Baseline serum/cerebrospinal fluid ratio of carcinoembryonic antigen and carbohydrate antigen series biomarkers in non-neoplastic diseases: a cross-sectional study on 224 patients.

BACKGROUND: The measurement of carcinoembryonic antigen, carbohydrate antigen series biomarkers in cerebrospinal fluid (CSF), is useful for the diagnosis of brain metastasis and leptomeningeal metastases to a certain extent. Their serum/CSF ratios may be of benefit to earlier diagnosis and treatment. However, the normal reference values of the ratios were not available. Accordingly, in this study we analyzed the serum/CSF ratios of tumor markers levels in non-neoplastic diseases patients for possible normal values. MATERIAL AND METHODS: We screened our database for paired CSF and serum samples which have been collected by lumbar puncture. 224 pairs of CSF and serum samples were obtained and compared. The 97.5th percentile, maximum value, and their serum/CSF ratios were obtained. RESULTS: The 97.5th percentile and maximum value of CSF CEA, CA125, CA19-9, CA15-3, CA724, and CYFRA21-1 concentration for overall participants were 0.572 µ/mL, 4.343 µ/mL, 2.872 µ/mL, 2.108 µ/mL, 1.62 µ/mL, and 1.997 µ/mL, respectively. Gender had no significant difference in these CSF biomarkers except CA15-3. The 97.5th percentile serum/CSF ratio of CEA, CA125, CA19-9, CA15-3, CA724, and CYFRA21-1 level were 34.554, 44.772, 51.232, 20.941, 20.737, and 5.389 respectively. The serum/CSF ratios in different age groups were also described. CONCLUSIONS: Here, serum/CSF ratios of six tumor markers were determined in non-neoplastic diseases. The usefulness of this index for diagnosis, management, and prognostic utility of leptomeningeal metastases must be validated in larger cohort studies over the long term.

Fibromyalgia and unexplained widespread pain: The idiopathic cerebrospinal pressure dysregulation hypothesis.

Fibromyalgia (FM) is a debilitating, widespread pain disorder that is assumed to originate from inappropriate pain processing in the central nervous system. Psychological and behavioral factors are both believed to underlie the pathogenesis and complicate the treatment. This hypothesis, however, has not yet been sufficiently supported by scientific evidence and accumulating evidence supports a peripheral neurological origin of the symptoms. We postulate that FM and several unexplained widespread pain syndromes are caused by chronic postural idiopathic cerebrospinal hypertension. Thus, the symptoms originate from the filling of nerve root sleeves under high pressure with subsequent polyradiculopathy from the compression of the nerve root fibers (axons) inside the sleeves. Associated symptoms, such as bladder and bowel dysfunction, result from compression of the sacral nerve root fibers, and facial pain and paresthesia result from compression of the cranial nerve root fibers. Idiopathic Intracranial Hypertension, Normal Pressure Hydrocephalus and the clinical entity of symptomatic Tarlov cysts share similar central and peripheral neurological symptoms and are likely other manifestations of the same condition. The hypothesis presented in this article links the characteristics of fibromyalgia and unexplained widespread pain to cerebrospinal pressure dysregulation with support from scientific evidence and provides a conclusive explanation for the multitude of symptoms associated with fibromyalgia.

Sphingomyelin as a myelin biomarker in CSF of acquired demyelinating neuropathies.

Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p = 3.81 * 10 - 8) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development.

Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy.

BACKGROUND: Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1-expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology. METHODS: Serological and other immunological studies, and retrospective analysis of patient records. RESULTS: The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barré syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A 3H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization. CONCLUSIONS: Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases.

Analysis of Cerebrospinal Fluid Carbohydrate Antigen Series Biomarkers in Non-neoplastic Diseases.

BACKGROUND: Carbohydrate antigen series biomarkers in cerebrospinal fluid (CSF) are important for the diagnosis of brain metastasis and meningeal carcinomatosis. Its relationship with CSF and serum in non-neoplastic diseases may be beneficial for earlier diagnosis and treatment. MATERIALS AND METHODS: 161 pairs of CSF and serum samples were obtained and compared. The 97.5th percentile and maximum value of carbohydrate antigen series biomarkers were obtained. RESULTS: The 97.5th percentile and maximum value of CSF CA125, CA15-3 and CA19-9 concentration for overall participants was 4.31 u/ml and 4.59 u/ml, 2.01 and 3.65 u/ml, 2.71 u/ml and 3.00 u/ml, respectively. Gender had no significant effect on these three CSF biomarkers. The concentration of these three biomarkers in CSF were all lower than the paired serum concentration. The ratio of CA125, CA15-3 and CA19-9 level (CSF / serum) were from 0.018 to 0.69, 0.038 to 0.893, 0.017 to1, respectively. CONCLUSIONS: Evaluation of intrathecal tumor markers synthesis is a specific, sensitive, reliable, and reproducible diagnostic tool. The values determined in this study of CSF carbohydrate antigen series biomarkers are significantly lower than what is usually used in clinical practice.

Metabolomics in cerebrospinal fluid of patients with amyotrophic lateral sclerosis: an untargeted approach via high-resolution mass spectrometry.

Amyotrophic lateral sclerosis (ALS) is characterized by the absence of reliable diagnostic biomarkers. The aim of the study was to (i) devise an untargeted metabolomics methodology that reliably compares cerebrospinal fluid (CSF) from ALS patients and controls by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS); (ii) ascertain a metabolic signature of ALS by use of the LC-HRMS platform; (iii) identify metabolites for use as diagnostic or pathophysiologic markers. We developed a method to analyze CSF components by UPLC coupled with a Q-Exactive mass spectrometer that uses electrospray ionization. Metabolomic profiles were created from the CSF obtained at diagnosis from ALS patients and patients with other neurological conditions. We performed multivariate analyses (OPLS-DA) and univariate analyses to assess the contribution of individual metabolites as well as compounds identified in other studies. Sixty-six CSF samples from ALS patients and 128 from controls were analyzed. Metabolome analysis correctly predicted the diagnosis of ALS in more than 80% of cases. OPLS-DA identified four features that discriminated diagnostic group (p < 0.004). Our data demonstrate that untargeted metabolomics with LC-HRMS is a robust procedure to generate a specific metabolic profile for ALS from CSF and could be an important aid to the development of biomarkers for the disease.

Neuroinflammation and complexes of 17ß-hydroxysteroid dehydrogenase type 10--amyloid ß in Alzheimer's disease.

Multifunctional mitochondrial enzyme 17ß-hydroxysteroid dehydrogenase type 10 plays a role in the development of Alzheimer's disease. However, changes in its expression in the brain or cerebrospinal fluid are not fully specific for this type of dementia. Our previous study revealed that complexes of the enzyme and amyloid ß in cerebrospinal fluid could serve as a more specific biomarker of Alzheimer's disease than either the enzyme or amyloid ß individually when compared to autoimmune multiple sclerosis. In this study, enzyme-linked immunosorbent assay and the surface plasmon resonance biosensor method were used to analyse cerebrospinal fluid of patients with various neuroinflammatory diseases. Significant differences in the levels of the total enzyme, complexes, amyloid ß 1-42 and total τ/phospho-τ were found in Alzheimer's disease patients while differences in complexes, total amyloid ß and amyloid ß 1- 42 were observed in patients with neuroinflammatory diseases (except for multiple sclerosis) when compared to non-neuroinflammatory controls. The interactions of the enzyme with amyloid ß appeared to depend strongly on neuroinflammation-sensitive amyloid ß. Our data demonstrated that oligomerisation/aggregation of intracellular amyloid ß peptides was important in Alzheimer's disease while extracellular amyloid ß could play a role in neuroinflammatory diseases. Phospho-τ is currently the best biomarker of Alzheimer's disease.

Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-ß peptides.

PURPOSE: Carboxyterminally elongated and aminoterminally truncated Aß peptides as well as their pyroglutamate and oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to characterize aminoterminally truncated or oxidized Aß38, Aß40, and Aß42 peptide species in immunoprecipitated human cerebrospinal fluid (CSF). EXPERIMENTAL DESIGN: We invented a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and used the Aß-SDS-PAGE/immunoblot for subsequent analysis of CSF Aß peptide patterns. RESULTS: In the present study, we identified the aminoterminally truncated Aß peptides 2-40 and 2-42 as well as oxidized forms of Aß1-38 and Aß1-42 in CSF. Our protocol allowed the quantification of a pattern of Aß peptides 1-38(ox), 2-40, and 2-42 in addition to the well known panel of Aß 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42 in a group of seven patients with peripheral polyneuropathy. CONCLUSIONS AND CLINICAL RELEVANCE: In the present approach, we could broaden the range of quantifiable Aß peptides described in previous studies (i.e., 1-37, 1-38, 1-39, 1-40, 1-40(ox), and 1-42) by Aß 1-38(ox), 2-40, and 2-42. An exact analysis of CSF Aß peptides regarding their carboxy- and aminoterminus as well as posttranslational modification seems promising with respect to diagnostic and pathogenic aspects.

Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond.

OBJECTIVE: To investigate the full extent of Purkinje cell cytoplasmic autoantibody type 1 autoimmunity (classically associated with paraneoplastic cerebellar degeneration) from clinical, immunohistochemical, and neuropathological perspectives. DESIGN: Case series. SETTING: Mayo Clinics, 3 sites (Minnesota, Arizona, and Florida). PATIENTS: Of 133,138 patients tested over a 21-year period, 83 (0.06%) were identified as seropositive for Purkinje cell cytoplasmic autoantibody type 1 IgG. MAIN OUTCOME MEASURES: The frequency of cerebellar and noncerebellar disorders and the clinical outcomes (neurological and oncological) of the patients. RESULTS: All patients were women. At initial presentation, 64 patients (77%) had a cerebellar disorder, and 19 patients (23%) had an extracerebellar disorder. Over the clinical course, neurological symptoms and signs were multifocal in 50 patients (60%), and they involved the cerebellum (89% of patients), the pyramidal tract (30%), the brainstem (13%), and the spinal anterior horn cells or peripheral nerve (10%; frequently upper limb predominant); 11% of patients did not develop cerebellar ataxia. Serological and neuropathological findings were observed in the cerebellum, the brainstem, the spinal cord, the anterior horn, and the dorsal root ganglion that paralleled the diversity of clinical signs. After a median follow-up of 18 months, 1 or more carcinomas had been detected in 88% of patients: ovarian epithelial cancer (53%), breast cancer (22%), fallopian tubal cancer (11%), primary peritoneal cancer (5%), metastases of unknown primary cancer (4%), and other cancers (4%). Sustained improvement was reported in 15% of patients following oncological or immunological therapies. Voltage-gated calcium channel antibodies coexisted in 23 patients (28%). CONCLUSIONS: Purkinje cell cytoplasmic autoantibody type 1 autoimmunity most commonly affects the cerebellum, but the spectrum of neurological symptoms and presentations is broad. Neurological outcomes are usually poor, even when cancer remission is achieved.

Nonlinear dimension reduction and clustering by Minimum Curvilinearity unfold neuropathic pain and tissue embryological classes.

MOTIVATION: Nonlinear small datasets, which are characterized by low numbers of samples and very high numbers of measures, occur frequently in computational biology, and pose problems in their investigation. Unsupervised hybrid-two-phase (H2P) procedures-specifically dimension reduction (DR), coupled with clustering-provide valuable assistance, not only for unsupervised data classification, but also for visualization of the patterns hidden in high-dimensional feature space. METHODS: 'Minimum Curvilinearity' (MC) is a principle that-for small datasets-suggests the approximation of curvilinear sample distances in the feature space by pair-wise distances over their minimum spanning tree (MST), and thus avoids the introduction of any tuning parameter. MC is used to design two novel forms of nonlinear machine learning (NML): Minimum Curvilinear embedding (MCE) for DR, and Minimum Curvilinear affinity propagation (MCAP) for clustering. RESULTS: Compared with several other unsupervised and supervised algorithms, MCE and MCAP, whether individually or combined in H2P, overcome the limits of classical approaches. High performance was attained in the visualization and classification of: (i) pain patients (proteomic measurements) in peripheral neuropathy; (ii) human organ tissues (genomic transcription factor measurements) on the basis of their embryological origin. CONCLUSION: MC provides a valuable framework to estimate nonlinear distances in small datasets. Its extension to large datasets is prefigured for novel NMLs. Classification of neuropathic pain by proteomic profiles offers new insights for future molecular and systems biology characterization of pain. Improvements in tissue embryological classification refine results obtained in an earlier study, and suggest a possible reinterpretation of skin attribution as mesodermal. AVAILABILITY: https://sites.google.com/site/carlovittoriocannistraci/home.

Release of plasmid DNA-encoding IL-10 from PLGA microparticles facilitates long-term reversal of neuropathic pain following a single intrathecal administration.

PURPOSE: Interleukin-10 (IL-10) is an anti-inflammatory molecule that has achieved interest as a therapeutic for neuropathic pain. In this work, the potential of plasmid DNA-encoding IL-10 (pDNA-IL-10) slowly released from biodegradable microparticles to provide long-term pain relief in an animal model of neuropathic pain was investigated. METHODS: PLGA microparticles encapsulating pDNA-IL-10 were developed and assessed both in vitro and in vivo. RESULTS: In vitro, pDNA containing microparticles activated macrophages, enhanced the production of nitric oxide, and increased the production of IL-10 protein relative to levels achieved with unencapsulated pDNA-IL-10. In vivo, intrathecally administered microparticles embedded in meningeal tissue, induced phagocytic cell recruitment to the cerebrospinal fluid, and relieved neuropathic pain for greater than 74 days following a single intrathecal administration, a feat not achieved with unencapsulated pDNA. Therapeutic effects of microparticle-delivered pDNA-IL-10 were blocked in the presence of IL-10-neutralizing antibody, and elevated levels of plasmid-derived IL-10 were detected in tissues for a prolonged time period post-injection (>28 days), demonstrating that therapeutic effects are dependent on IL-10 protein production. CONCLUSIONS: These studies demonstrate that microparticle encapsulation significantly enhances the potency of intrathecally administered pDNA, which may be extended to treat other disorders that require intrathecal gene therapy.

Neurotrophins in the cerebrospinal fluid of patient cohorts with neuropathic pain, nociceptive pain, or normal pressure hydrocephalus.

OBJECTIVE: The pathophysiology of neuropathic pain is still poorly understood. Studies in experimental animals showed that neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and nerve growth factor (NGF) might be involved in the pathophysiology of neuropathic pain. On the basis of these findings it is conceivable that neurotrophic factors also play a role in pain processing in man. Thus far, it remains unknown whether neurotrophic factors are altered in the cerebrospinal fluid (CSF) of patients with different pain syndromes. Here, we analyzed the concentrations of neurotrophic factors in the CSF of patients with chronic neuropathic pain in comparison to controls with nociceptive pain or hydrocephalus. METHODS: The concentrations of GDNF, BDNF, CNTF, and NGF were analyzed in the lumbar CSF of 10 patients with chronic neuropathic pain, in 20 patients with lumbar back pain undergoing myelography, and in 10 patients with normal pressure hydrocephalus, by using enzymes-linked immunosorbent assay techniques. RESULTS: The CSF concentrations of CNTF, BDNF, and NGF did not differ between the 3 patient cohorts. For GDNF a trend toward lower concentrations in neuropathic pain versus nociceptive back pain (P=0.17) was found. DISCUSSION: We did not detect any difference between patients with neuropathic versus nociceptive pain and nonpainful controls for spinal CNTF, BDNF, and NGF levels. Lower GDNF concentrations found in neuropathic pain patients might be associated with increased receptor expression. Possible alterations of neurotrophic factors at spinal relays, however, might not be reflected adequately in changes of CSF concentrations.

On the spectrum of leprosy neuropathies: multifocal inflammatory neuropathy heralding leprosy relapse.

We report a 52 year-old woman with a past history of lepromatous leprosy (14 years prior to our first evaluation) who presented with progressive weakness and severe arm/leg pain. CSF analysis revealed elevated protein level with normal cell count. Skin and sural nerve biopsy showed no bacilli. Immunomodulatory treatment led to major improvement on clinical, CSF and electrodiagnostic grounds, but after one year of treatment, skin test revealed leprosy relapse. To our knowledge, this is the first report of a multifocal inflammatory neuropathy heralding leprosy relapse. Extended neurological work-up may be important in unexplained neuropathy progression after leprosy treatment.

Changes in immune and glial markers in the CSF of patients with Complex Regional Pain Syndrome.

Complex Regional Pain Syndrome is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. The pain in CRPS is continuous, it worsens over time, and it is usually disproportionate to the severity and duration of the inciting event. This study compares cerebrospinal fluid (CSF) levels of pro- and anti-inflammatory cytokines, chemokines and several biochemical factors (glial fibrillary acidic protein (GFAP), the nitric oxide metabolites (nitrate plus nitrite), the excitatory amino acid neurotransmitter glutamate, calcium, total protein and glucose) in patients afflicted with CRPS to levels found in patients suffering with other non-painful or painful conditions. The aim of the study is to determine the degree of involvement of glial cells and immune system mediators in the pathophysiology of CRPS. There was no elevation or reduction of a CSF marker that was specific for CRPS patients. However, there were several patterns of markers that could be helpful in both elucidating the mechanisms involved in the disease process and supporting the diagnosis of CRPS. The most common pattern was found in 50% (11 out of 22) of the CRPS patients and consisted of; elevated IL-6, low levels of IL-4 or IL-10, increased GFAP or MCP1 and increases in at least two of the following markers NO metabolites, calcium or glutamate. The results from this and other similar studies may aid in elucidating the mechanisms involved in the pathophysiology of CRPS. A better understanding of these mechanisms may lead to novel treatments for this very severe, life-altering illness.

Compartmentalization and evolution of feline immunodeficiency virus between the central nervous system and periphery following intracerebroventricular or systemic inoculation.

The emergence of distinct neuropathogenic strains resulting from the adaptation and the unique evolution of human immunodeficiency virus (HIV) in the brain may contribute to the development of HIV-induced neurological diseases. In this study, the authors tracked early changes in virus evolution and compartmentalization between peripheral tissues and the central nervous system (CNS) after intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) inoculation of animals with cell-free feline immunodeficiency virus (FIV). Using the FIV-NCSU1 envelope V3-V4 heteroduplex tracking assay (HTA), the authors observed a rapid compartmentalization of envelope variants between the CNS and periphery. Animals receiving the i.c.v. inoculation showed two peaks of viral RNA in the cerebrospinal fluid (CSF) with very different HTA patterns. Compared to the initial viral peak in CSF, the second peak showed an increased compartmentalization from plasma, reduced viral diversity, and more divergence from the proviral DNA in peripheral blood mononuclear cells (PBMCs) and the choroid plexus. In contrast, changes in plasma over the same time period were small. Different animals harbored different FIV DNA genotypes with varied regional compartmentalization within the brain. These results demonstrated that the virus within the CNS experienced a relatively independent but variable evolution from the periphery. Initial penetration of virus into the CSF facilitated the development of brain-specific reservoirs and viral diversification within the CNS.

Identification of potential CSF biomarkers in ALS.

BACKGROUND: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis. OBJECTIVE: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects. METHODS: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry-directed peptide sequencing. RESULTS: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF. CONCLUSION: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.

An ELISA for glial fibrillary acidic protein.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein of the astrocyte, and body fluid levels of GFAP are an important tool for estimating astrogliosis and astrocytic activation in vivo. This paper presents a new sandwich ELISA allowing quantification of GFAP(SMI26) from the cerebrospinal fluid (CSF). The sensitivity of the GFAP(SMI26) ELISA is 5 pg/ml with a recovery of 94% and a mean within- and between-batch precision of 6% and 10%, respectively. The upper reference value for CSF GFAP(SMI26) levels (9 pg/ml) was defined as the 95% cumulative frequency from 315 CSF samples. Based on this cut-off, a significantly higher proportion of patients with subarachnoid hemorrhage (100%), traumatic brain injury (100%), dementia (76%) and normal pressure hydrocephalus (85%) had pathologically elevated CSF GFAP(SMI26) levels compared to patients with peripheral nervous system disorders (0%). In a critical review of the literature, we compare the analytical and clinical sensitivity of previous GFAP ELISA methods with particular reference to patients with dementia.

Nervous system lymphoid infiltration in Waldenström's macroglobulinemia. A case report.

Neurological complications may occur in the course of Waldenström's macroglobulinemia (Wm). These complications affect both the central and peripheral nervous system. Pathogenesis is debated and several mechanisms have been suggested. Direct malignant lymphoid infiltration (MLI) is very rare and has only been reported in a few cases. Case report. A 67-year-old woman suffered from Wm for 10 years before she presented neurological complications of the disease. She did not receive any specific treatment for Wm owing to a lack of symptoms. The neurological complications consisted of peripheral demyelinating polyneuropathy and MLI of the nervous system. This infiltration was located in the lower perimedullary and cauda equina roots regions, with possible centromedullary involvement. Indirect demonstration of MLI was achieved through non-invasive tests including magnetic resonance imaging and detailed cerebrospinal fluid examination. General and intrathecal chemotherapy led to clinical, biological and radiological improvement over a four-year period.