Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Autoimmune Epilepsy in Children: Unraveling the Mystery.

Although many neurologists are familiar with the clinical presentations of anti-N-methyl-d-aspartate receptor or limbic encephalitides, there remains much mystery surrounding autoimmune etiologies of subacute and chronic epilepsies. In addition, the subtleties and differences in presentation in the pediatric population limit diagnosis and challenge clinicians. In the absence of an acute encephalitic picture, it is likely that many clinicians do not test for autoimmune disorders due to the uncertainty surrounding the selection of appropriate candidates for testing and immunomodulation. Recent developments have expanded the definition of epilepsy related to autoimmune mechanisms. Based on current knowledge, autoimmune epilepsy can best be thought of as a subset of autoimmune encephalitis where seizures and epilepsy are the primary presenting factor. Autoimmune epilepsy has been increasingly recognized as a contributor to drug-resistant epilepsies; however, identification of affected individuals remains challenging, particularly in the pediatric population. Our understanding of autoimmune epilepsy continues to evolve as more individuals with epilepsy are tested for antibodies to neuronal proteins and as additional antibodies are being identified. This article provides an overview of the clinical features most commonly associated with positive antibody testing in epilepsy and the scales that are currently available to screen patients for antibody testing and response to immunotherapy. Literature-based recommendations are presented for the modification and validation of current scales to increase applicability to children.

Testing blood and CSF in people with epilepsy: a practical guide.

Laboratory investigations, whilst not essential to the diagnosis of seizures or of epilepsy, can be fundamental to determining the cause and guiding management. Over 50% of first seizures have an acute symptomatic cause, including a range of metabolic, toxic or infectious cause. The same triggers can precipitate status epilepticus, either de novo or as part of a deterioration in control in individuals with established epilepsy. Some, such as hypoglycaemia or severe hyponatraemia, can be fatal without prompt identification and treatment. Failure to identify seizures associated with recreational drug or alcohol misuse can lead to inappropriate AED treatment, as well as a missed opportunity for more appropriate intervention. In individuals with established epilepsy on treatment, some laboratory monitoring is desirable at least occasionally, in particular, in relation to bone health, as well as in situations where changes in AED clearance or metabolism are likely (extremes of age, pregnancy, comorbid disorders of renal or hepatic function). For any clinician managing people with epilepsy, awareness of the commoner derangements associated with individual AEDs is essential to guide practice. In this article, we review indications for tests on blood, urine and/or cerebrospinal fluid in patients presenting with new-onset seizures and status epilepticus and in people with established epilepsy presenting acutely or as part of planned monitoring. Important, but rare, neurometabolic and genetic disorders associated with epilepsy are also mentioned.

CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor, nerve growth factor) and neuropeptides (neuropeptide Y, galanin) in epileptic children.

This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.

Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy.

To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine.

[Pyridoxine-dependent epilepsy due to deficiency in the PNPO gene]. / Epilepsia dependiente de piridoxina por deficiencia en el gen PNPO.

TITLE: Epilepsia dependiente de piridoxina por deficiencia en el gen PNPO.

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus.

OBJECTIVE: To investigate intrathecal inflammation using cerebrospinal fluid (CSF) cytokines and chemokines in a subgroup of pediatric epilepsy patients with frequent daily seizures. METHODS: We measured 32 cytokines/chemokines using multiplex immunoassay in CSF collected from pediatric patients with febrile infection-related epilepsy syndrome (FIRES)/FIRES-related disorders (FRD; n = 6), febrile status epilepticus (FSE; n = 8), afebrile status epilepticus (ASE; n = 8), and chronic epilepsy with frequent daily seizures (n = 21) and compared the results with noninflammatory neurological disorders (NIND; n = 20) and encephalitis (n = 43). We also performed longitudinal CSF cytokine/chemokine studies in three cases with FIRES/FRD. RESULTS: The median age of onset of seizures was 2.4 years (range = 0.08-12.5). Median CSF timing from the onset of seizures was longer in chronic epilepsy (540 days), whereas FIRES, FSE, and ASE had CSF tested within 1-2 days of onset of seizures (P < .001). The elevation of cytokines/chemokines was higher in FIRES followed by FSE, when compared to chronic epilepsy and NIND controls. Th1-associated cytokines/chemokines (TNF-α, CXCL9, CXCL10, CXCL11), IL-6, CCL2, CCL19, and CXCL1 (P < .05) were elevated in FIRES, in contrast to the elevation of a broader network of cytokines/chemokines in encephalitis. The cytokines/chemokines (CXCL9, CXCL10, CXCL11, and CCL19) were elevated in FSE when compared to ASE despite the similar median seizure duration and timing of CSF testing in relation to seizures. Chronic epilepsy generally lacked significant elevation of cytokines/chemokines despite frequent daily seizures. The median concentrations of the cytokines/chemokines rapidly declined on serial testing during the course of illness in all three FIRES/FRD cases. SIGNIFICANCE: We identify significant differences in CSF cytokine/chemokine profile between FIRES/FRD and encephalitis. The prominent elevation of CSF cytokines and chemokines in FIRES/FRD and to a lesser extent FSE highlights that the cytokine/chemokine elevation is significantly associated with the etiology of the underlying process rather than purely reactive. However, it is unclear whether the immune activation contributes to the disease process.

Evaluation of IL-1ß levels in epilepsy and traumatic brain injury in dogs.

BACKGROUND: Epilepsy is a common neurological disease in dogs affecting approximately 0.6-0.75% of the canine population. There is much evidence of neuroinflammation presence in epilepsy, creating new possibilities for the treatment of the disease. An increased expression of interleukin-1 beta (IL-1ß) was reported in epileptogenic foci. We hypothesized that there is an elevation of IL-1ß in serum and CSF of dogs with epilepsy, as well as in serum of dogs with TBI, reflecting involvement of this cytokine in pathophysiology of naturally occurring canine epilepsy in a clinical setting. RESULTS: IL-1ß levels were evaluated in CSF and serum of six healthy and 51 dogs with epilepsy (structural and idiopathic). In 16 dogs with TBI, only serum was tested. IL-1ß concentrations in CSF were not detectable. Serum values were not elevated in dogs with TBI in comparison to healthy controls (p > 0.05). However, dogs with epilepsy had increased levels of IL-1ß in serum (p = 0.003) regardless of the underlying cause of the disease (p = 0.0045). There was no significant relationship between the variables and IL-1ß levels. Statistically noticeable (p = 0.0630) was that approximately 10% of dog with epilepsy (R2 = 0.105) had increased seizure frequency and IL-1ß elevation. CONCLUSION: Increased IL-1ß levels were detected in the peripheral blood in dogs with idiopathic and structural epilepsy leading to the assumption that there is an involvement of inflammation in pathophysiology of epilepsy which should be considered in the search for new therapeutic strategies for this disease. However, to better understand the pathogenic role of this cytokine in epilepsy, further evaluation of IL-1ß in brain tissue is desired.

Analysis of blood degradation products and ferritin in the cerebrospinal fluid of dogs with acute thoracolumbar intervertebral disk extrusion, a prospective pilot study.

BACKGROUND: Hemorrhage in the spinal canal leads to further damage of the spinal cord influencing outcome in dogs with intervertebral disk (IVD) extrusion. The aim of the study was to evaluate blood degradation products and ferritin in the cerebrospinal fluid (CSF) of dogs with thoracolumbar IVD extrusion, and their association to clinical parameters and MRI findings. RESULTS: In the CSF of dogs with IVD extrusion, both net oxyhemoglobin absorption (NOA) and net bilirubin absorption (NBA) were significantly higher compared to the control groups of dogs with steroid responsive meningitis arteritis (SRMA) and idiopathic epilepsy (IE) (P < 0.001), but NOA compared to the idiopathic epilepsy group contaminated artificially with blood (IEc) was not (P = 0.890). Ferritin concentration was significantly higher in dogs with IVD extrusion compared to dogs with IE (P = 0.034), but not to dogs with SRMA (P = 0.526). There was no association between NOA, NBA or ferritin concentration and severity or duration of clinical signs. In dogs with a higher ferritin concentration the outcome was better (P = 0.018). In dogs with evidence of hemorrhage on MRI, NOA and NBA were significantly higher (P = 0.016, P = 0.009), but not ferritin (P = 0.0628). CONCLUSION AND CLINICAL IMPORTANCE: Quantification of blood degradation products and ferritin in the CSF of dogs to assess subarachnoidal hemorrhage is feasible; however, larger case numbers are needed to evaluate the relevance of NBA and ferritin as prognostic indicators.

Cerebral folate deficiency: Analytical tests and differential diagnosis.

Cerebral folate deficiency is typically defined as a deficiency of the major folate species 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) in the presence of normal peripheral total folate levels. However, it should be noted that cerebral folate deficiency is also often used to describe conditions where CSF 5-MTHF is low, in the presence of low or undefined peripheral folate levels. Known defects of folate transport are deficiency of the proton coupled folate transporter, associated with systemic as well as cerebral folate deficiency, and deficiency of the folate receptor alpha, leading to an isolated cerebral folate deficiency associated with intractable seizures, developmental delay and/or regression, progressive ataxia and choreoathetoid movement disorders. Inborn errors of folate metabolism include deficiencies of the enzymes methylenetetrahydrofolate reductase, dihydrofolate reductase and 5,10-methenyltetrahydrofolate synthetase. Cerebral folate deficiency is potentially a treatable condition and so prompt recognition of these inborn errors and initiation of appropriate therapy is of paramount importance. Secondary cerebral folate deficiency may be observed in other inherited metabolic diseases, including disorders of the mitochondrial oxidative phosphorylation system, serine deficiency, and pyridoxine dependent epilepsy. Other secondary causes of cerebral folate deficiency include the effects of drugs, immune response activation, toxic insults and oxidative stress. This review describes the absorption, transport and metabolism of folate within the body; analytical methods to measure folate species in blood, plasma and CSF; inherited and acquired causes of cerebral folate deficiency; and possible treatment options in those patients found to have cerebral folate deficiency.

Cerebrospinal fluid changes following epileptic seizures unrelated to inflammation.

BACKGROUND AND PURPOSE: Analyzing cerebrospinal fluid (CSF) is crucial in the diagnostic workup of epileptic seizures to rule out autoimmunity or infections as the underlying cause. Therefore, the description of post-ictal changes in CSF is essential to differentiate between negligible and etiopathologically relevant changes in the CSF profile. METHODS: A retrospective analysis of 247 patients newly diagnosed with epileptic seizures and CSF analysis during diagnostic workup was conducted. Patients with possible or definitive autoimmune or infectious encephalitis were excluded. CSF results were evaluated for associations with seizure types, seizure etiology and electroencephalography (EEG) findings. RESULTS: An increased cell count (>4/µL) was found in 4% (n = 10), increased lactate concentration (>2.5 mmol/L) in 28% (n = 70), increased total protein (>500 mg/L) in 51% (n = 125) and a dysfunction of the blood-brain barrier in 29% (n = 71) of patients. Intrathecal immunoglobulin G production was observed in 5% (n = 12) of patients. Higher lactate concentrations were found in seizures with motor onset (P = 0.02) compared with those with non-motor onset. Patients with generalized slow activity on EEG had significantly higher lactate values (P = 0.01) and albumin quotient (P = 0.05) than those with normal EEG. CONCLUSIONS: Compared with mild pleocytosis and immunoglobulin synthesis, elevated lactate and total protein concentrations as well as blood-brain barrier dysfunction are frequently found following epileptic seizures. Our data suggest that seizure semiology might impact CSF profiles. The highest lactate concentrations were found following motor-onset seizures. Our findings may help clinicians to avoid over-interpretation of minor CSF changes; however, the exclusion of alternative causes should always be carefully considered, taking into account further clinical features.

Correlations between the level of antibody against peptide of glutamate receptor NR3B subunit in the CSF and cognitive comorbidities of patients with epilepsy.

OBJECTIVE: Autoimmune epilepsy is an under-recognized condition, and the mechanisms of antibody-mediated epileptogenesis are unknown. The N-methyl-D-aspartate (NMDA) receptor subunit 3 peptide B (NR3B) modulates Mg2+ sensitivity and Ca2+ mobilization of glutamate responses in the central nervous system (CNS). The levels of antibodies against NR3B (NR3B Ab's) in the cerebrospinal fluid (CSF) and the correlations between NR3B Ab's and cognitive comorbidities of epilepsy patients remain unclear. PATIENTS AND METHODS: CSF samples were collected from 36 patients with consecutive epilepsy and 17 healthy controls. The levels of NR3B Ab's in the CSF were measured by ELISA. The cognitive function was assessed by Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). RESULTS: The results showed that the levels of NR3B Ab's were significantly higher in patients with epilepsy than those in the controls (p<0.01). Thirteen of 36 patients had higher levels of NR3B Ab's exceeding mean+ 2SD of all patients, and the scores of MMSE and MoCA of these 13 patients were significantly lower than the other 23 patients and controls (p<0.01; p<0.001). However, there were no significant differences in the scores of MMSE and MoCA between the 23 patients and the controls. Correlation analysis indicated a significant negative correlation between the levels of NR3B Ab's and the scores of MMSE (correlation coefficient: r=-0.543; p<0.01) or the scores of MoCA (correlation coefficient: r=-0.548; p<0.01). CONCLUSIONS: We suggest that some patients with epilepsy may have immune process after onset and the presence of NR3B Ab's may be associated with cognitive comorbidities in patients with epilepsy.

A case of early onset life-threatening epilepsy associated with a novel ATP1A3 gene variant.

INTRODUCTION: Mutations of the ATP1A3 gene are associated with a wide spectrum of neurological disorders including rapid onset dystonia-parkinsonism and alternating hemiplegia of childhood (AHC). The genotype-phenotype correlations in these cases remain unclear however. We here report a pediatric case of catastrophic early life epilepsy, respiratory failure, postnatal microcephaly, and severe developmental disability associated with a novel heterozygous ATP1A3 mutation. SUBJECT: A boy with a normal birth to nonconsanguineous parents was transferred to the NICU due to postnatal respiratory failure at 2 days. He showed extreme hypotonia, episodic oculomotor abnormality and tachycardia, and frequent epileptic seizures. Mechanical ventilation was required but his epileptic seizures were intractable to multiple antiepileptic drugs, including extremely high doses of phenobarbital. METHODS AND RESULTS: Whole exome sequencing analysis of the case and his parents identified a de novo heterozygous mutation in the ATP1A3 gene (c.2736_2738CTTdel, p.Phe913del). DISCUSSION: The Phe913 residue in the ATP1α3 protein that is deleted in our case is highly conserved among vertebrates. Notably, an amino acid deletion in the same transmembrane domain of this protein, p.Val919del, has been reported previously in typical AHC cases, suggesting that p.Phe913del is a pathogenic mutation. Several reported cases with severe symptoms and very early onset epilepsy harbor ATP1α3 mutations at structural positions in this protein that differ from that of Phe913. Further functional studies are required to clarify the relationship between the loss of Phe913 and the very distinct resulting phenotype.

Alzheimer's disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology.

Although amyloid pathology plays a role in epilepsy, little is known about the relationship between beta amyloid and progression to Alzheimer's disease (AD) among patients with late-onset epilepsy of unknown origin (LOEU). This multicenter, observational, prospective study enrolled 40 consecutive nondemented adults diagnosed with LOEU, together with 43 age- and sex-matched healthy controls. All patients completed neuropsychological tests, core CSF AD biomarkers assessment (Aß1-42, total tau, and phosphorylated tau), and follow-up for a mean of 3 years to verify cognitive decline. Despite age and baseline cognitive performance were similar to healthy controls, patients with LOEU had significant prevalence of CSF pathological Aß1-42 (<500 pg/mL; 37.5%), 7.5% displaying an AD-like CSF pattern. Moreover, 17.5% of patients with LOEU converted to AD dementia, versus none among healthy controls (p < 0.005). Patients with LOEU with pathological Aß1-42 had a hazard ratio 3.4 (CI 0.665-17.73) for progression to AD dementia at follow-up. Patients with LOEU have a high prevalence of abnormal CSF Aß1-42 and progression to AD dementia compared with healthy controls, and therefore should be monitored for cognitive decline.

Nonlesional late-onset epilepsy: Semiology, EEG, cerebrospinal fluid, and seizure outcome characteristics.

INTRODUCTION: Incidence and prevalence of epilepsy increase with advancing age. Although the majority of late-onset epilepsies are of lesional origin, a considerable proportion of patients present with unknown etiology. The aim of this study was to evaluate the semiological, electroencephalographic (EEG), and cerebrospinal fluid (CSF) characteristics as well as the 12-month seizure outcome in a cohort of patients with nonlesional late-onset epilepsy (≥55 years). METHOD: A total of 54 patients with newly diagnosed nonlesional late-onset epilepsy (NLLOE) were retrospectively evaluated for seizure type using the most recent International League Against Epilepsy (ILAE) classification of seizure types, EEG characteristics, and CSF profile and followed-up for at least 12 months after epilepsy onset. Results were compared with a gender-matched control group of 58 patients with nonlesional early-onset epilepsy (NLEOE). RESULTS: The predominant seizure types in NLLOE were focal to bilateral tonic-clonic seizures (30%) as well as focal onset impaired awareness motor seizures (IAMS) (22%) and focal onset impaired awareness nonmotor seizures (IANMS) (22%). The predominant seizure types in NLEOE were focal to bilateral tonic-clonic seizures (43%) as well as focal onset aware nonmotor seizures (ANMS) (31%) and IAMS (31%). Focal onset impaired awareness nonmotor seizures were found to be more characteristic in patients with NLLOE (p = 0.019; α < 0.05; NLLOE: 22.2% vs. NLEOE: 8.6%). Electroencephalography revealed no significant differences between groups. Of interest, three patients with NLLOE (8%) presented with oligoclonal bands (OCB) in CSF albeit absence of antineuronal antibodies. Seizure-free rate was 70%. Adverse effects from medication leading to antiepileptic drug (AED) change were reported in 12 patients (22%), valproate was the best tolerated AED in patients with NLLOE [adverse effects in 9%, compared with 12% (gabapentin) and 26% (levetiracetam)]. CONCLUSIONS: Using the most recent classification system, different patterns of semiological characteristics were identified: NLLOE more frequently present with IANMS, whereas patients with NLEOE rather have ANMS. Oligoclonal bands were only detected in patients with NLLOE, indicating that careful exclusion of autoimmune encephalitis in this patient group is warranted. Our findings may help to more accurately identify and characterize patients with NLLOE to improve targeted diagnostics and adequate treatment in this challenging group of patients.

5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination.

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.

Activation of bradykinin B2 receptor induced the inflammatory responses of cytosolic phospholipase A2 after the early traumatic brain injury.

Phospholipase A2 is a known aggravator of inflammation and deteriorates neurological outcomes after traumatic brain injury (TBI), however the exact inflammatory mechanisms remain unknown. This study investigated the role of bradykinin and its receptor, which are known initial mediators within inflammation activation, as well as the mechanisms of the cytosolic phospholipase A2 (cPLA2)-related inflammatory responses after TBI. We found that cPLA2 and bradykinin B2 receptor were upregulated after a TBI. Rats treated with the bradykinin B2 receptor inhibitor LF 16-0687 exhibited significantly less cPLA2 expression and related inflammatory responses in the brain cortex after sustaining a controlled cortical impact (CCI) injury. Both the cPLA2 inhibitor and the LF16-0687 improved CCI rat outcomes by decreasing neuron death and reducing brain edema. The following TBI model utilized both primary astrocytes and primary neurons in order to gain further understanding of the inflammation mechanisms of the B2 bradykinin receptor and the cPLA2 in the central nervous system. There was a stronger reaction from the astrocytes as well as a protective effect of LF16-0687 after the stretch injury and bradykinin treatment. The protein kinase C pathway was thought to be involved in the B2 bradykinin receptor as well as the cPLA2-related inflammatory responses. Rottlerin, a Protein Kinase C (PKC) δ inhibitor, decreased the activity of the cPLA2 activity post-injury, and LF16-0687 suppressed both the PKC pathway and the cPLA2 activity within the astrocytes. These results indicated that the bradykinin B2 receptor-mediated pathway is involved in the cPLA2-related inflammatory response from the PKC pathway.

Elevated cerebrospinal fluid protein in POLG-related epilepsy: Diagnostic and prognostic implications.

OBJECTIVE: Epilepsy is common in individuals with mutations in POLG, the gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma. Early recognition and aggressive seizure management are crucial for patient survival. Disruption of the blood-brain barrier (BBB) is implicated in various neurological disorders including epilepsy. The aim of this study was to assess whether POLG-related disease is associated with BBB dysfunction and what clinical implications this has for patients. METHODS: Our retrospective study used data from 83 patients with pathogenic POLG mutations from 4 countries--Norway, Sweden, Finland, and the United Kingdom. Data were collected using a structured questionnaire. We used the presence of raised cerebrospinal fluid (CSF) protein and a raised CSF/serum ratio of albumin (Q-alb) to evaluate the integrity of the blood-CSF barrier. RESULTS: Raised CSF protein was found in 70% of patients (n = 58/83) and appeared to be associated with the most severe phenotypes. In those in whom it was measured, the Q-alb ratio was markedly elevated (n = 18). The majority of those with epilepsy (n = 50/66, 76%) had raised CSF protein, and this preceded seizure debut in 75% (n = 15/20). The median survival time from symptom onset for those with raised CSF protein was decreased (13 months) compared to those with normal CSF protein (32 months). SIGNIFICANCE: Our results indicate that there is disruption of the BBB in POLG-related disease, as evidenced by a raised CSF protein and Q-alb ratio. We also find that raised CSF protein is a common finding in patients with POLG disease. Our data suggest that the presence of BBB dysfunction predicts a poorer outcome, and elevated CSF protein may therefore be an additional biomarker both for early diagnosis and to identify those at high risk of developing epilepsy.

Comparison between cerebrospinal fluid and serum lactate concentrations in neurologic dogs with and without structural intracranial disease.

The objectives of this study were to investigate the relationship between cerebrospinal fluid lactate and serum concentrations in dogs with clinical signs of central nervous system disease and to establish if cerebrospinal fluid lactate (CSF) concentrations are higher in dogs with structural intracranial disease (Group Pos-MRI) compared to dogs that have clinical signs of intracranial disease but no structural brain disease (Group Neg-MRI) based on magnetic resonance imaging (MRI) findings. Using a prospective study canine blood and cerebrospinal fluid were collected in 24 dogs with neurological signs after undergoing brain MRI. Dogs were divided in 2 groups. No significant difference between serum lactate (1.57 ± 0.9 mmol/L) and CSF lactate concentration (1.34 ± 0.3 mmol/L) was detected. There was a direct correlation between CSF and serum lactate concentration (R = 0.731; P = 0.01). No significant difference was found in CSF lactate concentration between the 2 groups of dogs (P = 0.13).

Les objectifs de la présente étude étaient d'examiner la relation entre les concentrations de lactate du liquide céphalo-rachidien (LCR) et du sérum chez des chiens présentant des signes cliniques de pathologie du système nerveux central et établir si les concentrations de lactate du LCR sont plus élevées chez les chiens avec une maladie intracrânienne structurale (Groupe Pos-IRM) comparativement à des chiens avec des signes cliniques de maladie intracrânienne mais sans maladie structurale du cerveau (Groupe Nég-IRM) sur la base des trouvailles en imagerie par résonnance magnétique (IRM). Utilisant une étude prospective, du sang canin et du LCR ont été prélevés chez 24 chiens avec des signes neurologiques après un examen par IRM du cerveau. Les chiens ont été séparés en deux groupes. Aucune différence significative ne fut détectée entre les concentrations de lactate sérique (1,57 ± 0,9 mmol/L) et de lactate du LCR (1,34 ± 0,3 mmol/L). Il y avait une corrélation directe entre les concentrations de lactate du LCR et du sérum (R = 0,731; P = 0,01). Aucune différence significative dans la concentration de lactate du LCR ne fut trouvée entre les deux groupes de chiens (P = 0,13).(Traduit par Docteur Serge Messier).