Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury.

IMPORTANCE: Evidence is accumulating that repeated mild traumatic brain injury (mTBI) incidents can lead to persistent, long-term debilitating symptoms and in some cases a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy. However, to our knowledge, there are no objective tools to examine to which degree persistent symptoms after mTBI are caused by neuronal injury. OBJECTIVE: To determine whether persistent symptoms after mTBI are associated with brain injury as evaluated by cerebrospinal fluid biochemical markers for axonal damage and other aspects of central nervous system injury. DESIGN, SETTINGS, AND PARTICIPANTS: A multicenter cross-sectional study involving professional Swedish ice hockey players who have had repeated mTBI, had postconcussion symptoms for more than 3 months, and fulfilled the criteria for postconcussion syndrome (PCS) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) matched with neurologically healthy control individuals. The participants were enrolled between January 2014 and February 2016. The players were also assessed with Rivermead Post Concussion Symptoms Questionnaire and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: Neurofilament light protein, total tau, glial fibrillary acidic protein, amyloid ß, phosphorylated tau, and neurogranin concentrations in cerebrospinal fluid. RESULTS: A total of 31 participants (16 men with PCS; median age, 31 years; range, 22-53 years; and 15 control individuals [11 men and 4 women]; median age, 25 years; range, 21-35 years) were assessed. Of 16 players with PCS, 9 had PCS symptoms for more than 1 year, while the remaining 7 returned to play within a year. Neurofilament light proteins were significantly increased in players with PCS for more than 1 year (median, 410 pg/mL; range, 230-1440 pg/mL) compared with players whose PCS resolved within 1 year (median, 210 pg/mL; range, 140-460 pg/mL) as well as control individuals (median 238 pg/mL, range 128-526 pg/mL; P = .04 and P = .02, respectively). Furthermore, neurofilament light protein concentrations correlated with Rivermead Post Concussion Symptoms Questionnaire scores and lifetime concussion events (ρ = 0.58, P = .02 and ρ = 0.52, P = .04, respectively). Overall, players with PCS had significantly lower cerebrospinal fluid amyloid-ß levels compared with control individuals (median, 1094 pg/mL; range, 845-1305 pg/mL; P = .05). CONCLUSIONS AND RELEVANCE: Increased cerebrospinal fluid neurofilament light proteins and reduced amyloid ß were observed in patients with PCS, suggestive of axonal white matter injury and amyloid deposition. Measurement of these biomarkers may be an objective tool to assess the degree of central nervous system injury in individuals with PCS and to distinguish individuals who are at risk of developing chronic traumatic encephalopathy.

Atención a pacientes con estados alterados de conciencia en un hospital de pacientes crónicos y larga estancia / Care for patients with altered states of consciousness in a hospital for chronic and long-stay patients

Introducción. Un 30-40% de los pacientes con daño cerebral presenta alteraciones del nivel de conciencia, y algunos casos, estados alterados de conciencia: síndrome de vigilia sin respuesta (SVSR) o estado de mínima conciencia (EMC). La recuperación es variable y la supervivencia está amenazada por múltiples complicaciones. Objetivos. Presentar la metodología de trabajo del Hospital La Pedrera (HLP) para pacientes en SVSR o EMC y analizar las características clínicas de los pacientes atendidos, la evolución, y la situación funcional y cognitiva en el momento del alta. Pacientes y métodos. Estudio descriptivo prospectivo de pacientes atendidos en el HLP durante el período 2009-2013, con diagnóstico de SVSR o EMC. Resultados. El HLP trabaja mediante el método gestión de caso, ofreciendo una atención integral por un equipo multidisciplinar. Los pacientes se clasifican según objetivos asistenciales. Los pacientes con SVSR o EMC se incluyen en el programa de cuidados integrales y adaptación. Se atendió a 23 pacientes (86,9% varones), con una edad media de 54,9 años. Etiología: hemorragia cerebral, 30,4%; encefalopatía anóxica, 26,6%; encefalopatía metabólica, 17,3%; y otras causas, 17,3%. El 73,9% ingresó en SVSR y el resto en EMC. Evolución: el 43,4% mejoró su situación cognitiva inicial y el 88,8% presentaba una situación de dependencia total en el momento del alta. Las complicaciones más frecuentes fueron infecciones respiratorias y urinarias (53,6%). El 65,2% de los casos fueron exitus. Conclusiones. La asistencia en SVSR o EMC es compleja y precisa cuidados multidisciplinares. Casi la mitad de los pacientes mejoró su situación cognitiva, lo que justifica una actitud proactiva que intente mejorar la calidad de vida de los pacientes y sus familias (AU)

Introduction. Between 30% and 40% of patients with brain damage present alterations in their level of consciousness and, in some cases, altered states of consciousness: unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS). Recovery varies and survival is threatened by a number of complications. Aims. The purpose of this study is to present the working methodology used at the Hospital La Pedrera (HLP) for patients in UWS or MCS and to analyse the clinical characteristics of the patients attended to, their progress, and the functional and cognitive situation at the time of their discharge from hospital. Patients and methods. The work consisted in a prospective descriptive study of patients seen at the HLP over the period 2009-2013, who had been diagnosed with UWS or MCS. Results. The HLP uses the case management method, offering integrated care dispensed by a multidisciplinary team. Patients are classified according to healthcare goals. Patients with UWS or MCS are included in the integrated care and adaptation programme. A total of 23 patients (86.9% males) were attended to, the mean age being 54.9 years. Aetiology: brain haemorrhage, 30.4%; anoxic encephalopathy, 26.6%; metabolic encephalopathy, 17.3%; and other causes, 17.3%. Altogether 73.9% were admitted in UWS and the rest in MCS. Course: 43.4% improved their initial cognitive situation and 88.8% presented a situation of total dependence at the time of discharge. The most frequent complications were respiratory and urinary infections (53.6%). Death occurred in 65.2% of cases. Conclusions. Medical attention in UWS or MCS is complex and requires multidisciplinary care. Almost half of the patients improved their cognitive situation, which justifies a proactive attitude that attempts to improve the quality of life of both patients and their families (AU)

Quantitative proteomic analyses of cerebrospinal fluid using iTRAQ in a primate model of iron deficiency anemia.

Iron deficiency affects nearly 2 billion people worldwide, with pregnant women and young children being most severely impacted. Sustained anemia during the first year of life can cause cognitive, attention and motor deficits, which may persist despite iron supplementation. We conducted iTRAQ analyses on cerebrospinal fluid (CSF) from infant monkeys (Macaca mulatta) to identify differential protein expression associated with early iron deficiency. CSF was collected from 5 iron-sufficient and 8 iron-deficient anemic monkeys at weaning age (6-7 months) and again at 12-14 months. Despite consumption of iron-fortified food after weaning, which restored hematological indices into the normal range, expression of 5 proteins in the CSF remained altered. Most of the proteins identified are involved in neurite outgrowth, migration or synapse formation. The results reveal novel ways in which iron deficiency undermines brain growth and results in aberrant neuronal migration and connections. Taken together with gene expression data from rodent models of iron deficiency, we conclude that significant alterations in neuroconnectivity occur in the iron-deficient brain, which may persist even after resolution of the hematological anemia. The compromised brain infrastructure could account for observations of behavioral deficits in children during and after the period of anemia.

Expression of soluble Fas in the cerebrospinal fluid of preterm infants with posthemorrhagic hydrocephalus and cystic white matter damage.

Perinatal brain damage may result in impaired neurological development in extremely preterm infants. The underlying pathophysiological mechanisms are complex, and biomarkers of prognostic value are not available. The aim of this study was to analyze soluble Fas (sFas) concentrations in the cerebrospinal fluid (CSF) representative for involvement of apoptotic processes in preterm infants developing posthemorrhagic hydrocephalus (PHHC) and to link them to white matter damage (WMD) diagnosed by cranial ultrasound. A total of 29 preterm infants with PHHC were included in the study; 17 of them had signs of cystic WMD (cWMD) on ultrasound examinations. CSF samples were obtained at first ventriculostomy, and results were compared to those of a reference group of 24 preterm and term infants without neurologic diseases. sFas concentrations were elevated in CSF samples of PHHC patients compared to the reference group. In patients with cWMD, sFas concentrations were significantly higher than in patients without cWMD. These results indicate that apoptosis via the Fas pathway is involved in the pathogenesis of cWMD in the context of PHHC, and that sFas in the CSF may serve as a marker of cWMD development.

Persistence of herpes simplex virus DNA in cerebrospinal fluid of neonates with herpes simplex virus encephalitis.

OBJECTIVE: The significance of detecting herpes simplex virus (HSV) DNA in the cerebrospinal fluid (CSF) of infants with HSV encephalitis after receipt of prolonged therapy with high-dose (60 mg kg(-1) day(-1)) acyclovir is unknown. We report the clinical and laboratory characteristics, neuroimaging studies and outcomes of four neonates with HSV encephalitis who had persistence of CSF HSV DNA, by polymerase chain reaction (PCR) after 15 to 21 days of high-dose acyclovir therapy. STUDY DESIGN: Retrospective chart review. RESULTS: All four infants had abnormal neuroimaging studies and subsequently experienced severe developmental delay or death. CONCLUSION: A persistently positive CSF HSV PCR in neonates may be another risk factor for worse neurodevelopmental outcome. Prospective studies are needed to document how often HSV DNA persists in CSF, elucidate whether it represents an initially high CSF viral load, ongoing viral replication or viral resistance, and determine its possible association with neurodevelopmental impairment.

Neurochemical markers of brain damage in cerebrospinal fluid during induction treatment of acute lymphoblastic leukemia in children.

BACKGROUND: Central nervous system (CNS) irradiation has been replaced by systemic high-dose methotrexate (MTX) and intrathecal MTX in acute lymphoblastic leukemia treatment due to the risk of late effects. However, treatment without CNS irradiation might also cause brain damage. PROCEDURE: Cerebrospinal fluid (CSF) was analyzed in 121 patients in an attempt to detect CNS injury. Seventy-three samples were analyzed for neuron-specific enolase (NSE), 108 for glial fibrillary acidic protein (GFAp), 110 for neurofilament protein light chain (NFp), and 70 for ascorbyl radical (AsR). Samples were taken at day 0, 8, 15, and 29 during induction treatment, including intrathecal MTX. Levels at days 8, 15, and 29 were compared with the levels before treatment. RESULTS: NSE levels were 9.0 (+/-3.5) microg/L (mean (+/-SD)) at day 0, 15.0 (+/-5.3) at day 8 (P < 0.001), 13.6 (+/-4.7) at day 15 (P < 0.001) and 11.1 (+/-4.3) at day 29 (P < 0.001). GFAp were 177 (+/-98) ng/L at day 0, 206 (+/-101) at day 8 (P < 0.001), 200 (+/-106) at day 15 (n.s.) and 228 (+/-137) at day 29 (P < 0.001). NFp were below the detection limit 125 ng/L at day 0 in all 110 CSF samples analyzed, and increased significantly above the detection limit in 6/77 samples at day 8, in 11/84 at day 15 and in 22/91 at day 29. The AsR content did not change significantly. CONCLUSIONS: Levels of NSE, GFAp, and NFp increased in CSF, which can be interpreted as early signs of brain damage. AsR levels do not show any convincing signs of oxidative stress.

Changes in brain functional activation during resting and locomotor states after unilateral nigrostriatal damage in rats.

To evaluate functional neuronal compensation after partial damage to the nigrostriatal system, we lesioned rats unilaterally in the striatum with 6-hydroxydopamine. Five weeks later, cerebral perfusion was mapped at rest or during treadmill walking using [(14)C]-iodoantipyrine. Regional CBF-related tissue radioactivity (CBF-TR) was quantified by autoradiography and analyzed by statistical parametric mapping and region-of- interest analysis. Lesions were confirmed by tyrosine hydroxylase immunohistochemistry and changes in rotational locomotor activity. Functional compensations were bilateral and differed at rest and during treadmill walking. Consistent with the classic view of striatopallidal connections, CBF-TR of lesioned compared to sham-lesioned rats increased in the ipsilateral subthalamic nucleus (STN) and internal globus pallidus, and decreased in the striatum and external globus pallidus. Contrary to the classic view, CBF-TR increased in the ipsilateral ventral lateral, ventral anterior thalamus and motor cortex, as well as in the central medial thalamus, midline cerebellum, and contralateral STN. During walking, perfusion decreased in lesioned compared to sham-lesioned rats across the ipsilateral striato-pallidal-thalamic-cortical motor circuit. Compensatory increases were seen bilaterally in the ventromedial thalamus and red nucleus, in the contralateral STN, anterior substantia nigra, subiculum, motor cortex, and in midline cerebellum. Enhanced recruitment of associative sensory areas was noted cortically and subcortically. Future models of compensatory changes after nigrostriatal damage need to address the effects of increased neural activity by residual dopaminergic neurons, interhemispheric interactions and differences between resting and locomotor states. Identification of sites at which functional compensation occurs may define useful future targets for neurorehabilitative or neurorestorative interventions in Parkinson's disease.

Intrathecal immunoglobulin G synthesis and brain injury by quantitative MRI in multiple sclerosis.

OBJECTIVES: It was the aim of this study to evaluate if the quantitative intrathecal immunoglobulin G (IgG) synthesis correlates with the brain atrophy and the total lesion volume (TLV) in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients. METHODS: A total of 50 patients with relapsing-remitting MS were included in this study. MRIs were performed and cerebrospinal fluid samples were collected during the diagnostic determination when patients were in remission without treatment. RESULTS: At study baseline, IgG index values were elevated in 36 patients (72%), and oligoclonal IgG bands were positive in 42 of 50 patients (84%). Brain MRI was abnormal in 94% of patients, and, compared with healthy controls, brain atrophy was observed in MS patients. A positive correlation among IgG index, cerebrospinal fluid leukocyte count and TLV was observed; the Expanded Disability Status Scale correlated positively with TLV and the number of lesions, although a significant relationship between disability and brain atrophy was not demonstrated. CONCLUSIONS: Although new parameters will be necessary in longitudinal studies to characterize the axonal injury in various stages of the disease, the data suggest that the high intrathecal IgG synthesis may predict a greater brain lesion burden.

Sequential analyses of neurobiochemical markers of cerebral damage in cerebrospinal fluid and serum in CNS infections.

OBJECTIVE: To elucidate the relation between release patterns and cerebrospinal fluid/serum concentrations of neurobiochemical markers of cerebral damage and their potential value as monitoring parameters in central nervous system infections. METHODS: We investigated protein S-100B and neuron-specific enolase (NSE) in 102 sequential cerebrospinal fluid (CSF)-serum-pairs in patients with bacterial (n = 11) or viral (n = 13) meningitis/meningoencephalitis and neuroborreliosis (n = 8) in comparison with controls (n = 13). RESULTS: Highest S-100B values in CSF and serum were found on admission and showed a significant decrease afterwards. Comparison between disease groups revealed significant differences between bacterial and viral meningitis and neuroborreliosis for S-100B and also when compared with controls. NSE was not significantly elevated. CONCLUSIONS: S-100B is altered in CNS infection but does not provide additional benefit in the differential diagnosis when compared with standard CSF parameters. Nevertheless, S-100B values might be used as an additional monitoring parameter especially when sequential lumbar punctures are contraindicated.

Nitrite/nitrate (NOx) and zinc concentrations in influenza-associated encephalopathy in children with different sequela.

NOx (NO2 and NO3) in CSF obtained from 22 patients with influenza-associated encephalopathy were higher than those of a control group. Within the different prognosis, there were no significant differences in NOx levels. By analyzing the serum obtained from patients infected with influenza, including encephalopathy, with others, the serum zinc levels did show marked differences between them. Four out of eleven patients with influenza-associated encephalopathy showed low zinc levels below the normal range. However, there were no significant differences in the zinc levels between the group with sequela and without sequela. These results indicate that the increase of NOx levels detected in influenza-associated encephalopathy relates to the low zinc levels, and both low molecules might play an important role for the cause of encephalopathy.

Acción de la procalcitonina sobre la temperatura corporal / Procalcitonin action on body temperature

La procalcitonina (PCT) una proteína de 116 aminoácidos precursora de la hormona calcitonina, es un nuevo marcador diagnóstico de infección bacteriana e inflamación sistémica que presenta alta sensibilidad y especificidad, sin que se alteren los valores de calcitonina. En infecciones bacterianas severas se encuentran valores altos de PCT en plasma, sin embargo en personas sanas los niveles de PCT son indetectables. Al contrario que la interleucina-1 (IL-1), interleucina-6 (IL-6), factor de necrosis tumoral (TNF) u otros pirógenos endógenos ( marcadores de la respuesta inflamatoria), los niveles sanguíneos de PCT no se incrementan frente a infección viral, traumas, enfermedades autoinmunes o reacciones alérgicas. Por ello la PCT se usa para el diagnóstico diferencial entre infección bacteriana y viral. A pesar de desconocerse el papel biológico de este péptido, se ha demostrado que sus concentraciones plasmáticas se correlacionan con el inicio, curso y severidad de la inflamación. Así se ha demostrado que la PCT se libera tras la inyección de endotoxina bacteriana, este incremento está relacionado con los niveles séricos de IL-1, IL-6 y TNF. Estas características indican que la PCT puede ser algo mas que un simple marcador y que puede estar implicada en la respuesta febril. La región termorreguladora de las ratas se localiza en el área preóptica del hipotálamo anterior (AH/POA). En este trabajo se estudió el papel de la PCT en la termorregulación y en la fiebre inducida por endotoxina bacteriana a nivel central. En ratas Wistar se hizo un estudio dosis-respuesta de PCT frente a la temperatura corporal microinyectando diferentes dosis de PCT : 2, 4, 10, 100, 1000 y 5000 ng en el ventrículo lateral (icv) y registrando los cambios de temperatura corporal. También se inyectó una dosis de PCT: 100ng icv media hora antes de la endotoxina (lipopolisacárido (LPS) 50ƒÝg/kg ip). Asi mismo se realizo un estudio inmunohistoquimico de la presencia y localizacion de PCT en el AH/POA. Los resultados demostraron que la administracion de PCT icv provoca una ligera disminucion de la temperatura corporal pero no de un modo dosis-respuesta. El pretratamiento con PCT disminuye levemente la respuesta febril inducida por LPS. Se demostro la presencia del peptido PCT en la Pars Tuberal del hipotalamo. Este trabajo se ha realizado gracias a la Fundacion Valme y la Junta de Andalucia (AU)

Procalcitonin (PCT), a 116 amino acid protein with identical sequence to the precursor protein of calcitonin hormone, is a new high sensitive and specific diagnostic parameter of bacterial infection and systemic inflammation in the absence of its precur- sor protein. High plasma concentrations of PCT are induced during severe bacterial infection but not in controls. Unlike interleukin-1 (IL-1), interleukin-6 (IL-6), tumor ne- crosis factor (TNF) or other endogenous pyrogens (parameters of the inflammatory re- sponse), PCT is generally not induced by viral infection, operation trauma, autoimmune or allergic disorders. Hence, PCT can be used for differential diagnosis of bacterial and non bacterial inflammation. Although the biological role of this peptide is still largely unknown, it has been shown that PCT plasma concentrations correlate closely with the onset, course and severity of the inflammatory reaction. Moreover, it has been demon- strated that PCT is released following endotoxin injection and that the increase of plasma PCT levels, are positively correlated with IL-1, IL-6 and TNF. These characteristics of PCT might well give it not only a role as a marker in clinical infections but also a potential role in fever of bacterial origin. The thermosensitive region of the rat is the anterior hypothalamic pre-optic area (AH/POA). Therefore, the rationale for this study was to study the role of PCT in the thermoregulation and in the febrile response induced by a bacterial endotoxin on the CNS. In Wistar rats we carried out a dose-response study with PCT and body temperature microinjecting different doses of PCT: 2, 4, 10, 100, 1000 and 5000 ng in the rat lateral ventricle (icv) and we measured their body temperature. We also microinjected one dose of PCT 100ng icv half an hour before endotoxin (lipopolysaccharide (LPS) 50g/kg). We also designed an immunohistochemical study in the AH/POA to find the peptide PCT and its localization. The results demonstrated that the administration of PCT icv produced a low diminution in the body temperature but not in a dose-response manner. The pre-treatment with PCT lightly reduce the fever induced by endotoxin. We have found the peptide PCT in the endothelial cells of the hy- pothalamic Pars Tuberal (AU)

Hashimoto's encephalopathy: epidemiologic data and pathogenetic considerations.

BACKGROUND: Hashimoto's encephalopathy (HE) is a condition believed to complicate Hashimoto's thyroiditis (HT). The diagnosis is suspected in the presence of high levels of serum anti-thyroid antibodies. We have recently demonstrated that in patients with HE there is an intrathecal synthesis of anti-thyroid antibodies, and concluded that the diagnosis of HE should be based on this cerebrospinal fluid (CSF) finding. OBJECTIVE: getting an estimate of the prevalence of the disease, verifying the association with HT and investigating the pathogenetic role of anti-thyroid antibodies. METHODS: 34-months prospective study in a hospital setting serving a community of 150,000 people. Patients with unexplained symptoms of acute or subacute encephalopathy or myelopathy or with a history of thyroid disorders were selected for the measurement of anti-thyroid antibodies. In the presence of high serum levels of autoantibodies, the same tests were performed in the CSF. RESULTS: Twelve patients had increased concentrations of serum autoantibodies but HE was diagnosed only in nine patients. The estimated prevalence of HE is 2.1/100,000. Only six HE patients had also HT. Four patients received corticosteroids, five patients were not treated. Five patients improved, four patients spontaneously, one patient after corticosteroids. Repeated CSF examinations showed that the titer of CSF autoantibodies did not correlate with the clinical stage of the disease nor was influenced by corticosteroids. In addition, the course of symptoms was independent of therapy. CONCLUSIONS: The association of encephalopathy and high titers of anti-thyroid antibodies is not sufficient to make a diagnosis of HE. Independent of the clinical status of the thyroid gland, the intrathecal synthesis of autoantibodies is a distinctive marker of this elusive condition.

Analysis of cerebrospinal fluid glial fibrillary acidic protein after seizures in children.

PURPOSE: To evaluate pediatric seizure patients for astrocytic injury by measuring cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP), determine risk factors for GFAP elevation after seizures, and compare seizure-induced astrocyte injury with neuronal injury by concurrent measurement of CSF neuron-specific enolase (NSE). METHODS: CSF obtained from pediatric patients (n = 52) within 24 h of seizure was assayed for GFAP and NSE. Retrospective chart review was performed for seizure type, duration, and etiology. RESULTS: Overall, children with seizures had elevated CSF GFAP compared with controls (p = 0.0075), but no elevation of NSE (p = 0.1437). No effect of seizure type or etiology was found, but a significant positive effect of seizure duration (p = 0.0010) and status epilepticus (p = 0.0296) was seen on CSF GFAP. Individually, seven children (13%) had elevated GFAP (>440 pg/ml); in five children, the increased GFAP was not accompanied by elevations in NSE (<12 ng/ml). Five children with elevated GFAP had symptomatic etiologies for their seizures, but the etiology of one child with elevated GFAP was cryptogenic, and one had febrile seizures. CONCLUSIONS: Elevation of CSF GFAP after seizures suggests that astrocytic injury may occur in a subgroup of children, primarily in the context of prolonged seizures and symptomatic etiologies. Increased GFAP levels may occur in patients with normal NSE, suggesting that GFAP may be a more sensitive marker of brain injury in some cases.

[Level of S-100 and neuron-specific enolase in cerebrospinal fluid from subjects with neurological pathologies]. / Niveles de S-100 y enolasa neuroespecífica en líquido cefalorraquídeo de enfermos con patología neurológica.

AIM: To evaluate S-100 and neuro specific enolase (NSE) levels in cerebrospinal fluid (CSF) from patients with differents neurological disorders in order to study possible differences in their protein concentrations. MATERIAL AND METHODS: We analysed samples of CSF taked by spinal puncture in subjects either from of the Casualty Department or from the Department of Neurology. Patients displaying neurological symptoms capable of being diagnostically tested. The total number of patients-samples examined was 43 (23 males and 20 females; mean age 43 y, range 1-78 y). Five patients groups were studied: a control group, meningitis, dementia, polyneuropathy-motorneuron disease, and acute cerebral infarction group (ACV). S-100 and NSE concentrations were measured by immunoradiometric procedures. RESULTS: Highest S-100 median levels in CSF were found in dementia and ACV group, with elevate concentrations in meningitis groups. The increased S-100 levels in these groups was significant compared with control group (Mann-Withney U test). For NSE concentrations, there is a significant differences between dementia group and control group. No other significant differences were found between groups. There were positive correlation between S-100 levels and total protein. CONCLUSION: Our results suggest that S-100 and NSE can be a sensitive marker of brain damage in different neurological disorders. However, levels must be considered individually, since these concentrations depend on several factors, such as age, severity of brain damage or interval between the onset of brain damage and the taking of the sample.

Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury.

OBJECTIVE: To determine whether CSF amyloid beta 1-42 (Abeta-42) and tau have predictive value for prognosis after head injury. METHODS: CSF samples were collected from 29 patients with severe head trauma between 1 and 284 days post-trauma. Abeta-42 and tau levels were measured using sandwich ELISA techniques and compared with CSF levels in patients with cognitive disorders and headache. RESULTS: At all time points, concentrations of Abeta-42 were significantly lower in patients with traumatic brain injury (TBI) than in control groups. A significant correlation existed for Abeta-42 levels and outcome of patients. Below a cutoff of 230 pg/mL, the sensitivity of Abeta-42 to discriminate between good outcome (Glasgow Outcome Score 4 and 5) and poor outcome (Glasgow Outcome Score 1 through 3) was 100% at a specificity of 82%. CSF tau levels were significantly higher in patients with TBI than in any control group. In patients with multiple CSF samples collected at various time points between 1 and 32 days after the trauma, tau levels increased early after TBI, peaked in the second week post-trauma, and slowly decreased thereafter. Independent of outcome, all patients had normal tau levels when CSF was collected more than 43 days post-trauma. CONCLUSIONS: Abeta-42 and tau may play a potential role in the pathophysiology of TBI. Furthermore, the results of this study suggest that Abeta-42 may be a supportive early predictor for recovery after severe head injury.

Serum- and CSF-concentrations of brain specific proteins in hydrocephalus.

OBJECT: Hydrocephalus is characterised by elevated intracranial pressure (ICP) and gives rise to brain damage. The aim of this study was to investigate the significance of brain specific proteins as markers in the evaluation of brain damage in hydrocephalus. Therefore we determined the levels of four brain specific proteins in cerebrospinal fluid (CSF) and serum of symptomatic hydrocephalic patients. METHODS: During 41 CSF shunt-operations (both primarily placed shunts and shunt-revisions) CSF and blood samples were obtained and analysed for neuron-specific enolase (NSE), S-100b, glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). The results were compared with an age-matched control group. Patients with varying clinical symptoms, denoting different levels of increased intracranial pressure prior to surgery, were included in this study. RESULTS: We observed significantly increased CSF-levels of S-100b and GFAP in the hydrocephalic patients, whereas NSE and MBP were markedly increased only in patients with very severe symptoms. Serum levels of all proteins were only minimally increased and did not correlate with CSF-levels. The slightly elevated levels of CSF-NSE in most of the patients suggest only subtle neuronal damage, which is not related to permanent neurological symptoms. The elevated levels of S-100b and GFAP are indicative of a reactive astrogliosis, which has also been demonstrated in histopathological studies. No demyelination seems to occur, according to the normal levels of MBP observed in this study. CONCLUSIONS: Although CSF levels of brain specific proteins are elevated in hydrocephalic patients, indicating brain damage due to hydrocephalus, neither CSF- nor serum-concentrations of brain specific proteins seem to be valuable tools in the clinical evaluation of the severity of hydrocephalus.

Lack of neuronal damage in atypical absence status epilepticus.

PURPOSE: Whether status epilepticus of nonconvulsive epileptic seizures is harmful still remains controversial. To investigate this, the presence and/or extent of neuronal damage in patients with absence status epilepticus (ASE) and patients with complex partial status epilepticus (CPSE) was examined and compared. METHODS: Neuron-specific enolase (NSE) in CSF was examined in the patients with ASE and compared with that of the patients having CPSE. Clinical aspects of these patients also were investigated. RESULTS: CSF NSE levels in ASE patients were lower than those of CPSE patients and were considered as the normal values. No clinical symptoms indicated neuronal damage in the ASE patients. CONCLUSIONS: This study suggests that ASE does not induce neuronal damage. Serum NSE is not always correlated to CSF NSE, and determination of serum NSE levels may be an inappropriate method of estimating neuronal damage in some cases of ASE.

Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency.

Aromatic L-amino acid decarboxylase (AADC) is a vitamin B 6 requiring enzyme involved in the biosynthesis of the neurotransmitters dopamine (DA) and serotonin. Lack of AADC leads to a combined deficiency of the catecholamines DA, norepinephrine (NE), epinephrine (E) as well as of serotonin. Here we describe premature twins who presented with severe seizures, myoclonus, rotatory eye movements and sudden clonic contractions. The patients showed an improvement of the clonic contractions under vitamin B 6 supplementation but died in the third week of life. In CSF and urine a biochemical pattern indicative of AADC deficiency was revealed. Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were decreased, in association with increased concentrations of 3-ortho-methyldopa (3-OMD) in CSF and significantly increased vanillactic acid in urine. The AADC enzyme substrates L-dopa and 5-hydroxytryptophan (5-HTP) were elevated in CSF. Elevated concentrations of threonine as well as of an unidentified compound in CSF rounded off the biochemical pattern. AADC activity was found to be increased in plasma and deficient in the liver. Molecular studies effectively ruled out a genetic defect in the AADC gene. The basis for the epileptic encephalopathy in the twins may be located in the metabolism of vitamin B 6 and remains to be defined.

Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage?

OBJECT: Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH. METHODS: Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001). CONCLUSIONS: The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.

Aicardi-Goutieres syndrome in siblings.

Two siblings with familial encephalopathy, calcification of the basal ganglia, and cerebrospinal fluid lymphocytosis, constituting the triad of Aicardi-Goutieres syndrome, are reported. This syndrome resembles congenital intrauterine infections, which must be meticulously excluded. Aicardi-Goutieres syndrome is extremely rare and is being reported from the Arab world for the first time to our knowledge.