More MS news articles for Nov 2001

A Global Perspective on Multiple Sclerosis

http://neurology.medscape.com/medscape/cno/2001/WCNCME/Story.cfm?story_id=2315

XVII World Congress of Neurology
Day 1 - June 17, 2001
Patricia K. Coyle, MD, Syed Rizvi, MD, MBBS

The 17th World Congress of Neurology included a wealth of presentations about multiple sclerosis (MS). The scope of information provided a truly global perspective on the investigations into the pathophysiology, epidemiology, and management of MS.

MS Main Theme

The day-long MS Main Theme section involved 10 presentations comprising a broad spectrum of topics ranging from genetic epidemiology to rehabilitation, and included a case discussion.

Genetics

Dr. D.A.S. Compston, from Cambridge, UK, discussed the genetics of MS.[1] He noted that there are genes associated with increased disease risk, as well as disease severity, and reviewed a number of candidate genes involving immune/inflammatory, trophic, and CNS factors. MS shows genetic heterogeneity, so linked genes are likely to differ between distinct MS subgroups. It will be critical to identify and examine meaningful subsets for gene analysis.

Immunopathology

Dr. H. Lassman,[2] from Vienna, Austria, reviewed his work on immunopathologic heterogeneity in MS, which focuses on the pathology of active brain plaques based on degree of inflammation, presence of antibody/activated complement, oligodendrocyte loss, and remyelination. These observations have been made on a relatively small dataset; many of the brain samples came from patients with an atypical presentation. This raises concern about the ultimate generalization of this cut-and-dry 4-pattern division.

His presentation stimulated a provocative discussion about whether ischemic injury could be a critical factor in the distal oligodendrogliopathy pattern III. Axon damage occurs during active demyelination, most likely due to a release of toxic factors by macrophages, the most plentiful cell population within active lesions. Axon damage also occurs in chronic inactive plaques, which show no remyelination, implying 2 distinct mechanisms.

Dr. H. Wekerle,[3] from Munich, Germany reviewed the immunopathogenesis of MS. In addition to discussing the role for autoreactive T cells, local glia, macrophages, and myelin-specific B cells, he emphasized the growing appreciation of the importance of neurons, which help to regulate local immune reactions within the central nervous system (CNS) microenvironment.

A related study[4] evaluated the role of apoptosis (programmed cell death) in removing autoreactive T cells. Activated T cells were examined in cerebrospinal fluid (CSF) and serum of patients with MS, patients with other neurologic disease, and healthy controls. CSF T cells from MS patients showed much higher levels of survivin (an antiapoptosis protein). Survivin levels were also elevated (although less marked) in peripheral blood T cells of patients with MS. These findings were interpreted to indicate impaired apoptosis in MS, which could play a role in allowing an ongoing immune attack against the CNS.

Axonal Conduction

Dr. K. Smith,[5] from London, UK, discussed the role of axonal conduction in MS. Axonal conduction can be impaired by demyelination, inflammation, or degeneration of the axon itself. Inflammatory factors such as nitric oxide, the pentapeptide QYNAD, and ion channel antibodies can produce reversible conduction block. Conduction block can be circumvented by insertion of sodium channels into the axolemma and development of internodal excitability. When demyelination is severe, or when axons degenerate, permanent conduction loss occurs. Axon structure and function is an exciting area that will provide a new therapeutic target for development over the next few years.

Animal Models, Imaging Techniques, Future Therapies

Others in this Main Theme section discussed the mouse model of Pelizaeus-Merzbacher disease, which involves mutations in the proteolipid protein gene;[6] newer magnetic resonance imaging (MRI) techniques (MR spectroscopy, magnetization transfer imaging, diffusion-weighted and diffusion-tensor imaging), which allow detection of microscopic changes in normal appearing brain tissue;[7] and creative healthcare services.[8]

Dr. J. Kesselring[9] from Valens, Switzerland, emphasized the beneficial role of rehabilitation in MS and reviewed several studies which showed that physical exercise programs could improve both physiologic and psychologic measures. The final 2 papers focussed on current and future disease-modifying therapies.[10,11] The emphasis on early treatment of MS is increasing, even in the European community. Dr. J. Noseworthy,[11] from Rochester, Minnesota, covered a wide range of new approaches to MS that are under evaluation. He also considered the difficulty of performing blinded placebo-controlled trials in an era of accepted and widely used therapeutics.

Drug Therapies

The EVIDENCE Study

Does the amount and frequency of interferon (IFN) beta-1a dosing affect efficacy? Results of the Evidence for Interferon Dose-effect: European-North American Comparative Efficacy (EVIDENCE) study,[12] a comparative head-to-head trial of 2 interferon beta-1a products (high-dose Rebif, 44 mcg given subcutaneously 3 times a week vs Avonex 30 mcg given intramuscularly once a week), were reported during the Late-Breaking News Section on Friday.

This ongoing study involves 56 centers (36 in the US) and 677 relapsing MS patients (443 from the US). The study runs 48 weeks, however, the primary outcome (proportion of relapse-free patients) and main secondary outcome (number of combined unique active T1- and T2-weighted contrast lesions on brain MRI) involved assessment at 24 weeks (6 months). Although patients and treating physicians were not blinded to treatment (this was felt to be impractical), the primary outcome was determined by a blinded evaluating physician, and all MRI readings were blinded. Therefore, both the primary and main secondary outcomes are based on blinded assessments.

At 6 months, the proportion of relapse-free patients was 74.9% in the Rebif arm vs 63.3% in the Avonex arm (P = .005), a 32% relative reduction in the proportion of Rebif treated patients with relapses. Patients treated with Rebif had 27% fewer relapses (P = .022), 47% fewer steroid treated relapses (P = .004), and a 37% longer duration to first relapse (P = .001). Combined unique brain MRI lesions averaged 0.8 new lesions per scan in the Rebif-treated group compared with 1.2 new lesions per scan with Avonex (P < .0001). The proportion of active MRI scans was 24% in the Rebif group vs 37.3% in the Avonex group (P < .001). Both drugs were well tolerated. Although the Rebif-treated group had more injection-site reactions and laboratory abnormalities in liver enzymes and white blood cell counts, virtually all of these were mild reactions.

This is the largest head-to-head comparison of 2 MS disease-modifying therapies. The study provides convincing evidence that high-dose/frequently dosed IFN beta-1a is superior to low-dose/infrequently dosed IFN beta-1a.

Steroids

In a small study of approximately 80 patients with relapsing MS, half were treated with regular pulses of intravenous methylprednisolone,[13] and half received steroids only at the time of clinical relapse. MRI was examined at baseline and after 5 years. The group who received regular steroids (total steroid dose about 3.5 times that of the control group) showed less brain atrophy and T1-weighted holes on MRI and less disease progression. There was no effect on T2-weighted lesions or relapses. This is a surprising observation. The investigators suggest that pulse steroids may exert a protective effect to limit atrophy. This hypothesis is consistent with an observation made by National Institutes of Health (NIH) investigators that acute treatment with steroids is associated with less reduction in magnetization transfer ratios within acute lesions. Of course the study arms were fairly small, and only 2 MRI scans were done. This is not as convincing as a study involving frequent MRI scans. Nonetheless, it raises intriguing questions about novel steroid benefits for MS.

Other Drugs

A small study[14] of 15 MS patients reported that treatment with a potassium-channel blocker 4-aminopyridine 10 mg intramuscularly twice daily for 1 month resulted in improvement in cognitive function. Controlled-release oral forms of 4-aminopyridine are being evaluated.
Lycke and associates,[15] from Sweden and Denmark, reported on a phase II trial of valaciclovir in relapsing MS. Valaciclovir, an antiviral agent with broad anti-herpes virus activity, was given at a dose of 1000 mg 3 times daily for 24 weeks. Seventy patients were randomized to receive active drug or placebo. The main outcome measure was total number of active brain MRI lesions.

Results indicated no reductions in MRI lesion formation with valaciclovir, although a trend toward benefit was found in a subgroup of MS patients with very high MRI activity. The researchers concluded that this observation should be pursued, even though overall study results did not indicate a role for antiviral therapy in MS. Thus far, there has been no convincing data to support use of routine antivirals in MS.

Markers of Disease

CSF Markers

Several studies examined CSF levels of axon components, including actin, tubulin, and neurofilament protein.[16,17] Levels of axon components in MS patients were elevated compared with control CSF samples, and more elevated in patients with longer-duration MS and more disabled patients with progressive MS. These are cross-sectional studies, with fewer than 100 MS patients evaluated. Larger numbers of patients and longitudinal (multiple time point) studies are needed to validate whether axonal markers in CSF have real predictive value for future MS course, or can be used as markers for disease severity.

T-Cell Responses

Weissert and colleagues[18] from Tuebingen, Germany, examined T-cell reactivity to various peptides of myelin oligodendrocyte glycoprotein (MOG) in MS patients and controls. T cells from control patients showed stronger and broader ranges of reactivity compared with T cells from MS patients. MOG may be an important antigen target in MS, so further studies are needed to determine whether the T-cell responses of MS patients to this myelin component are truly altered.

Evoked Potentials

Drory and associates,[19] from Tel Aviv, Israel, reported on the use of somatosensory-evoked potentials (SSEPs) and visual-evoked potentials to follow disease progression in MS. Patients were analyzed at 2 time points, separated by about 20 months. Tibial nerve SSEP latencies as well as median nerve SSEP amplitude and latencies showed significant changes over time, but no relationship to Expanded Disability Status Scale (EDSS) except for changes in median nerve SSEP latency.

The investigators suggested that SSEP responses could be used to assess disease progression. However, the data were not convincing. Further studies using much more frequent time points and better correlations with disease features (including MRI) would be needed to make a case for use of evoked potentials as a severity marker.

Epidemiology

MS in Libya

An interesting study from Libya reported on newly diagnosed MS cases identified from September 1994 to December 1997.[20] MRI was used to support the diagnosis, and diagnosis was made within 1 year of initial symptoms in 80% of cases. Several interesting features emerged. There was a slightly lower female predominance in Libya than in North America (1.4:1 vs >2:1, respectively). Almost half of patients presented with a multiphasic syndrome, and more than 25% of patients were considered to have severe disease; 35% had a progressive form of the disease.

This study suggests that MS is more common than previously realized in this population, and may take a more severe course. It will be important to determine whether genetic features can distinguish Libyan from North American MS patients.

Race and Optic Neuritis

In a study that tracked outcomes of optic neuritis based on race -- whites and blacks in the Optic Neuritis Treatment Trial (ONTT) --[21] blacks experienced more severe vision loss and higher EDSS at 5 years. A study from Martinique confirmed that French African-Caribbean MS patients are more likely to suffer severe vision loss after optic neuritis.[22] Deficits of these patients were compared with those of patients in the American ONTT. Only growing up in France was associated with better outcome, suggesting that environmental factors played a role in outcome.

Late-onset MS

An interesting report[23] from Germany described 15 patients with onset of MS at age 60 or later. They made up less than 0.01% of a consecutive MS inpatient population. Compared with younger MS patients, this older-age-onset group was more likely to have female predominance (6:1 vs 2:1); primary progressive subtype (93% vs 28%); and initial paraparesis (87% vs 33%). Older-age onset of MS is considered a poor prognostic feature. Surprisingly, almost half of patients showed only very gradual worsening rather than a more severe course.

Specific Symptoms

Dysphagia

A study from Belgium investigated dysphagia (difficulty with swallowing/chewing) in MS patients.[24] Among 308 consecutive patients, 19% suffered ongoing dysphagia problems, while an additional 5% had experienced transient difficulties. Most affected patients were at higher EDSS/disability ranges. Among very disabled patients (EDSS 8 to 9), 65% noted dysphagia. Early symptoms included changes in eating habits (93%), and coughing or choking during eating (59%). Formal swallowing assessment (manofluoroscopy) was helpful to document problems and guide therapeutic recommendations.

Premenstrual Worsening

In a small study[25] involving 28 women with MS (mean age, 40 years; mean disease duration, 8 years), 78% had premenstrual worsening of leg weakness, pain, and nocturia, as detected by a daily questionnaire. This study adds to a small but growing literature reporting fluctuations in MS symptoms related to the menstrual cycle. This small but prospective study should be pursued in a larger patient population.

Cognitive Changes

An interesting functional MRI (fMRI) study[26] evaluated 21 patients with early relapsing MS and 22 matched controls. They were given a cognitive test to assess processing speed (the paced auditory serial addition test [PASAT]). Different control areas were activated in the MS group (frontal cortex areas 44 and 819) vs controls (frontal cingulate gyrus area 32). Despite this change, there were no significant cognitive differences between the 2 groups.

The investigators interpreted this as an example of brain plasticity in the MS patients, with cognitive function transferred to more intact brain areas. It also suggests a subtle cognitive disturbance even in those with very early, mild MS. fMRI offers a unique tool to evaluate MS, since it allows cortical circuitry to be examined in response to both cognitive and physical tasks.

Pain

Pöllman and associates,[27] from Berg, Germany, presented information on pain in MS. They interviewed 158 consecutive inpatients to determine whether they had experienced significant pain problems within the past year. A total of 97 patients (61%) had noted problems, including multiple pain syndromes. In 12% of patients pain was rated as their worst MS symptom. Syndromes included migraine headache (23%), dysesthesia of a limb (21%), back pain (18%), and painful leg spasms (11%). Most patients felt their physicians did not adequately diagnose and treat their problem. This study confirms pain as an important symptom in MS, and highlights that it is not optimally managed.

References

  1. Compston DAS. Genetic epidemiology of multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S320. Abstract 43.01.
  2. Lassman H. Pathology of multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S320. Abstract 43.02.
  3. Wekerle H. Immune mechanisms in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S320. Abstract 43.03.
  4. Sharief M. T lymphocyte activation in multiple sclerosis: surviving the immunological onslaught. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S433. Abstract 65.01.
  5. Smith K. Mechanisms underlying loss of function in inflammatory demyelinating disease. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S320. Abstract 43.04.
  6. Nave KA, Griffiths IR, Klugmann, M, Werner H. Demyelination and axonal loss in mouse models of X-linked leukodystrophy. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S321. Abstract 43.05.
  7. Filippi M. Imaging the CNS. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S321. Abstract 43.06.
  8. Battaglia MA. Complementing healthcare through creative service provision in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S321. Abstract 43.07.
  9. Kesselring J. Rehabilitation in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S321. Abstract 43.08.
  10. Polman C. Disease modifying treatments: effects and indications. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S322-323. Abstract 43.10.
  11. Noseworthy J. Disease modifying treatments: future prospects. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S323. Abstract 43.11.
  12. Coyle PK. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S436. Abstract 66.04.
  13. Zivadinov A, Rudick RA, De Masi R, et al. Long-term effect of intravenous methylprednisolone therapy on brain atrophy in relapsing-remitting multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S434. Abstract 65.05.
  14. Nikolova G, Traykov l, Yancheva S, et al. Therapeutic efficacy of 4-Aminopyridine on neurological and cognitive deficit in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S457. Abstract P1305.
  15. Lycke J, Bech E, Jakobsen J, et al. Anti-herpesvirus treatment with Valaciclovir in relapsing-remitting MS: results of a phase II double-blind, placebo controlled, two-centre trial. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S461. Abstract P1318.
  16. Semra Y, Seidi OA, Sharief MK. High intrathecal levels of actin and tubulin in patients with multiple sclerosis correlate with disease progression and neurological disability. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1)::S431. Abstract 61.05.
  17. Petzold A, Eikelenboom J, Lazeron RCH, et al. The prognostic value of brain specific proteins in patients with multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S431. Abstract 61.06.
  18. Weissert R, Kuhle J, Wienhold W, et al. Narrowing of T cell reactivity towards an intracellular stretch of myelin-oligodendrocyte-glycoprotein in MS patients. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S430. Abstract 61.03.
  19. Drory VE, Chapman J, Hilkevich O, et al. Somatosensory evoked responses are a sensitive measure of disease progression in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S341. Abstract P0967.
  20. Elzawawi H, Shavlak O, Boushala S. An epidemiological study of multiple sclerosis in Benghazi Libya. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S430. Abstract 61.02.
  21. Nazarian SM. Patterns of multiples sclerosis in black and white patients in the optic neuritis treatment trial (ONTT). Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S462. Abstract P1324.
  22. Cabre P, Merle H, Poman G, Smadja D. Visual loss after optic neuritis in an unselected cohort of Afro-Caribbean MS patients. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S339. Abstract P0959.
  23. Pöllmann W, Starck M, Albrecht H, König N. Late onset multiple sclerosis beyond the age of 60 years- a report of 15 cases. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S347. Abstract P0987.
  24. De Pauw A, Dejaeger E, D'Hooghe MB-, Carton H. Dysphagia in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S327. Abstract 52.02.
  25. Wilson S, Parratt J, O'Riordan, Swingler R. Premenstrual worsening of MS symptoms. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S336. Abstract P0950.
  26. Staffen W, Mair A, Unterrainer J, et al. Cognitive function and fMRI in patients with multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):338-339. Abstract p0957.
  27. Pöllmann W, Erasmus LP, Feneberg W. Pain is still an underestimated problem in multiple sclerosis. Program and abstracts of the 17th World Congress of Neurology; June 17-22, 2001; London, UK. J Neurol Sci. 2001;187(suppl 1):S347. Abstract P0986. 
 
 
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