Cerebrospinal Fluid Oligoclonal Bands Research Articles

Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases

We assayed IL-6 in 105 cerebrospinal fluid (CSF) samples from patients with ALS, MS, HTLV-1 associated myelopathy (HAM), and controls. There was considerable overlap in IL-6 levels in all patient groups. The mean IL-6 in 27 patients with ALS was significantly higher than in 21 patients in the other neurological disease (OND) group ( P=0.0075). There were no significant differences in MS or HAM and the OND control group. Overall, CSF IL-6 correlated with protein concentration but not with percentage IgG or IgG-albumin index. Patients with CSF oligoclonal bands were no more likely to have detectable IL-6 than patients without oligoclonal bands. Similarly, IL-6 did not correlate with clinical disease activity in MS when subgroups of patients were compared or when an individual patient was followed over time. The elevated IL-6 in ALS may reflect an ongoing humoral immune response, or IL-6 may be non-specifically expressed in these patients as a putative neurotrophic factor in response to nerve cell degeneration.

An improved, ultrasensitive method for the detection of IgM oligoclonal bands in cerebrospinal fluid

A new, 10-fold more sensitive method, based on an improved immunofixation technique, has been devised to detect oligoclonal IgM bands in unconcentrated cerebrospinal fluid (CSF). Using agarose gel electrophoresis, 5 μl of an unconcentrated sample containing oligoclonal bands was separated and blotted on to a polyvinyldifluoride membrane. To visualise the pattern, a peroxidase-labelled double-antibody technique was used. No prior concentration of CSF was needed and the process required only 5 h. The technique may prove very useful in diagnosing an early intrathecal immune response.

Multiple Sclerosis in Childhood: Report of 16 Cases

Sixteen children with definite multiple sclerosis (MS; aged 6-17 years, mean 11.4 +/- 2.7; 8 boys, 8 girls) were reviewed. Cerebellar symptoms and signs were frequent at initial presentation. Among laboratory studies, the cerebrospinal fluid (CSF) IgG index or oligoclonal bands were informative in 75%, evoked potentials in 70%, electroencephalography (EEG) in 83%, magnetic resonance imaging in 80% and computed tomography in 45%. When compared with patients with other neurological disorders and similar presentation (non-MS group, n = 13), MS patients were more likely to recover from the first attack without significant sequelae. CSF protein was usually normal in MS and high in non-MS patients. The CSF IgG index and/or oligoclonal bands were also helpful in differentiating these two groups. The absence of female preponderance, the frequency of EEG abnormalities and the lower yield from CSF analysis are particularly interesting in this childhood series. Different pathogenetic mechanisms may be involved in MS from different ages, genetic backgrounds, or environments.

Acute posterior multifocal placoid pigment epitheliopathy presenting as an aseptic meningitis

We report a 33-year-old patient with acute posterior multifocal placoid pigment epitheliopathy presenting as steroid-responsive aseptic meningitis. Four unusual biological abnormalities were present: an elevated erythrocyte sedimentation rate, circulating immunocomplexes, an oligoclonal banding in cerebrospinal fluid and a transient abnormal urine sediment All these and the prompt response to corticosteroids give support to the hypothesis of a systemic autoimmune disease.

Tonic “Seizures” in a patient with brainstem demyelination: MRI study of brain and spinal cord

Tonic seizures are a poorly understood manifestation of demyelinating disease, first reported in 4 patients with multiple sclerosis. We describe a patient with tonic extension of the left limbs caused by a right-sided brainstem lesion as the first manifestation of demyelinating disease. A 19-year-old man was referred with a 4-month history of spontaneous attacks of mild paresthesias of the left arm and leg, followed by 15–45 s of rigid extension of the left limbs, occurring up to 25 times per day. Two months after onset, an MRI scan revealed areas of T 2 abnormality in the lateral right cerebral peduncle and deep frontal white matter. The EEG was normal, including during hyperventilation which induced a typical episode. All attacks were successfully suppressed by carbamazepine, phenytoin, and valproate monotherapy. Serologic testing for toxoplasmosis, cytomegalovirus, Epstein-Barr virus, Lyme disease, and HIV was negative. Cerebrospinal fluid oligoclonal bands were absent but cerebrospinal fluid immunoglobulin G was mildly elevated (4.2 mg/dl). Over the next 30 months, serial MRIs revealed a normal spinal cord and persistence of the midbrain lesion, with resolution of some of the white matter lesions but reappearance of others. At 46 months, the midbrain lesion resolved on MRI, and the spasms no longer occurred spontaneously, nor could they be elicited by hyperventilation. While two previous reports have shown internal capsule lesions to underlie the tonic spasms in demyelinating disease, this is the first report in which a brainstem lesion has been causative.

Cladribine in treatment of chronic progressive multiple sclerosis

Summary Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0·7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1·0 (SE 0·4) for the Kurtzke scores, -13·9 (2·3) for the Scripps scores, 4 57 (1·17) mL for demyelinated volumes, and 7·3 (3·3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

Absence of oligoclonally restricted immunoglobulins in tears from multiple sclerosis patients

To study the extent of systemic immunodysregulation in multiple sclerosis (MS) we measured immunoglobulin (Ig)G, A, and M levels and studied their migrational properties after agarose isoelectric focusing in serum, cerebrospinal fluid (CSF) and tear samples from 18 MS patients with other neurological diseases (OND), and tears and serum samples from ten normal controls (NC). A slight elevation of total IgG, IgM and IgA levels was detected in tears from patients with MS and OND compared to NC. Of the five patients (two MS, three OND) that showed IgG oligoclonal bands (OCB) in tears, only one MS patient showed unique bands in tears not seen in the paired CSF and serum. We never found IgA, and IgM OCB in serum, CSF or tear samples. Our results suggest that polyclonal Igs are systemically elevated during chornic neurological inflammatory diseases. Oligoclonal Ig in MS, although ocassionally detectable in tears, is mainly confined to the central nervous system and appears restricted to class G.

Transverse myelitis. Retrospective analysis of 33 cases, with differentiation of cases associated with multiple sclerosis and parainfectious events.

A study was undertaken to determine whether cases of parainfectious-associated transverse myelitis (TM) and multiple sclerosis-associated TM could be distinguished on the basis of clinical criteria, radiologic features, or cerebrospinal fluid examination. A secondary objective was to determine the incidence of TM in a US population. A retrospective analysis of 33 cases was conducted. Cases were classified as being related to parainfectious multiple sclerosis, or spinal cord ischemia, or idiopathic. All cases occurring in the Albuquerque, NM, area from 1960 through 1990 were reviewed. The population base was 500,000. Clinical presentation, radiologic features, cerebrospinal fluid, recovery of ambulation and bladder function, and recurrence rates were compared. Thirty-three patients satisfied study criteria, corresponding to an incidence of 4.6 per million per year. Forty-five percent of these cases were categorized as parainfectious, 21% as associated with multiple sclerosis, 12% as associated with spinal cord ischemia, and 21% as idiopathic. Patients with parainfectious TM suffered from spinal shock more frequently than did those with multiple sclerosis-associated TM. Patients with parainfectious TM showed evidence of spinal cord swelling, whereas patients with multiple sclerosis-associated TM had spinal cord plaques on magnetic resonance images but none showed swelling. Oligoclonal bands were absent in patients with parainfectious TM and present in three of five patients with multiple sclerosis-associated TM. Parainfectious TM may be distinguishable from that associated with multiple sclerosis on the basis of presentation, findings on imaging, and the presence of cerebrospinal fluid oligoclonal bands.

The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study.

A 5-year follow-up study was performed on 89 patients who had undergone brain magnetic resonance imaging (MRI) at presentation with an acute clinically isolated syndrome of the optic nerves, brainstem or spinal cord of a type suggestive of multiple sclerosis. At presentation, MRI was abnormal, revealing one or more asymptomatic cerebral white matter lesions in 57 (64%), and was normal in 32 (36%). At follow-up, progression to clinically definite multiple sclerosis had occurred in 37 out of 57 (65%) with an abnormal MRI and one out of 32 (3%) with normal MRI. Human leucocyte antigen (HLA) typing was performed in 70 patients and cerebrospinal fluid (CSF) was examined at presentation in 36. The presence of HLA-DR2 antigen or cerebrospinal fluid oligoclonal IgG bands were both associated with a significantly increased risk of progression to multiple sclerosis, but MRI was much more powerful in predicting outcome. The presence of four or more MRI lesions at presentation was associated with a higher rate of progression to multiple sclerosis, more frequent development of moderate or severe disabilities and a greater number of new MRI lesions at follow-up. The results indicate that brain MRI at presentation with a clinically isolated syndrome suggestive of multiple sclerosis is a powerful predictor of the clinical course over the next 5 years. This observation, combined with an ability to detect other sometimes treatable disorders which can also cause such syndromes, suggests that MRI is the investigation of choice in evaluating this group of patients.

Distribution of cerebrospinal fluid oligoclonal IgM bands in neurological diseases: a comparison between agarose electrophoresis and isoelectric focusing

Isoelectric focusing (IEF) and agarose gel electrophoresis were used to detect oligoclonal IgM bands in cerebrospinal fluid and serum samples from 850 patients with diverse neurologic diseases. Oligoclonal IgM bands in cerebrospinal fluid were mainly detected in patients with infectious and inflammatory disorders of the nervous system. Both IEF and agarose electrophoresis revealed similar frequencies of oligoclonal IgM bands. Bands detected by IEF were mainly seen in the anodal range. Despite higher resolving capacity. IEF was less specific than agarose gel electrophoresis. It is concluded that oligoclonal IgM bands have important diagnostic significance and that agarose gel electrophoresis is more suitable for their detection in routine clinical work and use in differential diagnosis.

Effect of treatment on oligoclonal IgG bands and intrathecal IgG synthesis in sequential cerebrospinal fluid and serum from patients with subacute sclerosing panencephalitis

Oligoclonal IgG bands were analyzed in matching pairs of cerebrospinal fluid (CSF) and serum from 12 subacute sclerosing panencephalitis (SSPE) patients, using isoelectric focusing and immunofixation. Each patient was given isoprinosine, and four of the 12 patients were given alpha-interferon in addition. Two to 4 serial CSF and serum samples were collected from each SSPE patient during periods ranging from 1 to 16 months. In 3 SSPE patients in a small number of new oligoclonal bands were seen in the follow-up CSF samples. In the other 9 SSPE patients there was no change in CSF band patterns between initial and follow-up specimens. Band patterns in serum remained unchanged between initial and follow-up samples. Although all 12 SSPE cases had higher IgG indices and increased rate of intra blood-brain barrier (BBB) IgG synthesis in comparison to patients with other neurological diseases, the values did not significantly differ between the first and follow-up specimens. We conclude that treatment of SSPE patients with isoprinosine or with isoprisonine and alpha-interferon had no significant effect on the CSF oligoclonal band profiles or IgG synthesis within the central nervous system.

Tumor cell dissemination triggers an intrathecal immune response in neoplastic meningitis.

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.

Comparison of spinal fluid beta 2-microglobulin levels with CD4+ T cell count, in vitro T helper cell function, and spinal fluid IgG parameters in 163 neurologically normal adults infected with the human immunodeficiency virus type 1.

Beta 2-microglobulin levels were measured in the cerebrospinal fluid (CSF) and serum of 163 human immunodeficiency virus-positive (HIV+) persons with normal neurologic physical examinations. None were on antiretroviral therapy. Only 3% had a positive CSF HIV p24 antigen test. The CSF beta 2-microglobulin levels increased as the CD4+ T cell count decreased. Intrathecal production of beta 2-microglobulin was suggested by finding CSF concentrations greater than serum concentrations in 15% of patients. The CSF beta 2-microglobulin levels rose as in vitro T helper cell function deteriorated, independent of CD4+ T cell count. CSF beta 2-microglobulin levels paralleled CSF IgG, IgG index, and IgG synthesis. Higher CSF beta 2-microglobulin levels were found in persons with positive CSF oligoclonal bands. CSF beta 2-microglobulin concentration may serve as a marker for subclinical neurologic damage due to HIV. If this is established, defining the effect of anti-HIV interventions on CSF beta 2-microglobulin would be warranted.

INTRATHECAL IMMUNOGLOBULIN M SYNTHESIS IN MULTIPLE SCLEROSIS<subtitle>RELATIONSHIP WITH CLINICAL AND CEREBROSPINAL FLUID PARAMETERS</subtitle>

Intrathecal IgM synthesis was assessed through the detection of oligoclonal bands in cerebrospinal fluid (CSF) and through calculation of IgM index values and total CSF IgM amounts. Intrathecal production of IgM was then evaluated along with other CSF parameters and clinical variables in 150 patients with multiple sclerosis (MS). Intrathecal production of IgM was detected in 55% of patients and was found to correlate with disease activity, manifesting as a recent relapse, as well as the total number of relapses. An inverse correlation was found between CSF oligoclonal IgM and both the time interval between the last relapse and lumbar puncture, and duration of the disease process. It also correlated with the number of leucocytes, free kappa and lambda light chain bands in CSF. No correlation was found between intrathecal IgM synthesis and degree of disability (Kurtzke scale), disease progression index (Poser scale), or total cerebral plaque burden (detected by enhanced CT and MRI scans). Oligoclonal IgM bands were found to be more specific for active disease process than either IgM index or total CSF IgM amount. It is concluded that intrathecal synthesis of IgM, as detected by CSF oligoclonal bands, is a useful parameter in monitoring disease relapse activity in MS.

The predictive value of intrathecal immunoglobulin synthesis and magnetic resonance imaging in acute isolated syndromes for subsequent development of multiple sclerosis

The intrathecal synthesis of IgM in patients presenting with acute monosymptomatic syndromes may be relevant in predicting eventual progression to multiple sclerosis but has not been previously evaluated. We undertook a prospective 18-month combined clinical, cerebrospinal fluid, and magnetic resonance imaging study of 45 patients who had presented with acute isolated lesions of brainstem and spinal cord to evaluate the predictive value of intrathecal synthesis of IgM and IgG (through the detection of cerebrospinal fluid oligoclonal bands) and magnetic resonance imaging brain lesions at presentation, for the subsequent progression to multiple sclerosis. Results indicate that the highest risk of developing multiple sclerosis is seen in patients who are positive for oligoclonal IgM and IgG bands and who have disseminated cerebral white matter magnetic resonance imaging lesions at the initial presentation. Oligoclonal IgM bands predict progression to multiple sclerosis more frequently than oligoclonal IgG or magnetic resonance imaging alone. Our results confirm and further extend previous reports, and indicate that detection of cerebrospinal fluid oligoclonal IgM bands at presentation is a valuable prognostic indicator in patients presenting with acute isolated brainstem or spinal cord syndromes.

Lymphoma, motor neuron diseases, and amyotrophic lateral sclerosis

We studied 9 patients with motor neuron disease and lymphoma. The following several observations have not been recognized in the past: (1) Motor neuron syndromes are associated with either Hodgkin's disease or non-Hodgkin's lymphoma. (2) The syndromes are not restricted to lower motor neuron disorders; 8 of 9 patients had definite or probable upper motor neuron signs as well, qualifying for the diagnosis of amyotrophic lateral sclerosis. Corticospinal tracts were affected in both postmortem examinations. (3) The combination of motor neuron disease and lymphoma is often accompanied by paraproteinemia (3 of 7 patients studied), increased cerebrospinal fluid protein content (6 of 9 patients), and cerebrospinal fluid oligoclonal bands (3 of 9 patients). (4) In 2 patients, asymptomatic non-Hodgkin's lymphoma was found only because the discovery of paraproteinemia gave impetus to examine the bone marrow. (5) Patients with both upper and lower motor neuron signs (amyotrophic lateral sclerosis) may show physiological evidence of conduction block in peripheral nerves or autopsy abnormalities in peripheral nerves. The cause of this syndrome is not known. Both lymphoma and motor neuron disease could have a common cause, possibly a retroviral infection. The frequency of paraproteinemia suggests that an immunological disorder may play a role in the pathogenesis of the neurological disorder.

Discontinuos distribution of IgG oligoclonal bands in cerebrospinal fluid from multiple sclerosis patients

To test the effect of sampling on the detection of immunoglobulin (Ig) cerebrospinal fluid (CSF) abnormalities, we analyzed the first and last 1 ml fraction of 10 ml obtained during a single CSF removal from 27 multiple sclerosis (MS) patients and six patients with other neurological diseases. IgG index, hyperbolic function, and IgG synthesis rate decreased between the first and the last CSF aliquot. Discordant results were found in 4 27 (15%) MS patients. In 2 27 (7.5%) clinically definite MS patients, the number of CSF oligoclonal bands (OCB) decreased between the first and the last fraction. In one of the two patients, the three OCB visualized in the first fraction were not found in the last. We conclude that fractionated sampling may partially account for the absence of OCB in the CSF of some definite MS patients.

Elevated soluble interleukin‐2 receptor levels in patients with active multiple sclerosis

The level of soluble interleukin-2 receptor (sIL-2R) was quantitated with enzyme-linked immunosorbent assay in serum and cerebrospinal fluid obtained from 24 patients with multiple sclerosis and 10 patients with other neurological disorders in whom immunological mechanisms are unlikely to participate. The sIL-2R level in the serum and cerebrospinal fluid of patients with multiple sclerosis in relapse was significantly higher compared with patients with multiple sclerosis in remission and with controls. The sIL-2R level, especially in the cerebrospinal fluid, showed higher sensitivity and specificity than other clinical parameters including the cerebrospinal fluid IgG ratio, peripheral lymphocyte CD4/CD8 ratio, cerebrospinal fluid myelin basic protein and oligoclonal bands. Our data suggest that measurement of the sIL-2R level may be useful in evaluating disease activity in patients with multiple sclerosis.

Chronic encephalitis, epilepsy, and cerebrovascular immune complex deposits

Refractory epilepsy, electroencephalographic abnormalities, progressive hemiplegia, and contralateral hemicerebral atrophy developed in a previously healthy 3-year, 9-month-old girl. Extensive laboratory testing showed elevated serum antinuclear antibody titers, cerebrospinal fluid oligoclonal bands, and elevated immunoglobulin G (IgG): albumin ratio, IgG index, and IgG synthesis rate. Pathological study of a subtotal hemispherectomy specimen revealed widespread cerebral vasculitis with immunofluorescence staining for IgG, IgM, IgA, C3, and Clq, and ultrastructural evidence of vascular injury in addition to severe cortical atrophy with marked neuronal loss. Cerebrospinal fluid abnormalities in other reported patients suggest that immunological abnormalities may not be unique to this girl. These data suggest possible immunopathogenetic mechanisms in these patients.

Oligoclonal Borrelia burgdorjeri-Specific IgG Antibodies in Cerebrospinal Fluid in Lyme Neuroborreliosis

Cerebrospinal fluid (CSF) and serum from 45 patients with lymphocytic meningoradiculitis were examined by isoelectric focusing combined with immunoblotting to detect Borrelia burgdorferi-specific oligoclonal immunoglobulin G (IgG) bands. In pretreatment samples, 35 patients (78%) showed B. burgdorferi-specific oligoclonal IgG in CSF indicative of intrathecal antibody production. At 2, 3-6, and 6 weeks after onset, respectively, such bands were present in 5 (42%) of 12, 21 (88%) of 24, and in all of 9 patients (100%). Up to 1 year after therapy, specific oligoclonal bands in CSF tended to remain unchanged despite clinical recovery. B. burgdorferi-specific oligoclonal bands in serum were found in 7 patients. These bands had identical migration patterns as in CSF, but were fewer in number and in some patients showed a temporal evolution different from their CSF counterpart. Not all oligoclonal IgG in CSF reacted with B. burgdorferi. The 41-kDa flagellar antigen was shown to be a major antigen in the intrathecal immune response. The demonstration of B. burgdorferi-specific oligoclonal IgG in CSF is a sensitive and reliable indicator of Lyme neuroborreliosis.