CSF Cell Count Research Articles

Devastating epileptic encephalopathy in school-aged children (DESC): A pseudo encephalitis

Purpose To describe the characteristics of a previously overlooked devastating epileptic encephalopathy that presents as intractable bilateral perisylvian epilepsy starting with prolonged status epilepticus (SE) in normally developing school-aged children. Methods Retrospective study over 7 years of all normally developing children admitted in our institution for a prolonged SE following non-specific febrile illness with at least one seizure recorded on EEG. Results Fourteen children were included at a median age of 7.5 years (4–11) (median follow-up of 4 years (1–7)). Intractable SE lasted 4–60 days (median 30). CSF cell count was normal in five cases and moderately increased in the others. During SE, seizures were recorded in 11 patients and involved temporal lobes in 7; the other 4 patients exhibited perisylvian clinical features with secondary generalization. Intractable epilepsy followed SE in all cases without any latent period. Persisting seizures were recorded in 10 patients and involved temporo-perisylvian regions in 8, frontal regions in 2; 3 others had perisylvian ictal semiology. Spiking was bilateral in 10 cases. MRI showed bilateral hippocampal hypersignal and/or atrophy in 10 cases (extended to the neocortex in 3). All children had major cognitive sequelae. When feasible (six patients), detailed neuropsychology suggested fronto-temporal impairment. Conclusions Among so called grey matter encephalitis patients, we identified a recognizable pattern we propose to call Devastating Epileptic encephalopathy in School-age Children (DESC) that begins with prolonged SE triggered by fever of unknown cause, and persists as intractable perisylvian epilepsy with severe cognitive deterioration.

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.

Tuberculous meningitis in BCG vaccinated and unvaccinated children

Background: A modified clinical presentation of tuberculous meningitis (TBM) in children vaccinated with BCG has been described in the literature. However, most reports are old and not based on actual...

Expansion of antibody reactivity in the cerebrospinal fluid of multiple sclerosis patients – follow-up and clinical implications

BackgroundAn intrathecal polyspecific antibody response is a well known finding in multiple sclerosis. However, little is known about the evolution of intrathecal antibodies over time and their impact on the disease progress. Therefore, we focused in this study on the intrathecal polyspecific antibody response in multiple sclerosis.MethodsHere we present a follow-up study of 70 patients with multiple sclerosis over 1 to 106 months. Serum and cerebrospinal fluid sample pairs were obtained from 1 to 5 consecutive lumbar punctures. CSF cell count, the IgG index, local IgG synthesis, oligoclonal bands and the antibody index for measles, rubella or varicella zoster were calculated. Results were analysed with regard to clinical characteristics of the patients.ResultsOnce an intrathecal antibody response was established, it persisted. De novo antibody response against measles virus developed in 7% of the patients between the first and the second spinal tap. In two of seven patients where 5 consecutive CSF samples were available, the intrathecal antibody response expanded from one to three antigens. Furthermore, an intrathecal measles antibody production was associated with a rapid progression of the disease.ConclusionThese data stress the importance of activated B cells for the disease process and the clinical outcome in multiple sclerosis.

Personal History

The last thing I wanted to do that Friday was an LP in the MICU. It had been a long, difficult day in the office, and I was tired from the previous night on call. I had already consulted on the patient and knew that, regardless of how the CSF cell count and chemistry came out, the outcome of her illness was not likely to be good. I wasn’t eager to do the procedure, but my personal rule was to do it whenever I started to argue with myself about why I shouldn’t. As I walked from my office over to the hospital, the shadows were long in the canyons on the front range of the Santa Catalina Mountains, and a gibbous Moon was well up in the southeast. It was going to be a nice night—for somebody. I wasn’t looking forward to another late evening at work. I referred to MICU as the place with “so much work and so little hope.” Patients in MICU were not immediately post-operative from lifesaving cardiac, neurologic, or trauma surgery. They hadn’t been saved in the cardiac catheterization laboratory by having stents placed into multiple vessels or by being injected with antithrombolytic drugs. The nurses in the other intensive care units mirrored their work: SICU nurses were confident, aggressive, with a “let’s do it” attitude. Many were men, and most of the hospital’s basketball team came from SICU staff. CICU nurses, nearly all women, were superb at understanding rhythm strips, conduction physiology, and cardiac drugs. MICU nurses were different—a tightly knit group, they were quietly competent. Despite their knowledge, however, they never tried to show me up, even when they easily could have. Maybe that is why I liked them so much. The unit often received end-stage patients from the other two units …

B- and t-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes

Although an autoimmune etiology is likely, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood, and no immunologic abnormalities have correlated with neurologic severity. In addition, conventional immunotherapies often do not prevent relapse or permanent sequelae. In children, neuroblastoma and viral infections are the most common cause. The aim of this study was to test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity. The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in 4-color fluorescence-activated cell sorting. Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gamma/delta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities. The authors conclude that CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.—Valerie Biousse

B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes.

Although many lines of evidence suggest an autoimmune etiology, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood and no immunologic abnormalities have correlated with neurologic severity. Conventional immunotherapies often do not prevent relapse or permanent sequelae. To test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity. The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in four-color fluorescence-activated cell sorting. Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gammadelta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities. CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.

Single-cell PCR analysis of the immunoglobulin heavy chain CDR3 region for the diagnosis of leptomeningeal involvement of B-cell malignancies

Background: The diagnosis of leptomeningeal B-cell malignancies is based on identification of malignant B-cells in the CSF. Molecular analysis of B-cell clonality in CSF samples via amplification and size determination of the highly diverse CDR3-IgH region is a useful approach to distinguish neoplastic from reactive B-cell responses within the CSF and supplements standard diagnostic procedures such as cytology, immuncytochemistry, and flow cytometry. However, the molecular analysis of B-cells using whole CSF specimens is limited if leucemic or lymphomatous spread to the leptomeninges is accompanied by a reactive B-cell response and/or if the total CSF cell count is very low. Here, we applied this technique to assess the clonality of individual cells isolated from standard CSF cytospins using single cell PCR.

HLA-DPB1*0501-associated opticospinal multiple sclerosis: clinical, neuroimaging and immunogenetic studies.

In order to clarify the relationship between the clinical phenotype and the human leucocyte antigen (HLA) in multiple sclerosis in Asians, 93 Japanese patients with clinically definite multiple sclerosis underwent clinical MRI and HLA-DPB1 gene typing studies. According to a neurological examination, 29 patients were classified as opticospinal multiple sclerosis, 17 as spinal multiple sclerosis and 47 as Western type multiple sclerosis showing the involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem. The opticospinal multiple sclerosis showed a significantly higher age of onset, higher expanded disability status scale scores and higher CSF cell counts and protein content than the Western type multiple sclerosis. On brain and spinal cord MRI, the opticospinal multiple sclerosis showed a significantly lower number of brain lesions, but a higher frequency of gadolinium-enhancement of the optic nerve and a higher frequency of spinal cord atrophy than in Western type multiple sclerosis. The frequency of the HLA-DPB1*0501 allele was found to be significantly greater in opticospinal multiple sclerosis (93%) than in healthy controls (63%, corrected P value = 0.0091 and relative risk = 7.9), but not in Western type multiple sclerosis (66%) or spinal multiple sclerosis (82%). The marked differences in the clinical and MRI findings as well as in the immunogenetic backgrounds between the opticospinal multiple sclerosis and Western-type multiple sclerosis together suggest that HLA-DPB1*0501-associated opticospinal multiple sclerosis is a distinct subtype of multiple sclerosis.

Cerebrospinal fluid abnormalities in a phase III trial of Avonex® (IFNβ-1a) for relapsing multiple sclerosis

Background and objective: This report provides results of CSF analyses done in a subset of relapsing remitting MS patients participating in a placebo-controlled, double-blind, phase III clinical trial of IFNβ-Studies supported by the National Multiple Sclerosis Society (grants RG2019, RG2827),a (Avonex®, Biogen). The clinical trial demonstrated that IFNβ-1a treatment resulted in significantly reduced disability progression, annual relapse rate, and new brain lesions visualized by cranial magnetic resonance imaging. The objectives of the current study were to determine: (a) whether CSF abnormalities in MS patients correlated with disease or MRI characteristics, and (b) effects of IFNβ-1a therapy on these CSF abnormalities. Methods: CSF was analyzed from 262 (87%) of the 301 study subjects at entry into the clinical trial, and a second CSF sample was analyzed from 137 of these 262 subjects after 2 years of therapy. CSF cell counts, oligoclonal bands (OCB), IgG index, and free kappa light chains were measured using standard assays. Baseline CSF results were compared with demographic, disease, and MRI parameters. Differences in on-study relapse rate, gadolinium enhancement, and EDSS change according to baseline CSF status was used to determine the predictive value of CSF for subsequent clinical and MRI disease activity. Change in CSF parameters after 104 weeks were used to determine the effects of treatment. Results: (1) At study baseline, 37% of the subjects had abnormal CSF WBC counts, 61% had abnormal levels of CSF free kappa light chains, 84% had abnormal IgG index values, and 90% were positive for OCB. (2) Baseline IgG index, kappa light chains, and OCB showed weakly positive, statistically significant correlations with Gd-enhanced lesion volume and T2 lesion volume. WBC showed a statistically significant correlation with Gd-enhancing lesion volume but was uncorrelated with T2 lesion volume. (3) There was an associated between baseline CSF WBC counts and on-study clinical and MRI disease activity in placebo recipients. (4) IFNβ-1a treatment resulted in significantly reduced CSF WBC counts, but there was no treatment-related change in CSF IgG index, kappa light chains, or OCB, which remained relatively stable over time in both patient groups. Conclusions: The current study documents significant reductions in CSF WBC counts in patients treated with IFNβ-1a for 104 weeks. This finding is considered relevant to the therapeutic response, since CSF WBC counts were found to be positively correlated with subsequent clinical and MRI disease activity in placebo-treated relapsing MS patients.

Increased release of interleukin-12p40 in MS: association with intracerebral inflammation.

The p40 subunit of interleukin (IL)-12 was recently demonstrated in active lesions in MS. We tested whether the p40 subunit of IL-12 can also be detected in CSF and serum of patients with this disease and, if so, whether release is associated with inflammatory disease activity. This study demonstrates an increased (up to 1,000-fold) compartmentalized release of the p40 subunit but not of the heterodimer p70 in MS. Release of IL-12p40 correlated with classic markers of CNS inflammation (CSF cell counts, immunoglobulin G index) and was significantly increased in patients with gadolinium-enhancing plaques on MRI. Moreover, release of IL-12p40 was associated with CSF levels of myelin basic protein as a measure of myelin degradation. These results suggest a role of IL-12p40 in the pathophysiology of MS.

Effects of iatrogenic blood contamination on results of cerebrospinal fluid analysis in clinically normal dogs and dogs with neurologic disease

Objective To examine the effects that iatrogenic blood contamination would have on total protein concentration and nucleated cell count in CSF from clinically normal dogs and dogs with neurologic disease. Design Case-control study. Study Population 53 dogs confirmed to have neurologic disease and 21 clinically normal dogs. Procedure CSF samples were obtained from the cerebellomedullary cistern or the lumbar portion of the subarachnoid space. Red blood and nucleated cell counts were determined, and protein concentration was measured. Results RBC count was not significantly correlated with nucleated cell count or protein concentration in clinically normal dogs or dogs with neurologic disease. Clinical Implications High CSF nucleated cell counts and protein concentrations are indicative of neurologic disease, even if samples contain moderate amounts of blood contamination. (J Am Vet Med Assoc 1997;211:866–867)

Clinical and laboratory characteristics of bacterial meningitis in children

Data from the records of 528 children under 15 years old with diagnosis of acute bacterial meningitis, admitted at the Hospital Couto Maia between 1990 and 1992 were analyzed. Bacterial meningitis was more frequent in children under the age of 1 year (37.8%). The most common etiologic agent was H. influenzae (42.2%). The global lethality was 20.9%. Individual predictors of poor outcome were: absence of the "classic triad", CSF cell count under 1000/mm3, age under 2 years, presence of seizures, depressed sensorium, and S. pneumoniae as causal agent.

Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis

We describe the specificity and sensitivity of measuring a combination of basic CSF variables and Borrelia burgdorferi (Bb)-specific IgG and IgM antibody index (AI) values for the diagnosis of early neuroborreliosis. Basic CSF variables included total cell count, quantitation of activated B cells (IgG, IgA, and IgM classes), CSF/serum quotient diagrams for IgG, IgA, and IgM (to quantitate brain-derived immunoglobulin fractions in CSF), and CSF/serum albumin ratio as a measure of blood-CSF barrier function. The Bb-specific component of immunoglobulins in CSF and serum was quantitated by ELISA. Results are based on data from CSF and serum of 24 patients with definite neuroborreliosis, 45 patients with other neurologic diseases, and 28 control individuals. Combined evidence of an elevated CSF cell count, IgM-class dominance in both the cellular and intrathecal humoral immune response, and blood-CSF barrier dysfunction yielded 70% diagnostic sensitivity and 98% diagnostic specificity for detection of neuroborreliosis. Intrathecal production of Bb-specific IgM, evaluated as Bb-specific IgM antibody index (Bb-IgM-AI; pathologic value > 1.4) showed 79% diagnostic sensitivity and 96% diagnostic specificity. Correspondingly, elevated Bb-specific IgG antibody index (Bb-IgG-AI; pathologic value > 1.4) displayed 63% diagnostic sensitivity and 89% diagnostic specificity. Combined analysis of Bb-specific AI values and basic CSF variables gave the highest sensitivity (80%) and specificity (98%). Analysis of CSF variables over a disease course showed that acute versus past disease could be discriminated by a combination of basic CSF variables and Bb-specific AI.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone in the treatment of meningeal leukemia

To determine if dexamethasone has a role in the treatment of meningeal leukemia, 8 consecutive patients with acute lymphoblastic and signs or symptoms of CNS were included in the study. After the confirmation of leukemic blast cells on cerebrospinal fluid, they received intrathecal and IV dexamethasone; 3 days later the patients received "triple" intrathecal chemotherapy with dexamethasone, methotrexate and cytarabine, and the spinal fluid was studied again. All patients had good clinical response and 7 out of the 8 patients showed reduction on the CSF cell count after the use of dexamethasone alone. The results suggest that dexamethasone is a lymphocytic agent that could play a more active role in the prevention and therapy of meningeal leukemia and should be preferred over hydrocortisone in the so called "triple" intrathecal chemotherapy for the prevention and treatment of CNS leukemia.

Akute intermittierende hypothalamische Hypothermie bei Herpes-Simplex-Enzephalitis

Acute-onset hypothalamic hypothermia is a rare and usually prefinal symptom of severe damage of midline structures of the brain and accompanied by other vegetative and endocrine dysfunctions. We describe a 67-year-old female who developed an acute intermittent hypothalamic hypothermia in the course of a herpes simplex encephalitis involving the left temporal lobe and periventricular structures. After the clinical status and CSF cell count began to improve, the patient showed the vegetative and behavioural signs of active heat dissipation. Within 9 hours the rectal temperature fell from 37.5 to 32.7 °C. The clinical picture and the rapidity of cooling point to intermittent downregulation of the central hypothalamic thermostat. The patient showed rapid response to passive rewarming and intravenous application of catecholamines. Thermoregulation remained normal thereafter and there were no signs of endocrine disorders. The reported case demonstrates that acute hypothalamic hypothermia can occur in the course of Herpes simplex encephalitis. It can be an intermittent, isolated sign of hypothalamic involvement and full restitution of hypothalamic function is possible.

Blasts in CSF with a normal cell count do not justify alteration of therapy for acute lymphoblastic leukemia in remission: a Childrens Cancer Group study.

The Childrens Cancer Group (CCG) requires both a CSF WBC count of more than five cells per microliter and demonstration of blast cells in the cytocentrifuge specimen to support a diagnosis of CNS relapse. We reviewed the CSF examinations of patients with intermediate-risk acute lymphoblastic leukemia (ALL) to determine the clinical significance of blast cells reported in the cytocentrifuge when the total CSF cell count was normal. Children treated on CCG-105 for ALL had CSF examinations every 12 weeks during maintenance therapy. The outcome of children who had a positive CSF cytocentrifuge examination without an elevated CSF WBC count was compared with that of children who did not have any CSF blast cells observed. Sixty-four patients had 81 CSF examinations with blast cells and a normal cell count. By Cox life-table regression analysis, patients with blasts had a different disease-free survival (DFS) distribution, with relapses tending to occur earlier (P = .008). However, the DFS for these patients was 63% +/- 9.6% at 5 years from the time of the abnormal cytocentrifuge result as compared with 69% +/- 1.5% for 1,490 children who did not have blasts in their CSF. This difference is not significant. Blast cells were infrequently identified in cytocentrifuge preparations of CSF when the cell count was normal. The majority of patients in whom such an event was observed have not experienced a subsequent relapse as measured by life-table analysis at 5 years. The data do not justify changing or augmenting therapy based on cytocentrifuge results alone.

A characteristic ganglioside antibody pattern in the CSF of patients with amyotrophic lateral sclerosis.

Paired cerebrospinal fluid and serum samples of patients with amyotrophic lateral sclerosis (n = 35) revealed no consistent abnormalities of CSF cell count, CSF albumin, CSF IgG, CSF IgM, IgG or IgM index, or oligoclonal immunoglobulin band formation in the CSF. Determination of IgG and IgM CSF and serum antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b, and GT1b showed a characteristic pattern which allowed the differentiation of amyotrophic lateral sclerosis from controls and from patients with other neurological disorders including multiple sclerosis. Specifically, patients with the disease had elevated CSF IgM antibodies to all gangliosides except AGM1. The lack of correlation between the CSF findings and corresponding serum antibodies suggests a chronic, compartmental, intrathecal immune response of low activity in amyotrophic lateral sclerosis. Whether this immune response is primary and of pathogenetic significance, or an epiphenomenon of neuronal degeneration, remains to be investigated.

Evaluation of Febrile Infant

In Reply.— We appreciate Dr Levin's contribution to our analysis for febrile infants and agree that including the imperfect sensitivity of the CSF cell count in identifying meningitis improves the model's completeness. However, taken in perspective, the addition does not substantially alter our findings. In the original analysis, All Sepsis Tests + IV Antibiotics prevented 78% of sequelae, and All Sepsis Tests + IM Ceftriaxone prevented 76% of sequelae.1 Rodewald's study2 reported that a CSF cell count ≥6 had a sensitivity of 98.4% in identifying bacterial meningitis.

Determination of the IgG index for the detection of intrathecal immunoglobulin synthesis in dogs using an elisa

The IgG index is a calculated quotient using IgG and albumin contents of cerebrospinal fluid ( csf) and serum to detect intrathecal IgG synthesis, which is important in the diagnosis of inflammatory infectious diseases of the central nervous system ( cns). An elisa to measure IgG and albumin contents in blood and csf was developed to determine the IgG index. Twenty-three normal dogs and 98 dogs with various neurological diseases were examined. In most dogs with infectious inflammatory diseases, with the exception of the acute form of nervous canine distemper, there was an elevation of the IgG index. Tumours of the cns had an IgG index within the normal range. An elevation was found in lymphoid tumours or meningiomas with secondary cellular infiltration. Degenerative diseases, spinal cord compression and ischaemic myelopathy due to fibrocartilagenous embolism had normal or only slightly elevated IgG indices. In seven cases with inflammatory lesions there was no obvious csf pleocytosis but the IgG index was elevated. In 17 cases in which infectious inflammatory disease was suspected, based on elevated csf cell counts, inflammation could be excluded after determination of the IgG index. The reproducibility of the technique was found to be good and, considering the limited amount of time, expense and effort required, the determination of the IgG index in dogs is a useful extension of the conventional csf examination.