Clinically Definite Multiple Sclerosis Research Articles

Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis.

The detection of oligoclonal immunoglobulin free light chains (FLC) in the diagnosis of multiple sclerosis (MS) was compared to IgG isoelectric focusing. Cerebrospinal fluid and serum samples from 69 patients with possible first attacks of MS, 50 patients with clinically definite MS (CDMS), and 118 patients with other neurological diseases (OND) were analyzed. IgG and FLC oligoclonal bands were detected by isoelectric focusing and immunoperoxidase staining. Intrathecal synthesis of IgG, kappa FLC, and lambda FLC oligoclonal bands, respectively, was seen in 92%, 92%, and 86% of MS patients; in 61%, 62%, and 64% of patients with possible first attacks of MS; and in 3%, 3%, and 8% of the patients with OND. In control patients without IgG synthesis intrathecal lambda FLC synthesis was more common than kappa FLC synthesis (P=0.03). Kappa FLC detection proved as useful as IgG analysis for the laboratory diagnosis of MS whereas the presence of intrathecal lambda FLC synthesis was less specific.

The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Optic Neuritis Study Group.

The predictive value of CSF oligoclonal banding for the development of clinically definite MS (CDMS) within 5 years after optic neuritis was assessed in 76 patients enrolled in the Optic Neuritis Treatment Trial. The presence of oligoclonal bands was associated with the development of CDMS (p = 0.02). However, the results suggest that CSF analysis is only useful in the risk assessment of optic neuritis patients when brain MRI is normal and is not of predictive value when brain MRI lesions are present at the time of optic neuritis.

Subclinical saccadic adduction slowing in patients with monosymptomatic unilateral optic neuritis predicts the development of multiple sclerosis

Parameters of visually guided saccades were studied in 22 patients with monosymptomatic optic neuritis and 21 age-matched control subjects with a precise infrared reflection technique. Follow-up of the patients over 2.2 years, on average, allowed correlations of subclinical saccadic abnormalities, measured at study entry, with the development of clinically definite multiple sclerosis (CDMS). Subclinical adduction slowing defined on statistical grounds was observed in nine patients. Seven of these and four out of five patients with prolonged saccadic latency developed CDMS during the follow-up period. We conclude that subclinical adduction slowing in patients with optic neuritis represents an oculographic finding with pathological significance.

HLA typing in acute optic neuritis. Relation to multiple sclerosis and magnetic resonance imaging findings.

To study the association of brain magnetic resonance imaging (MRI) findings and HLA findings to clarify the relationship between monosymptomatic optic neuritis (ON) and ON as part of clinically definite multiple sclerosis (CDMS). Population-based cohort of patients with ON referred prospectively during 6 years by neurologists and ophthalmologists within 4 weeks of onset of ON. Referral center in the general community of greater Copenhagen (Denmark) (population, 1.5 million). A consecutive sample of 199 patients aged 12 to 59 years with ON (133 with idiopathic ON, 66 with ON + CDMS), ethnically matched with 192 healthy volunteers. Relation between the HLA-DR15, -DR17, -DQA-1B, and -DQB-1B polymorphisms as defined by restriction fragment length polymorphism analysis, and presence of plaques on T2-weighted brain MRI. The frequency of HLA-DR15 was significantly increased in patients with ON + CDMS (52%) and ON (47%) compared with control subjects (31%). The frequency of HLA-DR17 was almost equal in the ON + CDMS (18%), ON (23%), and control (23%) groups. The frequencies of HLA-DQA-1B (55% in ON + CDMS, 58% in ON) and HLA-DQB-1B (49% in ON + CDMS, 59% in ON) were significantly increased compared with control subjects (41%, HLA-DQA-1B; 37%, HLA-DQB-1B). Brain MRI was abnormal in 48 of 56 examined patients with ON + CDMS and in 64 of 120 examined patients with ON (P < .001). In contrast, the frequencies of HLA alleles did not differ between patients with and without demyelinating lesions. However, patients with ON and normal MRI findings did not show association with HLA-DR15. The frequencies of alleles were similar in patients with ON and ON + CDMS, confirming that they are not 2 immunogenetically distinct disease entities. The heterogeneity within the group of patients with ON suggests that the HLA-DR15 molecule is involved in susceptibility to initial demyelinating lesion formation.

Bilateral acute optic neuritis: prospective clinical, MRI, CSF, neurophysiological and HLA findings

This paper presents the clinical picture and the results of a battery of tests performed in a prospective study of 30 patients (aged 15-53 years; 14 females) consecutively referred during a six-and-a-half-year period and suffering from bilateral acute optic neuritis (BAON) according to clinical criteria. Both eyes were affected within a time span of six weeks. Ten patients showed papillitis in one or both eyes. Causes of BAON other than clinically definite multiple sclerosis (CDMS), present in 12 patients, were carefully ruled out and all relevant blood tests were normal, having excluded two patients with Leber's optic neuropathy. Tissue typing showed HLA-DR15 in 12 patients. The proportion of abnormal results at onset was 14/27=52% (cerebral MRI), 23/30=77% (VEP), 11/27=41% (SEP), 10/24= 42% (biotesiometry), 8/20=40% (CSF oligoclonal bands), 10/26=38% (IgG-index), and 9/25=36% (CSF leukocyte count). One year from onset, 24 patients were reexamined; another two patients were followed clinically and with VEP only. Abnormal results were observed by MRI in 13/21=62%, by VEP in 21/26=81%, by SEP in 6/23=26%, and by biotesiometry in 9/24=38%. Five patients had developed CDMS. The visual acuity improved in one or both eyes in 19, remained unchanged in four, and deteriorated in three patients. The frequency of abnormal VEP, IgG-index, and oligoclonal bands was significantly lower in idiopathic cases than in patients with CDMS. Abnormal results tended to be less frequent when symptoms occurred simultaneously (n=15), suggesting simultaneous BAON to be more rarely a part of MS. Bilateral idiopathic cases seemed to show abnormal CSF, MRI, and VEP findings less frequently than unilateral cases.

Blood‐brain barrier impairment in acute optic neuritis evaluated by Gadolinium—DTPA enhanced MRI and CSF studies

We prospectively compared the brain magnetic resonance imagings (MRIs) following Gadolinium‐DTPA (Gd‐DTPA) injection with unenhanced T2‐weighted MRIs in a well‐defined population‐based group of 76 patients aged 20–57 years with acute optic neuritis (ON). We aimed to evaluate the blood‐brain barrier impairment in ON and the interrelationships of findings by CSF analyses and MRI. Lumbar puncture and MRI were performed within a median of 19 and 13 days from onset respectively. MRI showed unenhanced lesions in 22 of 54 patients with monosymptomatic ON (AMON) compared to 19 of 22 patients with ON as part of clinically definite MS (CDMS) (p = 0.0002). Enhanced lesions (sized 2–38 mm) were revealed in 10 out of 54 patients with AMON vs 8 of 22 patients with CDMS (p = 0.06). The number of enhancing lesions in proportion to the number of unenhancing lesions was higher in patients with AMON than in patients with CDMS (p &gt; 0.05). Ten of altogether 30 enhancing lesions were situated periventricularly. An impaired blood‐brain barrier judged by increased albumin quotient was found in only five patients. The patients with AMON often had significantly less abnormal intrathecal IgG synthesis (p = 0.02), IgG‐index (p = 0.02) and oligoclonal bands (p = 0.04) than did the patients with CDMS. In AMON, the presence of oligoclonal bands was significantly related to abnormal unenhanced and enhanced MRI, p = 0.01 and p = 0.02, respectively. No other significant relationships were observed between the results of MRI and CSF findings, neither in AMON nor in CDMS.

Cerebrospinal fluid in acute optic neuritis: Experience of the Optic Neuritis Treatment Trial

The Optic Neuritis Treatment Trial (ONTT) is a prospective study of corticosteroid treatment of acute optic neuritis (ON), with subsequent longitudinal follow-up to determine development of clinically definite multiple sclerosis (CDMS). We analyzed the CSF of 83 patients with clinically isolated ON who underwent lumbar puncture within 24 hours of enrollment into the ONTT to determine the value of CSF changes in ON, especially regarding diagnostic utility, immunologic changes, MRI correlations, and progression to CDMS All patients had baseline MRI scans graded for changes typical of MS CSF measurements included immunoglobulin G (IgG) synthesis, IgG ratio, myelin basic protein, IgG kappa light chains, and oligoclonal banding. No patients had their diagnosis or management altered as a result of CSF findings. Except for oligoclonal bands, few patients showed any abnormalities on CSF tests, and no tests correlated with the 2-year development of CDMS. Oligoclonal banding, present at baseline in 11 of 13 patients who developed CDMS, did predict progression to CDMS, but this was not independent of MRI abnormalities. Two patients with oligoclonal bands and a normal MRI did progress to CDMS. We conclude that CSF analysis may not be necessary in the routine evaluation of patients presenting with a typical clinical profile of acute ON, and that most CSF tests add little additional information to MRI results for predicting the 2-year development of CDMS. However, the precise role of oligoclonal banding in the analysis of such patients awaits longer follow-up of this cohort. NEUROLOGY 1996,46 368-372

The clinical significance of a single abnormal immunoglobulin band in cerebrospinal fluid electrophoresis

The finding of oligoclonal immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is considered a cornerstone in the diagnosis of multiple sclerosis, but can be observed in other diseases as well. In a small subset of patients only a single Ig band, confined to the CSF, is identified. We evaluated the possible diagnostic significance of such a finding. Agarose gels of 6000 CSF samples were re-examined. In 1013 samples (16.8%) there were oligoclonal bands, and in 33 additional samples (0.55%) a single band was found (without a correlating band in the serum). Full data was available for 20 single band patients. Seven patients had clinical definite multiple sclerosis. Of these, 6 had a typically prominent affective disorder and 5 had a relatively malignant course of disease. Seven additional patients had other white matter diseases of the central nervous system (CNS). The remaining patients had inflammatory diseases of peripheral nerves or CNS gray matter and non-inflammatory brain diseases. The frequency of demyelinating diseases of the CNS in patients with a single abnormal Ig band in the CSF was significantly less than in a control group of patients with oligoclonal bands. In conclusion, the finding of a single Ig band confined to the CSF may hint for a disease other than multiple sclerosis, and mark an aggressive course with affective disorder in those who do have multiple sclerosis.

Acute Unilateral Papillitis versus Retrobulbar Neuritis: Relation to Multiple Sclerosis

Prospectively referred patients with unilateral acute optic neuritis (ON) (n = 223; aged 12-57; 158 women), either idiopathic or part of clinically definite multiple sclerosis (CDMS), were systematically examined by the same physician. We analysed whether the 161 patients with retrobulbar neuritis and the 62 patients with papillitis differed from each other clinically or according to paraclinical tests. The following characteristics were observed in retrobulbar ON respectively papillitis: median age 33 and 33 years, women 70% and 73%, clinically definite MS 30% and 27%. Abnormal results in retrobulbar ON and in papillitis (indicated in brackets) did not differ significantly and were found as follows: cerebral MRI in 56% (63%), VEP from the eye with acute ON in 82% (88%), VEP from the eye without acute ON in 38% (33%), SEP from median nerves in 9% (10%), SEP from tibial nerves in 22% (22%) and biotesiometry in 32% (27%). In the CSF, oligoclonal bands were present in 42% (53%), increased IgG-index in 40% (44%) and increased leucocyte count in 39% (29%). The HLA-DRI5 tissue type was present in 47% (43%). There were no significant differences between retrobulbar ON and papillitis when the idiopathic cases and cases with clinically definite MS were analysed separately. Our data document that unilateral retrobulbar ON and papillitis are both part of the MS spectrum and not different from each other with regard to clinical and paraclinical parameters, indicating that the two groups can be pooled in future treatment trials.

A study of oligoclonal band negative multiple sclerosis.

To determine whether oligoclonal band (OCB) negative multiple sclerosis is a reliable diagnosis and, if so, whether it has a distinctive prognosis. Retrospective and matched prospective comparison of the clinical and laboratory features of patients with clinical definite multiple sclerosis with and without intrathecal synthesis of oligoclonal IgG. Thirty four patients were identified with apparent OCB negative clinically definite multiple sclerosis. The results of oligoclonal banding proved to have been equivocal in 14 of 34; the clinical diagnosis of multiple sclerosis was questionable in 8 of 34. The remaining 12 patients with "true" OCB negative multiple sclerosis were significantly less disabled than matched OCB positive controls. Re-examination of CSF-serum pairs from six OCB negative patients showed that three remained OCB negative while three showed evidence of intrathecal synthesis of OCBs. OCB negative clinically definite multiple sclerosis is rare and should be diagnosed with caution; in unequivocal cases it seems to have a relatively benign prognosis.

Optic neuritis in children: Recurrence and subsequent development of multiple sclerosis

Recurrent optic neuritis and the subsequent development of multiple sclerosis in children, particularly in Asian countries, are not well known. We report on recurrent optic neuritis and subsequent multiple sclerosis in 22 Thai children who were younger than 15 years of age at the onset of optic neuritis, had no previous neurologic illness, and were monitored for 6–20 years. Improvement of vision was observed in 8, 10, and 2 patients after the first, second, and third week of onset, respectively. Two patients had recurrent optic neuritis and the other 2 patients subsequently developed clinical definite multiple sclerosis characterized by hemiparesis at 6 months and myelopathy at 2 years later in 1 patient and myelopathy and brainstem dysfunction in the other at 4 and 6 years later. The frequency of subsequent development of multiple sclerosis after optic neuritis may be similar to that reported from the United States and European countries.

A prospective study of “undiagnosed” isolated myelopathy: II. Value of magnetic resonance imaging, evoked potentials and CSF analysis

We aimed to determine the sensitivity of available "diagnostic" tests in detecting subclinical abnormalities characteristic of multiple sclerosis (MS) in patients with unexplained isolated myelopathy, and any relationship between test results and level of disability. The trial investigations were carried out in 69 prospectively selected patients with acute or chronic noncompressive myelopathies. Magnetic resonance scans were the most sensitive individual tests, revealing asymptomatic brain lesions in 51 patients (74%, C.I. 64-84). An abnormal IgG/albumin ratio (IgG/A) was present in 29 (42%, C.I. 30-54), oligoclonal bands (OCB) in 27 (39%, C.I. 17-39) and abnormal evoked potentials (EP) (visual and/or auditory brain stem) in 19 cases (28%, C.I. 17-39). OCB and abnormal EP were found significantly less often than in control patients with clinically definite MS (CDMS) and significantly more often than in patients with myelopathy due to other conditions. The number of anatomical brain areas with lesions on magnetic resonance imaging (MRI) was significantly associated with CSF abnormalities; abnormal EP were correlated with abnormal MRI and elevated CSF immunoglobulins. Clinical classifications, age, symptom duration, disability levels and genetic factors did not appear to influence the prevalence of abnormal MRI or CSF. For the exclusion of compressive and structural diseases of the spinal cord, myelography has been superceded by cervical and thoracic MRI. In addition, MRI of the brain is the investigation of choice in patients with myelopathies that remain unexplained after spinal MRI. However, whether used alone or in combination with other tests, the specificity and predictive value of brain MRI abnormalities for the risk of developing MS, as well as the associated "false positive" rates, remain to be defined by long-term follow-up of prospectively ascertained and representative cases.

Serial MRI, VEP, SEP and biotesiometry in acute optic neuritis: value of baseline results to predict the development of new lesions at one year follow up

Introduction - In an attempt to establish the value of MRI, VEP, SEP, and biotesiometry in monitoring disease evolution we undertook a one year follow up study of 70 untreated patients with acute optic neuritis (ON). Material & methods - ON was monosymptomatic in 48 patients (bilateral in 10) and part of clinically definite multiple sclerosis (CDMS) in 22 patients, examined as mentioned below. Results Results are given at onset and at follow up (in brackets). In monosymptomatic ON, brain MRI was abnormal in 53% (53%), VEP in the eye with acute ON in 79% (71%), VEP in the clinically unaffected eye in 34% (47%), SEP in 25% (23%), and biotesiometry in 29% (17%). In CDMS, brain MRI was abnormal in 95% (95%), VEP in the eye with acute ON in 86% (77%), VEP in the clinically unaffected eye in 50% (64%), SEP in 55% (50%), and biotesiometry in 63% (53%). Only minor changes in test scores were observed after one year except for significant improvement of VEP in eyes with acute ON. Eight of 32 patients, characterized by at least one abnormal paraclinical test at onset of monosymptomatic ON, had developed CDMS versus none of 16 patients with normal paraclinical results (p = 0.03 ; Fisher). Conclusion - Patients with monosymptomatic ON with paraclinical signs of multifocal involvement at onset had an increased risk of developing CDMS. No single test predicted the evolution of CDMS, perhaps due to the relatively short follow up time.

Paraclinical tests in acute-onset optic neuritis: basal data and results of a short follow-up

Up to now it is still doubtful whether there is a real risk of developing multiple sclerosis (MS) after initial monosymptomatic optic neuritis (ON). In this study we evaluated 43 patients with isolated acute-onset ON, in order to demonstrate the presence of oligoclonal bands (OBs) in the cerebrospinal fluid (CSF) and any additional clinically silent central nervous system (CNS) lesions. All examinations were performed from 5 days to 4 months (mean 43 days), from the onset of visual disturbances. Brain magnetic resonance imaging (MRI) detected white matter areas with increased signal in 21 patients (49%), while somatosensory and brainstem auditory evoked potentials revealed CNS abnormalities in only 5 patients (12%). OBs were present in the CSF of 20 patients (46%). Visual evoked potentials were abnormal in 39 patients (91%). Seven out of the 37 patients (19%) with at least one year follow-up, (mean duration of the follow-up = 32 months, range = 12-74), developed clinically definite MS (CDMS). All 7 patients had positive brain MRI and 6 had positive CSF examination at the basal evaluation. Our data suggest that MRI and CSF-OBs are the most reliable means of identifying patients with isolated ON who subsequently develop CDMS. They may therefore have a predictive value in defining MS risk.

Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: A prospective 2‐year follow‐up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT

We previously compared the diagnostic capabilities of MRI of the head with CT, evoked potentials, and CSF oligoclonal banding (OB) analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). To examine the ability of MRI and other paraclinical tests to predict the diagnosis of clinically definite MS (CDMS), we did a systematic clinical follow-up of 200 patients who were previously reported. In that study, 85 of 200 could be diagnosed as having laboratory-supported definite MS (LSDMS). In follow-up, we excluded one patient diagnosed as LSDMS who in retrospect was considered to have had CDMS at entry and 15 patients who were eventually diagnosed as having other diseases. After a mean follow-up of 2.1 years, 55 of the remaining 184 patients (30%) had developed CDMS. Thirty-eight of 84 patients with an original diagnosis of LSDMS (45%) and 17 of the remaining 100 patients with suspected MS (17%) had become CDMS. Forty-six of the 55 patients who developed CDMS in follow-up (84%) had an initial MRI that was strongly suggestive of MS. Fifty-two of those 55 CDMS patients (95%) had at least one MS-like abnormality on MRI when originally studied. In contrast, 38 of 55 (69%) had CSF OB, 38 of 55 (69%) had an abnormal VEP, 35 of 55 (64%) had an abnormal SEP, and 21 of 55 (38%) had an abnormal CT when first studied. MRI was the most sensitive single paraclinical test for predicting CDMS. CDMS developed during follow-up in 46 of the 94 patients (49%) whose initial MRI was strongly suggestive of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

CT scan changes in multiple sclerosis among Malaysian patients

A study of 12 patients with clinically definite multiple sclerosis (CDMS) using high dose infusion CT showed overall abnormality of 75% with an average of 2.5 lesions per patient. 75% of the patients showed abnormality of the cerebrum, mostly asymptomatic. The main changes were ventricular dilatation and asymmetry, isolated or generalized cerebral atrophy, areas of low attenuation mainly in the deeper parts of the cerebrum and the peri-ventricular area. 25% of the patients showed changes in the brainstem and none was seen in the cerebellum. The abnormality was more florid in patients with clinically disseminated forms of the disease. The study demonstrated that asymptomatic cerebral involvement is common among Asian patients with MS and CT is a useful tool in the overall assessment and diagnosis of Asian MS patients.

Magnetic resonance imaging in clinically‐definite multiple sclerosis

Forty-two patients with clinically-definite multiple sclerosis were examined by magnetic resonance imaging using a 1.5-T instrument. Magnetic resonance imaging detected an abnormality in 90% of patients. In four patients, no lesions were demonstrated. The number, size and site of the lesions by magnetic resonance imaging were compared with the patients' clinical status and other variables. The Kurtzke disability status scale score increased in patients with corpus callosum atrophy, and brainstem and basal ganglia lesions, and correlated with the total number of lesions. No correlation was shown between the findings of magnetic resonance imaging and disease duration, age, sex or pattern-reversal visual-evoked potentials. This article highlights the variety of magnetic resonance images that is obtained in patients with clinically-definite multiple sclerosis.

The long march of the cerebrospinal fluid profile indicative of clinical definite multiple sclerosis; and still marching

Much progress has been made, especially in the last two decades, in laboratory aids to diagnosis and to follow the course of patients with multiple sclerosis (MS). The cerebrospinal fluid (CSF) profile indicative of MS, though not pathognomonic of MS, is present in almost every case of clinical definite MS in a chronic progressive phase (probably also true for early MS). The cardinal aspect of the profile is intra-blood-brain barrier (BBB) IgG synthesis which can be qualitatively detected by determining unique CSF oligoclonal IgG bands and quantitated by rate formula, mg/day. We believe that intra-BBB IgG synthesis is caused by a persistent antigen, most likely a virus, possibly measles. A number of issues about the profile are proposed and opportunities are presented to resolve them.

Multiple sclerosis: correlation of magnetic resonance imaging with cerebrospinal fluid findings.

MRI examination of 41 patients with clinical definite multiple sclerosis showed white matter lesions of high proton T2 signal consistent with demyelination in 76% and CSF abnormalities present in 76%. Of patients with CSF abnormalities, 26% had normal MRI scans; conversely 26% of patients with MRI abnormalities had negative CSF studies. Thus a significant number of multiple sclerosis patients had negative results on either MRI or CSF examination, while only 5% had normal results on both tests.