Presence Of CSF Oligoclonal Bands Research Articles

Free Light Chains and Intrathecal B Cells Activity in Multiple Sclerosis: A Prospective Study and Meta-Analysis.

Background. The presence of CSF oligoclonal bands (OBs) is an independent prognostic factor for multiple sclerosis (MS), but the difficulties in the standardization of the test and the interlaboratory variation in reporting have contributed to its limited use in the diagnosis of the disease. Standard nephelometric assays to measure free light chains (FLC) levels have been recently developed and the test may improve the detection of intrathecal B cells activity. Methods. The presence of OBs, kappa and lambda FLC levels, and standard indices of intrathecal inflammation were assessed in 100 consecutive patients, including patients with MS, clinically isolated syndromes (CIS), other inflammatory diseases of the CNS, and other noninflammatory diseases. Results. Both KFLC and LFLC correlated strongly with the presence of OCBs and with all common tests for intrathecal inflammation (p < 0.001 for all comparisons). KFLC and LFLC were significantly different in patients with MS and CIS compared to the other groups (p < 0.001 and p < 0.001, resp.) and had a better diagnostic accuracy than all the other tests (area under the curve 82.3 % for KFLC index and 79.3 % for LFLC index). Conclusion. Nephelometric assays for KFLC in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate MS patients.

Pediatric MRI of the Brain: A Primer

1. Kamakshya P. Patra, MD* 2. Jeffrey D. Lancaster, MD* 3. Jeffery Hogg, MD† 4. Jeffrey S. Carpenter, MD† 1. *Department of Pediatrics, Section of Hospital Pediatrics, West Virginia University Children’s Hospital, Morgantown, WV. 2. †Department of Neuroradiology, West Virginia University Health Sciences Center, Morgantown, WV. * Abbreviations: ADHD: : attention-deficit/hyperactivity disorder CSF: : cerebrospinal fluid CT: : computed tomography DWI: : diffusion-weighted magnetic resonance imaging FLAIR: : fluid-attenuated inversion recovery fMRI: : functional magnetic resonance imaging MRI: : magnetic resonance imaging MRV: : magnetic resonance venography NAA: : N -acetylaspartate SDH: : subdural hematoma Because of recent advances in magnetic resonance imaging (MRI) techniques, pediatricians should be aware of the different modalities and their unique advantages and appropriateness in different clinical situations. After completing this article, readers should be able to: 1. Understand the pros and cons of MRI and computed tomography of the brain. 2. Know the basic principles of MRI and its different image modalities. 3. Be aware of the appropriateness of different modalities in specific clinical situations. Magnetic resonance imaging (MRI) is based on the absorption and emission of radiofrequency energy by hydrogen protons whose spin is influenced by changing magnetic fields (0.3 to 1.5 T). Unlike computed tomography (CT), there is no radiation exposure. T1-weighted images cause fat (eg, myelin in white matter) to appear bright and water (eg, cerebrospinal fluid [CSF] or edema) to appear dark on this sequence. The gray-white interfaces of the brain are well depicted on these sequences, especially if with the images are thinly sliced. T2-weighted images cause water (eg, CSF and edema) to appear bright and fat to appear dark. The MRI-based intravenous contrast agents (eg, gadolinium) are frequently used in T1-weighted images (Fig 1A and B) to make serum appear bright. The blood-brain barrier typically serves to limit the passage of many molecules out of the blood vessels. If disease processes break down this barrier (such as infection, tumors, or inflammation), intravenous contrast agents can cross into the brain, causing areas of contrast entry to appear very bright. Figure 1. T1-weighted image at the level of midbrain. A. The cerebrospinal fluid (CSF) appears dark. B. The CSF appears bright. Note the gray and white matter differentiation …

Isolated infratentorial demyelinating lesion

A 46-year-old man presented with subacute right-sided hemifacial sensory loss since 1 week. Brain MRI showed an isolated hyperintense lesion and a hypointense rim on T2-weighted imaging in the right-sided middle cerebellar peduncle associated with restricted diffusion in a concentric closed ring pattern, without gadolinium enhancement (Fig. 1). Spinal MRI was normal. C-reactive protein, antinuclear antibody, angiotensin-converting enzyme, paraneoplastic autoantibody evaluation, Lyme/HIV/syphilis serology were all normal. CSF analysis was normal apart from the presence of oligoclonal bands. Thoraco-abdominal-pelvic CT, whole-body FDG-PET, salivary gland biopsy, eye fundus, slit lamp examination, visual-evoked potentials, and optical coherence tomography scanner were all normal. While symptoms persisted, MRI 2 weeks later showed an increase in lesion size with a pattern of alternating bands of signal intensity (Balo-like) on T2-weighted imaging, partial gadolinium enhancement, and signal reversal (now hyperintense) on ADC map in the gadolinium-enhancing part of the lesion (Fig. 1). A stereotactic biopsy showed a demyelinating lesion (loss of myelin, foamy macrophages, perivascular inflammation, reactive astrocytes) in the absence of a tumoral process. Biopsy led to transient worsening of the hemifacial sensory loss. A diagnosis of an isolated infratentorial biopsy-proven demyelinating lesion was made. Intravenous methylprednisolone 500 mg od for 5 days led to improvement of the sensory symptoms. Nine months later, MRI still showed the (now only slightly) hyperintense T2-weighted lesion, in the absence of gadolinium enhancement or diffusion restriction (Fig. 1). No other lesions were seen. After 1 year of clinical and radiological follow-up, only very slight right-sided hemifacial paresthesias persisted (probably a sequella of the inflammatory lesion and/or the stereotactic biopsy performed). Restricted diffusion, T2-weighted hypointense rim, and Balo-like lesions seen in our patient correspond to what can be seen in patients with atypical idiopathic inflammatory or biopsy-proven demyelinating brain lesions [1, 2]. In a series of 69 patients with atypical idiopathic inflammatory demyelinating brain lesions (including megacystic, Balolike, infiltrative, ring-like, and unclassified type), only one had an infratentorial lesion (of the unclassified category) [2]. Recently, a series of 7 patients with a solitary demyelinating lesion in the brainstem (n = 2), the cervicomedullary junction (n = 3) or the upper cervical spinal cord (n = 2), called solitary sclerosis, has been described [3]. Evolution (follow-up of 6-year period) in these patients, in contrast to our patient (follow-up of only 1 year), was progressive leading to disability essentially due to motor impairment. In the reported 7 patients, none except one (with a post-mortem examination demonstrating an isolated pontine demyelinating lesion) had histological confirmation of demyelination. The presence of CSF oligoclonal bands, present in our case and in 4 of the 7 reported patients with solitary sclerosis, is concordant with a demyelinating process. Thus, overall, biopsy-proven isolated demyelinating lesions in the posterior fossa are very rare. Recognition of the radiological features of these often atypical lesions is D. Renard (&) G. Castelnovo P. Labauge Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, 30029 Nimes Cedex 4, France e-mail: dimitrirenard@hotmail.com

The Importance of CSF Oligoclonal Bands in the Diagnosis of Primary Progressive Multiple Sclerosis (P01.139)

Objective: To evaluate the importance of CSF OCBs in determining a diagnosis of PPMS. Background The 2010 McDonald revisions to the diagnosis of primary progressive MS (PPMS) have amended the criteria for evidence of dissemination in space (DIS) in the brain and spinal cord. Either of the latter may be replaced by the presence of CSF oligoclonal bands (CSFOBs). Visually evoked responses (VERs) are no longer useful in confirming DIS by reducing the number of T2 lesions on brain MRI. MRI brain changes due to small vessel disease may simulate MS lesions and spinal cord lesions may be too small to visualise on standard MRI. Thus the presence of CSFOBs may have high diagnostic importance in PPMS. Design/Methods: A retrospective review of all patients with a diagnosis of PPMS seen from 1985-2010. The age and mode of presentation, results of brain and spinal cord MRI were documented. Patients who had failed to satisfy the revised McDonald criteria on baseline imaging and identified patients in whom CSF contributed to establishing the diagnosis. Results: Of 118 PPMS patients, mean age at onset 41 years, baseline imaging data (brain or cord or both) was available in 99 (84%). Of 27/99 satisfying both imaging criteria, 21/27 had CSF; 86% had CSFOBs. Only 48 patients had MRI brain, cord & CSF. Of these, 39 patients had imaging which failed to meet the revised McDonald criteria (12 brain, 27 cord MRI). In 19 of these 39 patients the presence of CSFOBs satisfied the criteria. Five patients who did not meet either brain or cord MRI criteria had positive CSFOBs. VERs were performed in 10/39, two had a positive result; both had CSFOBs. Conclusions: In our PPMS cohort, 49% did not satisfy the McDonald criteria by MRI alone and CSFOBs aided the diagnosis. CSFOBs have significant utility in confirming DIS in PPMS. Disclosure: Dr. Kelly has received personal compensation for activities with Novartis, Biogen-Idec and Tysabri as a speaker. Dr. Kinsella has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals & Biogen Idec. Dr. Duggan has received personal compensation for activities with Novartis. Dr. McGuigan has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Tubridy has received research support from Bayer Pharmaceuticals Corporation, the Health Research Board of Ireland and MS Ireland. Dr. Hutchinson has received personal compensation for activities with Biogen Idec as a speaker.

Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australian multiple sclerosis cohort

High-resolution HLA-DRB1 genotyping was performed in 97 OCB-positive and 68 OCB-negative cases with demyelinating disease to determine the influence of HLA-DRB1 alleles on the presence of OCB in a West Australian multiple sclerosis (MS) cohort. Carriage of the HLA-DRB1*1501 allele was associated with both OCB-positive and OCB-negative MS compared with controls, but more strongly with the OCB-positive group, and increased the likelihood of having OCB 2.1-fold with evidence of a dominant dose–effect. The HLA-DRB1*0301 allele was negatively correlated with OCB, with all homozygotes OCB-negative, suggesting a possible recessive protective effect of HLA-DRB1*0301. There was no significant correlation between OCB and the DRB1*04 alleles which have been associated with OCB-negative MS in previous Swedish and Japanese studies. Evidence of allelic interactions was found with HLA-DRB1*1501/*1301 heterozygotes having a reduced frequency of OCB and HLA-DRB1*0301/*0401 heterozygotes all being OCB-negative. These findings confirm the strong association between HLA-DRB1*1501 and OCB which has been found in other populations but indicate that the influence of other HLA-DRB1 alleles varies in different populations. Our study is the first to show that HLA-DRB1 allele interactions and dose–effects influence the frequency of OCB.

Oligoclonal bands and antibody responses in multiple sclerosis.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System with multifocal areas of demyelination. Although its etiology and pathogenesis remain controversial, several lines of evidence indicate that MS is mediated by a misdirected immune response against one or several myelin proteins. The involvement of diverse leukocyte subsets and their products in MS is still the subject of considerable debate. The emphasis on T cells has derived mainly from the detection of activated T cells in MS plaques and analogies with animal models of MS. Because of these observations cell-mediated immunity has dominated the research field of MS to this day. However, in recent years the role of B cells, plasma cells and immunoglobulins in MS have been re-examined, and current findings indicate that humoral immunity also plays a major role in disease pathogenesis. B cells and their products could exert several potential effects during the course of MS. Firstly, autoantibodies against specific myelin antigens could mediate damage to myelin membranes. Secondly, some studies suggest that natural autoantibodies could enhance remyelination. Thirdly, antibodies directed against myelin components can participate in anti-idiotypic networks, which may regulate the course of MS. Increased intrathecal immunoglobulin synthesis reflected by raised IgG indices and an oligoclonal pattern is the most common abnormality detected in MS patients. The introduction of more sensitive procedures for protein detection has allowed demonstrating oligoclonal bands (OCBs) in up to 95 % of patients with clinically definite MS. Although the presence of OCBs in CSF of MS patients is now well established as a sensitive laboratory test to support the clinical diagnosis, OCBs may be present in other disorders, including those not directly related to infection or abnormal immune response. Nevertheless, the pathogenesis of OCBs in MS is still obscure, and despite extensive research their antigenic target(s) have yet to be established. Therefore, a critical task is to identify the specificity of such target(s), thus providing significant clues about MS etiology. For this purpose, novel molecular immunologic strategies have been recently developed to offer alternative approaches to identify putative antigens recognized by antibodies present in MS patients. The elucidation of the mechanisms and target(s) responsible for the onset of MS has obvious implications for the further development of specific therapies.

Heat shock protein immunoreactivity in CSF: correlation with oligoclonal banding and demyelinating disease.

The detection of raised immunoglobulin and the presence of oligoclonal bands (OCBs) on electrophoresis of multiple sclerosis (MS) CSF has been a useful diagnostic test, but a universal antigen to which these MS antibodies are directed has yet to be found. Potentially immunogenic heat shock proteins (HSPs) are preferential expressed in vitro in human oligodendrocytes compared with other glia, and in situ in oligodendrocytes found within the plaques of MS. Immunoreactivity directed against HSPs might therefore contribute to the immune-mediated demyelinating process found in MS. We examined this possibility by quantitatively (ELISA) measuring antibodies directed against a recombinant human HSP (HSP60) in CSF from 18 MS patients, and compared them with eight patients with acute disseminated encephalomyelitis, 12 with demyelinating peripheral neuropathies, and 59 with other neurologic diseases. Immunoblotting was used to confirm the specificity of the antibodies for binding to HSP60. We found a statistically significant correlation between antibody titers to HSP60 and the presence of OCBs in CSF. These results support the notion that HSP expression in the CNS, such as that observed in MS, may be immunogenic, leading to localized HSP antibody secretion. Such HSP-directed immunoreactivity could play a role in the pathogenesis of MS and other immune-mediated disorders of the nervous system.

Diagnostic usefulness of cerebrospinal fluid IgG in multiple sclerosis and other neurological disorders

MS is one of the most common neurologic disorders encountered in the United States. An increase in the CSF IgG index or IgG synthesis rate within CNS, and the presence of CSF oligoclonal bands, now serve as important tools for the diagnosis of MS. Although IEF shows better identification of a number of distinct oligoclonal bands compared to AGE, the latter appears to be a more convenient system for the average hospital's clinical laboratory. These findings are not specific to MS, and similar CSF abnormalities occur in other, more rarely neurologic diseases. It is generally easy to distinguish MS from these other diseases when a thorough clinical and laboratory evaluation is carried out. However, the detection of these CSF IgG abnormalities in non-MS patients may offer an important clue to the presence of a previously unsuspected chronic infection or inflammatory process involving the CNS.