Elevated Cerebrospinal Fluid Protein Concentration Research Articles

Prognostic and relapsing factors of primary autoimmune cerebellar ataxia: a prospective cohort study.

The objective of this study was to investigate the factors influencing relapse and prognosis in patients with primary autoimmune cerebellar ataxia (PACA), an area previously not well understood. This prospective cohort study included patients who satisfied the modified diagnostic criteria of PACA. A modified Rankin scale score ≤ 2 at the last follow-up was defined as a favorable prognosis. Cox and Logistic regression were utilized to identify relapsing and prognostic factors, respectively. A total of 68 patients were included and 35.3% were male. The median onset age was 42.9years (IQR 22.1-54.0). Neuronal autoantibodies were detected in 33 (50.8%) patients. Of the 65 patients who received first-line immunotherapy, 55 (84.6%) were responsive and 10 (15.4%) were not. Responsiveness to first-line immunotherapy emerged as an independent factor for favorable prognosis (HR 16.762; 95% CI 2.877-97.655; p = 0.002), as did the absence of peripheral neuropathy/radiculopathy (HR 14.286; 95% CI 2.41-83.333; p = 0.003). Relapses occurred in 19 (27.9%) patients. Onset age ≤ 43years (HR 5.245; 95% CI 1.499-18.35; p = 0.009), presence of peripheral neuropathy/radiculopathy (HR 4.280; 95% CI 1.622-11.298; p = 0.003) and elevated cerebrospinal fluid (CSF) protein concentration (HR 3.443; 95% CI 1.083-10.951; p = 0.036) were statistically significant relapsing factors. This study identified younger onset age, presence of peripheral neuropathy/radiculopathy and elevated CSF protein concentration as relapsing factors, and absence of peripheral neuropathy/radiculopathy and responsiveness to first-line immunotherapy as independent factors for favorable prognosis in PACA patients. These findings may guide individualized treatment strategies and potentially improve patient outcomes.

LGG-43. Reduction in the cerebrospinal fluid protein level after bevacizumab treatment in patients with optic pathway low-grade gliomas

Cases Presentations: Case 1: A 1-year-old boy with suprasellar pilocytic astrocytoma with previous history of shunting disfunction, treatment according vinblastine protocol due to anaphylactic reaction with carboplatin presented with ascites and necessity of ventricular-atrial shunt. Due to high protein cerebrospinal fluid (CSF) level (551mg/dl) he was submitted to external ventricular drainage and bevacizumab 10mg/kg was associated to his oncology treatment. After three cycles of bevacizumab, the patients’ CSF protein levels decreased dramatically 178 mg/dL, allowing the shunt procedure without complications and shorter hospital stay. Case 2: A ten-year-old boy with suprasellar pilocytic astrocytoma treated with three lines of chemotherapy showed tumor progression one year after the end of carboplatin-vincristine protocol and shunting disfunction. External ventricular drainage was performed, and the CSF showed 590mg/dl protein level. He was treated with vinblastine 6mg/m2 weekly and bevacizumab 10mg/kg each 14 days. After two cycles of bevacizumab, the protein level was 191mg/dl allowing another V-P shunt procedure. Discussion: Optic pathway gliomas frequently cause elevated cerebrospinal fluid protein concentrations leading to shunts occlusions and failures, necessity of external ventricular drainage and longtime hospitalization, implicating risk of serious infections. Bevacizumab is a monoclonal antibody with immunomodulatory and anti-vascular endothelial growth factor (VEGF) activities that has been used in combination with other chemotherapeutic agents such as irinotecan and vinblastine to treat low-grade gliomas and has been reported to decrease the CSF protein concentration.Final Comments: Bevacizumab treatment in patients with gliomas and high CSF protein levels seems effective in decreasing protein leakage from the vessels to the ventricles, thereby improving the scope for successful shunt placement.

Age-specific reference values for cerebrospinal fluid protein concentrations in children in southern China.

Cerebrospinal fluid (CSF) protein values decline over the first few months of life as the infant's blood-CSF barrier matures. However, published studies have not reported CSF protein reference values of Chinese infants and differ in the reported rate, timing, and magnitude of this decline. The objective of this study was to determine reference intervals for CSF protein using available data of children in southern China. This retrospective study included infants who had a lumbar puncture (LP) performed in the Department of Pediatrics of Southern Medical University Affiliated Maternal and Child Health Hospital of Foshan of an urban tertiary care children's hospital between January 1, 2008 and May 31, 2018. Infants with conditions suspected or known to cause elevated CSF protein concentrations were excluded. Of 3712 infants undergoing LP, 1043 (28.1%) met inclusion criteria. Results showed that there is an age-related decline in CSF protein concentration. The median CSF protein value was 62 mg/dL [interquartile range (IQR): 47-81 mg/dL] in infants aged 0 to 56 days (group 1). The 95th percentile values were 116 mg/dL for infants 0 to 28 days and 80 mg/dL for infants 29 to 56 days. The 95th percentile values by age category were as follows: ages 0 to 14 days, 117 mg/dL; ages 15 to 28 days, 107 mg/dL; ages 29 to 42 days, 96 mg/dL; and ages 43 to 56 days, 74 mg/dL. The median CSF protein value was 21 mg/dL (IQR: 16-31 mg/dL) in infants aged 2 months to <3 years (group 2). The 95th percentile values were 57 mg/dL for infants 2 to <6 months and 34 mg/dL for infants 6 to ≤24 months. The 95th percentile values by age category were as follows: ages 2 to <3 months, 66 mg/dL; ages 3 to <4 months, 52 mg/dL; ages 4 to <5 months, 53 mg/dL; and ages 5 to <6 months, 42 mg/dL. We quantify the age-related decline in CSF protein concentrations among infants 2 years of age and younger and provide age-specific reference values. The values reported here can be used to interpret the results of LP in infants ≤2 years of age.

The Influence of Blood Contamination on Cerebrospinal Fluid Diagnostics.

Background: Blood contamination due to traumatic lumbar puncture presents a diagnostic pitfall in cerebrospinal fluid (CSF) analysis. It is controversially discussed if phagocytosis of erythrocytes which can be found in the CSF after subarachnoid hemorrhage can also develop in vitro in the presence of artificial blood contamination. Furthermore, there is no consensus about the acceptable amount of artificial blood contamination on CSF protein results.Methods: Two measurement series were performed in order to investigate the role of artificial blood contamination on the possible development of erythrophages and siderophages in the CSF: (1) blood contamination was simulated in vitro by adding blood into the CSF. (2) CSF was investigated when blood contamination occurred during a traumatic lumbar puncture. In both types of experiments, CSF including blood was incubated for 24 h and for 72 h at room temperature or at 4°C. In the third measurement series, the effects of artificial blood contamination on CSF protein results were investigated. Blood contamination was simulated in vitro by adding different amounts of blood ending up with five different samples containing erythrocyte counts of 2,500, 5,000, 7,500, 10,000, and 20,000 per μl CSF.Results: Cytological examination revealed no evidence of erythrophages or siderophages in vitro. In contrast, already a low blood contamination (2,500 erythrocytes/μl CSF) led to false pathological results of total protein and albumin. Along with increasing amounts of blood, the frequency of false pathological protein results increased. A blood contamination of 5,000 erythrocytes/μl CSF resulted in a false positive intrathecal IgM production in nearly every fifth patient. In contrast, blood contamination with 5,000 erythrocytes/μl CSF was the acceptable amount of blood which did not lead to a false positive intrathecal synthesis of IgG and IgA.Conclusion: Erythrophages and siderophages do not develop in vitro. An extensive diagnostic work up for the source of blood in the CSF should be performed when erythrophages or siderophages are found in the CSF. The contamination of CSF with increasing volume of blood resulted in falsely elevated CSF protein concentrations. Hence, the amount of blood contamination has to be taken into consideration when interpreting CSF protein measurement results.

Clinical, Laboratory, Diagnostic, and Histopathologic Features of Diethylene Glycol Poisoning—Panama, 2006

Diethylene glycol is a toxic industrial solvent responsible for more than 13 mass poisonings since 1937. Little is known about the clinical spectrum, progression, and neurotoxic potential of diethylene glycol-associated disease because of its high mortality and the absence of detailed information in published mass poisoning reports. This incident includes the largest proportion of cases with neurotoxic signs and symptoms. We characterize the features of a diethylene glycol mass poisoning resulting from a contaminated cough syrup distributed in Panama during2006. This was a retrospective chart review and descriptive analysis in a tertiary level, urban health care facility. Acase was a person admitted to the Social Security Metropolitan Hospital in Panama City between June 1 and October 22, 2006, with unexplained acute kidney injury and a serum creatinine level of greater than or equal to 2 mg/dL, or unexplained chronic renal failure exacerbation (>2-fold increase in baseline serum creatinine level) and history of implicated cough syrup exposure. Main outcomes and measures were demographic, clinical, laboratory, diagnostic, histopathologic, and mortality data with descriptive statistics. Forty-six patients met inclusion criteria. Twenty-four (52%) were female patients; median age was 67 years (range 25 to 91 years). Patients were admitted with acute kidney injury or a chronic renal failure exacerbation (median serum creatinine level 10.0 mg/dL) a median of 5 days after symptom onset. Forty patients (87%; 95% confidence interval [CI] 74% to 95%) had neurologic signs, including limb (n=31; 77%; 95% CI 62% to 89%) or facial motor weakness (n=27; 68%; 95% CI 51% to 81%). Electrodiagnostics in 21 patients with objective weakness demonstrated a severe sensorimotor peripheral neuropathy (n=19; 90%; 95% CI 70% to 99%). In 14 patients without initial neurologic findings, elevated cerebrospinal fluid protein concentrations without pleocytosis were observed: almost all developed overt neurologic illness (n=13; 93%; 95% CI 66% to 100%). Despite use of intensive care and hemodialysis therapies, 27 (59%) died a median of 19 days (range 2 to 50 days) after presentation. A high proportion of patients with diethylene glycol poisoning developed progressive neurologic signs and symptoms in addition to acute kidney injury. Facial or limb weakness with unexplained acute kidney injury should prompt clinicians to consider diethylene glycol poisoning. Elevated cerebrospinal fluid protein concentrations without pleocytosis among diethylene glycol-exposed persons with acute kidney injury may be a predictor for progressive neurologic illness.

Cerebrospinal fluid abnormalities in HIV-negative patients with secondary and early latent syphilis and serum VDRL ≥ 1:32

Background:Syphilis is caused by a spirochete Treponema pallidum. Invasion of the central nervous system (CNS) by T. pallidum may appear early during the course of disease. The diagnosis of confirmed neurosyphilis is based on the reactive Venereal Disease Research Laboratory (VDRL) in cerebrospinal fluid (CSF). Recent studies indicated that serum RPR ≥ 1:32 are associated with higher risk of reactivity of CSF VDRL.Aims:The main aim of the current study was to assess cerebrospinal fluid serological and biochemical abnormalities in HIV negative subjects with secondary and early latent syphilis and serum VDRL ≥ 1:32.Materials and Methods:Clinical and laboratory data of 33 HIV-negative patients with secondary and early latent syphilis, with the serum VDRL titer ≥ 1:32, who underwent a lumbar puncture and were treated in Department of Dermatology at Jagiellonian University School of Medicine in Cracow, were collected.Results:Clinical examination revealed no symptoms of CNS involvement in all patients. 18% (n = 6) of patients met the criteria of confirmed neurosyphilis (reactive CSF-VDRL). In 14 (42%) patients CSF WBC count ≥ 5/ul was found, and in 13 (39%) subjects there was elevated CSF protein concentration (≥ 45 mg/dL). 10 patients had CSF WBC count ≥ 5/ul and/or elevated CSF protein concentration (≥ 45 mg/dL) but CSF-VDRL was not reactive.Conclusions:Indications for CSF examination in HIV-negative patients with early syphilis are the subject of discussion. It seems that all patients with syphilis and with CSF abnormalities (reactive serological tests, elevated CSF WBC count, elevated protein concentration) should be treated according to protocols for neurosyphilis. But there is a need for identification of biomarkes in order to identify a group of patients with syphilis, in whom risk of such abnormalities is high.

Elevated Cerebrospinal Fluid Neopterin Concentration Is Associated with Disease Severity in Acute Puumala Hantavirus Infection

Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is the most common hemorrhagic fever with renal syndrome (HFRS) in Europe. The infection activates immunological mechanisms that contribute to the pathogenesis and characteristics of the illness. In this study we measured cerebrospinal fluid (CSF) neopterin concentration from 23 acute-phase NE patients. We collected data on kidney function, markers of tissue permeability, haemodynamic properties, blood cell count, length of hospitalisation, inflammatory parameters, and ophthalmological properties. The neopterin levels were elevated (>5.8 nmol/L) in 22 (96%) NE-patients (mean 45.8 nmol/L); these were especially high in patients with intrathecal PUUV-IgM production (mean 58.2 nmol/L, P = 0.01) and those with elevated CSF protein concentrations (mean 63.6 nmol/L, P < 0.05). We also observed a correlation between the neopterin and high plasma creatinine value (r = 0.66, P = 0.001), low blood thrombocyte count (r = −0.42, P < 0.05), and markedly disturbed refractory properties of an eye (r = 0.47, P < 0.05). Length of hospitalisation correlated with the neopterin (r = 0.42, P < 0.05; male patients r = 0.69, P < 0.01). Patients with signs of tissue oedema and increased permeability also had high neopterin concentrations. These results reinforce the view that PUUV-HFRS is a general infection that affects the central nervous system and the blood-brain barrier.

Spontaneous intracranial hypotension syndrome may mimic aseptic meningitis

Spontaneous intracranial hypotension (SIH) is recognized with increasing frequency. A throbbing headache occurring or worsening in the upright position and improving after lying down, a so-called 'orthostatic headache', low cerebrospinal fluid (CSF) pressure, and diffuse pachymeningeal enhancement on brain magnetic resonance imaging (MRI) are the major features of the classic syndrome. These patients, who are admitted with fever, headache, and CSF findings revealing lymphocytic pleocytosis, elevated protein concentration, normal glucose levels, and negative culture results, are prone to be misdiagnosed with aseptic meningitis. The aims of this single-centre retrospective study were to determine the epidemiological, clinical, laboratory, and radiological features of patients initially evaluated as having aseptic meningitis but subsequently diagnosed with SIH, and to touch upon the key points of the differential diagnosis in daily infectious diseases practice. Patients referred to Cerrahpasa Medical School with a presumed diagnosis of aseptic meningitis or viral meningitis between 1 January 2006 and 1 January 2011 were reviewed. Epidemiological, clinical, laboratory, radiological, and follow-up data obtained from the hospital database were processed. Patients confirmed to have SIH syndrome were included for evaluation. Eleven cases of SIH syndrome were diagnosed during the study period (8 male and 3 female, median age 30 y, range 21-44 y). All had headache, hearing changes, and nausea. Vomiting (10/11) and posterior neck pain (9/11) were also frequent. Seven had fever and 5 had a stiff neck. Four cases had lymphocytic pleocytosis, 4 cases had elevated CSF protein concentrations (> 1.5 times the upper limit of normal), and 2 cases had slightly lower CSF glucose levels. Polymerase chain reaction (PCR) analyses of the CSF for Mycobacterium tuberculosis complex, herpes simplex viruses 1 and 2, and enteroviruses were negative in all cases. MRI of the 11 cases revealed signs of spontaneous CSF leaks with diffuse pachymeningeal gadolinium enhancement (11/11), sagging of the brain (9/11), enlargement of the pituitary (6/11), engorgement of the venous structures (5/11), and subdural fluid collections (2/11). CSF leaks were demonstrated by intrathecal magnetic resonance or computed tomography myelography at different levels along the thoracic spine (7/11), cervico-thoracic junction (2/11), and thoraco-lumbar junction (2/11). Autologous blood injection into the spinal epidural space ('blood patch') was performed for treatment. Strict bed rest followed, and all patients recovered fully within a week; no recurrence or complication was observed during the follow-up periods, which ranged from 6 months to 5 y. Findings of fever, headache, and meningeal irritation are generally accepted as the clinical features of meningitis. When CSF findings are not characteristically compatible with bacterial meningitis and particularly when the headache is orthostatic in nature, SIH should also be included in the differential diagnosis. MRI findings are characteristic and clearly contribute to the differential diagnosis between viral meningitis and SIH.

Age‐specific reference values for cerebrospinal fluid protein concentration in neonates and young infants

Cerebrospinal fluid (CSF) protein values decline over the first few months of life as the infant's blood-CSF barrier matures. However, published studies differ in the reported rate, timing, and magnitude of this decline. To quantify the age-related changes in CSF protein concentration and to determine accurate, age-specific reference values for neonates and young infants. This cross-sectional study included infants age 56 days or younger who had a lumbar puncture performed in the emergency department of an urban tertiary care children's hospital between January 1, 2005 and June 30, 2007. Infants with conditions associated with elevated CSF protein concentrations, including traumatic lumbar puncture and bacterial or viral meningitis, were excluded. Of 1064 infants undergoing lumbar puncture, 375 (35%) met inclusion criteria. The median CSF protein value was 58 mg/dL (interquartile range: 48-72 mg/dL). In linear regression, the CSF protein concentration decreased 6.8% (95% confidence interval [CI], 5.4%-8.1%; P < 0.001) with each 1 week increase in age. The 95th percentile values were 115 mg/dL for infants ≤28 days and 89 mg/dL for infants 29-56 days. The 95th percentile values by age category were as follows: ages 0-14 days, 132 mg/dL; ages 15-28 days, 100 mg/dL; ages 29-42 days, 89 mg/dL; and ages 43-56 days, 83 mg/dL. We quantify the age-related decline in CSF protein concentration among infants 56 days of age and younger and provide age-specific reference values. The values reported here represent the largest series to-date for this age group.

Hemorrhagic fever with renal syndrome in the Pomurje region of Slovenia – An 18-year survey

To determine the etiology of hemorrhagic fever with renal syndrome (HFRS) in the north-eastern part of Slovenia (Pomurje region) together with demographic, epidemiological and clinical data on 25 patients from this region who were diagnosed and treated at the General Hospital in Murska Sobota between 1986 and 2003. Medical records of patients with a discharge diagnosis of HFRS who were either hospitalized or referred to an infectiologist as outpatients were included in this retrospective study. Data on demographic characteristics, clinical manifestations and laboratory parameters were collected from the patients' records. In addition, all available follow-up records were examined and information on general health, blood pressure, basic blood and biochemical examination and urine analysis was collected. Infection with Puumala virus (PUUV) was indicated in 23 patients and Dobrava virus (DOBV) infection in two patients. The median age of patients was 39 years; 19 were male. The patients primarily had outdoor occupations. Most of the HFRS cases occurred between May and August. The most common findings were fever, vomiting, headache, myalgia, chills, cough, back and abdominal pain, and blurred vision. The most prominent laboratory abnormalities were elevated erythrocyte sedimentation rate and C-reactive protein concentration, thrombocytopenia, and leucocytosis with neutrophilia. The signs of renal dysfunction were observed in 24 of the 25 patients. Oliguric renal failure was seen in 13 of 23 (57%) PUUV-infected patients. Six of 23 (26%) patients infected with PUUV and one of two (50%) patients from the DOBV group had hypotension or developed signs of shock. Seven out of 15 (47%) patients had elevated protein concentration in cerebrospinal fluid (CSF). Sinus bradycardia was documented in 7 of 17 (41%) patients with PUUV infection. HFRS is endemic in the north-eastern part of Slovenia; PUUV and DOBV infections coexist, with PUUV being the main causative agent of HFRS. Demographic, clinical and laboratory findings in our patients with HFRS caused by PUUV were mostly in accordance with those published previously, but the ratio of patients with sinus bradycardia, oliguric renal failure and mildly elevated CSF protein concentration was rather high.

Post-traumatic Meningitis: Risk Factors, Clinical Features, Bacteriology, and Outcome

Patients with post-traumatic meningitis (PTM) at two trauma centers from January 1992-December 1999 were retrospectively analyzed. Twenty-seven of 4,788 (0.56%) patients with head injury developed meningitis. Twenty-one (78%) patients were male. Mean age was 31.3 years. Twenty-three (85%) patients sustained blunt trauma and four (15%) had penetrating injuries. Median initial Glasgow coma scale (GCS) was 6. Twenty-one (78%) patients had pneumocephalus. Twelve (44%) patients had a cerebrospinal fluid (CSF) leak. Fever was seen in all patients and 23 (85%) displayed a decrease (greater than 2 points) in GCS. Twelve (44%) patients had an intracranial pressure (ICP) monitor, eight (30%) a ventriculostomy, and 12 (44%) underwent craniotomy prior to developing meningitis. Median interval between injury and diagnosis was 10 days. Pathogens were isolated from the CSF in 15 patients and brain tissue in one. Treatment in the remainder was based on elevated CSF white blood cell count, elevated CSF protein concentration, and low CSF glucose concentration. Measured functional outcome was good in 10 (37%) patients while 8 (30%) had a residual disability requiring dependent care and 5 (19%) remained in a vegetative state. Four (15%) patients died. Admission GCS was predictive of a good functional outcome (p < 0.01), but did not predict death from infection.

Guillain-Barre syndrome and Campylobacter jejuni infection

Guillain-Barre syndrome (GBS) is the most common cause of acute neuromuscular paralysis, usually due to acute inflammatory demyelinating polyradiculoneuropathy. The presence of activated T lymphocytes and antibodies against peripheral nerve myelin suggests an autoimmune pathogenesis, although there is wide heterogeneity. Gangliosides are sialylated glycolipids widely distributed in nervous system membranes. GBS is usually preceded by an infection, most frequently Campylobacter jejuni enteritis, but also cytomegalovirus, Mycoplasma pneumoniae or Epstein-Barr virus. Patients with GBS and C. jejuni infection are more likely to have neurophysiological features of axonal neuropathy, antibodies to ganglioside GM1, pure motor GBS, a less elevated CSF protein concentration and a worse outcome than other GBS patients. Although molecular mimicry between peripheral nerve gangliosides and epitopes present on C. jejuni lipopolysaccharide could explain some of these associations, this hypothesis is inadequate to account for many aspects of the pathogenesis of GBS.

La maladie de Refsum

Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa.

Elevated cerebrospinal fluid leukocyte count and protein concentration at diagnosis: independent risk factors in children with acute lymphoblastic leukemia.

The aim of this study was to investigate whether determination of the initial cerebrospinal fluid (CSF) protein concentration and leukocyte count in children with acute lymphoblastic leukemia (ALL) could yield useful information about the patient's central nervous system status and prognosis. The population-based unselected series comprised 160 children. The mean follow-up time was 72 months (range 25-143 months). Both the CSF protein concentration and the leukocyte count, if elevated, were significantly, although not independently, associated with diminished probability of event-free survival. The patients were divided into three groups for the final analyses: those without any abnormalities in the CSF (n = 133), those with elevated protein concentration and/or elevated leukocyte count, but with no malignant lymphoblasts in the CSF (n = 21), and those with malignant lymphoblasts in the CSF (n = 6). The probabilities of 5-year event-free survival for the first and second group were 65% and 15%; the probability of 2-year event-free survival for the third group was 17%. These differences were statistically significant (p less than 0.001). In multivariate analysis the relative risks of death or relapse for these groups were 1, 2.8 (95% confidence limits 1.5-4.9), and 7.6 (2.4-24.3), respectively (p less than 0.001). The inclusion of an elevated CSF protein concentration or leukocyte count in the risk group criteria of further trials should be considered.