Clinical, MRI, CSF and electrophysiological findings in different stages of multiple sclerosis

Effective therapy in the earliest stages of multiple sclerosis (MS) demands early correct diagnosis. Retrospective analysis included 130 patients (90 women) with a median age of 35.5 years, median duration of the disease of 2 years and median EDSS score of 3.0. Twenty-seven patients had clinically isolated syndrome (CIS) suggestive of MS, 66 relapsing-remitting (RR) MS, 19 secondary progressive (SP) MS and 18 primary progressive (PP) MS. The predominant symptoms were sensory in 52% of the patients with CIS compared to 27% in patients with RRMS, whereas they were more often motor in patients with PPMS. Patients with CIS had higher CSF cell counts than patients diagnosed in later stages of the disease and oligoclonal bands were found in 89% of all patients without statistically significant differences between the subgroups. Prolonged latencies of visual evoked potentials (VEP) were found in only 29% of patients with CIS compared to 66% in RRMS, 75% in SPMS and 65% of PPMS patients. Fifty-six percent of patients with CIS, 88% with RRMS, 74% with SPMS and 78% of patients with PPMS fulfilled modified the Barkhof et al. MRI criteria at the time of diagnosis. Patients in early MS often present with sensory symptoms. Brain MRI can be inconclusive in over 40% of patients with CIS but the elevated CSF cell count and positive oligoclonal bands are helpful in establishing the diagnosis of CIS suggestive of MS. In later stages of the disease the combination of clinical features, MRI, prolonged VEP latencies and positive CSF oligoclonal bands secures the correct diagnosis.     

Lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in multiple sclerosis

Lymphocytes subpopulations in cerebro-spinal fluid (CSF) and peripheral blood (PB) from multiple sclerosis (MS) patients were studied. PB of MS patients contains the same prevalence of E and EA rosette forming cells compared with controls, consisting of patients affected by various "nonimmunological" neuropsychiatric diseases. Cytochemical identification by the method of acid esterases in PB demonstrated in MS a prevalence of lymphocyte subpopulations similar to controls, and a relatively high percentage of macrophages compared with other methods, especially in MS patients: this may partially account for variable results obtained by various authors with the rosette technique. In CSF a significant decrease of total T, and particularly of T gamma cells, was found. Since T gamma lymphocytes have a suppressor effect on B cell proliferation and Ig synthesis, their decrease could be related with Ig hypersynthesis commonly found in the central nervous system of MS patients.     

Albumin and immunoglobulin-G in the cerebrospinal fluid and the diagnosis of multiple sclerosis

Multiple sclerosis (MS) remains a diagnosis based mainly on clinical criteria. Definitive diagnostic tests are, despite numerous attempts, not available. However, some laboratory tests like electrophoresis of the cerebrospinal fluid proteins or the determination of immunoglobulin G in cerebrospinal fluid have proved useful in increasing the probability of MS. This paper describes how these laboratory tests have to be interpreted in relation to pathophysiological phenomena and how they correlate with each other. The electrophoresis of CSF proteins and the diagnostic quotients (Ralb and CSF-IgG-index) are valuable aids to the clinician. It especially can substantiate the diagnosis MS. The magnitude of the index cannot be correlated with the clinical stage of MS. The usefulness of these tests in terms of a possible gain of information in the diagnostic process is discussed.     

Determination of IgG subgroups in cerebrospinal fluid of multiple sclerosis patients and others

IgG subgroups (IgG1, IgG2, IgG3, IgG4) were determined by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) of controls, multiple sclerosis (MS), infectious diseases (ID) and other neurological diseases (OND). The proportion of IgG1 in the total IgG subgroup concentration was significantly higher in the MS group compared to the other groups while the IgG2 proportion was significantly lower; IgG3 and IgG4 did not show any consistent change. The inverse relationship between IgG1 and IgG2 was similar in all diagnostic groups: high concentration of IgG1 was associated with low concentrations of IgG2 and vice versa. Patients with a high relative concentration of IgG1 in their CSF have a seven to eight times higher statistical risk to be suffering from MS than ID or OND. In the MS group only the IgG1 concentration correlated with the total IgG concentration determined by radial immunodiffusion, while in controls, ID and OND each IgG subgroup correlated significantly with the IgG concentration. This demonstrates that in MS a selective increase of IgG1 subgroup is mainly responsible for the increase of total IgG, while all subgroups are involved in OND and ID showing an increased total IgG concentration.     

Diagnosis of multiple sclerosis

There is no pathognomonic symptom, sign, or paraclinical result that provides an unfailingly accurate diagnosis of multiple sclerosis (MS), and hence, MS remains largely a clinical diagnosis. However, being a clinical diagnosis does not mean that the diagnosis of MS is one of exclusion. Increasingly sophisticated guidelines and objective paraclinical findings are generally sufficient to allow the clinician to confirm or rule out the diagnosis with confidence. This article presents the most recent guidelines for using clinical, radiological, and other paraclinical information and the red flags that should alert the clinician to investigate other diagnostic possibilities.     

The effects of high-dose methylprednisolone on gadolinium-enhanced magnetic resonance imaging and cerebrospinal fluid measurements in multiple sclerosis

Blood-brain barrier (BBB) disruption is probably the first event in the lesion development in multiple sclerosis (MS). This stage can be visualized by gadolinium-enhanced magnetic resonance (MR) imaging of the brain. Serial MR imaging studies have indicated a continuous spectrum of disease activity with waxing and waning of acute lesions, even in clinically stable MS patients. High-dose intravenous methylprednisolone (MP) has a beneficial clinical effect; reduces gadolinium enhancement, indicating improvement of BBB integrity; and, in MS patients, decreases intrathecal immunoglobulin synthesis with reduction of cerebrospinal fluid (CSF) myelin basic protein (MBP). A correlative triad is noted between gadolinium enhancement, clinical improvement, and decrease of CSF MBP following MP treatment, indicating a relationship between restoration BBB integrity, clinical improvement and decrease of myelin breakdown. It is not clear whether MP interferes primarily with the process of demyelination or reacts non-specifically with its mediators.     

多发性硬化患者头颅磁共振、诱发电位和IgG指数的对比研究

报道43例多发性硬化(MS)患者头颅磁共振成像(MRI)、诱发电位(EP)和IgG指数(IgGIndex)的对比研究结果。发现MRI的检测异常率为81.4％,而VEP仅53.7％、BAEP47.5％、IgGIndex57.5％。MRI在显示空间脱髓鞘方面是最敏感的方法,但VEP、BAEP只要有一项异常即判断为EP异常则其异常率高达79.5％,接近MRI。作者认为三者同时检查可以提高诊断的准确性。     

Low somatostatin content in cerebrospinal fluid in multiple sclerosis

In 27 patients with multiple sclerosis (MS), and in 10 control subjects of comparable age, percent ideal body weight and sex ratio, the cerebrospinal fluid (CSF) content of somatostatin was measured by radioimmunoassay.
The results showed that the group of patients in relapse (n = 16) had significantly lower somatostatin content in CSF (95 ± 4.1 (SEM) pg/ml) than both the control group (142 ± 8.4 pg/ml) and the group of MS patients (n =11), who had been in a clinical stable phase for more than 6 months (131 ± 3.2 pg/ml). Duration of the disease and degree of neurological impairment were apparently without relation to the reduction of somatostatin content in the CSF. There was no relationship between CSF content of somatostatin and the content of total protein or IgG, neither of which showed any relationship to the activity of the disease.     

T-cell subsets in multiple sclerosis: relationships between peripheral blood and cerebrospinal fluid

We contemporarily studied cerebrospinal fluid (CSF) and peripheral blood (PB) T-cell subsets, defined by monoclonal antibodies, in 29 patients with multiple sclerosis (MS) and 10 patients with other neurological diseases (OND). All subjects showed a clear-cut prevalence of CSF T-cells. Similarly, T-helper and T-suppressor subsets tended to show higher percentages in CSF in almost all subjects except relapsing MS, who were characterized by low percentages of T-suppressors in PB and even much lower percentages in CSF. Helper/suppressor ratios were found to be almost similar in the two body compartments of OND patients, lower in CSF than in PB of chronic progressive MS, always higher in CSF than in PB of relapsing MS. MS patients in remission showed both patterns of progressive MS and OND patients. Our results demonstrate that the loss of PB T-suppressor in relapsing MS is not due to a migration of such cells into CSF. Furthermore, regarding T-lymphocyte subsets, a typical CSF/PB pattern characterizes relapsing MS from other patients.     

Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients

The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.     

原发性低颅压综合征18例临床、脑脊液和影像学特点分析

目的探讨原发性低颅压综合征的临床、脑脊液和影像学特点。方法回顾性分析18例原发性低颅压综合征的临床资料。结果原发性低颅压综合征以体位性头痛、恶心、呕吐、头晕、耳鸣为主要表现,部分伴有神经系统体征,腰穿脑脊液压力均低于70mmH2O,27%患者红细胞增多,33%脑脊液蛋白增高,影像学检查可见硬膜增厚、强化、硬膜下积液和硬膜下血肿等表现,给予大量补液治疗及对症支持治疗,效果良好。结论体位性头痛、腰穿脑脊液压力低为原发性低颅压综合征的主要临床特点,影像学可呈现硬膜增厚强化等特征性改变,治疗以大量补液为主。     

Prostaglandin levels in cerebrospinal fluid from multiple sclerosis patients in remission and relapse

Radioimmunoassay (RIA) techniques have been employed to determine prostaglandin (PG) levels in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients in remission and relapse and in subjects with other neurological diseases (OND). PGE and PGF₂α concentrations in spinal fluid from MS patients in relapse were significantly lower than values estimated during remission and in individuals with OND of the central nervous system (CNS). These observations are discussed in relation to the clinical state of patients with demyelinating disease together with a consideration of the concept that disordered immune mechanisms contribute a central role in the pathogenesis of MS.     

Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients

The concentrations of ferritin, transferrin and iron were measured in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) and control patients. Ferritin levels were significantly elevated in the CSF of chronic progressive active MS patients (4.71+/-0.54 ng/ml) compared to levels in normal individuals (3.07+/-0.17 ng/ml). MS patients with active or stable relapsing-remitting disease had ferritin levels that were comparable to those found in normal individuals. There were no significant differences in transferrin or iron levels in the CSF between MS and normal individuals. Both ferritin and transferrin levels were elevated in patients that had high CSF IgG values but not in patients with a high IgG index. Since ferritin binds iron, the increase of CSF ferritin levels in chronic progressive MS patients could be a defense mechanism to protect against iron induced oxidative injury. Ferritin levels could be a laboratory measure that helps to distinguish between chronic progressive and relapsing-remitting MS.     

HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis

The objective of the study was to examine the relationship between HLA genotypes and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with multiple sclerosis (MS). We studied 100 patients with MS and 122 age, sex-, ethnic- and residence-matched controls. The DNA extraction and the genomic typing (A, B, DRB1 and DQB1 loci) were obtained with sequence-specific oligonucleotide method, using a commercially available reversible line blot assay (INNO-LIPA). All patients underwent a 1.5 tesla MRI examination of the brain. Disease severity was assessed by clinical (Expanded Disability Status Scale (EDSS)) and MRI (T2- and T1-lesion load (LL) and brain parenchymal fraction (BPF)) outcome measures. HLA-DQB1* 02 (OR 19.9, 95% C. I. 16.2–24.3, uncorrected (uncorr)- p<0.00001, corr-p<0.0006), -DQB1*03 (OR 16.8, 95% C. I. 13.6–20.5, uncorr-p<0.00001, corrp< 0.0006), -DRB1*15 (OR 4.6, 95% C. I. 3.7–5.6, uncorrp= 0.0001, corr-p=0.006), and -DRB1*03 (OR 3.9, 95% C. I. 3.2–4.8, uncorr-p=0.0001, corrp= 0.006) alleles were associated with MS. T2-, T1-LL, BPF and EDSS were not significantly different according to the carrier status of these HLA alleles. No differences were found in the ratios of disease severity/disease duration according to the HLA car rier status. Multiple regression analysis showed that a higher T2-LL was associated with the presence of DRB1*04 (uncorr- R2=0.15, p=0.006 and corr- R2=0.11, p=0.025) and B7 alleles (uncorr-R2=0.08, p=0.02 and corr-R2=0.07, p=0.018), T1-LL was associated with B7 (uncorr- R2=0.30, p<0.0001 and corr- R2=0.27, p=0.0001) and DRB1*12 (uncorr-R2=0.25, p<0.0001 and corr-R2=0.21, p=0.0002) alleles, whereas the BPF was predicted only by the presence of DRB1*12 allele (uncorr-R2=0.24, p=0.002 and corr-R2=0.20, p=0.004). The study findings suggest that some HLA alleles may predict the destructive pathological processes visible on MRI. Since the size of the sample studied is relatively small, further studies are needed to draw any firm conclusion about genotype/phenotype correlation in patients with MS.     

Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis

The sensitivities and predictive values of visual, somatosensory, and brain auditory evoked potentials (EPs), cerebrospinal fluid oligoclonal banding (CSF-OB) and magnetic resonance imaging (MRI) were evaluated for the early diagnosis of clinically definite multiple sclerosis (CDMS). Paraclinical evidence of asymptomatic lesions allows a diagnosis of CDMS. Eighty-two patients in whom MS was suspected but diagnosis of CDMS was not possible entered the study prospectively. Paraclinical examinations were performed at entry. Patients were examined and underwent EPs every 6 months, and MRI yearly. After a mean follow-up of 2.9 years, 28 patients (34%) had developed CDMS (McDonald-Halliday criteria). The initial MRI was strongly suggestive of MS in 19 of these (68%), while 27 (96%) had at least one MS-like abnormality in the initial MRI. CSF-OB and EPs had lower sensitivities. CDMS developed during follow-up in 19 of the 36 patients (53%) who had an initial MRI strongly suggestive of MS but in only 1 of the 25 who had normal MRI when first studied. These results support previous conclusions that MRI is the most sensitive test for detecting white matter asymptomatic lesions, and the most predictive for the diagnosis of CDMS.Presented in part at the Third meeting of the European Neurological Society, Lausanne (Switzerland), June 1992     

Expression of leukemia inhibitory factor in the cerebrospinal fluid of patients with multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterized by infiltration of immune cells in the central nervous system, localized myelin destruction and loss of oligodendrocytes. Early detection of MS may be possible via blood and cerebrospinal fluid (CSF) tests based on disease pathology. Leukemia inhibitory factor (LIF), a neurotrophic cytokine, has previously been shown to limit autoimmune demyelination and oligodendrocyte loss in a murine model of MS. Given its potential role in neural cell death and survival, in the present study we measured expression of LIF in serum and CSF from patients with relapsing-remitting MS (n = 46) and control subjects (n = 42). We used western blot analysis and enzyme-linked immunosorbent assays (ELISA), to study LIF expression. Western blot analysis revealed that LIF was present in all CSF samples, and densitometric analysis showed that relative expression was significantly higher in CSF from patients with MS than in controls (p < 0.001). ELISA analysis showed that the concentrations of LIF in both the serum (87.5 ± 11.46 ng/mL) and CSF (56 ± 10.72 ng/mL) of MS patients were significantly higher than those in control subjects (52 ± 8.23 ng/mL, 7.8 ± 3.76 ng/mL, respectively; p < 0.0001 for both serum and CSF), despite there being no significant difference in total protein concentration between the two groups (p = 0.52 for serum, p = 0.2 for CSF). Our data suggest that serum and CSF concentrations of LIF may provide additional useful information during the differential diagnosis of MS. Our findings also indicate that LIF could be significantly involved in the pathophysiology of MS.     

T-cell subsets in the cerebrospinal fluid and blood of patients with multiple sclerosis

The absolute numbers and ratios of helper/inducer (T4) and cytotoxic/suppressor (T8) T-cells were determined in cerebrospinal fluid (CSF) and blood of patients with multiple sclerosis (MS) and various other neurologic diseases (OND). In patients with MS, the T4:T8 ratio was higher in both blood and CSF, and the increase was significantly greater in CSF than in blood. These findings were due to an increased proportion of T4-lymphocytes in the CSF and to a decreased proportion of T8-cells in blood. These results indicate the need for additional studies of CSF lymphocytes in patients with MS.     

不同类型多发性硬化的临床及影像学特点

目的探讨不同类型多发性硬化(MS)的临床及影像学特点。方法对57例晚发型MS(LOMS)患者和57例早发型MS(YOMS)患者的临床及影像学的资料进行分析和比较。结果 LOMS组首次发病的运动障碍及病程中括约肌功能障碍的出现率明显高于YOMS组(P<0.05～0.01),而首次发病的感觉障碍、视觉障碍,查体发现的运动、视觉和构音障碍、视神经炎及病程中新发运动障碍出现率明显低于YOMS组(P<0.05～0.01)。LOMS组78.9%多为原发进展型,而YOMS组70.2%为复发缓解型,两组间的差异有统计学意义(均P<0.001)。LOMS组脑脊液细胞增高的比率、脑脊液细胞数平均值(17.5%,5×106/L)与YOMS组(35.1%,14×106/L)比较差异具有统计学意义(均P<0.005)。MRI显示,YOMS组小脑病灶出现率(60.0%)明显高于LOMS组(25.0%),而LOMS组脊髓异常的比率(47.4%)明显高于YOMS组(24.6%)(P<0.05～0.01)。急性发作期大剂量糖皮质激素治疗LOMS组显效20例(35.1%),YOMS组为41例(71.9%),两组的差异具有统计学意义(P<0.05...