterioration of ambulation. The extent of axonal loss in CNS motor and sensory pathways is likely to be greater for the lower limbs than for the upper limbs, with the result that measurements of lower limb function may be less sensitive to immunosuppression than measurements of upper limb function. Currently, methotrexate appears to be the best immunosuppressive agent for slowing deterioration in progressive MS. Further clinical trials are needed to determine whether higher doses of oral methotrexate are more effective than the 7.5 mg weekly dose and to determine the relative benefits of methotrexate therapy and interferon beta

9 therapy in progressive MS. Oral low dose methotrexate is generally well tolerated but requires regular monitoring of the full blood count and liver function. It is important to name the day (for example, Monday) of the week on which the methotrexate is to be taken, in order to avoid the possibility of the patient taking the dose daily instead of weekly. If a dose exceeding 7.5 mg is used, the patient should take folic acid 5 mg, 3 days after the methotrexate dose. Cyclophosphamide Cyclophosphamide is too toxic to be used for the treatment of MS, with the possible exception of rapidly progressive MS not responding to methotrexate. 58 Conclusion In conclusion, several immunomodulating agents have now been shown to have beneficial effects in MS. Further research is needed to determine the optimal doses and combinations of these therapies and to develop better therapies, particularly for primary progressive MS. References 1. R Martin and HF McFarland, Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit Rev Clin Lab Sci 32 (1995), pp MP Pender, Multiple sclerosis. In: MP Pender and PA McCombe, Editors, Autoimmune Neurological Disease, Cambridge University Press, Cambridge (1995), pp CM Poser, DW Paty, L Scheinberg et al., New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13 (1983), pp JI O'Riordan, AJ Thompson, DPE Kingsley et al., The prognostic value of brain MRI in clinically isolated syndromes of the CNS: a 10-year follow-up. Brain 121 (1998), pp F Barkhof, M Filippi, DH Miller et al., Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120 (1997), pp FD Lublin and SC Reingold, Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 46 (1996), pp AJ Thompson, CH Polman, DH Miller et al., Primary progressive multiple sclerosis. Brain 120 (1997), pp GV McDonnell and SA Hawkins, Application of the Poser criteria in primary progressive multiple sclerosis. Ann Neurol 42 (1997), pp JW Thorpe, D Kidd, IF Moseley et al., Spinal MRI in patients with suspected multiple sclerosis and negative brain MRI. Brain 119 (1996), pp M Charcot, Histologie de la sclerose en plaques. Gaz Hosp 141 (1868), pp M Charcot, Histologie de la sclerose en plaques. Gaz Hosp 141 (1868), pp BD Trapp, J Peterson, RM Ransohoff, R Rudick, S Mörk and L Bö, Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338 (1998), pp B Ferguson, MK Matyszak, MM Esiri and VH Perry, Axonal damage in acute multiple sclerosis lesions. Brain 120 (1997), pp NA Losseff, SL Webb, JI O'Riordan et al., Spinal cord atrophy and disability in multiple sclerosis: a new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 119 (1996), pp CA Davie, GJ Barker, S Webb et al., Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 118 (1995), pp NA Losseff, L Wang, HM Lai et al., Progressive cerebral atrophy in multiple sclerosis: a serial MRI study. Brain 119 (1996), pp L Truyen, JHTM van Waesberghe, MAA van Walderveen et al., Accumulation of hypointense lesions ("black holes") on T 1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47 (1996), pp MAA Van Walderveen, W Kamphorst, P Scheltens et al., Histopathologic correlate of hypointense lesions on T1- weighted spin-echo MRI in multiple sclerosis. Neurology 50 (1998), pp MP Pender, Genetically determined failure of activation-induced apoptosis of autoreactive T cells as a cause of multiple sclerosis. Lancet 351 (1998), pp

10 19. GL Sheean, NMF Murray, JC Rothwell, DH Miller and AJ Thompson, An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain 120 (1997), pp U Roelcke, L Kappos, J Lechner-Scott et al., Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18 F-fluorodeoxyglucose positron emission tomography study. Neurology 48 (1997), pp MM Callanan, SJ Logsdail, MA Ron and EK Warrington, Cognitive impairment in patients with clinically isolated lesions of the type seen in multiple sclerosis: a psychometric and MRI study. Brain 112 (1989), pp NM Milligan, R Newcombe and DAS Compston, A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. clinical effects. J Neurol Neurosurg Psychiatry 50 (1987), pp L Durelli, D Cocito, A Riccio et al., High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology 36 (1986), pp RW Beck, PA Cleary, MM Anderson et al., A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 326 (1992), pp RL Oliveri, P Valentino, C Russo et al., Randomized trial comparing two different high doses of methylprednisolone in MS: a clinical and MRI study. Neurology 50 (1998), pp D Barnes, RAC Hughes, RW Morris et al., Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 349 (1997), pp F Sellebjerg, JL Frederiksen, PM Nielsen and J Olesen, Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 51 (1998), pp SM Alam, T Kyriakides, M Lawden and PK Newman, Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J Neurol Neurosurg Psychiatry 56 (1993), pp F Barkhof and C Polman, Oral or intravenous methylprednisolone for acute relapses of MS?. Lancet 349 (1997), pp The IFNB Multiple Sclerosis Study Group, Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43 (1993), pp DW PatyUBC MSAMRI Study Group, the IFNB Multiple Sclerosis Study Group and DKB Li, Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind placebo-controlled trial. Neurology 43 (1993), pp The IFNB Multiple Sclerosis Study Group, the University of British Columbia MS/MRI Analysis Group, Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45 (1995), pp LA Stone, JA Frank, PS Albert et al., The effect of interferon-β on blood-brain barrier disruptions demonstrated by contrast-enhanced magnetic resonance imaging in relapsing-remitting multiple sclerosis. Ann Neurol 37 (1995), pp D Katz, JK Taubenberger, B Cannella, DE McFadin, CS Raine and HF McFarland, Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 34 (1993), pp AG Kermode, AJ Thompson, P Tofts et al., Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis: pathogenetic and clinical implications. Brain 113 (1990), pp FD Lublin, JN Whitaker, BH Eidelman, AE Miller, BGW Arnason and JS Burks, Management of patients receiving interferon beta-1b for multiple sclerosis: report of a consensus conference. Neurology 46 (1996), pp The IFNB Multiple Sclerosis Study Group, the University of British Columbia MS/MRI Analysis Group, Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology 47 (1996), pp AR Pachner, Anticytokine antibodies in beta interferon-treated MS patients and the need for testing: plight of the practicing neurologist. Neurology 49 (1997), pp LD Jacobs, DL Cookfaïr, RA Rudick et al., Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 39 (1996), pp RA Rudick, NA Simonian, JA Alam et al., Incidence and significance of neutralizing antibodies to interferon beta- 1a in multiple sclerosis. Neurology 50 (1998), pp AH Cross and JP Antel, Antibodies to beta-interferons in multiple sclerosis: can we neutralize the controversy?. Neurology 50 (1998), pp PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group, Randomised double-blind placebo-controlled study of interferon β -1a in relapsing/remitting multiple sclerosis. Lancet 352 (1998), pp

11 43. A Munafo, I Trinchard-Lugan, TXQ Nguyen and M Buraglio, Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol 5 (1998), pp European Study Group on Interferon β-1b in Secondary Progressive MS, Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis. Lancet 352 (1998), pp PA Calabresi, LR Tranquill, JM Dambrosia et al., Increases in soluble VCAM-1 correlate with a decrease in MRI lesions in multiple sclerosis treated with interferon β-1b. Ann Neurol 41 (1997), pp PA Calabresi, CM Pelfrey, LR Tranquill, H Maloni and HF McFarland, VLA-4 expression on peripheral blood lymphocytes is downregulated after treatment of multiple sclerosis with interferon beta. Neurology 49 (1997), pp RA Rudick, RM Ransohoff, J-C Lee et al., In vivo effects of interferon beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 50 (1998), pp MB Bornstein, A Miller, S Slagle et al., A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 317 (1987), pp KP Johnson, BR Brooks, JA Cohen et al., Copolymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 45 (1995), pp F Fazekas, F Deisenhammer, S Strasser-Fuchs, G Nahler and B Mamoli, Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 349 (1997), pp A Achiron, U Gabbay, R Gilad et al., Intravenous immunoglobulin treatment in multiple sclerosis: effect on relapses. Neurology 50 (1998), pp PS Sorensen, B Wanscher, CV Jensen et al., Intravenous immunoglobulin G reduces MRI activity in relapsing multiple sclerosis. Neurology 50 (1998), pp PL Yudkin, GW Ellison, A Ghezzi et al., Overview of azathioprine treatment in multiple sclerosis. Lancet 338 (1991), pp The Multiple Sclerosis Study Group, Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 27 (1990), pp MP Pender, Cyclosporine and multiple sclerosis. Ann Neurol 29 (1991), p DE Goodkin, RA Rudick, S Vanderbrug Medendorp et al., Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 37 (1995), pp DE Goodkin, RA Rudick, S VanderBrug Medendorp, MM Daughtry and C Van Dyke, Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology 47 (1996), pp RA Rudick, JA Cohen, B Weinstock-Guttman, RP Kinkel and RM Ransohoff, Management of multiple sclerosis. N Engl J Med 337 (1997), pp