Clinical data and the identification of special forms of multiple sclerosis in 1271 cases studied with a standardized documentation system

doi:10.1016/0022-510X(79)90201-6

Journal of the Neurological Sciences

Volume 40, Issues 2–3, February 1979, Pages 159-168

https://doi.org/10.1016/0022-510X(79)90201-6 Get rights and content

Abstract

In a multicenter study the clinical data of 1271 patients with multiple sclerosis (MS) were recorded in a standardized manner and analysed by a computer program.

Some of the retrospective data are compared with previous reports. The frequency of optic nerve involvement in the present series was close to the Japanese figures.

The development of signs and symptoms during the course of MS was given for the 1271 patients and differences in the reversibility of symptoms are presented.

In this study, one of the chief purposes was the selection of groups of MS patients with particular symptomatology and course of the disease for prospective, detailed study.

The following groups were selected and are under further investigation: 109 patients with an exclusively spinal symptomatology throughout the course of their disease; 441 patients with optic neuritis as initial symptom; 110 patients with early brain-stem involvement; 64 benign cases (duration of the disease more than 14 years and disability not more than 3 according to Kurtzke); 35 malignant cases (duration of the disease under 5 years and disability grade of 7 or more); 83 families with more than one member with MS; 289 females with a history of pregnancy, childbirth and/or use of oral contraceptives.

In 339 patients a lumbar puncture was performed at the present examination. The parameters determined constitute a pathognomonic pattern highly indicative of the diagnosis of MS.

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There is wide evidence that subgroups of patients with multiple sclerosis (MS) may have a benign course (Lublin et al., 2014; Lublin and Reingold, 1996) or at least be clinically stable in a frequency ranging from 5 to 40% (Hutchinson, 1986; Pittock et al., 2004; Poser and Wikstrom, 1979).
Circulating levels of IgM anti-CD64, an immunosuppressive antibody recently identified in long-term stable multiple sclerosis (MS) patients, were found to fluctuate over time in MS patients. Antibody-positive patients showed a significantly lower annualized relapse rate value as well as reached sustained disability worsening and had a relapse in a significantly longer median time than those without antibody. Disease-modifying therapies (DMTs) only were the covariate influencing both the relapse occurrence and the disability accrual. Serum IgM anti-CD64 levels are associated with maintenance of clinical stability in MS and may be tested as a candidate biomarker predictive of benign course and favourable long-term response to DMTs treatment.
RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis
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Patients with benign MS reflect the capacity to withstand the deteriorating processes of the disease and the ability to endure or recover quickly from the acute demyelinating inflammatory insults. Thus, these patients are not harmed by the ongoing pathologic processes of myelin and neuronal loss that characterize active MS (Gauthier et al., 2009; Glad et al., 2009; Hawkins and McDonnell, 1999; Pittock and Rodriguez, 2008; Poser et al., 1979; Ramsaransing and De Keyser, 2007). Recently, using high throughput peripheral blood gene expression microarray analysis we identified a specific signature that characterizes benign MS (Achiron et al., 2012).
Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).
Contraceptive use among women with multiple sclerosis: a systematic review
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Excluded studies were mainly review papers and papers not relevant to our key question. Three studies were excluded because it was unclear if contraceptive use occurred after MS diagnosis [25–27]. Each of the four included studies examined OCs, two of which specified the type as combined oral contraceptives (COCs) [20,22].
Contraception is an important consideration for women with multiple sclerosis (MS); however, little is known about the possible effects of hormonal contraception on disease progression or other adverse outcomes (e.g., thrombosis, low bone mineral density).
To evaluate the evidence on the safety of contraceptive use among women with MS.
We searched the PubMed database for peer-reviewed articles published in any language from database inception through July 2015.
We included studies that examined health outcomes among women diagnosed with MS initiating or continuing a contraceptive method. We excluded case reports and case series but included all other study designs.
From 111 articles, we identified four studies (from 5 articles) that met our inclusion criteria. Evidence from one randomized controlled trial, two retrospective cohort studies, and one cross-sectional study suggests that use of combined oral contraceptives (COCs) or oral contraceptives (OCs) (type not specified) among women with MS does not worsen the clinical course of disease, defined as disability level, disease severity or progression, relapse or number of new brain lesions on magnetic resonance imaging (body of evidence grading Level I, fair to Level II-3, poor). No studies were identified that examined the safety of other contraceptive methods or examined other outcomes of interest (venous thromboembolism, changes in bone mineral density) related to contraceptive use among women with MS.
Limited evidence suggests that COC or OC use after MS onset does not worsen the clinical course of disease.
Pathophysiological background and clinical characteristics of sleep disorders in multiple sclerosis
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Traditionally, MS is viewed as a T-cell driven immune disorder in which primary dysregulation of peripheral immune responses leads to a CNS-directed autoimmune disease and inflammatory tissue injury which can also trigger degenerative process, a pathological hallmark of clinical progression of neurological impairment. Besides T-cells there are other mediators of cell immunity such as macrophage, reactive microglia, NK cells, NK T cells, gamma/delta T cells and mediator of hummoral immunity like antigen-specific CNS-reactive antibodies, proinflammatory cytokines, nitric oxide and reactive oxygen species, leukotrienes, plasminogen activators and matrixmetallo proteinases (MMPs) [1] Symptoms and sings of MS depend on the location of CNS affected [2] but fatigue is far most common symptom of MS [3]. Fatigue in MS can be caused either by multiple sclerosis per se or it can be result of other frequently encountered disturbances in MS such as depression, sleepiness, pain or due to various medication in the latter case it is usually called secondary fatigue [4].
Sleep disorders in multiple sclerosis (MS) are more common than in general population and are considered to be one of the important etiological factors in development of fatigue, most common and debilitating symptom of MS. Although almost all of the major subgroups of sleep disorders such as insomnia, sleep disordered breathing, REM sleep behavior disorder, narcolepsy and restless legs syndrome have been described in the MS patients their higher prevalence in MS population than in healthy controls in some of the sleep disorders is not fully elucidated. Immunological background in disease development in both multiple sclerosis and sleep disorders have been proposed as possible common pathophysiological mechanism and recent findings of disrupted melatonin pathways in MS patients suggest multi-level causative mechanism of the development of sleep disorders in MS.
Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis
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Patients with benign MS reflect the capacity to withstand the deteriorating processes of the disease and the ability to endure or recover quickly from the acute demyelinating inflammatory insult. Thus, these patients are not harmed by the ongoing pathologic processes of neuronal and myelin loss that characterize active MS (Poser et al., 1979; Hawkins and McDonnell, 1999; Ramsaransing and De Keyser, 2007; Pittock and Rodriguez, 2008; Glad et al., 2009). We have recently identified, using high throughput peripheral blood gene expression microarray analysis, a specific signature that characterizes benign MS (Achiron et al., 2012).
Applying high throughput gene expression microarrays we identified that the suppression of polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supports the rationale for direct targeting of the POL1 transcription machinery as an innovative strategy to suppress MS. To evaluate the effects of a specific polymerase I inhibitor (POL1-I) on experimental autoimmune encephalomyelitis (EAE), we immunized female C57BL/6J mice (8 weeks) with MOG35–55/CFA. A new POL1-I was administered at a daily dose of 12.5 mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model), at disease onset (EAE score = 1.0) for the following 14 days (treatment model), or by alternate daily dose of 25.0 mg/kg body weight, by oral gavage from the day of immunization for the following 25 days (combined model). POL1-I remarkably suppressed EAE in the immunization model; while in the Vehicle group the onset of EAE occurred on day 10.0 ± 0.4 with maximal clinical score of 3.2 ± 0.2, in the POL1-I treated mice onset was significantly delayed and occurred on day 16.9 ± 1.1 (p = 0.001), and maximal disease score 2.0 ± 0.1 was reduced (p = 0.004). In the treatment model POL1-I treatment significantly reduced disease activity; maximal score was 2.0 ± 0.5 while in the Vehicle group it reached a mean maximal score of 3.9 ± 0.1, (p = 0.0008). In the combined model, POL1-I treatment completely inhibited disease activity. The effect of POL1-I treatment was modulated through decreased expression of POL1 pathway key-related genes LRPPRC, pre-RNA, POLR1D and RRN3 together with activation of P53 dependent apoptosis of CD4 + splenocytes. Our findings demonstrate that POL1 pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that mainly destroys myelin but also causes axonal damage (Compston and Coles, 2002). In several studies from different countries, 5 to 40% of patients have been classified as having a benign course (Poser et al., 1979; Hutchinson, 1986). Some patients may experience a long interval between the first and second or consecutive attacks, supporting the concept of stable disease.
High intrathecal levels of anti-myelin basic protein (MBP) IgM were previously found to be significantly associated with early favorable course in a cohort of patients with multiple sclerosis (MS). A mAb to MBP 105–120 recognizing the 222–228 epitope of the extracellular domain of high affinity immunoglobulin gamma Fc-receptor I (CD64) was isolated from EBV⁺ B cell clones of long-term stable RRMS patients. This mAb exerted immunosuppressive activity on MS-derived T cell lines through induction and release of high amounts of interleukin-10 and decreased levels of interleukin-12 from activated monocytes providing the biological basis for a potential new treatment for MS and other immune-mediated neurological disorders.

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^☆: This work was supported by the Deutsche Forschungsgemeinschaft.

^∗: Senior physician.

^∗∗: Address: Department of Neurology, Haartmanink 4, 00290 Helsinki 29, Finland.

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Clinical data and the identification of special forms of multiple sclerosis in 1271 cases studied with a standardized documentation system☆

Abstract

Protein profile in multiple sclerosis

HLA antigens in multiple sclerosis

Neurology (Minneap.)

Dokumentation klinischer Befunde

Erfassung von neurologisch relevanten Labordaten mit einem kombinierten Klartext-Markierungsbeleg

Z. Neurol.

Complement-dependent cytotoxic activity against measles virus in multiple sclerosis

J. Neurol.

Nationwide survey of multiple sclerosis in Japan

Neurology (Minneap.)

On the evaluation of disability in multiple sclerosis

Neurology (Minneap.)

Studies on natural history of multiple sclerosis

Acta neurol. scand.

Multiple Sclerosis

The benign form of multiple sclerosis

Brain