52nd Annual Meeting of the American Academy of Neurology
Rohit Bakshi, MD
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects approximately 250,000 individuals in the United States. MS is the most common cause of progressive physical disability in young adults. Recent developments pertaining to the pathophysiology, immunomodulatory treatment, and symptomatic relief of MS were presented in San Diego, California. Following are highlights of the scientific presentations about MS given at the meeting. In addition to the key presentations below, a separate highlights summary of neuroimaging research includes a multiple sclerosis section.
Immunomodulatory Treatment of MS
T-cell Vaccination for MS
FDA-approved treatments for MS have limited the progression of the disease but have not been successful cures in most patients. Since autoimmunity plays an important role in MS, treatments targeting the immune system are most likely to be effective. Zhang and colleagues, from Houston, Texas, presented the results of a human trial of a novel T-cell vaccine in MS patients. Autoimmune T cells recognizing myelin antigens are thought to contribute to the pathogenesis of MS. A T-cell vaccination composed of irradiated autologous myelin-reactive T cells was administered to 65 patients with MS who were aware of the treatment (unblinded). During the next 2 years, the investigators noted a significant reduction in the rate of relapse as compared with an untreated natural history MS cohort. Improvement on physical disability and MRI lesion load was also observed. The vaccination reduced the number of activated T cells in the blood. This work provides an impetus to further study the role of myelin-reactive T-cell vaccination in a randomized, controlled, double-blinded, prospective study of MS patients.
Prevention of MS in Those at High Risk
The diagnosis of MS requires 2 attacks separated in space and time in the central nervous system. Since MS is a destructive process, the earliest possible treatment of high-risk individuals is desired to prevent long-term disability. After first clinical attacks of inflammatory demyelination such as optic neuritis or transverse myelitis, a subgroup of patients will go on to develop MS. It is not known whether these individuals at high risk for MS should be treated with chronic immunomodulatory agents to prevent or limit the progression to full-blown MS. Jacobs and coworkers, from Buffalo, New York, presented results of a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta 1-a (Avonex) in 383 patients at high -risk of developing MS. The patients were required to have an acute solitary clinical attack of demyelination and evidence of at least 2 other brain MRI lesions. Interferon beta 1-a significantly reduced the rate of development of clinically definite MS. Patients receiving interferon beta 1-a also had protection from the development of MS-related MRI lesions, including bright T2 plaques and gadolinium enhancement.
In a similar study, Comi and associates from Milan, Italy, reported the results of a multicenter trial of interferon beta 1-a (Rebif) in preventing the development of MS after a first clinical attack. The study enrolled 309 patients who were treated within 3 months of an initial clinical episode suggestive of MS. Interferon beta 1-a significantly reduced the rate of progression to MS, delayed the onset of MS, and improved MRI outcome. These studies indicate that a subgroup of high-risk patients after an initial inflammatory event can benefit from early treatment with interferon beta 1-a and that MRI is useful in identifying these patients. These trials are the first to show an effective method of preventing the development of MS.
Four-Year Efficacy of Interferon Beta-1a for MS
Freedman, from Ottawa, Canada, presented 4-year results from the PRISMS study of interferon beta-1a (Rebif) in relapsing MS patients. The treatment benefit on clinical and MRI measures was maintained over 4 years. The high-dose (3 x 44 micrograms [mcg]/week) Interferon beta 1-a was superior to 3 x 22 mcg in terms of relapse outcomes (Figure 1) and disease activity on T2-weighted MRI scans (Figure 2). Patients who received early treatment experienced more benefit than those in whom treatment was delayed (P = 0.047 in the higher dose group). Neutralizing antibodies to interferon-beta were detected and sustained in approximately 20% of patients, and this antibody presence was associated with a reduction of clinical and MRI efficacy.
Second-line Immunotherapy for MS
Some patients with CNS demyelinating diseases continue to experience relapses or disease progression despite the best available therapies. These include relapsing-remitting MS patients who fail self-injectable immunotherapies, secondary progressive patients who develop worsening physical disability, and patients with conditions related to MS for which proven therapies do not exist. Khan and colleagues, from Detroit, Michigan, used monthly cyclophosphamide (Cytoxan) in patients with MS who were rapidly deteriorating despite standard treatment. This was an open-label, retrospective series of patients with worsening by more than 3 points on the expanded disability status scale (EDSS) in the 12 months prior to initiating cyclophosphamide treatment despite continuous treatment with IV corticosteroid pulses and interferons or glatiramer acetate. Patients received 6 months of IV cyclophosphamide at doses achieving a serum WBC of 2000 to 2200/mm3. Three months after initiating treatment, 5 of 14 patients improved by 0.5 points, 4 by 1 point, and 5 by more than 1.5 points by EDSS. At 12 months, 7 of 14 improved by 1 point, 5 by more than 2 points, and 1 each by 1 and 0.5 points on the EDSS. None experienced adverse effects necessitating discontinuation of cyclophosphamide. Thus, cyclophosphamide may be a therapeutic option in MS patients who fail conventional therapies. A prospective, randomized, double-blinded, controlled trial is warranted to extend these findings.
Treatment of MS-related Syndromes
Devic's disease (neuromyelitis optica) is an MS-related inflammatory demyelinating syndrome affecting the spinal cord and optic nerves that is associated with a high morbidity. Unfortunately, proven disease-modifying therapies for Devic's disease are not available. Rensel and associates from Cleveland, Ohio, presented a retrospective study of the use of plasma exchange for acute severe relapses in 7 patients with Devic's disease who had failed IV corticosteroids. Patients were treated with 5 to 8 exchanges over 2 weeks. Six (86%) had improved gait at 8 weeks. Three of the patients were able to walk at the beginning of plasma exchange, and 5 were able to walk at 8 weeks after plasma exchange. Six of the patients experienced at least 1 relapse after treatment. Plasma exchange was well tolerated and appeared to improve neurologic function in the majority of the patients with attacks of Devic's disease.
Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the CNS that is related to MS. ADEM is usually monophasic with a peak disability a few days or weeks after the onset of illness, but recurrent or protracted episodes may occur. When ADEM is recurrent, the distinction from MS and its variants becomes difficult. Treatment options for ADEM include a variety of immunosuppressive agents such as high-dose corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis. Recovery from ADEM is variable, with permanent sequelae common when progression is rapid and the spinal cord is affected. With slower progression, response to steroids and a better outcome are likely. Inflammatory demyelination may occur in a solitary form in the brain (leukoencephalitis) or spinal cord (myelitis). These seem to lie on a spectrum of inflammatory diseases linking ADEM and MS for which the acute therapies are similar. In ADEM, MRI typically shows multifocal, asymmetric, white matter lesions involving the cerebral hemispheres, cerebellum, and brain stem that are usually larger than those seen in MS but also may resemble MS. Tenembaum and colleagues, from Argentina, reported a prospective study of 79 pediatric ADEM cases with neuroimaging correlation. A triggering event (viral infection or immunization) was present in 78% of cases. Multifocal white matter lesions were found in 74% of CT scans and in 97% of MRI scans. Treatment with high-dose IV corticosteroids (given for 91% of patients) seemed to hasten recovery. The prognosis was favorable in 90% of the study patients.
Treatment of Secondary Progressive MS
One of the goals of early treatment of MS patients in the relapsing-remitting stage is to prevent secondary progression. Secondary progressive (SP) MS is defined as sustained progression of physical disability occurring separate from relapses that develops in patients who previously had relapsing-remitting MS. Secondary progressive MS is a feared stage of disease that is difficult to treat and commonly leads to loss of ambulatory function and underemployment. Investigators presented results of 2 large, recently completed, randomized, multicenter, double-blind, placebo-controlled treatment trials of interferons in SPMS.[16,17] The SPECTRIMS study found that interferon beta 1-a (Rebif) reduced the relapse rate and MRI progression but did not lessen the development of sustained physical disability in 618 SP patients after 3 years. In agreement with these results, Goodkin from San Francisco, California, and his colleagues in North America found that interferon beta 1-b (Betaseron) also reduced relapses and MRI parameters but not the accumulation of disability in 939 SPMS patients. A subgroup analysis of the SPECTRIMS patients who had prestudy relapses showed a trend toward a significant protective effect on disability for the high-dose (44 micrograms [mcg]/wk) interferon beta 1-a group (Table 1). These studies provide valuable information about the disease course of MS and the role of immunomodulatory treatment. First, it is clear that early treatment of MS is highly desirable to prevent the development of an SPMS disease course that is less amenable to therapy. Second, these results indicate that interferons have at best a marginal effect on SPMS disease, especially in patients who no longer experience acute clinical relapses.
Pathophysiology of MS
Glutamate is the most abundant excitatory neurotransmitter in the human brain and has an important role in normal brain function. However, the excessive release of glutamate causes nerve cell death ("excitotoxicity"), which has been linked to a variety of disorders such as stroke, degenerative diseases, traumatic brain injury, and spinal cord injury. Recent work from Pitt and coworkers in New York, NY, implicated glutamate excitotoxicity in axonal damage, oligodendrocyte death, and clinical impairment in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). These same investigators presented data from autopsied brain MS lesions, in which activated inflammatory cells showed immunoreactivity for the glutamate-producing enzyme, glutaminase, indicating elevated levels of extracellular glutamate. Glutaminase immunoreactivity was present in areas with damaged axons. By contrast, the expression of glutamate catabolizing enzymes was reduced. This is the first human study to directly implicate excitotoxicity in the pathophysiology of MS. In a related study, the authors showed that a glutamate receptor antagonist was successful in limiting the axonal damage of EAE. Thus, blockade of glutamate receptors may prove to be a novel strategy in the treatment of MS, and further study of this line of research is warranted.
Limiting the Symptoms of MS
Fatigue is a common and disabling syndrome in MS that may contribute to depression and poor quality of life. Standard treatments of fatigue (amantadine and pemoline) may have only a palliative effect; thus, other means of improving fatigue in MS patients are desired. Modafinil is known to be effective and well tolerated for the treatment of excessive sleepiness in narcolepsy. Rammohan and associates, from Columbus, Ohio, presented results of the use of modafinil in the treatment of fatigue in 72 MS patients. At a dose of 200 mg per day, modafinil was effective as compared with placebo in improving fatigue. The most commonly reported side effect associated with modafinil was nervousness (placebo, 5%; 200 mg, 14%). Only 4 patients discontinued the drug because of a side effect. Dr. Rammohan stated that patients may be started at a dose of 100 mg and then increased to doses up to 400 mg per day as needed. The beneficial effect of modafinil in MS-related fatigue was confirmed in a similar study presented by Terzoudi and colleagues from Greece.
Intention tremor in MS is of rubro-cerebellar origin and is difficult to treat. von Widdern and colleagues, from Rostock, Germany, showed that ondansetron, a 5-HT3 antagonist, is effective in ameliorating intention tremor in MS patients. Sixteen patients with moderate to severe cerebellar tremor received 8 mg of ondansetron per day orally in an open-label study. Treatment with ondansetron resulted in a significant reduction in tremor severity that persisted for 30 days. Discontinuing the drug resulted in increased tremor. The effect of ondansetron should be studied further in randomized, placebo-controlled, double-blind studies.
Trigeminal neuralgia in MS is typically treated with anticonvulsants, baclofen, tricyclic antidepressants, or other analgesics but can be intractable. Din and colleagues, from Detroit, Michigan, reported an open-label series of topiramate therapy in 5 MS patients with trigeminal neuralgia refractory to conventional drug therapy. Treatment was initiated at 25 mg twice a day and increased by 50 mg a week to a maximum of 200 mg twice a day. Four patients (80%) experienced pain relief at 150 mg a day, with a maximal effect at 200 mg daily. One patient required 300 mg a day. The effect of topiramate was maintained at 6 months and was well tolerated. Mild nausea and dizziness were the most common side effects, but no one discontinued therapy. Thus, topiramate may be a useful therapeutic option in the treatment of trigeminal neuralgia in MS. Its effect should be studied further in randomized, placebo-controlled, double-blind, cross-over studies.
1.Zhang JZ, Rivera VM, Li
S, et al. Vaccination with myelin-reactive T cells: results of a clinical
trial in patients with multiple sclerosis. Neurology. 2000;54(suppl 3):A23.
2.Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983;13:227-231.
3.Bakshi R, Kinkel PR, Mechtler LL, et al. Magnetic resonance imaging findings in 22 cases of myelitis: comparison between patients with and without multiple sclerosis. Eur J Neurol. 1998;5:35-48.
4.Jacobs L, Beck R, Simon JH, et al. Results of a phase III trial of interferon beta 1-a treatment in patients at high risk of developing multiple sclerosis. Program and abstracts of the American Academy of Neurology 52nd Annual Meeting; April 29-May 6, 2000; San Diego, California. Abstract LBN.002.
5.Simon JH, Beck R, Jacobs L, et al. MRI Results of a phase III trial of interferon beta 1-a treatment in patients at high risk of developing multiple sclerosis. Program and abstracts of the American Academy of Neurology 52nd Annual Meeting; April 29-May 6, 2000; San Diego, California. Abstract LBN.003.
6.Comi G, Filippi M, Barkhof F, et al. Interferon beta 1-a (Rebif) in patients with acute neurological syndromes suggestive of multiple sclerosis: a multi-center, randomized, double-blind, placebo-controlled study. Neurology. 2000;54(suppl 3):A85-86. Abstract S17.003.
7.Freedman MS, and PRISMS Study Group. PRISMS 4-year results: evidence of clinical dose effect of interferon beta-1a in relapsing MS. Program and abstracts of the American Academy of Neurology 52nd Annual Meeting; April 29-May 6, 2000; San Diego, California. Abstract LBN.001.
8.Khan O, Zvartau-Hind M, Kamhol J, et al. Efficacy and tolerability of monthly intravenous (IV) cyclophosphamide (CTX) in rapidly deteriorating MS patients resistant to conventional therapy. Neurology. 2000;54(suppl 3):A337-338. Abstract P05.010.
9.Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444-1452.
10.Rensel MR, Weinstock-Guttman B, Kinkel R, et al. Clinical experience with plasma exchange for severe relapse in patients with Devic's disease. Neurology. 2000;54(suppl 3):A23. Abstract S11.003.
11.Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encephalomyelitis: MRI findings and the distinction from multiple sclerosis. Brain. 1990;113:291-302.
12.Kanter DS, Horensky D, Sperling RA, et al. Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology. 1995;45:824-827.
13.Bakshi R, Glass J, Louis DN, Hochberg FH. Magnetic resonance imaging features of solitary inflammatory brain masses. J Neuroimaging. 1998;8:8-14.
14.Tenembaum SN, Segura M, Chamoles N, et al. Acute disseminated encephalomyelitis (ADEM). Prospective study in 79 pediatric patients. Neurology. 2000;54(suppl 3):A247. Abstract S45.003.
15.Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911.
16.Hughes RAC and the SPECTRIMS group. Relapsing versus nonrelapsing SPMS: different prognosis and response to interferon therapy in the SPECTRIMS study. Neurology. 2000;54(suppl 3):A233. Abstract S38.003.
17.Goodkin DE and the North American Study Group on Interferon beta 1-b in Secondary Progressive MS. Interferon beta 1-b in secondary progressive MS: clinical and MRI results of a 3-year randomized controlled trial. Program and abstracts of the American Academy of Neurology 52nd Annual Meeting; April 29-May 6, 2000; San Diego, California. Abstract LBN.004.
18.Bakshi R, Newman AH, Faden AI. Dynorphin induces alterations of motor function, excitatory amino acids, and free fatty acids through an opiate receptor mechanism. J Neuroscience. 1990;10:3793-3800.
19.Pitt D, Werner P, Raine CS. Glutamate excitotoxicity as a mechanism for axonal damage in multiple sclerosis. Neurology. 2000;54(suppl 3):A258-259. Abstract S50.002.
20.Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Multiple Sclerosis. (In press.)
21.Rammohan KW, Rosenberg JH, Pollak CP, et al. Provigil (modafinil): efficacy and safety for the treatment of fatigue in patients with multiple sclerosis. Neurology. 2000;54(suppl 3):A24. Abstract S11.004.
22.Terzoudi M, Gavrielidou P, Heilako G, et al. Fatigue in multiple sclerosis. evaluation and a new pharmacological approach. Neurology. 2000;54(suppl 3):A61-62. Abstract P01.100.
23.von Widdern OC, Benecke R, Zettl UK. The effect of ondansetron (tetrahydro-methyl-carbazol-hydrochloride-dihydrate), a 5-HT3 antagonist, on intention tremor in multiple sclerosis. Neurology. 2000;54(suppl 3):A60. Abstract P01.095.
24.Din MU, Zvartau-Hind M, Gilani A, et al. Topiramate relieves refractory trigeminal neuralgia in multiple sclerosis patients. Neurology. 2000;54(suppl 3):A60. Abstract P01.096.