Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis

ObjectiveClinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), the second most common encephalopathy syndrome in Japan, is most often associated with viral infection. Bacterial MERS has been rarely reported but is mostly associated with acute focal bacterial nephritis (AFBN) for an unknown reason. We examined cytokines and chemokines in four MERS patients with AFBN to determine if they play an important role in the pathogenesis.MethodsWe examined the clinical charts and MRI results in four MERS patients with AFBN, and measured 10 cytokines and chemokines in serum and cerebrospinal fluid in the acute phase. These were analyzed using the Mann-Whitney U test, compared with the control group (cases with a non-inflammatory neurological disease). Longitudinal changes in the serum cytokine and chemokine levels were evaluated in two patients.ResultsHyponatremia was observed in all four patients with MERS associated with AFBN (128–134 mEq/L). CSF analysis revealed increased cytokines/chemokines associated with Th1 (CXCL10, TNF-α, IFN-γ), T reg (IL-10), Th17 (IL-6), and neutrophil (IL-8 and CXCL1). In serum, upregulation was observed in those associated with Th1 (CXCL10, TNF-α, IFN-γ), Th17 (IL-6), and inflammasome (IL-1ß). The increased serum cytokines/chemokines in the acute stage normalized within 2 weeks in patients 1 and 2, so examined, in accordance with their clinical improvement.ConclusionIncreased cytokines/chemokines and hyponatremia may be factors that explain why AFBN is likely to cause MERS.     

Comparison of mild encephalopathy with reversible splenial lesion with and without acute focal bacterial nephritis

ObjectiveClinically mild encephalitis/encephalopathy with a reversible lesion (MERS) is characterized by reversible lesions with transiently-reduced diffusion in the splenium of the corpus callosum on magnetic resonance imaging. Recently, cases of MERS with accompanying acute focal bacterial nephritis (AFBN) have been reported in children. This study aimed to clarify the clinical features of MERS with AFBN.MethodsA retrospective study of patients with MERS was conducted at Nagano Children’s Hospital, Japan, from April 2013 to March 2018. The clinical signs and laboratory findings of MERS patients with AFBN (AFBN group) and without AFBN (non-AFBN group) were measured and compared.ResultsOf 12 patients diagnosed as having MERS, 3 were also found to have AFBN. Seven of the 9 patients without AFBN were associated with infectious agents, including rotavirus and influenza viruses. No patient received steroids or intravenous immunoglobulin therapy, and none displayed neurological sequelae. Serum C-reactive protein (CRP) levels were significantly higher in the AFBN group than in the non-AFBN group (14.7 mg/dL versus 0.8 mg/dL, P = 0.009). AFBN group patients were also significantly older (97 months versus 27 months, P = 0.018) and experienced significantly less frequent seizures (33% versus 100%, P = 0.045). The mean duration of neurological symptoms was significantly longer in the AFBN group than in the non-AFBN group (4 days versus 1.7 days, P = 0.013).ConclusionsPediatric patients with AFBN often present with non-specific findings, such as fever and abdominal pain. Pediatricians should be aware of the possibility of AFBN in the clinical setting of MERS, particularly when the patient exhibits inexplicably high CRP.     

Oxidative stress in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)

We examined oxidative stress markers, tau protein and cytokines in the cerebrospinal fluid (CSF) in six patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). In the CSF, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and hexanoyl-lysine adduct levels increased over the cutoff index in four and one out of six MERS patients, respectively. The CSF IL-6 and IL-10 levels were increased in three out of six patients, two of which had extended lesion of the cerebral white matter. The CSF value of tau protein, marker of the axonal damage, was not increased, and neuron specific enolase (NSE) in the CSF was not increased. The increased 8-OHdG levels in the CSF, DNA oxidative stress marker, in four MERS patients, suggesting involvement of oxidative stress in MERS. MERS is occasionally accompanied with hyponatremia, although our patients lacked hyponatremia. It is possible that the disequilibrium of systemic metabolism including electrolytes may lead to facilitation of oxidative stress and reversible white matter lesion in MERS. The increase of cytokine production seems to be involved in the distribution of lesions in MERS.     

Serum and cerebrospinal fluid cytokines in children with acute encephalopathy

BackgroundThe pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified.MethodsLevels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis).ResultsThe CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC.ConclusionOur results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.     

The first pediatric case of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with Neisseria meningitidis

BackgroundMild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is a clinic-radiological syndrome characterized by neurological deficiencies and reversible magnetic resonance imaging findings in the splenium of the corpus callosum. Usually, it has a good prognosis, and patients recover without any sequelae. A viral infection has caused most MERS cases, and bacterial agents have rarely been reported as a cause of MERS.Case reportA 5-month-old male was admitted to the hospital with fever, poor feeding, decreased activity and groaning. He had focal seizures and required mechanical ventilation. A lumbar puncture was performed, and nucleic acid amplification tests (NAATs) of cerebral spinal fluid was positive for non-typeable serogroup of Neisseria meningitidis. Cranial magnetic resonance imaging (MRI) performed on day 3 of admission showed T2 hyperintensity and diffusion restriction at the splenium of corpus callosum (SCC). Diffusion restriction in the occipital horn of the left ventricular compatible with empyema was also obvious. According to the findings on cranial MRI, this clinical course was diagnosed as MERS associated with meningitis. His fever resolved in one week, cefotaxime was discontinued after 14 days, and the patient completely recovered. A follow-up MRI performed after three weeks of admission showed complete resolution of the signal intensity changes in the SCC and the occipital horn of the left lateral ventricle.ConclusionTo the best of our knowledge, this is the first report of MERS associated with Neisseria meningitidis in children. Bacterial agents as a cause of MERS should be kept in mind, and we should avoid unnecessary treatment strategies due to the good prognosis of MERS in children.     

Encephalopathy with a reversible splenial lesion is associated with hyponatremia

We have encountered several patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated hyponatremia. In order to better understand this phenomenon, Na levels were evaluated in a series of patients with MERS. Na was 131.8+/-4.1 mmol/l (mean+/-SD, range 121-140) in 30 patients with MERS; 138.3+/-2.7 mmol/l (range 134-144) in age-matched 21 patients with upper respiratory infection; 136.6+/-2.5 mmol/l (range 132-140) in nine patients with other type of encephalopathy; and 136.2+/-2.6 mmol/l (range 132-140) in 17 patients with febrile seizures. Twenty-five of the thirty patients with MERS had Na<136 mmol/l. There were significant differences between the Na levels of patients with MERS and those with other groups. It is not possible, from the clinical perspective, to completely separate MERS from hyponatremic encephalopathy or to rule out hyponatremia as a contributing factor of MERS.     

Expanding the Spectrum of MERS Type 2 Lesions,a Particular Form of Encephalitis

We report on a 13-year-old boy who presented with signs suggestive of encephalitis and in whom magnetic resonance imaging revealed lesions in the genu and splenium of the corpus callosum and symmetrical lesions bilaterally in the center semiovale. This clinical-radiologic entity was previously reported in the literature and was given the acronym MERS type 2 (mild encephalitis with reversible splenial) lesion. The clinical, radiologic, and biochemical characteristics of the patient with MERS type 2 lesions presented in this article show some differences with those in previously reported patients. His clinical recovery was particularly slow, cerebrospinal fluid was abnormal, and on magnetic resonance imaging the typical time course of MERS type 2 lesions resolving through a phase of solitary lesions in the splenium of the corpus callosum, the so-called type 1 lesions, was not seen. He is also the first patient in whom mycoplasma pneumoniae was found to be associated with MERS type 2 lesions. These findings further expand the spectrum of MERS type 2 lesions. The question raises whether the MERS type 2 lesion represents a new type of encephalitis or a particular radiologically recognizable subtype of postinfectious encephalitis. In the article, previously reported patients with MERS type 2 lesions are reviewed.     

Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes

A research committee supported by the Japanese government conducted a nationwide survey on the epidemiology of acute encephalopathy in Japan using a questionnaire. A total of 983 cases reportedly had acute encephalopathy during the past 3 years, 2007-2010. Among the pathogens of the preceding infection, influenza virus was the most common, followed by human herpesvirus-6 (HHV-6) and rotavirus. Among syndromes of acute encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was the most frequent, followed by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), acute necrotizing encephalopathy (ANE) and hemorrhagic shock and encephalopathy syndrome (HSES). Influenza virus was strongly associated with ANE and MERS, HHV-6 with AESD, and rotavirus with MERS. Mortality was high in ANE and HSES, but was low in AESD, MERS and HHV-6-associated encephalopathy. Neurologic sequelae were common in AESD and ANE, but were absent in MERS.     

Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder

Elevated peripheral levels of interleukin-6 (IL-6) are common findings in schizophrenia and depression. However, previous studies that measured cerebrospinal fluid (CSF) IL-6 levels in these disorders reported controversial results. The present study examined whether CSF IL-6 levels are altered in patients with schizophrenia and those with depression. Lumbar punctures were performed in 32 patients with schizophrenia, 30 with major depressive disorder (MDD), and 35 healthy controls. Serum samples were simultaneously collected from all subjects in the patient groups and from 32 of the control group. CSF and serum IL-6 levels were determined by enzyme-linked immunosorbent assay. Both the patients with schizophrenia and MDD had significantly higher CSF IL-6 levels compared to the controls (schizophrenia: P = 0.0027; MDD: P = 0.012). IL-6 levels were significantly higher in the CSF than in the serum. No significant correlation was observed between CSF and serum IL-6 levels. The present findings suggest that IL-6 of central origin is associated with the pathophysiology of schizophrenia and MDD, although confounding effect of smoking status can not be entirely excluded.     

Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection

Human herpesvirus-6 (HHV-6) is a causative agent of exanthema subitum. The immunological pathogenesis of acute encephalopathy associated with HHV-6 infection is still unclear. We measured the concentrations of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), IL-4, IL-6, IL-10, and soluble TNF receptor 1 (sTNFR1) in serum and cerebrospinal fluid (CSF) during the acute stage in 15 infants with acute encephalopathy and 12 with febrile seizures associated with HHV-6 infection. The serum IL-6, IL-10, sTNFR1, CSF IL-6, and sTNFR1 levels of infants with encephalopathy who had neurological sequelae (n = 9) were significantly higher than those with febrile seizures (p = 0.011, 0.043, 0.002, 0.029, and 0.005, respectively). In acute encephalopathy, serum IL-6, sTNFR1, and CSF IL-6 levels in infants with neurological sequelae were significantly higher than those without (n = 6) neurological sequelae (p = 0.043, 0.026, and 0.029, respectively), and serum IFN-γ, IL-6, IL-10, and sTNFR1 levels were significantly higher than those in the CSF (p = 0.037, 0.037, 0.001, and 0.021, respectively). There were no significant differences in serum or CSF cytokine levels between infants who were positive for HHV-6 DNA in the CSF (n = 6) compared to those who were negative (n = 9). We suggest that cytokines mediate the pathogenesis of acute encephalopathy associated with HHV-6 infection, and that the elevated levels of serum IL-6, sTNFR1, and CSF IL-6 are important for predicting neurological sequelae.     

Mild encephalitis/encephalopathy with reversible splenial lesion (MERS) due to dengue virus

A 14-year-old girl presented with encephalopathy, delirium and ophthalmoplegia following a 3 day history of high-grade fever. Brain MRI on day 6 of illness showed diffusion restricted ovoid lesion in the splenium of corpus callosum. Dengue virus encephalitis was diagnosed with positive PCR for dengue virus type-2 in both serum and cerebrospinal fluid. She made a complete recovery from day 10 of illness. Repeat brain MRI on day 12 of illness showed resolution of the splenial lesion. Serial diffusion tensor imaging (DTI) showed normal fractional anisotropy values on resolution of splenial lesion indicating that MERS was likely due to transient interstitial oedema with preservation of white matter tracts. This is the first reported case of MERS following dengue virus infection. It highlights the usefulness of performing serial DTI in understanding the underlying pathogenesis of MERS. Our case report widens the neurological manifestations associated with dengue infection and reiterates that patients with MERS should be managed supportively as the splenial white matter tracts are reversibly involved in MERS.     

Mild encephalopathy with reversible splenium lesion (MERS) in a patient with COVID-19

Neurological complications of coronavirus 2019 (COVID-19) are common, and novel manifestations are increasingly being recognized. Mild encephalopathy with reversible splenium lesion (MERS) is a syndrome that has been associated with viral infections, but not previously with COVID-19. In this report, we describe the case of a 69 year-old man who presented with fever and encephalopathy in the setting of a diffusion-restricting splenium lesion, initially mimicking an ischemic stroke. A comprehensive infectious workup revealed positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, and a pro-inflammatory laboratory profile characteristic of COVID-19 infection. His symptoms resolved and the brain MRI findings completely normalized on repeat imaging, consistent with MERS. This case suggests that MERS may manifest as an autoimmune response to SARS-CoV-2 infection and should be considered in a patient with evidence of recent COVID-19 infection and the characteristic MERS clinico-radiological syndrome.     

Kawasaki disease complicated by mild encephalopathy with a reversible splenial lesion (MERS)

We reported four patients (2 to 10 years) with Kawasaki disease complicated by clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). All were treated with γ-globulin (2 to 6 g/kg) after the diagnosis of Kawasaki disease, the fever being alleviated between day 6 and 25. One of two patients exhibiting a poor response to γ-globulin had a cardiac aneurysm as a sequela. Their neurological manifestations (delirious behavior and drowsiness), laboratorial hyponatremia, and radiological abnormalities completely disappeared. It is important for pediatricians to acknowledge that MERS can be observed in patients with Kawasaki disease, especially in older children, and that they might be at high risk for cardiac abnormalities.     

Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample

ObjectiveThe literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6), interleukin-8 (IL-8) and depression in a population-based sample of older women who were followed for 17 years.Methods86 dementia-free women aged 70–84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992–3. CSF IL-6 and CSF IL-8 were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria.ResultsAt baseline, women with ongoing major (n = 10) or minor depression (n = 9) had higher levels of CSF IL-6 (p = 0.008) and CSF IL-8 (p = 0.007) compared with those without depression (n = 67). Higher CSF IL-8 was related to higher MADRS score (p = 0.003). New cases of depression were observed in 9 women during follow-ups. No associations between CSF cytokine levels and future depression could be shown in women without depression at baseline.ConclusionHigher levels of CSF IL-6 and IL-8 were associated with current depression in this population-based sample. CSF IL-6 and CSF IL-8 may play a role in depression in late life.     

Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood-CSF barrier dysfunction

Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (n = 4100). In 41% of the psychiatric patients (n = 63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5-8/μL) and 29% had moderate blood-CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p = 0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective (n = 24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.     

Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy

ObjectivesAcute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes.MethodsThe case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test.ResultsMinor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome.ConclusionsThis study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.     

High mobility group box 1 in patients with 2009 pandemic H1N1 influenza-associated encephalopathy

Background: Patients with 2009 pandemic H1N1 influenza-associated encephalopathy (pIE) have been reported in Japan. The most common clinical symptoms of this condition are seizures and progressive coma with high-grade fever. We previously highlighted the cytokine profile of pIE; our results suggest that proinflammatory cytokines play an important role in the pathogenesis. High mobility group box 1 (HMGB1) protein is a late mediator of inflammation or sepsis. However, there are few reports regarding the serum and cerebrospinal fluid (CSF) levels of HMGB1 in pIE patients. Methods: We measured serum and CSF levels of HMGB1 in the following: pIE patients with poor outcomes, pIE patients without neurological sequelae, influenza patients without pIE, and control subjects. Results: Serum HMGB1 levels were significantly higher in pIE patients with poor outcomes compared to those without neurological sequelae. In contrast, there was no difference in CSF HMGB1 levels among all groups. Regarding pIE patients, we found a significant positive correlation between HMGB1 levels and IL-6 in the serum but not in the CSF. Conclusions: Our results suggest that HMGB1 protein may be involved in the pathogenesis of pIE and that a high serum, but not CSF, level of inflammatory cytokines plays an important role in the severity of pIE.     

Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial

Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-α, interferon-γ, interleukin (IL)-1α, IL-1β, IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P=0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself.     

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults

CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults.Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [¹⁸F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [¹⁸F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions.Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships.Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.     

Vitamin B6 in acute encephalopathy with biphasic seizures and late reduced diffusion

BackgroundThe initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD.MethodsWe obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5′-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection.ResultsThe subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS.ConclusionsAlthough it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation.